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Alshahrani MY, Al Amri FS, Alzahrani MA, Alshahrani AS, Abdel Kader DH, Almasabi F, Zafrah H, Dallak M, Osman OM, Al-Ani B, Alzamil NM. Metformin ameliorates diabetes-induced hepatic ultrastructural damage and the immune biomarker CD86 and inflammation in rats. Ultrastruct Pathol 2025; 49:58-66. [PMID: 39663585 DOI: 10.1080/01913123.2024.2440479] [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: 09/10/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 12/13/2024]
Abstract
Diabetes is a known inducer of hepatic ultrastructural alterations, and the expression of the immune biomarker that involves in T-cell immunity, cluster of differentiation 86 (CD86) is increased in diabetic patients with liver cirrhosis. The antidiabetic drug metformin has not previously been used to protect against type 2 diabetes mellitus (T2DM)-induced alternations in hepatic ultrastructure and the induction of the hepatic CD86/inflammation axis in diabetic animal models induced by streptozotocin and a high fat diet. To test our hypotheses, T2DM was induced in rats (model group) and the protective animals were treated with the antidiabetic drug metformin (200 mg/kg) until being sacrificed at week 12. A profound ultrastructural damage to the hepatocytes and liver tissue injury was induced by T2DM as demonstrated by hepatocytes with dark shrunken irregular nuclei, rarefied cytoplasm with lipid droplets, mitochondria with disrupted cristae, as well as depletion of glycogen granules and damaged of liver architecture, which were effectively (p < .0001) protected with metformin. Metformin also suppressed diabetes-induced hepatic gene expression of CD86 and inflammation as well as glycemia and liver injury markers. Furthermore, a significant correlation between hepatocyte damage and CD86, inflammation, glycemia, and biomarkers of liver injury was observed. These findings demonstrate that diabetes is associated with the induction of the hepatic CD86/inflammation axis and hepatocyte ultrastructural alterations while being protected by metformin.
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Affiliation(s)
- Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Fahad S Al Amri
- Department of Surgery, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohammed A Alzahrani
- Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Abdulaziz S Alshahrani
- Department of Internal Medicine, College of Medicine, Najran University, Najran, Saudi Arabia
| | - Dina H Abdel Kader
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Faris Almasabi
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Hind Zafrah
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohammad Dallak
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Osama M Osman
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Norah M Alzamil
- Department of Family and Community Medicine, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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Molavinia S, Moosavi M, Hejazi S, Azadnasab R, Mansouri E, Khodayar MJ. Metformin alleviates sodium arsenite-induced hepatotoxicity and glucose intolerance in mice by suppressing oxidative stress, inflammation, and apoptosis. J Trace Elem Med Biol 2023; 80:127299. [PMID: 37690370 DOI: 10.1016/j.jtemb.2023.127299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND Epidemiological studies have shown that exposure to sodium arsenite (NaAsO2) causes diabetes and hepatotoxicity. Metformin (MET), an oral hypoglycemic agent, has long been used in diabetes therapy. In addition, MET has been shown to have hepatoprotective effects. In this study, we investigated the effects of MET on NaAsO2-induced hepatotoxicity and glucose intolerance in mice. METHODS Mice were divided into four groups: Groups I and II received distilled water and NaAsO2 (10 mg/kg, p.o.) for five weeks, respectively. Groups III and IV were treated with NaAsO2 (10 mg/kg, p.o.) for three weeks, followed by MET (125 and 250 mg/kg, p.o.) for the last two weeks before NaAsO2. A glucose tolerance test was performed on day 35. The serum and tissue parameters were also evaluated. RESULTS Histopathological examination revealed NaAsO2-induced liver and pancreatic damage. NaAsO2 caused hyperglycemia, glucose intolerance, and a significant increase in liver function enzymes. Administration of NaAsO2 significantly reduced hepatic superoxide dismutase, catalase, glutathione peroxidase, and total thiol levels and increased the content of reactive thiobarbituric acid substances. In addition, it led to an increase in liver nitric oxide levels and protein expression of tumor necrosis factor-α, nuclear factor kappa B, and cysteine-aspartic proteases-3. In contrast, treatment with MET (250 mg/kg) significantly improved NaAsO2-induced biochemical and histopathological changes. CONCLUSION Our findings suggest that the significant effects of MET against NaAsO2-induced hepatotoxicity and glucose intolerance may be exerted via the regulation of oxidative stress, followed by suppression of inflammation and apoptosis.
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Affiliation(s)
- Shahrzad Molavinia
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehrnoosh Moosavi
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sara Hejazi
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Reza Azadnasab
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Cellular and molecular research center, Medical Basic Sciences Research Institute, Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Javad Khodayar
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Lin H, Ao H, Guo G, Liu M. The Role and Mechanism of Metformin in Inflammatory Diseases. J Inflamm Res 2023; 16:5545-5564. [PMID: 38026260 PMCID: PMC10680465 DOI: 10.2147/jir.s436147] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 11/17/2023] [Indexed: 12/01/2023] Open
Abstract
Metformin is a classical drug used to treat type 2 diabetes. With the development of research on metformin, it has been found that metformin also has several advantages aside from its hypoglycemic effect, such as anti-inflammatory, anti-aging, anti-cancer, improving intestinal flora, and other effects. The prevention of inflammation is critical because chronic inflammation is associated with numerous diseases of considerable public health. Therefore, there has been growing interest in the role of metformin in treating various inflammatory conditions. However, the precise anti-inflammatory mechanisms of metformin were inconsistent in the reported studies. Thus, this review aims to summarize various currently known possible mechanisms of metformin involved in inflammatory diseases and provide references for the clinical application of metformin.
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Affiliation(s)
- Huan Lin
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Haiyong Ao
- Jiangxi Key Laboratory of Nanobiomaterials & School of Materials Science and Engineering, East China Jiaotong University, Nanchang, Jiangxi, People’s Republic of China
| | - Guanghua Guo
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Mingzhuo Liu
- Medical Center of Burn Plastic and Wound Repair, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
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Piarulli F, Carollo M, Ragazzi E, Benacchio L, Piovanello F, Simoncello I, Lapolla A. Association of COVID-19 outcomes with diabetes in the Veneto region (north-east italy): Epidemiological insights for the endemic phase? Nutr Metab Cardiovasc Dis 2023; 33:2141-2150. [PMID: 37543520 PMCID: PMC10290544 DOI: 10.1016/j.numecd.2023.06.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/29/2023] [Accepted: 06/20/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND AND AIMS Diabetes mellitus is a prevalent chronic disease in patients who die of COVID-19. The aim of this study was to investigate the clinical and metabolic characteristics of diabetic patients with COVID-19 during the pre-vaccination phase. METHODS AND RESULTS A retrospective cohort study was conducted from February 2020 to February 2021 to examine the clinical and metabolic profiles of unvaccinated diabetic patients affected by COVID-19. Data were collected from claim databases, hospital discharge records, and clinical records within a healthcare district located in northeastern Italy with a population of 936,000. Potential prognostic indicators including sex, age, Body Mass Index (BMI), duration and type of diabetes, metabolic control, and the use of antidiabetic, antihypertensive, lipid-lowering, and antiplatelet therapies were investigated. For hospitalized patients, additional variables were recorded, such as length of hospital stay, blood pressure at admission, comorbidities, D-dimer levels, blood glucose (BG), in-hospital insulin and corticosteroid therapies, requirement for mechanical ventilation (i.e., orotracheal or tracheostomy), admission to the Intensive Care Unit (ICU), and mortality. Diabetic patients hospitalized for COVID-19 with a poorer prognosis were characterized by advanced age, longer diabetes duration, hypertension, higher usage of sulfonylureas, and lower usage of dietotherapy alone, metformin, Glucagon-Like Peptide-1 Receptor agonists (GLP1-Ra), and Renin-Angiotensin-Aldosterone System inhibitors (RAAS-i). CONCLUSION Considering the potential for COVID-19 to become endemic, special care should be taken in managing older diabetic patients' treatments.
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Affiliation(s)
| | - Massimo Carollo
- Department of Medicine, University of Padova, 35128, Padova, Italy.
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences (DSF), University of Padova School of Medicine and Surgery, 35131, Padova, Italy.
| | | | | | - Ivana Simoncello
- Public Health Department, Padua Local Health Unit, Padua, Italy.
