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Zheng Y, Ma X, Zhou S, Lei W, Luo X, Zhou L, Xu K, Zhong W. Alkaline Phosphatase and ATG4B Sequentially Activated Fluorescent Probe for Cancer Cell-Specific Live Imaging of Autophagy. Anal Chem 2025; 97:8370-8377. [PMID: 40197017 DOI: 10.1021/acs.analchem.4c06950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Tracking autophagy in cancer cells is crucial for enhancing cancer therapies. Existing methods are often inefficient and cannot distinguish cancer from normal cells during autophagy. Herein, a sequentially activated peptide probe, NBD-1p-Dabcyl, was developed for achieving cancer cell-specific imaging of autophagy. The probe self-assembled and fluoresced brightly upon sequential processing by alkaline phosphatase (ALP) and autophagy-related protease (ATG4B), where NBD-1p-Dabcyl was dephosphorylated by ALP to give NBD-1-Dabcyl, which was then processed by ATG4B into nanofibers emitting strong fluorescence. Notably, the bright fluorescence of NBD was observed in cancer cells MDA-MB-231 and HeLa, while normal cells NIH3T3 exhibited weaker fluorescence, allowing differentiation between cancer and normal cells using a rapamycin (Rap)-induced autophagy cell model. The enhanced fluorescence in cancer cells was attributed to the higher activities of intracellular ALP and ATG4B. Next, NBD-1p-Dabcyl was used to assess the inhibition efficiency of an autophagy inhibitor NSC 185058 in MDA-MB-231 cells, where a strong correlation between fluorescence intensity and inhibitor concentration suggested that NBD-1p-Dabcyl could predict the activity of autophagy inhibitors. Finally, animal experiments revealed that NBD-1p-Dabcyl effectively facilitated in situ fluorescence imaging of autophagy in tumor tissues. The design of this sequentially activated peptide probe offers a practical approach for monitoring autophagy in cancer cells, enabling high-throughput screening of autophagy inhibitors for cancer therapy.
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Affiliation(s)
- Yaxin Zheng
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Xinyue Ma
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Shuyao Zhou
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Wenwen Lei
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Xuan Luo
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Zhou
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China
| | - Keming Xu
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China
| | - Wenying Zhong
- Department of Chemistry, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China
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Manns MP, Bergquist A, Karlsen TH, Levy C, Muir AJ, Ponsioen C, Trauner M, Wong G, Younossi ZM. Primary sclerosing cholangitis. Nat Rev Dis Primers 2025; 11:17. [PMID: 40082445 DOI: 10.1038/s41572-025-00600-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/16/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.
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Affiliation(s)
- Michael P Manns
- Hannover Medical School (MHH) and Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Annika Bergquist
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Clinic of Surgery and Specialized medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew J Muir
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Union Hospital, Hong Kong SAR, China
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Barathi A, Krishnamoorthy Y, Kannan S, Govindhan D, Elangovan V, Subbiah P, Kuberan D. The mediating role of BMI in alcohol-linked liver enzyme elevation among adults at a tertiary care hospital in South India. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00491. [PMID: 39975998 DOI: 10.1097/meg.0000000000002949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BACKGROUND Excessive alcohol consumption is a major risk factor for liver disease, with significant variations in its impact across populations. BMI has been identified as a potential mediator in alcohol-related liver damage. This study aimed to examine the association between alcohol consumption and liver function and to explore the mediating role of BMI in a population from India, where both are rising public health concerns. MATERIALS AND METHODS A cross-sectional study was conducted using data from adult participants. Liver function was assessed using serum levels of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Alcohol consumption was self-reported, and BMI was calculated AST from height and weight measurements. Multiple linear regression models were used to evaluate the relationship between alcohol consumption and liver enzymes while adjusting for BMI as a mediator. Statistical significance was set at P < 0.05. RESULTS The results indicated that higher alcohol consumption was significantly associated with elevated levels of GGT, ALT, and AST. BMI was found to mediate this relationship, with individuals having higher BMI showing a greater increase in liver enzyme levels in response to alcohol consumption. However, no significant association was observed for ALP. BMI also independently correlated with higher levels of GGT, ALT, and AST. CONCLUSION This study highlights the mediating role of BMI in alcohol-induced liver dysfunction in the Indian population. Public health interventions focusing on both reducing alcohol intake and managing obesity may help mitigate the risk of liver disease in this high-risk population.
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Li Q, Ye C, Gao W. Prognostic Value of Combined Detection of MMP-7 and ALP Levels in Children With Biliary Atresia Post-Kasai Surgery. Pediatr Transplant 2025; 29:e70004. [PMID: 39777956 DOI: 10.1111/petr.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/25/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025]
Abstract
OBJECTIVE Biliary atresia (BA) remains a prevalent indication for pediatric liver transplantation (LT). We investigated the prognostic value of the serum matrix metalloproteinases 7 (MMP-7) and alkaline phosphatase (ALP) level combined detection for BA children post-Kasai surgery. METHODS This study retrospectively enrolled 85 BA children who underwent Kasai surgery. They were divided into the native liver (NL) and LT groups based on their three-year postoperative prognosis. Serum MMP-7 and ALP levels were measured by ELISA. The relationship of intraoperative serum MMP-7 and ALP levels with preoperative gamma-glutamyltransferase (GGT), and their impact on the risk of postoperative LT were analyzed by Pearson's correlation coefficient and Kaplan-Meier curves. The independent risk factors (IRFs) for postoperative LT and the predictive value of the serum MMP-7 and ALP level combined detection for postoperative LT in BA children were analyzed by Cox regression analysis and receiver operating characteristic (ROC) curves. MedCalc software compared the areas under the ROC curves (AUC). RESULTS Significant differences were observed between the two groups in BA classification, postoperative jaundice clearance rate, and cholangitis occurrence. Intraoperative serum MMP-7 and ALP levels were higher in the LT group and positively correlated with preoperative GGT. High MMP-7 and ALP levels were IRFs for postoperative LT, while significant jaundice clearance was a protective factor. Combined MMP-7 and ALP detection (0.926 AUC, 91.30% sensitivity, 87.18% specificity) significantly improved the prediction for LT. CONCLUSION High MMP-7 and ALP levels are IRFs for post-Kasai surgery LT in BA children, with their combination providing superior predictive value.
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Affiliation(s)
- Qingzhi Li
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
| | - Chaoxiang Ye
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
| | - Wei Gao
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
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Ajiboye BO, Famusiwa CD, Oyedare DI, Julius BP, Adewole ZO, Ojo OA, Akindele AFI, Hosseinzadeh H, Brai BIC, Oyinloye BE, Vitalini S, Iriti M. Effect of Hibiscus sabdariffa L. leaf flavonoid-rich extract on Nrf-2 and HO-1 pathways in liver damage of streptozotocin-induced diabetic rats. Z NATURFORSCH C 2024:znc-2024-0182. [PMID: 39565955 DOI: 10.1515/znc-2024-0182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/30/2024] [Indexed: 11/22/2024]
Abstract
This study investigated the effects of flavonoid-rich extract from Hibiscus sabdariffa L. (Malvaceae) leaves on liver damage in streptozotocin-induced diabetic rats by evaluating various biochemical parameters, including the molecular gene expressions of Nrf-2 and HO-1 as well as histological parameters. The extract was found to significantly reduce liver damage, as evidenced by lower levels of fragmented DNA and protein carbonyl concentrations. Oxidative stress markers, including malondialdehyde (MDA) level, were also significantly (p < 0.05) decreased, while antioxidant biomarkers, like reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were enhanced. Additionally, the extract improved the activities of key liver enzymes, including phosphatases and transaminases, and increased albumin levels. Importantly, the study demonstrated that H. sabdariffa extract effectively regulated the expression of Nrf-2 and HO-1, suggesting a significant role in mitigating liver damage. These findings highlight its potential as a therapeutic agent for liver protection in diabetic conditions.
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Affiliation(s)
- Basiru Olaitan Ajiboye
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Courage Dele Famusiwa
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Damilola Ifeoluwa Oyedare
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Biola Paul Julius
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Zainab Odunola Adewole
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Osun, Nigeria
| | - Ajoke Fehintola Idayat Akindele
- Department of Biosciences and Biotechnology, Environmental Management and Toxicology Unit, Faculty of Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bartholomew I C Brai
- Nutritional Biochemistry and Membrane Biochemistry, and Toxicology, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Babatunji Emmanuel Oyinloye
- Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, Ado-Ekiti, Nigeria
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti, Ekiti, Nigeria
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Sara Vitalini
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
| | - Marcello Iriti
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
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Zhu G, Liu Z, Wang H, Mou S, Li Y, Ma J, Li X. Risk Assessment of Fenpropathrin: Cause Hepatotoxicity and Nephrotoxicity in Common Carp ( Cyprinus carpio L.). Int J Mol Sci 2024; 25:9822. [PMID: 39337314 PMCID: PMC11432585 DOI: 10.3390/ijms25189822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 09/30/2024] Open
Abstract
The synthetic pyrethroid pesticide fenpropathrin (FEN) is extensively used worldwide and has frequently been detected in biota and the environment, whilst the negative effects and toxicological mechanisms of FEN on non-target organisms are still unknown. In the present study, healthy immature common carp were treated with FEN (0.45 and 1.35 μg/L) for a duration of 14 days, and the negative impacts and possible mechanisms of FEN on fish were investigated. Biochemical analyses results showed that FEN exposure altered the levels of glucose (GLU), total cholesterol (T-CHO), triglyceride (TG), albumin (ALB), alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) in carp serum, and caused histological injury of the liver and kidney, indicating that FEN may cause hepatotoxicity and nephrotoxicity in carp. In addition, FEN also altered the activities of superoxide dismutase (SOD) and catalase (CAT) in carp serum, upregulated the levels of reactive oxygen species (ROS), and elevated the levels of malondialdehyde (MDA) in the liver and kidney. Meanwhile, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were also upregulated, indicating that oxidative stress and inflammatory reaction may be involved in the hepatotoxicity and nephrotoxicity caused by FEN. Furthermore, RNA-seq analysis results revealed that FEN treatment induced a diverse array of transcriptional changes in the liver and kidney and downregulated differentially expressed genes (DEGs) were concentrated in multiple pathways, especially cell cycle and DNA replication, suggesting that FEN may induce cell cycle arrest of hepatocytes and renal cells, subsequently inducing hepatotoxicity and nephrotoxicity. Overall, the present study enhances our comprehension of the toxic effects of FEN and provides empirical evidence to support the risk assessment of FEN for non-target organisms.
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Affiliation(s)
- Gongming Zhu
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
- Pingyuan Laboratory, Xinxiang 453007, China
| | - Zhihui Liu
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
| | - Hao Wang
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
| | - Shaoyu Mou
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
| | - Yuanyuan Li
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
| | - Junguo Ma
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
- Pingyuan Laboratory, Xinxiang 453007, China
| | - Xiaoyu Li
- State Key Laboratory of Antiviral Drugs, College of Life Science, Henan Normal University, Xinxiang 453007, China; (G.Z.); (Z.L.); (H.W.); (S.M.); (Y.L.); (X.L.)
- Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, Henan Normal University, Xinxiang 453007, China
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Xie Y, Lin L, Sun C, Chen L, Lv W. Association between serum alkaline phosphatase and clinical prognosis in patients with acute liver failure following cardiac arrest: a retrospective cohort study. Eur J Med Res 2024; 29:453. [PMID: 39252119 PMCID: PMC11382480 DOI: 10.1186/s40001-024-02049-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) following cardiac arrest (CA) poses a significant healthcare challenge, characterized by high morbidity and mortality rates. This study aims to assess the correlation between serum alkaline phosphatase (ALP) levels and poor outcomes in patients with ALF following CA. METHODS A retrospective analysis was conducted utilizing data from the Dryad digital repository. The primary outcomes examined were intensive care unit (ICU) mortality, hospital mortality, and unfavorable neurological outcome. Multivariable logistic regression analysis was employed to assess the relationship between serum ALP levels and clinical prognosis. The predictive value was evaluated using receiver operator characteristic (ROC) curve analysis. Two prediction models were developed, and model comparison was performed using the likelihood ratio test (LRT) and the Akaike Information Criterion (AIC). RESULTS A total of 194 patients were included in the analysis (72.2% male). Multivariate logistic regression analysis revealed that a one-standard deviation increase of ln-transformed ALP were independently associated with poorer prognosis: ICU mortality (odds ratios (OR) = 2.49, 95% confidence interval (CI) 1.31-4.74, P = 0.005), hospital mortality (OR = 2.21, 95% CI 1.18-4.16, P = 0.014), and unfavorable neurological outcome (OR = 2.40, 95% CI 1.25-4.60, P = 0.009). The area under the ROC curve for clinical prognosis was 0.644, 0.642, and 0.639, respectively. Additionally, LRT analyses indicated that the ALP-combined model exhibited better predictive efficacy than the model without ALP. CONCLUSIONS Elevated serum ALP levels upon admission were significantly associated with poorer prognosis of ALF following CA, suggesting its potential as a valuable marker for predicting prognosis in this patient population.
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Affiliation(s)
- Yuequn Xie
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Liangen Lin
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Congcong Sun
- Department of Scientific Research Center, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, Wenzhou, 325000, Zhejiang, China
| | - Linglong Chen
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China
| | - Wang Lv
- Department of Emergency, The Third Affiliated to Shanghai University, Wenzhou People's Hospital, No. 299 Guan Road, Louqiao Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.
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Zhu J, Lu Y, Gao Z, Chong Y, Li M, Deng W, Xi D. Exploring the additive effect of Ampelopsis grossedentata flavonoids and Tween 80 on feeding Nubian goats. Front Vet Sci 2024; 11:1411071. [PMID: 39071786 PMCID: PMC11272655 DOI: 10.3389/fvets.2024.1411071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/25/2024] [Indexed: 07/30/2024] Open
Abstract
Introduction The ban on antibiotics in animal husbandry underscores the crucial need for safe, natural feed additives. This study investigates the effects of Ampelopsis grossedentata flavonoids (AGF) and Tween 80 on the growth performance, blood indexes, and rumen microbiota of Nubian goats, evaluating their potential as alternative feed additives in livestock management. Methods Thirty-two goats were randomly divided into four groups. The control group (CON group) was provided with a basal diet, while the experimental groups received diets supplemented with various dietary additives for a duration of 100 days: either a basal diet supplemented with 25 mg/kg of monensin (MN group), a basal diet containing 2.0 g/kg of Ampelopsis grossedentata flavonoids (AGF group), or a basal diet containing 7.5 mL/kg of Tween 80 (TW group). Blood and rumen fluid samples were collected for analysis at the end of the feeding period. Growth performance was monitored through regular weighing and feed intake measurements. Blood indexes were analyzed using standard biochemical techniques, while the microbial composition of the rumen fluid was determined through high throughput 16S rRNA gene sequencing to assess microbial diversity and function. The effects of the dietary treatments on growth performance, blood indexes, and rumen microbial composition were then evaluated. Results The AGF group exhibited significantly increased average daily gain, and decreased feed-to-gain ratio (p < 0.05). Blood indexes analysis revealed no differences between the CON and AGF groups, with both showing higher concentrations of triglyceride, low-density lipoprotein cholesterol, glutamic-pyruvic transaminase, alkaline phosphatase, and lactate dehydrogenase compared to the monensin group (p < 0.05). The TW group had significantly higher glucose, glutamic-oxaloacetic transaminase, and glutamic-pyruvic transaminase levels than the MN group (p < 0.05). Microbial diversity analysis revealed that the TW group had significantly greater alpha-diversity than other groups, while beta-diversity analysis showed closer similarity between the rumen microbiota of the AGF and CON groups. LEfSe analysis identified Proteobacteria, Deferribacteres, Ehryarchaeoia, and Elusimicrobia as biomarkers distinguishing the rumen microbiota among the groups. In conclusion, AGF supplementation increased the relative abundance of beneficial bacteria in the rumen of Nubian goats, and thus enhanced the growth performance. TW supplementation significantly increased rumen microbial diversity and abundance, suggesting benefits for rumen health despite poor palatability. These findings highlight the potential of AGF as a new green additive with important implications for the efficiency and development of animal husbandry.
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Affiliation(s)
| | | | | | | | | | | | - Dongmei Xi
- Yunnan Provincial Key Laboratory of Animal Nutrition and Feed, Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, China
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Shi L, Liu Y, Liu Q, Chang C, Liu W, Zhang Z. Adipose-derived stem cells can alleviate RHDV2 induced acute liver injury in rabbits. Res Vet Sci 2024; 172:105255. [PMID: 38608346 DOI: 10.1016/j.rvsc.2024.105255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/06/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024]
Abstract
Rabbit hemorrhagic disease virus (RHDV) can cause fatal fulminant hepatitis, which is very similar to human acute liver failure. The aim of this study was to investigate whether adipose-derived stem cells (ADSCs) could alleviate RHDV2-induced liver injury in rabbits. Twenty 50-day-old rabbits were divided randomly into two groups (RHDV2 group, ADSCs + RHDV2 group). Starting from the 1st day, two groups of rabbits were given 0.5 ml of viral suspensions by subcutaneous injection in the neck. Meanwhile, the ADSCs + RHDV2 group was injected with ADSCs cell suspension (1.5 × 107 cells/ml) via a marginal ear vein, and the RHDV2 group was injected with an equal amount of saline via a marginal ear vein. At the end of the 48 h experiment, the animals were euthanized and gross hepatic changes were observed before liver specimens were collected. Histopathological analysis was performed using hematoxylin-eosin (HE), periodic acid schiff (PAS) and Masson's trichrome staining. For RHDV2 affected rabbits, HE staining demonstrated disorganized hepatic cords, loss of cellular detail, and severe cytoplasmic vacuolation within hepatocytes. Glycogen was not observed with PAS staining, and Masson's Trichrome staining showed increased hepatic collagen deposition. For rabbits treated with ADSCs at the time of inoculation, hepatic pathological changes were significantly less severe, liver glycogen synthesis was increased, and collagen fiber deposition was decreased. For RHDV2 affected rabbits, Tunel and immunofluorescence staining showed that the number of apoptotic cells, TGF-β, and MMP-9 protein expression increased. And that in the ADSC treated group there was less hepatocyte apoptosis. In addition, RHDV2 induces liver inflammation and promotes the expression of IL-1β, IL-6, and TNF-α. In rabbits administered ADSCs at time of inoculation, the expression of inflammatory factors in liver tissue decreased significantly. Our experiments show that ADSCs can protect rabbits from liver injury by RHDV2 and reduce the pathological and inflammatory response of liver. However, the specific protective mechanism needs further study.
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Affiliation(s)
- Lihui Shi
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Yumei Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Qianni Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Chenhao Chang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Weiqi Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Ziqiang Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
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Wang Z, Li J, Jing J, Zhang Z, Xu Q, Liu T, Lin J, Jiang Y, Wang Y, Wang A, Meng X. Impact of alkaline phosphatase on clinical outcomes in patients with ischemic stroke: a nationwide registry analysis. Front Neurol 2024; 15:1336069. [PMID: 38419697 PMCID: PMC10899335 DOI: 10.3389/fneur.2024.1336069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/18/2024] [Indexed: 03/02/2024] Open
Abstract
Background Data on the association between serum alkaline phosphatase (ALP) levels and clinical outcomes in patients with ischemic stroke (IS) are inconsistent and limited. Therefore, this study aimed to investigate the correlation between ALP and prognosis in patients with IS. Methods Patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) from the Third China National Stroke Registry were divided into four groups according to the quartiles of serum ALP levels on admission. Cox proportional hazards and logistic regression models were used to evaluate the correlation between ALP and the risk of all-cause mortality, disability (modified Rankin Scale (mRS) score 3-5), and poor functional outcomes (mRS score 3-6). Results A total of 11,405 patients were included in the study. Higher levels of ALP were associated with all-cause mortality at 3 months (adjusted hazard ratio [HR] per standard deviation [SD]: 1.16; 95% confidence interval (CI): 1.07-1.27; p = 0.001) and 1 year (adjusted HR: 1.11; 95% CI: 1.03-1.20; p = 0.010). At the 3-month follow-up, each SD increase of ALP was associated with a 12 and 14% higher risk of disability (adjusted odds ratio (OR): 1.12; 95% CI: 1.06-1.18; p < 0.001) and poor functional outcomes (adjusted OR: 1.14; 95% CI: 1.08-1.20; p < 0.001). Similar results were observed at the 1-year follow-up. Higher ALP levels were associated with an increased risk of all-cause mortality, disability, and poor functional outcomes in patients with "others" subtypes (including other determined etiology and undetermined etiology) (p < 0.05). Conclusion Elevated ALP levels were associated with an increased risk of all-cause mortality, disability, and poor function outcomes in patients with IS. Heterogeneity was observed among the subtypes of different etiologies.
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Affiliation(s)
- Zhaobin Wang
- Affiliated Hospital of Hebei University, Baoding, China
- Clinical Medical College, Hebei University, Baoding, China
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Puyang Oilfield General Hospital, Puyang, China
| | - Jing Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jing Jing
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zhe Zhang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qin Xu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tao Liu
- Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Jinxi Lin
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yong Jiang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Anxin Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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Sevela S, Meisnerova E, Vecka M, Vavrova L, Rychlikova J, Lenicek M, Vitek L, Novakova O, Novak F. High Dose Fish Oil Added to Various Lipid Emulsions Normalizes Superoxide Dismutase 1 Activity in Home Parenteral Nutrition Patients. Nutrients 2024; 16:485. [PMID: 38398809 PMCID: PMC10891535 DOI: 10.3390/nu16040485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven.
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Affiliation(s)
- Stanislav Sevela
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
| | - Eva Meisnerova
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
| | - Marek Vecka
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
| | - Lucie Vavrova
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
| | - Jana Rychlikova
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
| | - Martin Lenicek
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic;
| | - Libor Vitek
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic;
| | - Olga Novakova
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic;
- Institute of Physiology, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic
| | - Frantisek Novak
- 4th Department of Internal Medicine, 1st Faculty of Medicine and General University Hospital, Charles University, 128 08 Prague, Czech Republic (E.M.); (M.V.); (L.V.); (J.R.); (L.V.)
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Sohal A, Kayani S, Kowdley KV. Primary Sclerosing Cholangitis: Epidemiology, Diagnosis, and Presentation. Clin Liver Dis 2024; 28:129-141. [PMID: 37945154 DOI: 10.1016/j.cld.2023.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Primary sclerosing cholangitis (PSC) is considered an immunologically mediated disease. However, some of its features are not consistent with the typical profile of autoimmune conditions. PSC is characterized by progressive biliary fibrosis that may ultimately result in the eventual development of cirrhosis. In recent years, multiple studies have reported that the incidence and prevalence of this disease are on the rise. Consequently, patients are often diagnosed without symptoms or signs of advanced liver disease, although many still present with signs of decompensated liver disease. This article discusses the epidemiology, clinical presentation, and diagnostic workup in patients with PSC.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, , 3216 Northeast 45th Place, Suite 212, Seattle, WA 98105, USA
| | - Sanya Kayani
- Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA
| | - Kris V Kowdley
- Liver Institute Northwest, , 3216 Northeast 45th Place, Suite 212, Seattle, WA 98105, USA; Elson Floyd College of Medicine, Spokane, WA, USA.