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Agamia NF, Sorror OA, Sayed NM, Ghazala RA, Echy SM, Moussa DH, Melnik BC. Overexpression of hypoxia-inducible factor-1α in hidradenitis suppurativa: the link between deviated immunity and metabolism. Arch Dermatol Res 2023; 315:2107-2118. [PMID: 36961533 PMCID: PMC10366312 DOI: 10.1007/s00403-023-02594-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/13/2023] [Accepted: 02/23/2023] [Indexed: 03/25/2023]
Abstract
Hypoxia-inducible factor-1α (HIF-1α) is the master transcription factor of glycolysis, Th17 cell differentiation and suppression of regulatory T cells. In the skin and serum of patients with psoriasis vulgaris, increased expression of HIF-1α has been reported, whereas HIF-1α expression in the skin and serum of patients with hidradenitis suppurativa (HS) has not yet been studied. The objective of the study is to demonstrate is there a role for HIF-1α in the pathogenesis of hidradenitis suppurativa, and its relation to HS severity. Twenty patients suffering from hidradenitis suppurativa were included in the study. Punch biopsies were taken from lesional skin for the determination of HIF-1α expression by immunohistochemical staining, and HIF-1α gene expression by quantitative reverse transcription real time PCR. Quantification of HIF-1α protein concentration was done by enzyme-linked immunosorbent assay. Twenty socio-demographically cross-matched healthy volunteers served as controls. We found increased serum levels of HIF-1α. Literature-derived evidence indicates that the major clinical triggering factors of HS, obesity, and smoking are associated with hypoxia and enhanced HIF-1α expression. Pro-inflammatory cytokines such as tumor necrosis factor-[Formula: see text] via upregulation of nuclear factor [Formula: see text]B enhance HIF-1α expression. HIF-1α plays an important role for keratinocyte proliferation, especially for keratinocytes of the anagen hair follicle, which requires abundant glycolysis providing sufficient precursors molecules for biosynthetic pathways. Metformin via inhibition of mTORC1 as well as adalimumab attenuate HIF-1α expression, the key mediator between Th17-driven deviated immunity and keratinocyte hyperproliferation. In accordance with psoriasis, our study identifies HS as an HIF-1α-driven inflammatory skin disease and offers a new rationale for the prevention and treatment of HS by targeting HIF-1[Formula: see text] overexpression.
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Affiliation(s)
- Naglaa Fathi Agamia
- Department of Dermatology, Andrology and Venereology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
| | - Osama Ahmed Sorror
- Department of Dermatology, Andrology and Venereology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Naglaa Mohamed Sayed
- Department of Dermatology, Andrology and Venereology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Rasha Abdelmawla Ghazala
- Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Sammar Mohamed Echy
- Department of Clinical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Doaa Helmy Moussa
- Department of Dermatology, Andrology and Venereology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Bodo Clemens Melnik
- Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany
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Malaekeh-Nikouei A, Shokri-Naei S, Karbasforoushan S, Bahari H, Baradaran Rahimi V, Heidari R, Askari VR. Metformin beyond an anti-diabetic agent: A comprehensive and mechanistic review on its effects against natural and chemical toxins. Biomed Pharmacother 2023; 165:115263. [PMID: 37541178 DOI: 10.1016/j.biopha.2023.115263] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/24/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023] Open
Abstract
In addition to the anti-diabetic effect of metformin, a growing number of studies have shown that metformin has some exciting properties, such as anti-oxidative capabilities, anticancer, genomic stability, anti-inflammation, and anti-fibrosis, which have potent, that can treat other disorders other than diabetes mellitus. We aimed to describe and review the protective and antidotal efficacy of metformin against biologicals, chemicals, natural, medications, pesticides, and radiation-induced toxicities. A comprehensive search has been performed from Scopus, Web of Science, PubMed, and Google Scholar databases from inception to March 8, 2023. All in vitro, in vivo, and clinical studies were considered. Many studies suggest that metformin affects diseases other than diabetes. It is a radioprotective and chemoprotective drug that also affects viral and bacterial diseases. It can be used against inflammation-related and apoptosis-related abnormalities and against toxins to lower their effects. Besides lowering blood sugar, metformin can attenuate the effects of toxins on body weight, inflammation, apoptosis, necrosis, caspase-3 activation, cell viability and survival rate, reactive oxygen species (ROS), NF-κB, TNF-α, many interleukins, lipid profile, and many enzymes activity such as catalase and superoxide dismutase. It also can reduce the histopathological damages induced by many toxins on the kidneys, liver, and colon. However, clinical trials and human studies are needed before using metformin as a therapeutic agent against other diseases.
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Affiliation(s)
- Amirhossein Malaekeh-Nikouei
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Shokri-Naei
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sobhan Karbasforoushan
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bahari
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Heidari
- Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran; Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
| | - Vahid Reza Askari
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran; Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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Su Y, Hou C, Wang M, Ren K, Zhou D, Liu X, Zhao S, Liu X. Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis. Int J Biochem Cell Biol 2023; 157:106375. [PMID: 36716817 DOI: 10.1016/j.biocel.2023.106375] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/27/2022] [Accepted: 01/26/2023] [Indexed: 01/30/2023]
Abstract
The activation and proliferation of hepatic stellate cells (HSCs) are critical processes for the treatment of liver fibrosis. It is necessary to identify effective drugs for the treatment of liver fibrosis and elucidate their mechanisms of action. Metformin can inhibit HSCs; however, no systematic studies demonstrating the effects of metformin on mitochondria in HSCs have been reported. This study demonstrated that metformin induces mitochondrial fission by phosphorylating AMPK/DRP1 (S616) in HSCs to decrease the expression of α-SMA and collagen. Additionally, metformin repressed the total ATP production rate, especially the production rate of ATP produced through mitochondrial oxidative phosphorylation, by inhibiting the enzymatic activity of complex I. Further analysis revealed that metformin strongly constrained the transcription of mitochondrial genes (ND1-ND6 and ND4L) that encode the core subunits of respiratory chain I. Upregulation of the mRNA expression of HK2 and GLUT1 slightly enhanced glycolysis. Additionally, metformin increased mitochondrial DNA (mtDNA) copy number to suppress the proliferation and activation of HSCs, indicating that mtDNA copy number can alter the fate of HSCs. In conclusion, metformin can induce mitochondrial fragmentation and low-level energy metabolism in HSCs, thereby suppressing HSCs activation and proliferation to reverse liver fibrosis.
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Affiliation(s)
- Ying Su
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Chenjian Hou
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Meili Wang
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Kehan Ren
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Danmei Zhou
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xiaoli Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Shanyu Zhao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xiuping Liu
- Department of Pathology, Shanghai Fifth People's Hospital, School of Basic Medical Sciences, Fudan University, Shanghai 200240, China.
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Yang T, Guan Q, Shi JS, Xu ZH, Geng Y. Metformin alleviates liver fibrosis in mice by enriching Lactobacillus sp. MF-1 in the gut microbiota. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166664. [PMID: 36893671 DOI: 10.1016/j.bbadis.2023.166664] [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: 09/23/2022] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND Liver fibrosis is associated with gut dysbiosis. Metformin administration has emerged as a promising method for the treatment of organ fibrosis. We aimed to investigate whether metformin ameliorates liver fibrosis by enhancing the gut microbiota in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and the underlying mechanism. MATERIALS AND METHODS A liver fibrosis mouse model was established, and the therapeutic effects of metformin were observed. We administered antibiotic treatment and performed fecal microbiota transplantation (FMT), and 16S rRNA-based microbiome analysis to evaluate the effects of the gut microbiome on metformin-treated liver fibrosis. We isolated the bacterial strain preferably enriched by metformin and assessed its antifibrotic effects. RESULTS Metformin treatment repaired the gut integrity of the CCl4-treated mice. It reduced the number of bacteria in colon tissues and reduced the portal vein lipopolysaccharide (LPS) levels. The FMT performed on the metformin-treated CCl4 mice alleviated their liver fibrosis and reduced their portal vein LPS levels. The markedly changed gut microbiota was screened out from the feces and named Lactobacillus sp. MF-1 (L. sp. MF-1). In the CCl4-treated mice, daily gavage of L. sp. MF-1 maintained gut integrity, inhibited bacterial translocation, and reduced liver fibrosis. Mechanistically, metformin or L. sp. MF-1 inhibited the apoptosis of intestinal epithelial cells and restored CD3+ intestinal intraepithelial lymphocytes in the ileum and CD4+Foxp3+ lamina propria lymphocytes in the colon. CONCLUSIONS Metformin and its enriched L. sp. MF-1 can reinforce the intestinal barrier to alleviate liver fibrosis by restoring immune function.
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Affiliation(s)
- Tao Yang
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China; National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China; Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Qijie Guan
- National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China; Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China
| | - Jin-Song Shi
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China
| | - Zheng-Hong Xu
- The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu, China; National Engineering Research Center for Cereal Fermentation and Food Biomanufacturing, Jiangnan University, Wuxi, China; Jiangsu Provincial Engineering Research Center for Bioactive Product Processing, Jiangnan University, Wuxi, China.
| | - Yan Geng
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
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Research progress of metformin in the treatment of liver fibrosis. Int Immunopharmacol 2023; 116:109738. [PMID: 36696857 DOI: 10.1016/j.intimp.2023.109738] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/12/2023] [Indexed: 01/24/2023]
Abstract
Liver fibrosis is a disease with significant morbidity and mortality. It is a chronic pathological process characterized by an imbalance of extracellular matrix production and degradation in liver tissue. Metformin is a type of hypoglycemic biguanide drug, which can be used in the treatment of liver fibrosis, but its anti-fibrotic effect and mechanism of action are unclear. The purpose of this article is to review the research progress of metformin in the treatment of liver fibrosis and to provide a theoretical basis for its application in the treatment of liver fibrosis.
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Al-Hashem F, Abd Ellatif M, ShamsEldeen AM, Kamar SS, Al-Ani B, Haidara MA. Vitamin E protects against the modulation of TNF-α-AMPK axis and inhibits pancreas injury in a rat model of L-arginine-induced acute necrotising pancreatitis. Arch Physiol Biochem 2023; 129:148-156. [PMID: 32783662 DOI: 10.1080/13813455.2020.1806330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/22/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) associated with the modulation of TNF-α-AMPK axis in the presence and absence of vitamin E has not been investigated before. MATERIAL AND METHODS Rats were either injected with L-arginine (2.5 gm/kg) before being sacrificed after 48 h or were pre-treated with vitamin E (60 mg/kg) and continued receiving vitamin E until the end of the experiment. RESULTS AP was developed as demonstrated by infiltration of inflammatory cells and profound pancreas tissue damage, which were substantially protected by vitamin E. In addition, L-arginine injections significantly (p < .0001) increased the expression of TNF-α mRNA and protein, and decreased phospho-AMPK and IL-10 mRNA and protein that was significantly (p < .0001) protected by vitamin E. Furthermore, vitamin E inhibited L-arginine-induced blood levels of LDH, amylase, and myeloperoxidase. CONCLUSIONS L-arginine-induced acute pancreatitis modulates TNF-α-AMPK axis, IL-10 and other AP biomarkers, which is protected by vitamin E; thus, may offer therapeutic potential in humans.
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Affiliation(s)
- Fahaid Al-Hashem
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohamed Abd Ellatif
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Asmaa M ShamsEldeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samaa S Kamar
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohamed A Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
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ElBaset MA, Salem RS, Ayman F, Ayman N, Shaban N, Afifi SM, Esatbeyoglu T, Abdelaziz M, Elalfy ZS. Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis. Antioxidants (Basel) 2022; 11:2152. [PMID: 36358524 PMCID: PMC9686640 DOI: 10.3390/antiox11112152] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin's (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally with EMPA (3 or 6 mg/kg) with TAA (100 mg/kg, IP) thrice weekly for 6 weeks. EMPA in both doses retracted the serum GGT, ALT, AST, ammonia, triglycerides, total cholesterol, and increased serum albumin. At the same time, EMPA (3 or 6 mg/kg) replenished the hepatic content of GSH, ATP, AMP, AMPK, or SIRT-1 and mitigated the hepatic content of MDA, TNF-α, IL-6, NF-κB, or HIF-1α in a dose-dependent manner. Likewise, hepatic photomicrograph stained with hematoxylin and eosin or Masson trichrome stain of EMPA (3 or 6 mg/kg) revealed marked regression of the hepatotoxic effect of TAA with minimal injury. Similarly, in rats given EMPA (3 or 6 mg/kg), the immunohistochemically of hepatic photomicrograph revealed minimal stain of either α-SMA or caspase-3 compared to the TAA group. Therefore, we concluded that EMPA possessed an antifibrotic effect by targeting AMPK/SIRT-1 activity and inhibiting HIF-1α. The present study provided new insight into a novel treatment of liver fibrosis.
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Affiliation(s)
- Marwan A. ElBaset
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo P.O. Box 12622, Egypt
| | - Rana S. Salem
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Fairouz Ayman
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Nadeen Ayman
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Nooran Shaban
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Sherif M. Afifi
- Pharmacognosy Department, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt
| | - Tuba Esatbeyoglu
- Department of Food Development and Food Quality, Institute of Food Science and Human Nutrition, Gottfried Wilhelm Leibniz University Hannover, Am Kleinen Felde 30, 30167 Hannover, Germany
| | - Mahmoud Abdelaziz
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Science and Arts, Cairo 12451, Egypt
| | - Zahraa S. Elalfy
- Pathology Department Medical Research and Clinical Studies Institute, National Research Centre, 33 El-Bohouth St., Dokki, Cairo P.O. Box 12622, Egypt
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Abstract
Metabolic adaptation to viral infections critically determines the course and manifestations of disease. At the systemic level, a significant feature of viral infection and inflammation that ensues is the metabolic shift from anabolic towards catabolic metabolism. Systemic metabolic sequelae such as insulin resistance and dyslipidaemia represent long-term health consequences of many infections such as human immunodeficiency virus, hepatitis C virus and severe acute respiratory syndrome coronavirus 2. The long-held presumption that peripheral and tissue-specific 'immune responses' are the chief line of defence and thus regulate viral control is incomplete. This Review focuses on the emerging paradigm shift proposing that metabolic engagements and metabolic reconfiguration of immune and non-immune cells following virus recognition modulate the natural course of viral infections. Early metabolic footprints are likely to influence longer-term disease manifestations of infection. A greater appreciation and understanding of how local biochemical adjustments in the periphery and tissues influence immunity will ultimately lead to interventions that curtail disease progression and identify new and improved prognostic biomarkers.
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Affiliation(s)
- Clovis S Palmer
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA, USA.
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13
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Al-Hashem F, Dawood AF. Dysregulation of Inflammatory Cytokines by Endotoxin Induces Tissue iNOS Expression and Pulmonary Injury in Rats. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1412.1419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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14
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Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy. Cells 2022; 11:cells11182811. [PMID: 36139386 PMCID: PMC9496732 DOI: 10.3390/cells11182811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/27/2022] [Accepted: 09/05/2022] [Indexed: 12/05/2022] Open
Abstract
Previous studies have shown that tumors under a hypoxic environment can induce an important hypoxia-responsive element, hypoxia-induced factor-1α (HIF-1α), which can increase tumor migration, invasion, and metastatic ability by promoting epithelial-to-mesenchymal transition (EMT) in tumor cells. Currently, with the deeper knowledge of long noncoding RNAs (lncRNAs), more and more functions of lncRNAs have been discovered. HIF-1α can regulate hypoxia-responsive lncRNAs under hypoxic conditions, and changes in the expression level of lncRNAs can regulate the production of EMT transcription factors and signaling pathway transduction, thus promoting EMT progress. In conclusion, this review summarizes the regulation of the EMT process by HIF-1α and lncRNAs and discusses their relationship with tumorigenesis. Since HIF-1α plays an important role in tumor progression, we also summarize the current drugs that inhibit tumor progression by modulating HIF-1α.
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15
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Ebrahim HA, Kamar SS, Haidara MA, Latif NSA, Ellatif MA, ShamsEldeen AM, Al-Ani B, Dawood AF. Association of resveratrol with the suppression of TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and systemic hypertension in thioacetamide-induced liver injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1087-1095. [PMID: 35729229 DOI: 10.1007/s00210-022-02264-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 06/09/2022] [Indexed: 10/17/2022]
Abstract
Chronic liver injury can lead to hepatic failure and the only available method of treatment would be liver transplantation. The link between inflammation (TNF-α), nuclear factor-kappa B (NF-kB), nitrosative stress (iNOS) and hypoxia-inducible factor-1α (HIF-1α) in thioacetamide (TAA) induced liver fibrosis, and hypertension with and without the incorporation of the anti-inflammatory and antioxidant resveratrol (RES) has not been investigated before. Consequently, we injected rats with either 200 mg/kg TAA for 8 weeks starting at week 2 (model group) or pretreated them before TAA injections with RES (20 mg/kg) for 2 weeks and continued them on RES and TAA until being culled at week 10 (protective group). In the model group, we documented the induction of hepatic fibrosis and upregulation of tumor necrosis factor-α (TNF-α), NF-kB, inducible nitric oxide synthase (iNOS), HIF-1α and the profibrotic biomarkers alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-9 (MMP-9) that was significantly (p ≤ 0.0014) ameliorated by RES. RES also significantly (p ≤ 0.0232) reduced triglycerides (TG), cholesterol (CHOL), very low-density lipoprotein (vLDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, and heart rate (HR) induction by TAA. Also, a significant (p < 0.0001) positive correlation between TNF-α/NF-kB/iNOS/HIF-1α axis-mediated fibrosis and hypertension and liver injury biomarkers was observed. These findings suggest that in the hepatotoxic compound, TAA is associated with TNF-α/NF-kB/iNOS/HIF-1α-mediated fibrosis and hypertension, whilst being inhibited by RES.