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Jiang H, Yu Y, Hu X, Du B, Shao Y, Wang F, Chen L, Yan R, Li L, Lv L. The fecal microbiota of patients with primary biliary cholangitis (PBC) causes PBC-like liver lesions in mice and exacerbates liver damage in a mouse model of PBC. Gut Microbes 2024; 16:2383353. [PMID: 39105259 PMCID: PMC11305030 DOI: 10.1080/19490976.2024.2383353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 06/24/2024] [Accepted: 07/18/2024] [Indexed: 08/07/2024] Open
Abstract
The role of the gut microbiota in the occurrence and progression of primary biliary cholangitis (PBC) is not fully understood. First, the fecal microbiota of patients with PBC (n = 4) (PBC-FMT) or healthy individuals (n = 3) (HC-FMT) was transplanted into pseudo germ-free mice or 2OA-BSA-induced PBC models. The functions, histology and transcriptome of the liver, and microbiota and metabolome of the feces were analyzed. Second, the liver transcriptomes of PBC patients (n = 7) and normal individuals (n = 7) were analyzed. Third, the liver transcriptomes of patients with other liver diseases were collected from online databases and compared with our human and mouse data. Our results showed that PBC-FMT increased the serum ALP concentration, total bile acid content, liver injury and number of disease-related pathways enriched with upregulated liver genes in pseudo germ-free mice and increased the serum glycylproline dipeptidyl aminopeptidase level and liver damage in a 2OA-BSA-induced PBC model. The gut microbiota and metabolome differed between PBC-FMT and HC-FMT mice and reflected those of their donors. PBC-FMT tended to upregulate hepatic immune and signal transduction pathways but downregulate metabolic pathways, as in some PBC patients. The hematopoietic cell lineage, Toll-like receptor, and PPAR signaling pathway were not affected in patients with alcoholic hepatitis, HBV, HCV, HCV cirrhosis, or NASH, indicating their potential roles in the gut microbiota affecting PBC. In conclusion, the altered gut microbiota of PBC patients plays an important role in the occurrence and progression of PBC. The improvement of the gut microbiota is worthy of in-depth research and promotion as a critical aspect of PBC prevention and treatment.
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Affiliation(s)
- Huiyong Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Yu
- School of Public Health, Hangzhou Medical College, Hangzhou, China
| | - Xiaoxiang Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Bingbing Du
- Microecological Laboratory, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Yini Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Feiyu Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lifeng Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ren Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Kim Y, Park HC, Ryu H, Kim YC, Ahn C, Lee KB, Kim YH, Han S, Bae EH, Jeong K, Choi J, Oh KH, Oh YK. Factors Associated With the Development and Severity of Polycystic Liver in Patients With Autosomal Dominant Polycystic Kidney Disease. J Korean Med Sci 2023; 38:e296. [PMID: 37750370 PMCID: PMC10519778 DOI: 10.3346/jkms.2023.38.e296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/31/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Factors related to the development and severity of polycystic liver disease (PLD) have not been well established. We aimed to evaluate the genetic and epidemiologic risk factors of PLD in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS Adult patients with inherited cystic kidney disease were enrolled from May 2019 to May 2021. Demographic, clinical, and laboratory data were collected at the initial study visit. The severity of PLD was graded based on the height-adjusted total liver volume: < 1,000 mL/m (Gr1), 1,000-1,800 mL/m (Gr2), and > 1,800 mL/m (Gr3). Targeted exome sequencing was done by a gene panel including 89 ciliopathy-related genes. We searched out the relative factors to the presence and the severity of PLD using logistic regression analysis. RESULTS Of 602 patients with typical ADPKD, 461 (76.6%) patients had PLD. The patients with PLD showed female predominance and a higher frequency of other ADPKD-related complications. The genetic variants with truncating mutation of PKD1 (PKD1-protein-truncating [PT]) or PKD2 commonly affected the development and severity of PLD. An older age, female sex, and higher kidney volume with Mayo classification 1C-1E was significantly associated with the development of PLD, but not with the severity of PLD. On the other hand, higher body mass index, lower hemoglobin, and higher alkaline phosphatase (ALP) were the significant risk factors of severe PLD (≥ Gr2). CONCLUSION Hepatic involvement in ADPKD could be related to kidney manifestations and genetic variants including PKD1-PT or PKD2. Monitoring hemoglobin and ALP and evaluating the genetic variants might help predict severe PLD. TRIAL REGISTRATION Clinical Research Information Service Identifier: KCT0005580.
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Affiliation(s)
- Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hayne Cho Park
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea
| | - Hyunjin Ryu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Curie Ahn
- Department of Internal Medicine, National Medical Center, Seoul, Korea
| | - Kyu-Beck Lee
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yeong Hoon Kim
- Department of Internal Medicine, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Kyungjo Jeong
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea
| | - Jungmin Choi
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yun Kyu Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea.
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Li D, Chen Z, Shan Y, Hu T, Hong X, Zhu J, Zhu Y, Fu G, Wang M, Zhang W. Liver enzymes mediate the association between aldehydes co-exposure and hypertriglyceridemia. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 263:115346. [PMID: 37579588 DOI: 10.1016/j.ecoenv.2023.115346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/18/2023] [Accepted: 08/06/2023] [Indexed: 08/16/2023]
Abstract
Aldehydes are recognized environmental toxicants that may affect lipid metabolism. For instance, acrolein has been found to increase serum triglyceride (TG) levels exclusively. However, it remains unclear whether other aldehydes are also associated with hypertriglyceridemia (HTG), and what mechanisms may be involved. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2013-2014) to identify associations between serum aldehydes, liver enzymes, and HTG. Serum aldehydes included crotonaldehyde (CRAL), propanaldehyde (3AL), butyraldehyde (4AL), pentanaldehyde (5AL), isopentanaldehyde (I5AL), and heptanaldehyde (7AL). Liver enzymes included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). HTG was defined as fasting TG levels ≥ 1.7 mmol/L. Aldehyde co-exposure was quantified using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), while mediation analysis was performed to investigate the role of liver enzymes. Among 1474 participants (mean age 38.6 years, male 50.0%), 426 were diagnosed with HTG. 4AL, 5AL, I5AL, and 7AL were shown to be positively associated with HTG (all P values <0.05). Aldehydes co-exposure was also positively associated with HTG (OR 1.706, 95%CI 1.299-2.240), with 5AL contributing the highest weight (35.3%). Furthermore, aldehydes co-exposure showed positive associations with ALT, AST, and GGT (all P values <0.05), and all four liver enzymes were positively associated with HTG (all P values <0.05). Mediation analysis revealed that liver enzymes (ALT, AST, and GGT) may mediate the associations of 5AL and 7AL with HTG (all P values <0.05). This study identified a positive association between aldehyde co-exposure and HTG, which may be partially mediated by liver enzymes.
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Affiliation(s)
- Duanbin Li
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Zhezhe Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Yu Shan
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Tianli Hu
- Department of Cardiology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, Zhejiang, People's Republic of China
| | - Xulin Hong
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Jun Zhu
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Yunhui Zhu
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Guosheng Fu
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Min Wang
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China
| | - Wenbin Zhang
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang, People's Republic of China; Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou 310000, Zhejiang, People's Republic of China.
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Zhu YJ, Li J, Liu YG, Jiang Y, Cheng XJ, Han X, Wang CY, Li J. Role of biochemical markers and autoantibodies in diagnosis of early-stage primary biliary cholangitis. World J Gastroenterol 2023; 29:5075-5081. [PMID: 37753365 PMCID: PMC10518739 DOI: 10.3748/wjg.v29.i34.5075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/15/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic progressive autoimmune cholestatic disease. The main target organ of PBC is the liver, and nonsuppurative inflammation of the small intrahepatic bile ducts may eventually develop into cirrhosis or liver fibrosis. AIM To explore the clinical characteristics of early-stage PBC, identify PBC in the early clinical stage, and promptly treat and monitor PBC. METHODS The data of 82 patients with PBC confirmed by pathology at Tianjin Second People's Hospital from January 2013 to November 2021 were collected, and the patients were divided into stage I, stage II, stage III, and stage IV according to the pathological stage. The general data, serum biochemistry, immunoglobulins, and autoimmune antibodies of patients in each stage were retrospectively analyzed. RESULTS In early-stage (stages I + II) PBC patients, 50.0% of patients had normal alanine aminotransferase (ALT) levels, and 37.5% had normal aspartate aminotransferase (AST) levels. For the remaining patients, the ALT and AST levels were mildly elevated; all of these patients had levels of < 3 times the upper limit of normal values. The AST levels were significantly different among the three groups (stages I + II vs stage III vs stage IV, P < 0.05). In the early stage, 29.2% of patients had normal alkaline phosphatase (ALP) levels. The remaining patients had different degrees of ALP elevation; 6.3% had ALP levels > 5 times the upper limit of normal value. Moreover, γ-glutamyl transferase (GGT) was more robustly elevated, as 29.2% of patients had GGT levels of > 10 times the upper limit of normal value. The ALP values among the three groups were significantly different (P < 0.05). In early stage, the jaundice index did not increase significantly, but it gradually increased with disease progression. However, the above indicators were significantly different (P < 0.05) between the early-stage group and the stage IV group. With the progression of the disease, the levels of albumin and albumin/globulin ratio tended to decrease, and the difference among the three groups was statistically significant (P < 0.05). In early-stage patients, IgM and IgG levels as well as cholesterol levels were mildly elevated, but there were no significant differences among the three groups. Triglyceride levels were normal in the early-stage group, and the differences among the three groups were statistically significant (P < 0.05). The early detection rates of anti-mitochondria antibody (AMA) and AMA-M2 were 66.7% and 45.8%, respectively. The positive rate of anti-sp100 antibodies was significantly higher in patients with stage IV PBC. When AMA and AMA-M2 were negative, in the early stage, the highest autoantibody was anti-nuclear antibody (ANA) (92.3%), and in all ANA patterns, the highest was ANA centromere (38.5%). CONCLUSION In early-stage PBC patients, ALT and AST levels are normal or mildly elevated, GGT and ALP levels are not elevated in parallel, GGT levels are more robustly elevated, and ALP levels are normal in some patients. When AMA and AMA-M2 are negative, ANA especially ANA centromere positivity suggests the possibility of early PBC. Therefore, in the clinic, significantly elevated GGT levels with or without normal ALP levels and with ANA (particularly ANA centromere) positivity (when AMA and AMA-M2 are negative) may indicate the possibility of early PBC.