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Affiliation(s)
- Hasnaa A Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Samaa S Kamar
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha S Abdel Latif
- Department of Medical Pharmacology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Abd Ellatif
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Department of Medical Biochemistry, College of Medicine, Mansoura University, Mansoura, Egypt
| | - Asmaa M ShamsEldeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Amal F Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
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16
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Dawood AF, Al Humayed S, Momenah MA, El-Sherbiny M, Ashour H, Kamar SS, ShamsEldeen AM, Haidara MA, Al-Ani B, Ebrahim HA. MiR-155 Dysregulation Is Associated with the Augmentation of ROS/p53 Axis of Fibrosis in Thioacetamide-Induced Hepatotoxicity and Is Protected by Resveratrol. Diagnostics (Basel) 2022; 12:1762. [PMID: 35885665 PMCID: PMC9322790 DOI: 10.3390/diagnostics12071762] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/14/2022] [Accepted: 07/19/2022] [Indexed: 11/17/2022] Open
Abstract
Liver fibrosis is a hallmark of thioacetamide (TAA) intoxications. MicroRNAs (miRs), such as miR-155, have been implied in the pathogenesis of liver disease, and regulated by the antioxidant and anti-inflammatory compound resveratrol (RES). The link between reactive oxygen species (ROS), tumour suppressor p53 (p53), and liver fibrosis-during the pathogenesis of TAA-induced liver injury-associated with miR-155 dysregulation with and without RES incorporation has not been previously studied. Therefore, one group of rats received TAA injections of 200 mg/kg; twice a week at the beginning of week 3 for 8 weeks (TAA group; or model group), whereas the protective group was pretreated daily with RES suspension (20 mg/kg; orally) for the first two weeks and subsequently sustained on receiving both RES and TAA until being sacrificed at the 10th week. Liver injuries developed in the model group were confirmed by a significant (p < 0.0001) elevation of hepatic tissue levels of miR-155, ROS, p53, and the profibrogenic biomarkers: tissue inhibitor of metalloproteinases-1 and α-smooth muscle actin, as well as collagen deposition (fibrosis). All these parameters were significantly (p ≤ 0.0234) protected by resveratrol (RES + TAA). In addition, we observed a significant (p < 0.0001) correlation between ROS/p53 axis mediated liver fibrosis and miR-155. Thus, TAA intoxication induced miR-155 imbalance and ROS/p53-mediated liver fibrosis, with resveratrol, conversely displaying beneficial hepatic pleiotropic effects for a period of 10 weeks.
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Affiliation(s)
- Amal F. Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Suliman Al Humayed
- Department of Internal Medicine, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia;
| | - Maha A. Momenah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia;
| | - Hend Ashour
- Department of Physiology, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia; (H.A.); (B.A.-A.)
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12624, Egypt; (A.M.S.); (M.A.H.)
| | - Samaa S. Kamar
- Department of Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12624, Egypt;
| | - Asmaa M. ShamsEldeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12624, Egypt; (A.M.S.); (M.A.H.)
| | - Mohamed A. Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12624, Egypt; (A.M.S.); (M.A.H.)
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia; (H.A.); (B.A.-A.)
| | - Hasnaa A. Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
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17
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Al-Hashem F. Metformin Ameliorates Infiltration of Inflammatory Cells and Pancreatic Injury Biomarkers Induced by L-Arginine. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1038.1046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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18
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Jin X, Li Y, Li J, Cheng L, Yao Y, Shen H, Wang B, Ren J, Ying H, Xu J. Acute bone damage through liver-bone axis induced by thioacetamide in rats. BMC Pharmacol Toxicol 2022; 23:29. [PMID: 35526079 PMCID: PMC9080193 DOI: 10.1186/s40360-022-00568-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Background Thioacetamide (TAA) is used in various fields, such as synthetic drugs, organic chemical synthesis, and materials chemistry. TAA is mainly used to establish animal liver injury models and other organ damage models to explore their mechanisms for helping patients with liver disease. Liver damage can lead to abnormal expression of some enzymes in the serum, so we detected the appropriate enzyme levels in the serum of SD rats to verify the damage of TAA to the liver. More importantly, TAA caused bone damage is barely understood. Therefore, our research aims to establish a rat model reflecting the acute bone damage injury caused by TAA. Methods The SD rats were intraperitoneally injected with normal saline (0.9%) or TAA (200 mg/kg, 400 mg/kg) for 1 month (once the other day). After the last intraperitoneal injection, serum samples from rats were used for biochemical tests. Masson staining is used to detect liver damage, and micro-CT is used to detect the changes in bone. Moreover, the three-point bending experiment was used to detect the force range of the hind limbs of SD rats. Results Compared with the control group, after the intraperitoneal injection of TAA, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid (UA), total bile acid (TBA), alkaline phosphatase (ALP), carbamide (UREA) and creatinine (CREA) rose sharply, while the levels of serum content of total protein (TP), lactate dehydrogenase (LDH), calcium (Ca) and phosphorus (P) were severely reduced. After TAA administration, collagen fibers were deposited and liver fibrosis was obvious. Micro-CT results showed that the bone surface, tissue surface, bone volume, and tissue volume of rats with an intraperitoneal injection of TAA were significantly reduced. In addition, the bones of rats with an intraperitoneal injection of TAA can resist less pressure and are prone to fractures. Conclusions TAA can cause liver damage in SD rats, which is explained by the changes in serum biochemical indicators and the deposition of liver collagen. More importantly, TAA can reduce bone mineral density and increase the separation of bone trabeculae in SD rats, and finally lead to bone injury. This suggests that TAA may become an ideal model to investigate abnormal bone metabolism after liver injury.
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Affiliation(s)
- Xiaoli Jin
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yang Li
- FUDAN University, school of basic medical sciences, Shanghai, 200433, PR China
| | - Jianghua Li
- Department of The Third Orthopaedic, The First Affiliated Hospital of Shihezi University School of Medicine Xinjiang Shihezi, Shihezi, 832008, China
| | - Linyan Cheng
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yetao Yao
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hao Shen
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Bili Wang
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jun Ren
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Hang Ying
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jian Xu
- School of medical technology and information engineering, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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19
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Dawood AF, Alzamil NM, Hewett PW, Momenah MA, Dallak M, Kamar SS, Abdel Kader DH, Yassin H, Haidara MA, Maarouf A, Al-Ani B. Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin-Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis. Biomedicines 2022; 10:984. [PMID: 35625721 PMCID: PMC9139128 DOI: 10.3390/biomedicines10050984] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/09/2022] [Accepted: 04/20/2022] [Indexed: 02/05/2023] Open
Abstract
The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.
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Affiliation(s)
- Amal F. Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
- Department of Physiology, Kasr al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
| | - Norah M. Alzamil
- Department of Clinical Science, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Peter W. Hewett
- Institute of Cardiovascular Sciences, College of Medicine and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK;
| | - Maha A. Momenah
- Department of Biology, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Mohammad Dallak
- Department of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia;
| | - Samaa S. Kamar
- Department of Medical Histology, Kasr al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (S.S.K.); (D.H.A.K.)
| | - Dina H. Abdel Kader
- Department of Medical Histology, Kasr al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt; (S.S.K.); (D.H.A.K.)
| | - Hanaa Yassin
- Department of Physiology, Kasr al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
| | - Mohamed A. Haidara
- Department of Physiology, Kasr al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
| | - Amro Maarouf
- Department of Clinical Biochemistry, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B9 5SS, UK;
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia;
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20
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Al-Ani B, ShamsEldeen AM, Kamar SS, Haidara MA, Al-Hashem F, Alshahrani MY, Al-Hakami AM, Kader DHA, Maarouf A. Lipopolysaccharide induces acute lung injury and alveolar haemorrhage in association with the cytokine storm, coagulopathy and AT1R/JAK/STAT augmentation in a rat model that mimics moderate and severe Covid-19 pathology. Clin Exp Pharmacol Physiol 2022; 49:483-491. [PMID: 35066912 DOI: 10.1111/1440-1681.13620] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
Progress in the study of Covid-19 disease in rodents has been hampered by the lack of angiotensin-converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)-induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid-19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)-like effect was observed in the model group as demonstrated by the development of a "cytokine storm" (>2.7 fold increase in blood levels of IL-6, IL-17A, GM-CSF, and TNF-α), high blood ferritin, demonstrable coagulopathy, including elevated D-dimer (approximately 10-fold increase), PAI-1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)-JAK-STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid-19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT-mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid-19 disease noted in humans.
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Affiliation(s)
- Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Asmaa M ShamsEldeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samaa S Kamar
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Fahaid Al-Hashem
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohammad Y Alshahrani
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Ahmed M Al-Hakami
- Department of Microbiology and Clinical Parasitology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Dina H Abdel Kader
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amro Maarouf
- Department of Clinical Biochemistry, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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21
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Su Y, Lu S, Hou C, Ren K, Wang M, Liu X, Zhao S, Liu X. Mitigation of liver fibrosis via hepatic stellate cells mitochondrial apoptosis induced by metformin. Int Immunopharmacol 2022; 108:108683. [PMID: 35344814 DOI: 10.1016/j.intimp.2022.108683] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 11/05/2022]
Abstract
Liver fibrosis, a disease characterized by the excessive accumulation of extracellular matrix originating from activated hepatic stellate cells (HSCs), is a common pathological response to chronic liver injury resulting from a variety of insults. However, drugs that effectively block the activation of HSCs have still not been adequately investigated. This study demonstrates that metformin decreased the number of activated-HSCs through induction of apoptosis, but did not impact numbers of hepatocytes. Metformin upregulated BAX activation with facilitation of BIM, BAD and PUMA; downregulated Bcl-2 and Bcl-xl, but did not affect Mcl-1. Additionally, metformin induced cytochrome c release from mitochondria into the cytoplasm, directly triggering caspase-9-mediated mitochondrial apoptosis. The decline in mitochondrial membrane potential (ΔΨm) and deposition of superoxide in mitochondria accelerated the destruction of the integrity of mitochondrial membrane. Moreover, we verified the therapeutic effect of metformin in our mouse model of liver fibrosis associated with nonalcoholic steatohepatitis (NASH) in which hepatic function, NASH lesions and fibrosis were improved by metformin. In conclusion, this study indicated that metformin has significant therapeutic value in NASH-derived liver fibrosis by inducing apoptosis in HSCs, but does not affect the proliferation of hepatocytes.