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Affiliation(s)
- Yu-Jin Zhu
- Graduate School, Tianjin Medical University, Tianjin 300041, China
| | - Jing Li
- Graduate School, Tianjin Medical University, Tianjin 300041, China
| | - Yong-Gang Liu
- Department of Pathology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Xiao-Jing Cheng
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Xu Han
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Chun-Yan Wang
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Jia Li
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
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Li D, Chen Z, Shan Y, Hu T, Hong X, Zhu J, zhu Y, Fu G, Wang M, Zhang W. Liver enzymes mediate the association between aldehydes co-exposure and hypertriglyceridemia. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 263:115346. [DOI: https:/doi.org/10.1016/j.ecoenv.2023.115346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
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18
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van den Beukel MD, Stoelinga AEC, van der Meer AJ, van der Meulen S, Zhang L, Tushuizen ME, van Hoek B, Trouw LA. Antibodies against multiple post-translationally modified proteins aid in diagnosis of autoimmune hepatitis and associate with complete biochemical response to treatment. Front Med (Lausanne) 2023; 10:1195747. [PMID: 37564051 PMCID: PMC10411548 DOI: 10.3389/fmed.2023.1195747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 06/14/2023] [Indexed: 08/12/2023] Open
Abstract
Background (Auto)immune mediated and cholestatic liver disease (AILD) includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Especially AIH is characterized by the presence of autoantibodies and elevated serum immunoglobulins. In rheumatoid arthritis, autoantibodies against post-translational modifications (PTMs) such as citrullination (Cit) and carbamylation (CarP) are used as diagnostic and prognostic markers, respectively. We studied the presence of six anti-PTM antibodies in patients with the three AILDs and non-AILD. Methods Antibodies against six PTMs (malondialdehyde-acetaldehyde adducts (MAA), advanced glycation end-products (AGE), CarP, acetylation (AL), Cit, and nitration (NT)) were tested in sera of patients with AILD (n = 106), non-AILD (n = 101) and compared with healthy controls (HC) (n = 100). Levels and positivity were correlated with clinical and biochemical features in a well-defined cohort of untreated AIH patients. Results Anti-PTM antibodies were more often detectable in sera from AILD patients compared with HCs (anti-MAA: 67.9% vs. 2.0%, anti-AGE: 36.8% vs. 4.0%, anti-CarP: 47.2% vs. 5.0% and anti-AL: 18.9% vs. 5.0%). In untreated AIH, time to complete biochemical response (CBR) was associated with anti-MAA, anti-AGE, anti-CarP and anti-AL antibodies. Significantly more patients with at least three anti-PTM antibodies attained CBR at 12 months of treatment (13 vs. 3 p = 0.01). Conclusion Anti-PTM antibodies are frequently present in AILD. The presence of anti-MAA, anti-AGE and anti-CarP antibodies correlates with the presence of AIH within this cohort. In AIH, harboring at least three anti-PTM antibody responses is positively associated with CBR. Determination of anti-PTM antibodies in liver disease may have diagnostic and prognostic value.
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Affiliation(s)
| | - Anna E. C. Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Adriaan J. van der Meer
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, Netherlands
| | - Stef van der Meulen
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Lu Zhang
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands
| | - Leendert A. Trouw
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
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Hradicka P, Adamkova P, Lenhardt L, Gancarcikova S, Iannaccone SF, Demeckova V. Addressing safety concerns of long-term probiotic use: In vivo evidence from a rat model. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
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20
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Qian XJ, Wen ZM, Huang XM, Feng HJ, Lin SS, Liu YN, Li SC, Zhang Y, Peng WG, Yang JR, Zheng ZY, Zhang L, Zhang DW, Lu FM, Liu LJ, Pan WD. Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin. World J Gastroenterol 2023; 29:1359-1373. [PMID: 36925461 PMCID: PMC10011960 DOI: 10.3748/wjg.v29.i8.1359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/30/2022] [Accepted: 02/16/2023] [Indexed: 02/28/2023] Open
Abstract
BACKGROUND Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance.
AIM To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC.
METHODS This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively.
RESULTS Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone.
CONCLUSION Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.
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Affiliation(s)
- Xiang-Jun Qian
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Zhu-Mei Wen
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Xiao-Ming Huang
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Hui-Juan Feng
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Shan-Shan Lin
- Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, United States
| | - Yan-Na Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Sheng-Cong Li
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Yu Zhang
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Wen-Guang Peng
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Jia-Rui Yang
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Zhe-Yu Zheng
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Lei Zhang
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Da-Wei Zhang
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
| | - Feng-Min Lu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Li-Juan Liu
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Wei-Dong Pan
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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Role of Hepatocyte Transporters in Drug-Induced Liver Injury (DILI)-In Vitro Testing. Pharmaceutics 2022; 15:pharmaceutics15010029. [PMID: 36678658 PMCID: PMC9866820 DOI: 10.3390/pharmaceutics15010029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/16/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Bile acids and bile salts (BA/BS) are substrates of both influx and efflux transporters on hepatocytes. Canalicular efflux transporters, such as BSEP and MRP2, are crucial for the removal of BA/BS to the bile. Basolateral influx transporters, such as NTCP, OATP1B1/1B3, and OSTα/β, cooperate with canalicular transporters in the transcellular vectorial flux of BA/BS from the sinusoids to the bile. The blockage of canalicular transporters not only impairs the bile flow but also causes the intracellular accumulation of BA/BS in hepatocytes that contributes to, or even triggers, liver injury. In the case of BA/BS overload, the efflux of these toxic substances back to the blood via MRP3, MRP4, and OST α/β is considered a relief function. FXR, a key regulator of defense against BA/BS toxicity suppresses de novo bile acid synthesis and bile acid uptake, and promotes bile acid removal via increased efflux. In drug development, the early testing of the inhibition of these transporters, BSEP in particular, is important to flag compounds that could potentially inflict drug-induced liver injury (DILI). In vitro test systems for efflux transporters employ membrane vesicles, whereas those for influx transporters employ whole cells. Additional in vitro pharmaceutical testing panels usually include cellular toxicity tests using hepatocytes, as well as assessments of the mitochondrial toxicity and accumulation of reactive oxygen species (ROS). Primary hepatocytes are the cells of choice for toxicity testing, with HepaRG cells emerging as an alternative. Inhibition of the FXR function is also included in some testing panels. The molecular weight and hydrophobicity of the drug, as well as the steady-state total plasma levels, may positively correlate with the DILI potential. Depending on the phase of drug development, the physicochemical properties, dosing, and cut-off values of BSEP IC50 ≤ 25-50 µM or total Css,plasma/BSEP IC50 ≥ 0.1 may be an indication for further testing to minimize the risk of DILI liability.
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22
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Protective Effect of SeMet on Liver Injury Induced by Ochratoxin A in Rabbits. Toxins (Basel) 2022; 14:toxins14090628. [PMID: 36136566 PMCID: PMC9504919 DOI: 10.3390/toxins14090628] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/30/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
Ochratoxin A (OTA) is second only to aflatoxin in toxicity among mycotoxins. Recent studies have shown that selenomethionine (SeMet) has a protective effect on mycotoxin-induced toxicity. The purpose of this study was to investigate the protective effect and mechanism of SeMet on OTA-induced liver injury in rabbits. Sixty 35-day-old rabbits with similar body weight were randomly divided into five groups: control group, OTA group (0.2 mg/kg OTA), OTA + 0.2 mg/kg SeMet group, OTA + 0.4 mg/kg SeMet group and OTA + 0.6 mg/kg SeMet group. Rabbits were fed different doses of the SeMet diet for 21 d, and OTA was administered for one week from day 15 (the control group was provided the same dose of NaHCO3 solution). The results showed that 0.4 mg/kg SeMet could significantly improve the liver injury induced by OTA poisoning. SeMet supplementation can improve the changes in physiological blood indexes caused by OTA poisoning in rabbits and alleviate pathological damage to the rabbit liver. SeMet also increased the activities of SOD, GSH-Px and T-AOC and significantly decreased the contents of ROS, MDA, IL-1β, IL-6 and TNF-α, effectively alleviating the oxidative stress and inflammatory response caused by OTA poisoning. In addition, OTA poisoning inhibits Nrf2 and HO-1 levels, ultimately leading to peroxide reaction, while SeMet activates the Nrf2 signaling pathway and enhances the expression of the HO-1 downstream Nrf2 gene. These results suggest that Se protects the liver from OTA-induced hepatotoxicity by regulating Nrf2/HO-1 expression.
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23
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Guo W, Liu Z, Lu Q, Liu P, Lin X, Wang J, Wang Y, Chang Q, Wang F, Wu S. Non-Linear Association Between Serum Alkaline Phosphatase and 3-Month Outcomes in Patients With Acute Stroke: Results From the Xi'an Stroke Registry Study of China. Front Neurol 2022; 13:859258. [PMID: 35911898 PMCID: PMC9334812 DOI: 10.3389/fneur.2022.859258] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/21/2022] [Indexed: 11/23/2022] Open
Abstract
Background Alkaline phosphatase (ALP) is associated with an increased risk of cardiovascular events and is closely related to adverse outcomes after stroke. However, the regional investigation into the associations of ALP with acute stroke (AS) outcomes is limited. This study aimed to identify the association between serum ALP levels and clinical outcomes 3 months after AS in the Xi'an district of China. Methods We enrolled all patients with AS from 4 hospitals in the Xi'an district from January to December 2015. ALP levels and related patient information were collected at admission, and the events of stroke outcomes were followed up 1 and 3 months after diagnosis. ALP levels were analyzed as continuous variables and quartiles (Q1–Q4). The outcomes included all-cause mortality, recurrent stroke, and poor functional outcomes (modified Rankin Scale score of 3–6) within 3 months. A multivariate logistic regression and interaction analyses were performed to evaluate the independent association between serum ALP level and 3-month stroke outcomes. Results Overall, 2,799 patients with AS were enrolled in this study. The mean age was 63.9 ± 12.5 years. In the Q4 (≥93.0 U/L) group, the incidences of all-cause mortality, recurrent stroke, and poor functional outcomes were 7.8, 2.7, and 24.9%, respectively. After being adjusted for confounding variables, patients in Q4 (≥93.0 U/L) were related to an increased risk of all-cause mortality [odds ratio (OR) = 2.17, 95% CI: 1.19–3.96; P = 0.011] and patients in Q3 (76.8–92.9 U/L) were related to a lower risk of recurrent stroke (OR = 0.37, 95% CI: 0.14–0.97; P = 0.043) at the 3-month time point, compared to those in Q2 (63.0–76.7 U/L). The optimal range of ALP for all-cause mortality was seen in Q2, with a nadir level of 70 U/L. However, differences were statistically insignificant between ALP levels and poor functional outcomes (P > 0.05). Moreover, there was no significant interaction between ALP levels and age, gender, drinking status, smoking status, or pneumonia (P > 0.05) for all outcomes. Conclusion Non-linear associations were observed between serum ALP levels and 3-month outcomes in patients with AS. It might be beneficial to reduce the risk of all-cause mortality and recurrent stroke by maintaining ALP at optimal ranges.
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Affiliation(s)
- Weiyan Guo
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Zhongzhong Liu
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
- Department of Epidemiology and Biostatistics, School of Public Health of Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Qingli Lu
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Pei Liu
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Xuemei Lin
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Jing Wang
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Yuanji Wang
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Qiaoqiao Chang
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Fang Wang
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
| | - Songdi Wu
- Department of Neurology, The First Affiliated Hospital of Northwest University, Xi'an No.1 Hospital, Xi'an, China
- *Correspondence: Songdi Wu
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Liu L, Xu Y, Jia S, Chen X, He S. Prognostic significance of serum alkaline phosphatase for all-cause mortality in patients with hypertrophic cardiomyopathy: A cohort of the hospitalized population. Ann Clin Biochem 2022; 59:387-395. [PMID: 35815613 DOI: 10.1177/00045632221113986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Higher levels of serum alkaline phosphatase (ALP) as a novel risk factor was recently found associated with mortality in different population, whereas, the relationship remains unknown in hypertrophic cardiomyopathy (HCM) population. In this study, we hypothesized that increased ALP could predict all-cause mortality in the adult HCM population. In this cohort study, retrospective data from 538 HCM patients consecutively recruited in West China Hospital were collected. Patients were divided into two groups by baseline ALP with 80 IU/L as the cutoff. All-cause mortality was set as the endpoint. Subgroup analysis was conducted in patients with normal liver function. In total, 461 adult HCM patients were included. After a median follow-up of 4.7 years, 91 patients died. Alkaline phosphatase was an independent predictor of all-cause mortality since patients in the higher ALP group had an increased risk (adjusted HR 2.0, 95% CI: 1.3-3.3, P < 0.01) compared with those in the lower ALP group. In subgroup analysis, the relationship was consistent with the overall (adjusted HR: 3.0, 95% CI: 1.7-5.3, P < 0.01 for the higher ALP group). In the Chinese cohort study of HCM patients, serum ALP is independently associated with all-cause mortality. Patients with a measured value above 80 IU/L had an increased risk of all-cause mortality and this cutoff might help with risk stratification in HCM population.
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Affiliation(s)
- Lu Liu
- Department of Cardiology, 34753West China Hospital of Sichuan University, Chengdu, China
| | - Ying Xu
- Department of Cardiology, 34753West China Hospital of Sichuan University, Chengdu, China
| | - Shanshan Jia
- Department of Cardiology, 34753West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoping Chen
- Department of Cardiology, 34753West China Hospital of Sichuan University, Chengdu, China
| | - Sen He
- Department of Cardiology, 34753West China Hospital of Sichuan University, Chengdu, China
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Laurain A, Rubera I, Razzouk-Cadet M, Bonnafous S, Albuquerque M, Paradis V, Patouraux S, Duranton C, Lesaux O, Lefthériotis G, Tran A, Anty R, Gual P, Iannelli A, Favre G. Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation. Biomedicines 2022; 10:1496. [PMID: 35884801 PMCID: PMC9312703 DOI: 10.3390/biomedicines10071496] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/11/2022] [Accepted: 06/14/2022] [Indexed: 11/24/2022] Open
Abstract
Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh−Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh−Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37−44] vs. 35 [30−40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07−1.86] vs. 0.68 [0.53−0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.
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Affiliation(s)
- Audrey Laurain
- Department of Nephrology, Pasteur 1 University Hospital, 06001 Nice, France;
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- LP2M CNRS UMR 7370, Tour Pasteur, 28 Avenue de Valombrose, 06000 Nice, France
| | - Isabelle Rubera
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- LP2M CNRS UMR 7370, Tour Pasteur, 28 Avenue de Valombrose, 06000 Nice, France
| | | | - Stéphanie Bonnafous
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol” Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M) Bâtiment Universitaire ARCHIMED? 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, France
- Digestive Unit, Archet 2 University Hospital, 06200 Nice, France
| | - Miguel Albuquerque
- Pathology Department, Beaujon University Hospital, AP-HP, 92110 Clichy, France; (M.A.); (V.P.)
- Inserm U1149, Beaujon University Hospital, 92110 Clichy, France
| | - Valérie Paradis
- Pathology Department, Beaujon University Hospital, AP-HP, 92110 Clichy, France; (M.A.); (V.P.)
- Inserm U1149, Beaujon University Hospital, 92110 Clichy, France
| | - Stéphanie Patouraux
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Pathology Department, Pasteur 1 University Hospital, 06000 Nice, France
| | - Christophe Duranton
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- LP2M CNRS UMR 7370, Tour Pasteur, 28 Avenue de Valombrose, 06000 Nice, France
| | - Olivier Lesaux
- Department Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813-5534, USA;
| | - Georges Lefthériotis
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- LP2M CNRS UMR 7370, Tour Pasteur, 28 Avenue de Valombrose, 06000 Nice, France
- Department of Vascular Medicine and Surgery, Pasteur 1 University Hospital, 06000 Nice, France
| | - Albert Tran
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol” Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M) Bâtiment Universitaire ARCHIMED? 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, France
- Digestive Unit, Archet 2 University Hospital, 06200 Nice, France
| | - Rodolphe Anty
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol” Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M) Bâtiment Universitaire ARCHIMED? 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, France
- Digestive Unit, Archet 2 University Hospital, 06200 Nice, France
| | - Philippe Gual
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol” Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M) Bâtiment Universitaire ARCHIMED? 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, France
| | - Antonio Iannelli
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- Team 8 “Chronic Liver Diseases Associated with Obesity and Alcohol” Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M) Bâtiment Universitaire ARCHIMED? 151 Route Saint Antoine de Ginestière BP 2 3194, 06204 Nice, France
- Digestive Unit, Archet 2 University Hospital, 06200 Nice, France
| | - Guillaume Favre
- Department of Nephrology, Pasteur 1 University Hospital, 06001 Nice, France;
- Faculty of Medicine, Tour Pasteur, 28 Avenue de Valombrose, University of Côte d’Azur, 06000 Nice, France; (I.R.); (S.B.); (S.P.); (C.D.); (G.L.); (A.T.); (R.A.); (P.G.); (A.I.)
- LP2M CNRS UMR 7370, Tour Pasteur, 28 Avenue de Valombrose, 06000 Nice, France
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Dietary phytochemical consumption is inversely associated with liver alkaline phosphatase in Middle Eastern adults. World J Hepatol 2022. [DOI: 10.4254/wjh.v14.i5.1007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Darabi Z, Webb RJ, Mozaffari-Khosravi H, Mirzaei M, Davies IG, Khayyatzadeh SS, Mazidi M. Dietary phytochemical consumption is inversely associated with liver alkaline phosphatase in Middle Eastern adults. World J Hepatol 2022; 14:1006-1015. [PMID: 35721289 PMCID: PMC9157700 DOI: 10.4254/wjh.v14.i5.1006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 01/28/2022] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The hepatoprotective effects of phytochemicals are controversial. A dietary phytochemical index (DPI) has been suggested as an alternative method for quantifying the phytochemical content of foods.
AIM To assess the DPI in relation to liver function tests among a representative sample of Iranian adults.
METHODS A total of 5111 participants aged 35-70 years old were included in this cross-sectional study by a multistage cluster random sampling method. Dietary intakes were collected by a validated and reliable food frequency questionnaire with 121 items. DPI was calculated by the percent of daily energy intake taken from phytochemical-rich foods. Fasting serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) were determined. Linear regression was used to investigate the association between DPI and levels of liver enzymes using crude and adjusted models.
RESULTS There was an inverse association between DPI score and serum ALP in the crude model (β = -0.05; P < 0.001). This association remained significant after adjustment for body mass index, age, smoking, energy intake, history of diabetes, and education (β = -0.03; P = 0.01). No significant associations were found between DPI score and serum levels of AST, ALT, and GGT. The individuals with the highest DPI scores consumed significantly higher amounts of fruits, vegetables, legumes, nuts, and cereals, yet were shown to have significantly higher serum total cholesterol and low-density lipoprotein cholesterol, as well as several other metabolic abnormalities.
CONCLUSION Higher adherence to phytochemical-rich foods was associated with lower levels of ALP, but no change in other liver enzymes. Those with higher DPI scores also consumed food items associated with a healthier overall dietary pattern; however, they also presented several unexpected metabolic derangements. Additional randomised trials are needed to better determine the effects of phytochemical-rich foods on liver function.
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Affiliation(s)
- Zahra Darabi
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Richard James Webb
- School of Health Sciences, Liverpool Hope University, Liverpool L16 9JD, United Kingdom
| | - Hassan Mozaffari-Khosravi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Nutrition and Food Security Research Center, Shahid Sadoghi University of Medical Sciences, Yazd, Iran
| | - Masoud Mirzaei
- Yazd Cardiovascular Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ian Glynn Davies
- School of Sports and Exercise Sciences, Faculty of Science, Liverpool John Moores University, IM Marsh Campus, Barkhill Road, Liverpool L17 6AF, United Kingdom
| | - Sayyed Saeid Khayyatzadeh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohsen Mazidi
- Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom
- Department of Twin Research & Genetic Epidemiology, King’s college London, South Wing St Thomas', London SE1 7EH, United Kingdom
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Baharoon B, Shaik A, El-Hamidy SM, Eid El-Araby R, Batawi AH, Abdel Salam M. Influence of halloysite nanotubes on the efficiency of Asparaginase against mice Ehrlich solid carcinoma. Saudi J Biol Sci 2022; 29:3626-3634. [PMID: 35844382 PMCID: PMC9280262 DOI: 10.1016/j.sjbs.2022.02.058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 02/26/2022] [Accepted: 02/28/2022] [Indexed: 11/25/2022] Open
Abstract
Herein, the impact of the halloysite nanotubes to suppress the side effects of Asparaginase (ANase) cellular proliferation was investigated. Methods: A total of 100 adult male mice was employed. These mice were divided into four equal groups; Group 1 (control), Group 2 (ESC group) of a single dose of 0.15 ml Ehrlich cells (2 × 106) intraperitoneal infusion(IP), Group 3 (ESC + ANase group) received six doses equal treatments of Intratumoral (IT) 0.07 ml Aspragnase (7 mg/kg) over two weeks. For two weeks, Group 4 (ESC + ASNase + HNTs) received an IT administration of 0.07 ml Asparaginase stocked on Halloysite nanotubes (HNTs) (30 mg/kg) three times per week. A blood specimen was collected, and the liver was removed to be investigated histologically. Results: TEM measurements for the Halloysite nanoclay showed their tubular cylindrical shape with a mean diameter of 50 nm and an average length of 1 μm, whereas The X-ray diffraction pattern of the Halloysite nanoclay showed their characteristic peaks. ESC increases the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin than control and other groups, even as albumin and total protein were decreasing. After using Halloysite Nanotube, the rates of these variables were enhanced up to 75%. The hepatocytes histological studies showed protection against Ehrlich Solid carcinoma-induced degenerative, necrotic, and inflammatory changes up to 70%. In conclusion, halloysite nanotubes have demonstrated effective removal of Ehrlich solid carcinoma in mice using an ASNase delivery system. It promoted the ASNase to inhibit the adverse effect of ANase's on the liver and remove the tumour cells.