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Affiliation(s)
- Ying Su
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Shan Lu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Chenjian Hou
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Kehan Ren
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Meili Wang
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
| | - Xiaoli Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Shanyu Zhao
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xiuping Liu
- Department of Pathology, School of Basic Medical Sciences, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
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22
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Protocatechuic acid protects against thioacetamide-induced chronic liver injury and encephalopathy in mice via modulating mTOR, p53 and the IL-6/ IL-17/ IL-23 immunoinflammatory pathway. Toxicol Appl Pharmacol 2022; 440:115931. [PMID: 35202709 DOI: 10.1016/j.taap.2022.115931] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 01/28/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Protocatechuic acid (PCA), a natural phenolic acid, is known for antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic activities. However, the protective mechanisms of PCA on thioacetamide (TAA)-induced liver/brain injury are not well addressed. Chronic liver injury was induced in mice by intraperitoneal injection of TAA (200 mg/kg, 3 times/week) for 8 weeks. Simultaneously, PCA (100, 150 mg/kg/day, p.o.) was given daily from the 4th week. Protocatechuic acid ameliorated liver and brain damage indicated by the decrease in serum activities of aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, levels of bilirubin, and ammonia concomitant with restoration of normal albumin levels. Additionally, PCA treatment ameliorated oxidative stress in liver and brain, confirmed by the decrease in malondialdehyde and nitric oxide levels and the increase in antioxidant activities. Moreover, PCA showed anti-inflammatory actions through downregulation of TNF-α expression in the liver and IL-6/IL-17/IL-23 levels in the brain, which is confirmed by the decrease in CD4+ T brain cell numbers. Most importantly, PCA treatment showed a significant decrease in mTOR level and number of LC3 positive cells in both liver and brain tissues. Consequently, PCA could inhibit mTOR-induced apoptosis, as it showed anti-apoptotic actions through downregulation of caspase-3 expression in liver and p53 expression in liver and brain. Furthermore, liver and brain tissues of treated mice showed restoration of normal histology. It can be concluded that, several mechanisms, including: antioxidant, anti-inflammatory, anti-autophagic and anti-apoptotic activities can be implicated in the hepato- and neuroprotective potentials of PCA.
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Huang Q, Liu X, Guo SW. Changing prostaglandin E2 (PGE 2) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE 2 receptor EP2 and EP4. Reprod Med Biol 2021; 21:e12426. [PMID: 34938150 PMCID: PMC8660993 DOI: 10.1002/rmb2.12426] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/20/2021] [Accepted: 10/31/2021] [Indexed: 11/10/2022] Open
Abstract
Purpose We investigated the change, if any, in prostaglandin E2 (PGE2) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX-2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX-2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis-associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE2 signaling dose-dependently. In contrast, treatment with metformin resulted in increased PGE2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE2 signaling.
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Affiliation(s)
- Qingqing Huang
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,Third Affiliated Hospital of Guangzhou Medical University Guangzhou China
| | - Xishi Liu
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases Fudan University Shanghai China
| | - Sun-Wei Guo
- Shanghai OB/GYN Hospital Fudan University Shanghai China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases Fudan University Shanghai China
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24
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Xiong M, Zhao Y, Mo H, Yang H, Yue F, Hu K. Intermittent hypoxia increases ROS/HIF-1α 'related oxidative stress and inflammation and worsens bleomycin-induced pulmonary fibrosis in adult male C57BL/6J mice. Int Immunopharmacol 2021; 100:108165. [PMID: 34560512 DOI: 10.1016/j.intimp.2021.108165] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/05/2021] [Accepted: 09/14/2021] [Indexed: 10/20/2022]
Abstract
Obstructive sleep apnea (OSA) has been increasingly recognized as a risk factor for idiopathic pulmonary fibrosis (IPF). The intermittent hypoxia (IH) and re-oxygenation of OSA contribute to poor outcomes of IPF, however, the potential mechanism remains unknown. Here, C57BL/6J mice were administered intratracheal injection of Bleomycin (BLM) or saline and then exposed to IH (alternating cycles of FiO2 21% for 60S and FiO2 10% for 30 s, 40 cycles/hour, 8 h/day) to mimic OSA or intermittent air (IA) for 4 days, 8 days or 21 days. This study found that pulmonary fibrosis in BLM + IH treated mice was more severe than that in BLM + IA group at day 8 and 21, but not observed at day 4. Besides, the expression of reactive oxygen species (ROS) and hypoxia inducible factor-1α (HIF-1α),which are related to hypoxia reduced oxidative stress and inflammation, were higher in BLM + IH treated mice than BLM + IA mice, and IH increased these indexes in BLM treated mice from day 4 to day 21. Interestingly, a positive linear correlation between the HIF-1α expression and hydroxyproline (HYP) content was observed. We further found some inflammatory cells in bronchoalveolar lavage fluid were increased significantly from day 4 to 21, and there was a positive correlation between inflammation and ROS expression. Our results demonstrated that IH aggravated BLM-induced pulmonary fibrosis, and ROS/HIF-1α related oxidative stress and inflammation involved. The increase of ROS/HIF-1α related oxidative stress and inflammation may be a potential mechanism of moderate-to-severe OSA in potentiating pulmonary fibrosis of IPF, which warrants further study.
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Affiliation(s)
- Mengqing Xiong
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Yang Zhao
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Huaheng Mo
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Haizhen Yang
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Fang Yue
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
| | - Ke Hu
- Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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25
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ShamsEldeen AM, Al-Ani B, Ebrahim HA, Rashed L, Badr AM, Attia A, Farag AM, Kamar SS, Haidara MA, Al Humayed S, Ali Eshra M. Resveratrol suppresses cholestasis-induced liver injury and fibrosis in rats associated with the inhibition of TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. Clin Exp Pharmacol Physiol 2021; 48:1402-1411. [PMID: 34157155 DOI: 10.1111/1440-1681.13546] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/30/2021] [Accepted: 06/18/2021] [Indexed: 02/05/2023]
Abstract
Cholestasis caused by slowing or blockage of bile flow is a serious liver disease that can lead to liver fibrosis and cirrhosis. The link between transforming growth factor beta 1 (TGFβ1), Smad family member 3 (Smad3), and microRNA 21 (miR21) in bile duct ligation (BDL)-induced liver fibrosis in the presence and absence of the anti-inflammatory and antioxidant compound, resveratrol (RSV), has not been previously studied. Therefore, we tested whether RSV can protect against BDL-induced liver fibrosis associated with the inhibition of the TGFβ1-Smad3-miR21 axis and profibrogenic and hepatic injury biomarkers. The model group of rats had their bile duct ligated (BDL) for 3 weeks before being killed, whereas, the BDL-treated rats were separated into three groups that received 10, 20, and 30 mg/kg RSV daily until the end of the experiment. Using light microscopy and ultrasound examinations, we documented in the BDL group, the development of hepatic injury and fibrosis as demonstrated by hepatocytes necrosis, bile duct hyperplasia, collagen deposition, enlarged liver with increased echogenicity, irregular nodular border and dilated common bile duct, which were more effectively inhibited by the highest used RSV dosage. In addition, RSV significantly (p ≤ 0.0027) inhibited BDL-induced hepatic TGFβ1, Smad3, miR21, the profibrogenic biomarker tissue inhibitor of metalloproteinases-1 (TIMP-1), malondialdehyde (MDA), interleukin-17a (IL-17a), and blood levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin. These findings show that RSV at 30 mg/kg substantially protects against BDL-induced liver injuries, which is associated with the inhibition of TGFβ1-Smad3-miR21 axis, and biomarkers of profibrogenesis, oxidative stress, and inflammation.
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Affiliation(s)
- Asmaa M ShamsEldeen
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Hasnaa A Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Laila Rashed
- Medical Biochemistry and Molecular Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amul M Badr
- Medical Biochemistry and Molecular Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Abeer Attia
- Public Health, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ayman M Farag
- Radiology Department, Military Medical Academy, Cairo, Egypt
| | - Samaa S Kamar
- Histology and Cell Biology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Haidara
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Suliman Al Humayed
- Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Eshra
- Departments of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
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26
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Abdel-Latif AS, Abu-Risha SE, Bakr SM, EL-Kholy WM, EL-Sawi MR. Potassium bromate-induced nephrotoxicity and potential curative role of metformin loaded on gold nanoparticles. Sci Prog 2021; 104:368504211033703. [PMID: 34293965 PMCID: PMC10358642 DOI: 10.1177/00368504211033703] [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: 11/16/2022]
Abstract
Potassium bromate (KBrO3) is classified by the International Agency for Research on Cancer as a carcinogenic compound, where it causes renal tumors. The present study investigated the potential curative effect of metformin loaded on gold nanoparticles (MET AuNPs) in attenuating KBrO3-induced nephrotoxicity. Rats were divided into eight groups (control, MET, AuNPs, MET AuNPs, KBrO3, KBrO3/MET, KBrO3/AuNPS, and KBrO3/MET AuNPs). KBrO3 administration resulted in a significant elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (Alb), total bilirubin (TB), direct bilirubin (DB), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, urea, uric acid. Also, KBrO3 significantly increased renal malondialdehyde (MDA), protein carbonyl (PC), and nitric oxide (NO) levels and reduced the activities of antioxidant molecules superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and Reduced glutathione (GSH). It also caused damaged DNA spots in comet assay and increased inflammatory IL-6 and apoptotic markers (caspase 3, Bax) while antiapoptotic Bcl-2 was significantly reduced. MET, AuNPS, MET AuNPS reduced the extent of renal damage induced by KBrO3 as indicated by decreased (AST, ALT, ALP, Alb, TP, TB, DB, creatinine, urea, uric, Lipid profile). MET, AuNPS, MET AuNPS showed a good curative effect against KBrO3-induced nephrotoxicity and MET AuNPS group showed better results compared with monotherapy.
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Affiliation(s)
- Ahmed S Abdel-Latif
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Sally E Abu-Risha
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Samaa M Bakr
- Department of Zoology, Faculty of Science, Kafrelsheikh University, Kafr el-Sheikh, Egypt
| | - Wafaa M EL-Kholy
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Mamdouh R EL-Sawi
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
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Lin CY, Adhikary P, Cheng K. Cellular protein markers, therapeutics, and drug delivery strategies in the treatment of diabetes-associated liver fibrosis. Adv Drug Deliv Rev 2021; 174:127-139. [PMID: 33857552 PMCID: PMC8217274 DOI: 10.1016/j.addr.2021.04.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/18/2021] [Accepted: 04/08/2021] [Indexed: 02/08/2023]
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix due to chronic injuries, such as viral infection, alcohol abuse, high-fat diet, and toxins. Liver fibrosis is reversible before it progresses to cirrhosis and hepatocellular carcinoma. Type 2 diabetes significantly increases the risk of developing various complications including liver diseases. Abundant evidence suggests that type 2 diabetes and liver diseases are bidirectionally associated. Patients with type 2 diabetes experience more severe symptoms and accelerated progression of live diseases. Obesity and insulin resistance resulting from hyperlipidemia and hyperglycemia are regarded as the two major risk factors that link type 2 diabetes and liver fibrosis. This review summarizes possible mechanisms of the association between type 2 diabetes and liver fibrosis. The cellular protein markers that can be used for diagnosis and therapy of type 2 diabetes-associated liver fibrosis are discussed. We also highlight the potential therapeutic agents and their delivery systems that have been investigated for type 2 diabetes-associated liver fibrosis.
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Affiliation(s)
- Chien-Yu Lin
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States
| | - Pratik Adhikary
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, United States.
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28
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Al-kuraishy HM, Al-Gareeb AI, Alblihed M, Guerreiro SG, Cruz-Martins N, Batiha GES. COVID-19 in Relation to Hyperglycemia and Diabetes Mellitus. Front Cardiovasc Med 2021; 8:644095. [PMID: 34124187 PMCID: PMC8189260 DOI: 10.3389/fcvm.2021.644095] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 03/29/2021] [Indexed: 12/17/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic β-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, Baghdad, Iraq
| | - M. Alblihed
- Department of Microbiology, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Susana G. Guerreiro
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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29
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Han S, Zhu F, Huang X, Yan P, Xu K, Shen F, Sun J, Yang Z, Jin G, Teng Y. Maternal obesity accelerated non-alcoholic fatty liver disease in offspring mice by reducing autophagy. Exp Ther Med 2021; 22:716. [PMID: 34007325 PMCID: PMC8120514 DOI: 10.3892/etm.2021.10148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by an excessive accumulation of triacylglycerol in the liver. Autophagy is a lysosome-dependent degradation product recovery process, which widely occurs in eukaryotic cells, responsible for the vital maintenance of cellular energy balance. Previously published studies have demonstrated that autophagy is closely related to NAFLD occurrence and maternal obesity increases the susceptibility of offspring to non-alcoholic fatty liver disease, however, the underlying mechanism of this remains unclear. In the present study, NAFLD mouse models (offspring of an obese mother mouse via high-fat feeding) were generated, and the physiological indices of the liver were observed using total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein serum assay kits. The morphological changes of the liver were also observed via HE, Masson and oil red O staining. Reverse transcription-quantitative-PCR and western blotting were performed to detect changes of autophagy-related genes in liver or fibrosis marker proteins (α-smooth muscle actin or TGF-β1). Changes in serum inflammatory cytokine IL-6 levels were determined via ELISA. The results of the present study demonstrated that the offspring of an obese mother were more likely to develop NALFD than the offspring of a chow-fed mother, due to their increased association with liver fibrosis. When feeding continued to 17 weeks, the worst cases of NAFLD were observed and the level of autophagy decreased significantly compared with the offspring of a normal weight mouse. In addition, after 17 weeks of feeding, compared with the offspring of a chow-fed mother, the offspring of an obese mouse mother had reduced adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation levels and increased mammalian target of rapamycin (mTOR) phosphorylation levels. These results suggested that a reduced level of AMPK/mTOR mediated autophagy may be of vital importance for the increased susceptibility of offspring to NAFLD caused by maternal obesity. In conclusion, the current study provided a new direction for the treatment of NAFLD in offspring caused by maternal obesity.
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Affiliation(s)
- Shuguang Han
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Feng Zhu
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Xiaoxia Huang
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China.,The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China
| | - Panpan Yan
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Ke Xu
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Fangfang Shen
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Jiawen Sun
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Zeyu Yang
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Guoxi Jin
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Yiqun Teng
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
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30
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Hussein RM, Sawy DM, Kandeil MA, Farghaly HS. Chlorogenic acid, quercetin, coenzyme Q10 and silymarin modulate Keap1-Nrf2/heme oxygenase-1 signaling in thioacetamide-induced acute liver toxicity. Life Sci 2021; 277:119460. [PMID: 33811899 DOI: 10.1016/j.lfs.2021.119460] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/22/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The normal functioning of Kelch-like ECH-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) complex is necessary for the cellular protection against oxidative stress. We investigated the effect of chlorogenic acid (CGA), quercetin (Qt), coenzyme Q10 (Q10) and silymarin on the expression of Keap1/Nrf2 complex and its downstream target; heme oxygenase-1 (HO-1) as well as inflammation and apoptosis in an acute liver toxicity model induced by thioacetamide (TAA). MAIN METHODS Wistar rats were divided into 13 groups: Control, silymarin, CGA, Qt, Q10, TAA (single dose 50 mg/kg, i.p.), TAA + silymarin (400 mg/kg, p.o.), TAA + CGA (100 & 200 mg/kg, p.o.), TAA + Qt (200 &300 mg/kg, p.o.) and TAA+ Q10 (30&50 mg/kg, p.o.) and treated for 8 days. KEY FINDINGS The results showed improved liver functions and hepatic tissue integrity in all tested doses of TAA + silymarin, TAA + CGA, TAA + Qt and TAA + Q10 groups compared to the TAA group. Furthermore, these groups showed significantly lower ROS, malondialdehyde and nitric oxide levels but higher glutathione content and superoxide dismutase activity compared to the TAA group, p < 0.05. In these groups, Keap1 expression was significantly decreased while Nrf2 expression and HO-1 activity were increased. In addition, the number of apoptotic cells and the expression level of TNF-α in the liver tissues were significantly decreased compared to the TAA group. SIGNIFICANCE CGA, Qt, Q10 and silymarin protect against TAA-induced acute liver toxicity via antioxidant, anti-inflammatory, anti-apoptotic activities and regulating Keap1-Nrf2/HO-1 expression.
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Affiliation(s)
- Rasha M Hussein
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, 61710 Al-Karak, Jordan; Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, 62514 Beni-Suef, Egypt.
| | - Doaa M Sawy
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Mohamed A Kandeil
- Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Hatem S Farghaly
- Department of Biochemistry, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
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31
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Xu J, Chen D, Jin L, Chen Z, Tu Y, Huang X, Xue F, Xu J, Chen M, Wang X, Chen Y. Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling. J Cell Mol Med 2021; 25:1140-1150. [PMID: 33295107 PMCID: PMC7812299 DOI: 10.1111/jcmm.16180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/13/2020] [Accepted: 11/25/2020] [Indexed: 12/27/2022] Open
Abstract
Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.