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Key Words
- ALB, Albumin
- ALP, Alkaline Phosphatase
- ALT, Aniline Aminotransferase
- ASNase, Asparaginase
- AST, Aspartate Aminotransferase
- Asparaginase
- BCP, bromocresol purple
- BD, Bile Duct
- CV, Central Vein
- DDS, Drug Delivery Systems
- EAC, Ehrlich ascites carcinoma
- ESC, Ehrlich Solid Carcenoma
- HNTs, Halloysite Nanotubes
- Halloysite nanotubes, Cancer
- Histopathology
- IFCC, international federation of clinical chemistry
- IM, Intramuscularly
- IP, Intraperitoneal
- IT, Intratumorally
- KAU, King Abdulaziz University
- KFMRC, King Fahd Medical Research Center
- Liver
- Liver functions
- PV, Portal Vein
- TBIL, Total Bilirubin
- TEM, Transmission Electron Microscope
- TP, Total protein
- XRD, X-Ray Diffraction
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Affiliation(s)
- B.M.M. Baharoon
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - A.M. Shaik
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Princess Dr. Najla Bint Saud Al Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Salim M. El-Hamidy
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Princess Dr. Najla Bint Saud Al Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rady Eid El-Araby
- Central Lab, Theodor Bilharz Research Institute (TBRI) Ministry of Scientific Research, Egypt
| | - Ashwaq H. Batawi
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohamed Abdel Salam
- Department of Chemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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Postoperative liver function tests can predict anastomotic dysfunction after bile duct injury repair. Updates Surg 2022; 74:937-944. [PMID: 35415799 DOI: 10.1007/s13304-022-01275-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 03/07/2022] [Indexed: 12/07/2022]
Abstract
Liver function tests help in the follow-up of postoperative patients with iatrogenic bile duct injury. There is not clear evidence regarding their predictive role on anastomosis dysfunction. We describe our experience with postoperative liver function tests and a predictive model of long-term patency after repair. This is retrospective cohort study of patients with bilioenteric anastomosis for bile duct injury and their long-term follow-up. A binomial logistic regression model was performed to ascertain the effects of the grade of bile duct injury and liver function test in the postoperative period. A total of 329 patients were considered for the analysis. In the logistic regression model two predictor variables were statistically significant for anastomosis stenosis: type of bilioenteric anastomosis and alkaline phosphatase levels. A ROC curve analysis was made for alkaline phosphatase with an area under the curve of 0.758 (95% CI 0.67-0.84). A threshold of 323 mg/dL was established (OR 6.0, 95% CI 2.60-13.83) with a sensitivity of 75%, specificity of 67%, PPV of 20%, NPV of 96%, PLR of 2.27 and NLR of 0.37. Increased alkaline phosphatase (above 323 mg/dL) after the fourth operative week was found to be a predictor of long-term dysfunction.
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Zhang F, Xie H, Guo B, Zhu C, Xu J. AIE-active macromolecules: designs, performances, and applications. Polym Chem 2022. [DOI: 10.1039/d1py01167g] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Aggregation-induced emission (AIE) macromolecules as emerging luminescent materials gained increasing attention owing to their good processability, high brightness, wide functionality, and smart responsiveness, with great potential in many fields.
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Affiliation(s)
- Fei Zhang
- Institute of Low-Dimensional Materials Genome Initiative, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong, 518060, China
- School of Chemistry, Cardiff University, Cardiff, CF10 3AT, UK
| | - Hui Xie
- Institute of Low-Dimensional Materials Genome Initiative, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong, 518060, China
- Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China
| | - Bing Guo
- School of Science and Shenzhen Key Laboratory of Flexible Printed Electronics Technolog, Harbin Institute of Technology, Shenzhen, 518055, China
| | - Caizhen Zhu
- Institute of Low-Dimensional Materials Genome Initiative, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Jian Xu
- Institute of Low-Dimensional Materials Genome Initiative, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong, 518060, China
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Ponsioen CY, Assis DN, Boberg KM, Bowlus CL, Deneau M, Thorburn D, Aabakken L, Färkkilä M, Petersen B, Rupp C, Hübscher SG. Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process. Gastroenterology 2021; 161:1764-1775.e5. [PMID: 34384749 DOI: 10.1053/j.gastro.2021.07.046] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands
| | - David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Kirsten M Boberg
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California
| | - Mark Deneau
- University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, Utah
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free Hospital and Institute for Liver and Digestive Health, University College London, London, United Kingdom; ERN RARE Liver, Hamburg, Germany
| | - Lars Aabakken
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland; ERN RARE Liver, Hamburg, Germany
| | - Bret Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Christian Rupp
- Department of Internal Medicine IV, Gastroenterology, and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham and, Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
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Wu H, Wang Y, Yao Q, Fan L, Meng L, Zheng N, Li H, Wang J. Alkaline phosphatase attenuates LPS-induced liver injury by regulating the miR-146a-related inflammatory pathway. Int Immunopharmacol 2021; 101:108149. [PMID: 34634739 DOI: 10.1016/j.intimp.2021.108149] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/09/2021] [Accepted: 09/07/2021] [Indexed: 11/27/2022]
Abstract
Lipopolysaccharide (LPS) can remain in dairy products after the sterilization of milk powder and may pose a threat to the health of infants and young children. There is a large amount of alkaline phosphatase (ALP) in raw milk, which can remove the phosphate bond of LPS, thus, detoxifying it. ALP is regarded as an indicator of the success of milk sterilization due to its strong heat resistance. ALP can alleviate the toxicity of LPS in enteritis and nephritis models, but the mechanism by which oral-intake of ALP protects liver tissue from LPS stimulation is unclear. In this study, an in vivo acute mouse liver injury model was induced by C. sakazakii LPS (200 μg/kg) and used to verify the protective mechanism of ALP (200 U/kg) on mice livers. The related pathways were also verified by in vitro cell culture. Enzyme linked immunosorbent assays (ELISAs), quantitative reverse transcription PCR (RT-qPCR) and western blotting were used to detect the levels of inflammatory factors at the protein level and RNA level, and to confirm the inflammation of liver tissue caused by LPS. ALP was found to alleviate acute liver injury in vitro by activating miR-146a. We found that ALP could up-regulate the level of miR146a and subsequently alleviates the expression of TLR4, TNF-α, matured IL-1β, and NF-κB in mouse liver tissue and hepatocytes; thus, reducing liver inflammation. Herein, we demonstrated for the first time that oral-intake of ALP protected liver tissue by up-regulating the expression of miR-146a and alleviating inflammatory reactions; thus, providing a research basis for the proper processing of milk. This study also suggests that producers should improve the awareness of the protective effects of bioactive proteins in raw milk.
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Affiliation(s)
- Haoming Wu
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Yang Wang
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qianqian Yao
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Linlin Fan
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Lu Meng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Nan Zheng
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Huiying Li
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Jiaqi Wang
- State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Laboratory of Quality and Safety Risk Assessment for Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
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Briolay A, Bessueille L, Magne D. TNAP: A New Multitask Enzyme in Energy Metabolism. Int J Mol Sci 2021; 22:ijms221910470. [PMID: 34638808 PMCID: PMC8509042 DOI: 10.3390/ijms221910470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/17/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Tissue-nonspecific alkaline phosphatase (TNAP) is mainly known for its necessary role in skeletal and dental mineralization, which relies on the hydrolysis of the mineralization inhibitor inorganic pyrophosphate (PPi). Mutations in the gene encoding TNAP leading to severe hypophosphatasia result in strongly reduced mineralization and perinatal death. Fortunately, the relatively recent development of a recombinant TNAP with a bone anchor has allowed to correct the bone defects and prolong the life of affected babies and children. Researches on TNAP must however not be slowed down, because accumulating evidence indicates that TNAP activation in individuals with metabolic syndrome (MetS) is associated with enhanced cardiovascular mortality, presumably in relation with cardiovascular calcification. On the other hand, TNAP appears to be necessary to prevent the development of steatohepatitis in mice, suggesting that TNAP plays protective roles. The aim of the present review is to highlight the known or suspected functions of TNAP in energy metabolism that may be associated with the development of MetS. The location of TNAP in liver and its function in bile excretion, lipopolysaccharide (LPS) detoxification and fatty acid transport will be presented. The expression and function of TNAP in adipocyte differentiation and thermogenesis will also be discussed. Given that TNAP is a tissue- and substrate-nonspecific phosphatase, we believe that it exerts several crucial pathophysiological functions that are just beginning to be discovered.
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Xiang Y, Kong X, Zhang C, He C, Cai J, Lu R, Zhang B, Lu L, Yang Y. Free fatty acids and triglyceride change in the gallbladder bile of gallstone patients with pancreaticobiliary reflux. Lipids Health Dis 2021; 20:97. [PMID: 34465364 PMCID: PMC8408976 DOI: 10.1186/s12944-021-01527-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/10/2021] [Indexed: 11/18/2022] Open
Abstract
Background Pancreaticobiliary reflux (PBR) causes chronic inflammation of the gallbladder mucosa and changes in the bile components, which are known to promote gallstone formation. This study aimed to investigate the bile biochemistry changes in gallstone patients with PBR and provide new clues for research on the involvement of PBR in gallstone formation. Methods Patients undergoing surgery for gallstones between December 2020 and May 2021 were eligible for inclusion. The bile biochemistry (including amylase, lipase, triglyceride, cholesterol, free fatty acids [FFAs], alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [γ-GT]) of the included gallstone patients was analysed to determine correlations with PBR. Results In this study, 144 gallstone patients who underwent surgery were enrolled. Overall, 15.97 % of the patients had an increased bile amylase level, which was associated with older age and significantly higher bile levels of ALP, lipase, triglyceride, and FFAs. Positive correlations were observed between amylase and lipase, triglyceride, FFAs levels in the gallbladder bile. However, the bile levels of triglyceride, FFAs, and lipase were positively correlated with each other only in the PBR group and showed no significant correlation in the control (N) group. In addition, elevated bile FFAs levels were found to be an independent risk factor for gallbladder wall thickening. Conclusions In conclusion, PBR-induced increase in FFAs and triglyceride in the gallbladder bile is a cause of gallstone formation, and an increase in bile ALP suggests the presence of cholestasis in PBR.
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Affiliation(s)
- Yukai Xiang
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Xiangyu Kong
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Cheng Zhang
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Chuanqi He
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Jingli Cai
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Ruiqi Lu
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Bosen Zhang
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Liu Lu
- Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, 200092, Shanghai, China
| | - Yulong Yang
- Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, 200092, Shanghai, China.
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Wang LJ, Liu H, Zou X, Xu Q, Zhang CY. 3'-Terminal Repair-Powered Dendritic Nanoassembly of Polyadenine Molecular Beacons for One-Step Quantification of Alkaline Phosphatase in Human Serum. Anal Chem 2021; 93:10704-10711. [PMID: 34292701 DOI: 10.1021/acs.analchem.1c02285] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Alkaline phosphatase (ALP) is an important hydrolase with crucial roles in biological processes, and the dysregulation of ALP may cause various human diseases. The conventional ALP assays usually involve cumbersome procedures with poor sensitivity. Herein, taking advantage of intrinsic superiorities of molecular beacons (MBs) and unique features of terminal deoxynucleotidyl transferase (TdT), we demonstrate for the first time the 3'-terminal repair-powered dendritic nanoassembly of polyadenine (A) MBs for one-step quantification of ALP in human serum. When ALP is present, it catalyzes 3'-terminal dephosphorylation of poly-A MBs to induce TdT-mediated template-free polymerization, generating long chains of polythymidine (T) sequences. The long poly-T chains can function as the anchoring templates to hybridize with many poly-A MBs, leading to the unfolding of loop structures and the dissociation of FAM/BHQ1 pairs (the 1st amplification stage). Subsequently, all 3'-hydroxylated poly-A MBs can be extended with the assistance of TdT to generate the branched long poly-T chains, leading to the hybridization of more poly-A MBs and the dissociation of more FAM/BHQ1 pairs (the 2nd amplification stage). Through multiple rounds of extension, assembly, and activation of poly-A MBs, dendritic DNA nanostructures are automatically formed, resulting in the dissociation of abundant fluorophores from the FAM/BHQ1 pairs to generate an exponentially amplified fluorescence signal (the nth amplification stage). This strategy possesses high sensitivity and excellent specificity, and the detection limit can reach 1 cell. Moreover, it can evaluate kinetic parameters, screen inhibitors, estimate cellular inhibition effects, and measure ALP in human serums.