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Affiliation(s)
- Jie Xu
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Dazhi Chen
- Department of Gastroenterology, The First Hospital of Peking University, BeiJing, China
| | - Lanling Jin
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhengkang Chen
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yulu Tu
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaozhe Huang
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Feiben Xue
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jialu Xu
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mingzhuan Chen
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaodong Wang
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongping Chen
- Department of Infectious Diseases, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou Key Laboratory of Hepatology, Hepatology Institute of Wenzhou Medical University, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Li TT, Zhu HB. LKB1 and cancer: The dual role of metabolic regulation. Biomed Pharmacother 2020; 132:110872. [PMID: 33068936 DOI: 10.1016/j.biopha.2020.110872] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/07/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023] Open
Abstract
Liver kinase B1 (LKB1) is an essential serine/threonine kinase frequently associated with Peutz-Jeghers syndrome (PJS). In this review, we provide an overview of the role of LKB1 in conferring protection to cancer cells against metabolic stress and promoting cancer cell survival and invasion. This carcinogenic effect contradicts the previous conclusion that LKB1 is a tumor suppressor gene. Here we try to explain the contradictory effect of LKB1 on cancer from a metabolic perspective. Upon deletion of LKB1, cancer cells experience increased energy as well as oxidative stress, thereby causing genomic instability. Meanwhile, mutated LKB1 cooperates with other metabolic regulatory genes to promote metabolic reprogramming that subsequently facilitates adaptation to strong metabolic stress, resulting in development of a more aggressive malignant phenotype. We aim to specifically discuss the contradictory role of LKB1 in cancer by reviewing the mechanism of LKB1 with an emphasis on metabolic stress and metabolic reprogramming.
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Affiliation(s)
- Ting-Ting Li
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hai-Bin Zhu
- Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China.
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Kotb El-Sayed MI, Al-Massarani S, El Gamal A, El-Shaibany A, Al-Mahbashi HM. Mechanism of antidiabetic effects of Plicosepalus Acaciae flower in streptozotocin-induced type 2 diabetic rats, as complementary and alternative therapy. BMC Complement Med Ther 2020; 20:290. [PMID: 32967670 PMCID: PMC7509926 DOI: 10.1186/s12906-020-03087-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 09/15/2020] [Indexed: 01/11/2023] Open
Abstract
Background Diabetes and its related complications remain to be a major clinical problem. We aim to investigate the antidiabetic mechanistic actions of Plicosepalus Acaciae (PA) flowers in streptozotocin (STZ)-induced diabetic rats. Methods After diabetes induction, rats were divided randomly into five groups, including: 1) normal control group, 2) diabetic control group, 3) diabetic group treated with 150 mg/kg of ethanolic extract of PA flowers, 4) diabetic group treated with 300 mg/kg of ethanolic extract of PA flowers, and 5) diabetic group treated with 150 mg/kg of metformin. After 15 days of treatment; fasting blood glucose, glycated hemoglobin (HBA1c%), insulin, C-peptide, superoxide dismutase (SOD), catalase, reduced glutathione (GSH), malondialdehyde (MDA), triglyceride (TGs), total cholesterol (Tc), low density lipoprotein cholesterol (LDL-c), very LDL (VLDL), high DLc (HDL-c), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were assessed. Histopathology of pancreas was also assessed. Results The results showed that PA flower ethanolic extract significantly reduced blood glucose, HBA1c%, MDA, TGs, Tc, VLDL, LDL-c, TNF-α, and IL-6 levels in a dose-dependent manner. All these parameters were already increased by diabetic induction in the untreated diabetic group. Treatment of diabetic rats with PA flower increased insulin, HDL-c, GSH, catalase, and SOD levels. Histological examination showed that the PA flower caused reconstruction, repair, and recovery of damaged pancreas when compared with the untreated group. Conclusions PA flower has a potential role in the management of diabetes as complementary and alternative therapy, due to its antioxidant, anti-inflammatory, hypolipidemic, hypoglycemic and insulin secretagogue effects.
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Affiliation(s)
- Mohamed-I Kotb El-Sayed
- Department of Biochemistry and molecular Biology, Faculty of Pharmacy, Helwan University, Ain Helwan, Helwan, P.O. Box 11790, Cairo, Egypt. .,Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt.
| | - Shaza Al-Massarani
- Department of Pharmacognosy, Pharmacy College, King Saud University, Riyadh, Saudi Arabia
| | - Ali El Gamal
- Department of Pharmacognosy, Pharmacy College, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Amina El-Shaibany
- Department of Pharmacognosy, Faculty of Pharmacy, Sana'a University, Sana'a, Yemen
| | - Hassan M Al-Mahbashi
- Department of Forensic Medicine and Clinical toxicology, Faculty of Medicine, Sana'a University, Sana'a, Yemen
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Dawood AF, Alzamil N, Ebrahim HA, Abdel Kader DH, Kamar SS, Haidara MA, Al-Ani B. Metformin pretreatment suppresses alterations to the articular cartilage ultrastructure and knee joint tissue damage secondary to type 2 diabetes mellitus in rats. Ultrastruct Pathol 2020; 44:273-282. [PMID: 32404018 DOI: 10.1080/01913123.2020.1762815] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/27/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023]
Abstract
Osteoarthritis (OA) secondary to diabetes affects millions of people worldwide and can lead to disability. The protective effect of metformin pretreatment against alterations to the articular cartilage ultrastructure induced by type 2 diabetes mellitus (T2DM) associated with the inhibition of oxidative stress and inflammation has not been investigated before. Therefore, we induced T2DM in rats (the model group) using high carbohydrate and fat diet and a single injection of streptozotocin (50 mg/kg body weight). The protective group of rats started metformin (200 mg/kg body weight) treatment 14 days before diabetic induction and continued on metformin until the end of the experiment at week 12. Harvested tissues obtained from knee joints were prepared for staining with hematoxylin and eosin (H&E), safranin o staining, and electron microscopy. Histology images showed that OA was developed in the T2DM rats as demonstrated by a substantial damage to the articular cartilage and profound chondrocyte and territorial matrix ultrastructural alterations, which were partially protected by metformin. In addition, metformin significantly (p < .05) reduced hyperglycemia, glycated hemoglobin (HbA1 c), malondialdehyde (MDA), high sensitivity C-reactive protein (hs-CRP), and interleukin-6 blood levels induced by diabetes. Furthermore, a significant (p ≤ 0.015) correlation between either OA cartilage grade score or the thickness of the articular cartilage and the blood levels of HbA1 c, hs-CRP, MDA, superoxide dismutase (SOD) were observed. These findings demonstrate effective protection of the articular cartilage by metformin against damage induced secondary to T2DM in rats, possibly due to the inhibition of hyperglycemia and biomarkers of oxidative stress and inflammation.
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Affiliation(s)
- Amal F Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University , Riyadh, Saudi Arabia
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Norah Alzamil
- Department of Clinical Science, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University , Riyadh, Saudi Arabia
| | - Hasnaa A Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University , Riyadh, Saudi Arabia
- Department of Anatomy, College of Medicine, Mansoura University , Mansoura, Egypt
| | - Dina H Abdel Kader
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Samaa S Kamar
- Department of Medical Histology, Kasr Al-Aini Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Mohamed A Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University , Cairo, Egypt
- Department of Physiology, College of Medicine, King Khalid University , Abha, Saudi Arabia
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University , Abha, Saudi Arabia
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Lin H, Zhou W, Huang Y, Ren M, Xu F, Wang H. Systemic hypoxia potentiates anti-tumor effects of metformin in hepatocellular carcinoma in mice. Acta Biochim Biophys Sin (Shanghai) 2020; 52:421-429. [PMID: 32250393 DOI: 10.1093/abbs/gmaa010] [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] [Received: 07/22/2019] [Revised: 01/17/2020] [Accepted: 01/17/2020] [Indexed: 01/10/2023] Open
Abstract
Local hypoxia is a universal phenomenon in most solid tumors. The role of local hypoxia in the tumor microenvironment and cancer growth and metastasis has been well established. However, the effect of acute systemic hypoxia (exposing the whole body to 10% O2 environment) on cancer has not yet been investigated. In this study, we investigated the potential effects of acute systemic hypoxia itself and in combination with metformin on hepatocellular carcinoma (HCC) growth and metastasis in a mouse model of HCC. Acute systemic hypoxia significantly decreased tumor volume and weight in H22 tumor-bearing mice. Interestingly, the combined treatment of acute systemic hypoxia and metformin showed a more pronounced effect in reducing tumor volume and weight. Moreover, acute systemic hypoxia and metformin in combination had a potent inhibitory effect on tumor progression. More importantly, the expressions of hypoxia response genes including hypoxia-inducible factor-1 α, vascular endothelial growth factor, and matrix metalloproteinase 2 were significantly decreased in the tumor tissues with combination treatment. Our study demonstrated that acute systemic hypoxia repressed tumor progression of the HCC and potentiated the anti-tumor activities of metformin. This study supports that combination of systemic hypoxia and metformin treatment may represent a novel strategy for HCC.
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Affiliation(s)
- Hui Lin
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wenfang Zhou
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
- Agricultural and Health Center, Jiangxi Center for Disease Control and Prevention, Nanchang 330006, China
| | - Yonghong Huang
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Min Ren
- Medical Laboratory Education Center, Nanchang University, Nanchang 330006, China
| | - Fangyun Xu
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hongmei Wang
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
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Packer M. Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors. J Am Soc Nephrol 2020; 31:907-919. [PMID: 32276962 DOI: 10.1681/asn.2020010010] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation-sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)-can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas .,Imperial College, London, United Kingdom
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Wang K, Yang X, Wu Z, Wang H, Li Q, Mei H, You R, Zhang Y. Dendrobium officinale Polysaccharide Protected CCl 4-Induced Liver Fibrosis Through Intestinal Homeostasis and the LPS-TLR4-NF-κB Signaling Pathway. Front Pharmacol 2020; 11:240. [PMID: 32226380 PMCID: PMC7080991 DOI: 10.3389/fphar.2020.00240] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
We explored the therapeutic effects of Dendrobium officinale polysaccharide (DOP) on CCl4-induced liver fibrosis with respect to the intestinal hepatic axis using a rat model. Histopathological staining results showed that DOP alleviated extensive fibrous tissue proliferation in interstitium and lessened intestinal mucosal damage. Western blot and PCR results showed that DOP maintained intestinal balance by upregulating the expression of tight junction proteins such as occludin, claudin-1, ZO-1, and Bcl-2 proteins while downregulating the expression of Bax and caspase-3 proteins in the intestine. The transepithelial electrical resistance (TEER) value of the LPS-induced Caco-2 monolayer cell model was increased after DOP administration. These illustrated that DOP can protect the intestinal mucosal barrier function. DOP also inhibited activation of the LPS-TLR4-NF-κB signaling pathway to reduce the contents of inflammatory factors TGF-β and TNF-α, increased the expression of anti-inflammatory factor IL-10, and significantly decreased α-SMA and collagen I expression. These results indicated that DOP maintained intestinal homeostasis by enhancing tight junctions between intestinal cells and reducing apoptosis, thereby inhibiting activation of the LPS-TLR4-NF-κB signaling pathway to protect against liver fibrosis.
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Affiliation(s)
- Kaiping Wang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xiawen Yang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Zhijing Wu
- Department of Pharmacy, Union Hospital of Huazhong University of Science and Technology, Wuhan, China
| | - Hongjing Wang
- Puai Hospital, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Li
- Department of Pharmacy, Union Hospital of Huazhong University of Science and Technology, Wuhan, China
| | - Hao Mei
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ruxu You
- Department of Pharmacy, Union Hospital of Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital of Huazhong University of Science and Technology, Wuhan, China
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Meshkani SE, Mahdian D, Abbaszadeh-Goudarzi K, Abroudi M, Dadashizadeh G, Lalau JD, De Broe ME, Hosseinzadeh H. Metformin as a protective agent against natural or chemical toxicities: a comprehensive review on drug repositioning. J Endocrinol Invest 2020; 43:1-19. [PMID: 31098946 DOI: 10.1007/s40618-019-01060-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Metformin is the first prescribed drug for hyperglycemia in type 2 diabetes mellitus. Mainly by activating AMPK pathway, this drug exerts various functions that among them protective effects are of the interest. PURPOSE Herein, we aimed to gather data about the protective impacts of metformin against various natural or chemical toxicities. RESULTS An extensive search among PubMed, Scopus, and Google Scholar was conducted by keywords related to protection, toxicity, natural and chemical toxins and, metformin. Our literature review showed metformin alongside its anti-hyperglycemic effect has a wide range of anti-toxic effects against anti-tumour and routine drugs, natural and chemical toxins, herbicides and, heavy metals. CONCLUSION It is evident that metformin is a potent drug against the toxicity of a broad spectrum of natural, chemical toxic agents which is proved by a vast number of studies. Metformin mainly through AMPK axis can protect different organs against toxicities. Moreover, metformin preserves DNA integrity and can be an option for adjuvant therapy to ameliorate side effect of other therapeutics.
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Affiliation(s)
- S E Meshkani
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - D Mahdian
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
- Department of Pharmacology, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - K Abbaszadeh-Goudarzi
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
- Department of Biochemistry, School of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - M Abroudi
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - G Dadashizadeh
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - J-D Lalau
- Department of Endocrinology, Université de Picardie Jules Verne, Amiens, France
| | - M E De Broe
- Department of Biomedical Sciences, Universiteit Antwerpen, Antwerp, Belgium
| | - H Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhang YZ, Yao JN, Zhang LF, Wang CF, Zhang XX, Gao B. Effect of NLRC5 on activation and reversion of hepatic stellate cells by regulating the nuclear factor-κB signaling pathway. World J Gastroenterol 2019; 25:3044-3055. [PMID: 31293340 PMCID: PMC6603813 DOI: 10.3748/wjg.v25.i24.3044] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 04/27/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The formation of liver fibrosis is mainly caused by the activation of hepatic stellate cells (HSCs) and the imbalance of extracellular matrix (ECM) production and degradation. The treatment of liver fibrosis mainly includes removing the cause, inhibiting the activation of HSCs, and inhibiting inflammation. NOD-like receptor (NLR) family, caspase activation and recruitment domain (CARD) domain containing 5/NOD27/CLR16.1 (NLRC5) is a highly conserved member of the NLR family and is involved in inflammation and immune responses by regulating various signaling pathways such as nuclear factor-κB (NF-κB) signaling. It has been found that NLRC5 plays an important role in liver fibrosis, but its specific effect and possible mechanism remain to be fully elucidated.
AIM To investigate the role of NLRC5 in the activation and reversion of HSCs induced with transforming growth factor-β (TGF-β) and MDI, and to explore its relationship with liver fibrosis.
METHODS A total of 24 male C57BL/6 mice were randomly divided into three groups, including normal, fibrosis, and recovery groups. Twenty-four hours after a liver fibrosis and spontaneous reversion model was established, the mice were sacrificed and pathological examination of liver tissue was performed to observe the degree of liver fibrosis in each group. LX-2 cells were cultured in vitro and treated with TGF-β1 and MDI. Real-time quantitative PCR (qPCR) and Western blot were used to analyze the expression levels of NLRC5, α-smooth muscle actin (α-SMA), and collagen type I alpha1 (Col1a1) in each group. The activity of NF-κB in each group of cells transfected with NLRC5-siRNA was detected.
RESULTS Compared with the normal mice, the expression level of NLRC5 increased significantly (P < 0.01) in the fibrosis group, but decreased significantly in the recovery group (P < 0.01). In in vitro experiments, the content of NLRC5 was enhanced after TGF-β1 stimulation and decreased to a lower level when treated with MDI (P < 0.01). The expression of α-SMA and Col1a1 proteins and mRNAs in TGF-β1-mediated cells was suppressed by transfection with NLRC5-siRNA (P < 0.01). Western blot analysis showed that the expression of NF-κB p65 protein and phosphorylated IκBα (p-IκBα) was increased in the liver of mice in the fibrosis group but decreased in the recovery group (P < 0.01), and the protein level of nuclear p65 and p-IκBα was significantly increased after treatment with NLRC5-siRNA (P < 0.01).
CONCLUSION NLRC5 may play a key role in the development and reversal of hepatic fibrosis through the NF-κB signaling pathway, and it is expected to be one of the clinical therapeutic targets.
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Affiliation(s)
- Yan-Zhen Zhang
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Jian-Ning Yao
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Lian-Feng Zhang
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Chun-Feng Wang
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Xue-Xiu Zhang
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing Gao
- Department of Second Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Berg G, Barchuk M, Miksztowicz V. Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling. Cells 2019; 8:cells8020158. [PMID: 30769840 PMCID: PMC6406870 DOI: 10.3390/cells8020158] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/22/2019] [Accepted: 02/01/2019] [Indexed: 02/06/2023] Open
Abstract
Extracellular matrix (ECM) remodeling is required for many physiological and pathological processes. Metalloproteinases (MMPs) are endopeptidases which are able to degrade different components of the ECM and nucleus matrix and to cleave numerous non-ECM proteins. Among pathological processes, MMPs are involved in adipose tissue expansion, liver fibrosis, and atherosclerotic plaque development and vulnerability. The expression and the activity of these enzymes are regulated by different hormones and growth factors, such as insulin, leptin, and adiponectin. The controversial results reported up to this moment regarding MMPs behavior in ECM biology could be consequence of the different expression patterns among species and the stage of the studied pathology. The aim of the present review was to update the knowledge of the role of MMPs and its inhibitors in ECM remodeling in high incidence pathologies such as obesity, liver fibrosis, and cardiovascular disease.
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Affiliation(s)
- Gabriela Berg
- Laboratorio de Lípidos y Aterosclerosis, Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
- Facultad de Farmacia y Bioquímica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
- Facultad de Farmacia y Bioquímica, CONICET, Universidad de Buenos Aires, Buenos Aires C1425FQB, Argentina.
| | - Magalí Barchuk
- Laboratorio de Lípidos y Aterosclerosis, Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
- Facultad de Farmacia y Bioquímica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
| | - Verónica Miksztowicz
- Laboratorio de Lípidos y Aterosclerosis, Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
- Facultad de Farmacia y Bioquímica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
- Facultad de Farmacia y Bioquímica, CONICET, Universidad de Buenos Aires, Buenos Aires C1425FQB, Argentina.
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