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Affiliation(s)
- Li-Juan Wang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China.,School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China
| | - Hao Liu
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Xiaoran Zou
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
| | - Qinfeng Xu
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
| | - Chun-Yang Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Shandong Provincial Key Laboratory of Clean Production of Fine Chemicals, Shandong Normal University, Jinan 250014, China
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Zhang Z, Ai S, Yang Z, Li X. Peptide-based supramolecular hydrogels for local drug delivery. Adv Drug Deliv Rev 2021; 174:482-503. [PMID: 34015417 DOI: 10.1016/j.addr.2021.05.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/26/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022]
Abstract
Peptide-based supramolecular hydrogels have shown great promise as drug delivery systems (DDSs) because of their excellent biocompatibility, biodegradability, biological function, synthetic feasibility, and responsiveness to external stimuli. Self-assembling peptide molecules are able rationally designed into specific nanoarchitectures in response to the different environmental factors under different circumstances. Among all stimuli that have been investigated, utilizing inherent biological microenvironment, such as metal ions, enzymes and endogenous redox species, to trigger self-assembly endows such systems spatiotemporal controllability to transport therapeutics more accurately. Materials formed by weak non-covalent interactions result in the shear-thinning and immediate recovery behavior. Thus, they are injectable via a syringe or catheter, making them the ideal vehicles to deliver drugs. Based on the above merits, self-assembling peptide-based DDSs have been applied to treat various diseases via direct administration at the lesion site. Herein, in this review, we outline the triggers for inducing peptide-based hydrogels formation and serving as DDSs. We also described the advancements of peptide-based supramolecular hydrogels for local drug delivery, including intratumoral, subcutaneous, ischemia-related tissue (intramyocardial, intrarenal, and ischemic hind limb), and ocular administration. Finally, we give a brief perspective about the prospects and challenges in this field.
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Affiliation(s)
- Zhenghao Zhang
- Institute of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China
| | - Sifan Ai
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, PR China
| | - Zhimou Yang
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Xingyi Li
- Institute of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou 325027, PR China.
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Lou Z, Lin W, Zhao H, Jiao X, Wang C, Zhao H, Liu L, Liu Y, Xie Q, Huang X, Huang H, Zhao L. Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis. Cancer Cell Int 2021; 21:217. [PMID: 33858415 PMCID: PMC8050923 DOI: 10.1186/s12935-021-01919-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear. METHODS TCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD. RESULTS ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase in RhoA transcription, which enhanced LUAD cell metastasis. CONCLUSION ALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.
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Affiliation(s)
- Zhefeng Lou
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Weiwei Lin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Huirong Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xueli Jiao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Cong Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - He Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lu Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yu Liu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Qipeng Xie
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, the First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
| | - Haishan Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Lingling Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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Zheng S, Cao P, Yin Z, Wang X, Chen Y, Yu M, Xu B, Liao C, Duan Y, Zhang S, Han J, Yang X. Apigenin protects mice against 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestasis. Food Funct 2021; 12:2323-2334. [PMID: 33620063 DOI: 10.1039/d0fo02910f] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cholestasis can induce liver fibrosis and cirrhosis. Apigenin has anti-oxidant and anti-inflammatory effects. Herein, we determined whether apigenin can protect mice against cholestasis. In vitro, apigenin protected TFK-1 cells (a human bile duct cancer cell line) against H2O2-induced ROS generation and inhibited transforming growth factor-β-activated collagen type 1 alpha 1 and α-smooth muscle actin in LX2 cells (a human hepatic stellate cell line). In vivo, cholestatic mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were treated with apigenin. Apigenin potently blocked DDC-induced gallbladder atrophy and associated liver injury, fibrosis and collagen accumulation. Moreover, apigenin relieved the DDC-caused abnormality of bile acid metabolism and restored the balance between bile secretion and excretion by regulating the farnesoid X receptor signaling pathway. Furthermore, apigenin reduced inflammation or oxidative stress in the liver by blocking the DDC-activated Toll-like receptor 4, nuclear factor κB and tumor necrosis factor α, or DDC-suppressed superoxidase dismutase 1/2, catalase and glutathione peroxidase. Taken together, apigenin improves DDC-induced cholestasis by reducing inflammation and oxidative damage and improving bile acid metabolism, indicating its potential application for cholestasis treatment.
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Affiliation(s)
- Shihong Zheng
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Peichang Cao
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Zequn Yin
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Xuerui Wang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Maoyun Yu
- School of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, China
| | - Baocai Xu
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Chenzhong Liao
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Shuang Zhang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. and College of Life Sciences, Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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STAT3 Promotes Schistosome-Induced Liver Injury by Inflammation, Oxidative Stress, Proliferation, and Apoptosis Signal Pathway. Infect Immun 2021; 89:IAI.00309-20. [PMID: 33257536 DOI: 10.1128/iai.00309-20] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023] Open
Abstract
Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and Stat3flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.
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de Vries E, Bolier R, Goet J, Parés A, Verbeek J, de Vree M, Drenth J, van Erpecum K, van Nieuwkerk K, van der Heide F, Mostafavi N, Helder J, Ponsioen C, Oude Elferink R, van Buuren H, Beuers U. Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies: A Double-Blind, Randomized, Placebo-Controlled Trial. Gastroenterology 2021; 160:734-743.e6. [PMID: 33031833 DOI: 10.1053/j.gastro.2020.10.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 09/19/2020] [Accepted: 10/01/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC. METHODS Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat). RESULTS Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14). CONCLUSIONS Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC. TRIAL REGISTRATION Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).
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Affiliation(s)
- Elsemieke de Vries
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Ruth Bolier
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Jorn Goet
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Albert Parés
- Liver Unit, Hospital Clinic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacion Biomediques August Pi-Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jef Verbeek
- Department of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Marleen de Vree
- Department of Gastroenterology & Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Joost Drenth
- Department of Gastroenterology & Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Karel van Erpecum
- Department of Gastroenterology & Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Karin van Nieuwkerk
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Vrije Universiteit Medisch Centrum (VUmc), Amsterdam, the Netherlands
| | - Frans van der Heide
- Department of Gastroenterology & Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Nahid Mostafavi
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Jeltje Helder
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Ronald Oude Elferink
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Henk van Buuren
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands.
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De Anna JS, Castro JM, Darraz LA, Elías FD, Cárcamo JG, Luquet CM. Exposure to hydrocarbons and chlorpyrifos alters the expression of nuclear receptors and antioxidant, detoxifying, and immune response proteins in the liver of the rainbow trout, Oncorhynchus mykiss. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 208:111394. [PMID: 33031985 DOI: 10.1016/j.ecoenv.2020.111394] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/18/2020] [Accepted: 09/20/2020] [Indexed: 06/11/2023]
Abstract
The development of oil and gas production together with the fruit production in nearby areas of North Patagonia, Argentina, suggests aquatic pollution scenarios which include permanent oil pollution combined with short events of pesticides application. It has been reported that oil hydrocarbons activate the aryl hydrocarbon receptor (AhR) pathway in the rainbow trout, Oncorhynchus mykiss, and that the insecticide Chlorpyrifos (CPF) interacts with these effects. Thus, it is interesting to investigate whether hydrocarbons and insecticides, applied by separate or combined, can affect fish health and reproductive signaling by acting on different nuclear receptors' regulatory pathways. To study this kind of interactions, we exposed juvenile rainbow trout to water accommodated fraction (WAF) of crude oil (62 μg L-1 TPH) for 48 h and subsequently exposed the livers ex vivo to the insecticide Chlorpyrifos (CPF) (20 µg L-1) for 1 h. We analyzed the mRNA expression of nuclear receptors and proteins involved in detoxifying, antioxidant, immune and apoptosis responses by qRT-PCR. We also performed histopathological analysis. WAF induced the expression of the androgen (AR) and the Liver X receptor (LXR) by 8- and 3-fold, respectively. AR induction was reversed by subsequent exposure to CPF. The progesterone receptor (PR) and glucocorticoid receptor (GR) were increased 2-fold and 3-fold by WAF respectively, while estrogen and mineralocorticoid receptors were not affected. GR was also induced by CPF with an additive effect in the WAF-CPF treatment. The antioxidant genes, gamma glutamyl transferase (GGT), superoxide dismutase (SOD1) were induced by WAF (2-3-fold). WAF upregulated the ATP Binding Cassette Subfamily C Member 2 (ABCC2, MRP2) (4-fold) and downregulated alkaline phosphatase. WAF also induced the inflammatory interleukins (IL) IL-8, and IL-6 and the anti-inflammatory IL-10, while CPF induced the inflammatory tumor necrosis factor (-α) and IL-6, and activated the intrinsic apoptotic pathway through the induction of caspases 3 and 9. Both, WAF and CPF downregulated the expression of the extrinsic apoptosis initiator caspase 8 and the inflammatory caspase 1. In conclusion, WAF hydrocarbons alter O. mykiss endocrine regulation by inducing AR, PR and GR. The subsequent exposure to CPF reverses AR, suggesting a complex interaction of different pollutants in contaminated environments, WAF hydrocarbons alter liver metabolism by inducing the expression of LXR, GR, antioxidant and detoxifying enzymes, and both inflammatory and anti-inflammatory cytokines, and causing mild hepatic steatosis. CPF activates inflammatory and stress responses associated with the induction of inflammatory cytokines together with apoptosis initiator and executioner caspases.
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Affiliation(s)
- Julieta S De Anna
- Laboratorio de Ecotoxicología Acuática, Subsede INIBIOMA-CEAN (CONICET-Universidad Nacional del Comahue), Junín de los Andes, Neuquén, Argentina
| | - Juan M Castro
- Laboratorio de Ecotoxicología Acuática, Subsede INIBIOMA-CEAN (CONICET-Universidad Nacional del Comahue), Junín de los Andes, Neuquén, Argentina
| | - Luis Arias Darraz
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile
| | - Federico D Elías
- Centro Atómico Bariloche e Instituto Balseiro, CNEA, CONICET, Universidad Nacional de Cuyo, Bariloche, Argentina
| | - Juan G Cárcamo
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, Chile; Centro FONDAP, Interdisciplinary Center for Aquaculture Research (INCAR), Chile
| | - Carlos M Luquet
- Laboratorio de Ecotoxicología Acuática, Subsede INIBIOMA-CEAN (CONICET-Universidad Nacional del Comahue), Junín de los Andes, Neuquén, Argentina.
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Gámez-Belmonte R, Tena-Garitaonaindia M, Hernández-Chirlaque C, Córdova S, Ceacero-Heras D, de Medina FS, Martínez-Augustin O. Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet. Int J Mol Sci 2020; 22:ijms22010051. [PMID: 33374541 PMCID: PMC7793076 DOI: 10.3390/ijms22010051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/18/2020] [Accepted: 12/21/2020] [Indexed: 01/15/2023] Open
Abstract
The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP+/− haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP+/− and WT mice fed the MCD diet. In turn, TNAP+/− mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP+/− mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet.
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Affiliation(s)
- Reyes Gámez-Belmonte
- Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, 18071 Granada, Spain;
| | - Mireia Tena-Garitaonaindia
- Department of Biochemistry and Molecular Biology 2, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, 18071 Granada, Spain; (M.T.-G.); (C.H.-C.); (S.C.); (D.C.-H.); (O.M.-A.)
| | - Cristina Hernández-Chirlaque
- Department of Biochemistry and Molecular Biology 2, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, 18071 Granada, Spain; (M.T.-G.); (C.H.-C.); (S.C.); (D.C.-H.); (O.M.-A.)
| | - Samir Córdova
- Department of Biochemistry and Molecular Biology 2, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, 18071 Granada, Spain; (M.T.-G.); (C.H.-C.); (S.C.); (D.C.-H.); (O.M.-A.)
| | - Diego Ceacero-Heras
- Department of Biochemistry and Molecular Biology 2, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, 18071 Granada, Spain; (M.T.-G.); (C.H.-C.); (S.C.); (D.C.-H.); (O.M.-A.)
| | - Fermín Sánchez de Medina
- Department of Pharmacology, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, 18071 Granada, Spain;
- Correspondence: ; Tel.: +34-958-241747
| | - Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology 2, CIBERehd, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, 18071 Granada, Spain; (M.T.-G.); (C.H.-C.); (S.C.); (D.C.-H.); (O.M.-A.)
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Lleo A, Wang GQ, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet 2020; 396:1915-1926. [PMID: 33308474 DOI: 10.1016/s0140-6736(20)31607-x] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 06/27/2020] [Accepted: 07/10/2020] [Indexed: 12/14/2022]
Abstract
Primary biliary cholangitis is an autoimmune liver disease that predominantly affects women. It is characterised by a chronic and destructive, small bile duct, granulomatous lymphocytic cholangitis, with typical seroreactivity for antimitochondrial antibodies. Patients have variable risks of progressive ductopenia, cholestasis, and biliary fibrosis. Considerations for the cause of this disease emphasise an interaction of chronic immune damage with biliary epithelial cell responses and encompass complex, poorly understood genetic risks and environmental triggers. Licensed disease-modifying treatment focuses on amelioration of cholestasis, with weight-dosed oral ursodeoxycholic acid. For patients who do not respond sufficiently, or patients with ursodeoxycholic acid intolerance, conditionally licensed add-on therapy is with the FXR (NR1H4) agonist, obeticholic acid. Off-label therapy is recognised as an alternative, notably with the pan-PPAR agonist bezafibrate; clinical trial agents are also under development. Baseline characteristics, such as young age, male sex, and advanced disease, and serum markers of liver injury, particularly bilirubin and ALP, are used to stratify risk and assess treatment responsiveness. Parallel attention to the burden of patient symptoms is paramount, including pruritus and fatigue.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy
| | - Giu-Qiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China; Department of Infectious Diseases and Liver Diseases, Peking University International Hospital, Beijing, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, The University of California, Davis, CA, USA
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, ON, Canada.
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López-Riera M, Conde I, Castell JV, Jover R. A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients. Toxicol Sci 2020; 173:229-243. [PMID: 31198949 DOI: 10.1093/toxsci/kfz138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.
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Affiliation(s)
- Mireia López-Riera
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
| | - Isabel Conde
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, 46026 Valencia, Spain
| | - José V Castell
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ramiro Jover
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
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45
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Biochemical and Hematological Correlates of Elevated Homocysteine in National Surveys and a Longitudinal Study of Urban Adults. Nutrients 2020; 12:nu12040950. [PMID: 32235453 PMCID: PMC7230768 DOI: 10.3390/nu12040950] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023] Open
Abstract
Elevated blood homocysteine (Hcy) among middle-aged adults can increase age-related disease risk, possibly through other biochemical and hematological markers. We selected markers for hyperhomocysteinemia among middle-aged adults, studied time-dependent Hcy-marker associations and computed highly predictive indices of hyperhomocysteinemia, with cross-sectional and longitudinal validations. We used data from the National Health and Nutrition Examination Survey (NHANES III, phase 2, nmax = 4000), the NHANES 1999–2006 (nmax = 10,151) and pooled NHANES (cross-sectional validation). Longitudinal validation consisted of mixed-effects linear regression models (Hcy predicting markers’ annual rates of change), applied to the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS, n = 227–244 participants, k = 2.4 repeats/participant, Agebase: 30–65 years) data. Machine learning detected nine independent markers for Hcy > 14 µmol/L (NHANES III, phase 2): older age; lower folate and B-12 status; higher serum levels of creatinine, uric acid, alkaline phosphatase, and cotinine; mean cell hemoglobin and red cell distribution widths (RDW); results replicated in the 1999–2006 NHANES [AUC = 0.60–0.80]. Indices combining binary markers increased elevated Hcy odds by 6.9–7.5-fold. In HANDLS, first-visit Hcy predicted annual increase in creatinine, RDW and alkaline phosphatase, with third-visit index (2013–2018) directly predicting Hcy (2004–2009). We provide evidence of the internal and external validity of indices composed of several biomarkers that are strongly associated with elevated Hcy.
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Zhang X, Ren C, Hu F, Gao Y, Wang Z, Li H, Liu J, Liu B, Yang C. Detection of Bacterial Alkaline Phosphatase Activity by Enzymatic In Situ Self-Assembly of the AIEgen-Peptide Conjugate. Anal Chem 2020; 92:5185-5190. [PMID: 32207924 DOI: 10.1021/acs.analchem.9b05704] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Abnormal levels of alkaline phosphatase (ALP) activity are associated with various diseases, and many ALP probes have been developed to date. However, the development of ALP-sensitive probes for living cells, especially for the detection of bacterial ALP, remains challenging because of the complex and dynamic context. In this study, we constructed the first fluorescent probe (TPEPy-pY) for sensing bacterial ALP activity. TPEPy-pY is an AIEgen-peptide conjugate with property of aggregation-induced emission (AIE) and could turn on its fluorescence by ALP-catalyzed in situ self-assembly of the probe. The probe shows excellent selectivity and sensitivity for ALP activity, with a detection limit of 6.6 × 10-3 U mL-1. TPEPy-pY performs well in detection and in situ imaging of bacterial ALP activity against E. coli. Also, the detection does not require tedious washing steps and takes approximately 1 h, which is advantageous over commercial ALP kits. Therefore, the proposed strategy paved a new avenue for bacterial ALP detection, and we envision that more self-assembling fluorescent probes will be designed with higher sensitivity in the near future.
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Affiliation(s)
- Xue Zhang
- Department of Clinical Immunology, School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, China.,Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Chunhua Ren
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Fang Hu
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Yang Gao
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Zhongyan Wang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Huiqiang Li
- Department of Clinical Immunology, School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, China
| | - Jianfeng Liu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
| | - Bin Liu
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore
| | - Cuihong Yang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
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Lallès JP. Recent advances in intestinal alkaline phosphatase, inflammation, and nutrition. Nutr Rev 2020; 77:710-724. [PMID: 31086953 DOI: 10.1093/nutrit/nuz015] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In recent years, much new data on intestinal alkaline phosphatase (IAP) have been published, and major breakthroughs have been disclosed. The aim of the present review is to critically analyze the publications released over the last 5 years. These breakthroughs include, for example, the direct implication of IAP in intestinal tight junction integrity and barrier function maintenance; chronic intestinal challenge with low concentrations of Salmonella generating long-lasting depletion of IAP and increased susceptibility to inflammation; the suggestion that genetic mutations in the IAP gene in humans contribute to some forms of chronic inflammatory diseases and loss of functional IAP along the gut and in stools; stool IAP as an early biomarker of incipient diabetes in humans; and omega-3 fatty acids as direct inducers of IAP in intestinal tissue. Many recent papers have also explored the prophylactic and therapeutic potential of IAP and other alkaline phosphatase (AP) isoforms in various experimental settings and diseases. Remarkably, nearly all data confirm the potent anti-inflammatory properties of (I)AP and the negative consequences of its inhibition on health. A simplified model of the body AP system integrating the IAP compartment is provided. Finally, the list of nutrients and food components stimulating IAP has continued to grow, thus emphasizing nutrition as a potent lever for limiting inflammation.
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Affiliation(s)
- Jean-Paul Lallès
- Institut National de la Recherche Agronomique (INRA), Human Nutrition Division, Clermont-Ferrand, France, and the Centre de Recherche en Nutrition Humaine Ouest, Nantes, France
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Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Matono T, Kato J, Tokunaga S, Sugihara T, Hiramatsu A, Hyogo H, Tobita H, Sato S, Kawanaka M, Hara Y, Hino K, Chayama K, Murawaki Y, Isomoto H. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. PLoS One 2020; 15:e0219412. [PMID: 32106257 PMCID: PMC7046274 DOI: 10.1371/journal.pone.0219412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Methods Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Results Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Conclusions Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Kinya Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Masahiko Koda
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Toshiaki Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takumi Onoyama
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Kenichi Miyoshi
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Manabu Kishina
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Tomomitsu Matono
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Shiho Tokunaga
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi, Hiroshima, Japan
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Okayama, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Yoshikazu Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
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49
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Danilova IG, Shafigullina ZA, Gette IF, Sencov VG, Medvedeva SY, Abidov MT. Accelerated liver recovery after acute CCl 4 poisoning in rats treated with sodium phthalhydrazide. Int Immunopharmacol 2020; 80:106124. [PMID: 31927508 DOI: 10.1016/j.intimp.2019.106124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/07/2019] [Accepted: 12/10/2019] [Indexed: 12/23/2022]
Abstract
Pharmacotherapy of hepatobiliary disorders is an important issue due to the high prevalence of liver failure, toxic and viral hepatitis and cirrhosis. The number of stimuli that can potentially induce or accelerate liver recovery is limited; in our study we selected sodium phthalhydrazide, which has been found to promote liver regeneration after partial hepatectomy. We examined the effects of phthalhydrazide on liver morphometric, histological and biochemical parameters in rats intoxicated with CCl4. Accelerated liver recovery after CCl4 intoxication in phthalhydrazide-treated animals was evidenced by increased number of liver sinusoidal cells, reduced focal necrosis of hepatocytes and reduced perifocal leukocyte infiltration. Decreased plasma levels of pro-inflammatory cytokines TNF-α and IL-18 and decreased concentrations of IL-6 and IFN-γ in liver homogenates were associated with reduced severity of cholestasis and normalized hepatic protein synthesis in CCl4-intoxicated rats exposed to phthalhydrazide. Anti-inflammatory and immunomodulating properties of phthahlhydrazide can be an important factor contributing to accelerated liver recovery at early stages of acute CCl4-toxic liver impairment.
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Affiliation(s)
- Irina G Danilova
- Institute of Immunology and Physiology of the Ural Branch of the RAS, Yekaterinburg, Russian Federation; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Yekaterinburg, Russian Federation.
| | - Zlata A Shafigullina
- Institute of Immunology and Physiology of the Ural Branch of the RAS, Yekaterinburg, Russian Federation; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Yekaterinburg, Russian Federation
| | - Irina F Gette
- Institute of Immunology and Physiology of the Ural Branch of the RAS, Yekaterinburg, Russian Federation; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Yekaterinburg, Russian Federation
| | - Valentin G Sencov
- Federal State Budget Educational Institution of Higher Education «Ural State Medical University» of the Ministry of Health of the Russian Federation, Yekaterinburg, Russian Federation
| | - Svetlana Yu Medvedeva
- Institute of Immunology and Physiology of the Ural Branch of the RAS, Yekaterinburg, Russian Federation; Ural Federal University Named After the First President of Russia B.N. Yeltsin, Yekaterinburg, Russian Federation
| | - Musa T Abidov
- Institute of Immunopathology and Preventive Medicine, Povsetova ulica 29, 1000 Lublana, Slovenia
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Corpechot C, Poupon R, Chazouillères O. New treatments/targets for primary biliary cholangitis. JHEP Rep 2019; 1:203-213. [PMID: 32039371 PMCID: PMC7001536 DOI: 10.1016/j.jhepr.2019.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/11/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.
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Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
- Corresponding author. Address: Hepatology Department, Saint Antoine Hospital, 184 rue du Faubourg Saint Antoine, 75571 Paris Cedex 12, France.
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
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