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Wang B, Li Y, Ouyang Q, Xu MT, Wang YY, Fu SJ, Liu WQ, Liu XT, Ling H, Zhang X, Xiu RJ, Liu MM. Strain- and sex-dependent variability in hepatic microcirculation and liver function in mice. World J Gastroenterol 2025; 31:101058. [DOI: 10.3748/wjg.v31.i15.101058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 02/02/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND The integrity and functionality of the hepatic microcirculation are essential for maintaining liver health, which is influenced by sex and genetic background. Understanding these variations is crucial for addressing disparities in liver disease outcomes.
AIM To investigate the sexual dimorphism and genetic heterogeneity of liver microcirculatory function in mice.
METHODS We assessed hepatic microhemodynamics in BALB/c, C57BL/6J, and KM mouse strains using laser Doppler flowmetry and wavelet analysis. We analyzed the serum levels of alanine transaminase, glutamic acid aminotransferase, total bile acid, total protein, alkaline phosphatase, and glucose. Histological and immunohistochemical staining were employed to quantify microvascular density and the expression levels of cluster of differentiation (CD) 31, and estrogen receptor α, and β. Statistical analyses, including the Mantel test and Pearson correlation, were conducted to determine the relationships among hepatic function, microcirculation, and marcocirculation between different sexes and across genetic backgrounds.
RESULTS We identified sex-based disparities in hepatic microhemodynamics across all strains, with males exhibiting higher microvascular perfusion and erythrocyte concentration, but lower blood velocity. Strain-specific differences were evident, particularly in the endothelial oscillatory characteristics of the erythrocyte concentration. No sex-dependent differences in estrogen receptor expression were observed, while significant variations in CD31 expression and microvascular density were observed. The correlations highlighted relationships between hepatic microhemodynamics and liver function indicators.
CONCLUSION Our findings indicate the influence of genetic and sex differences on hepatic microcirculation and liver function, highlighting the necessity of incorporating both genetic background and sex into hepatic physiology studies and potential liver disease management strategies.
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Affiliation(s)
- Bing Wang
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Yuan Li
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Qin Ouyang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Science, Beijing 100102, China
| | - Meng-Ting Xu
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Ying-Yu Wang
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Sun-Jing Fu
- Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Wei-Qi Liu
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Xue-Ting Liu
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Hao Ling
- Department of Radiology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, Hunan Province, China
| | - Xu Zhang
- Laboratory of Electron Microscopy, Ultrastructural Pathology Center, Peking University First Hospital, Beijing 100034, China
| | - Rui-Juan Xiu
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
| | - Ming-Ming Liu
- Institute of Microcirculation, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- International Center of Microvascular Medicine, Chinese Academy of Medical Sciences, Beijing 100005, China
- Diabetes Research Center, Chinese Academy of Medical Sciences, Beijing 100005, China
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da Silva Pereira ENG, Franco RLC, Santos RDCD, Daliry A. Statins and non-alcoholic fatty liver disease: A concise review. Biomed Pharmacother 2025; 183:117805. [PMID: 39755024 DOI: 10.1016/j.biopha.2024.117805] [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: 10/16/2024] [Revised: 12/12/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common hepatic manifestation of metabolic syndrome affecting 20-30 % of the adult population worldwide. This disease, which includes simple steatosis and non-alcoholic steatohepatitis, poses a significant risk for cardiovascular and metabolic diseases. Lifestyle modifications are crucial in the treatment of NAFLD; however, patient adherence remains challenging. As there is no specific treatment, drug repositioning is being researched as an alternative strategy. Statins, which are known for their cholesterol-lowering effects, are considered potential interventions for NAFLD. This review aimed to present the current understanding of the effects of statins on liver physiology in the context of NAFLD. The pathophysiology of NAFLD includes steatosis, inflammation, and fibrosis, which are exacerbated by dyslipidemia and insulin resistance. Statins, which inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, have pleiotropic effects beyond cholesterol-lowering and affect pathways related to inflammation, fibrogenesis, oxidative stress, and microcirculation. Although clinical guidelines support the use of statins for dyslipidemia in patients with NAFLD, more studies are needed to demonstrate their efficacy in liver disease. This comprehensive review serves as a foundation for future studies on the therapeutic potential of statins in NAFLD.
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Affiliation(s)
| | - Rafaela Luiza Costa Franco
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Rafaele Dantas Cruz Dos Santos
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| | - Anissa Daliry
- Laboratory of Clinical and Experimental Physiopathology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
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AbdelMagid AM, Abbassi MM, Ebeid FS, El-Sayed MH, Farid SF. Population Pharmacokinetics of Ledipasvir/Sofosbuvir in Pediatric Patients: Impact of Acute Lymphoblastic Leukemia. Clin Ther 2025; 47:e5-e15. [PMID: 39706761 DOI: 10.1016/j.clinthera.2024.11.022] [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: 09/03/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
PURPOSE The pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF), might be altered in patients with acute lymphoblastic leukemia (ALL), affecting the optimum dose needed for hepatitis C virus treatment. Limited data are available evaluating the population PK of LDV/SOF and SOF metabolite GS-331007. We aimed to study whether ALL could affect population PK parameters of LDV, SOF, and the SOF major metabolite GS-331007 in hepatitis C virus-infected children, develop and validate a predictive PK model of LDV/SOF disposition in this special population, and identify their explained and unexplained sources of variability. METHODS Population PK modeling was performed using MonolixSuite software using the non-linear mixed effect modeling approach. Different compartmental models, absorption models, and lag times for absorption parameters were tested to find out the best-fitting base model. For final model development, data-driven systematic covariate analysis using conditional sampling for the stepwise approach based on the correlation tests method has been performed. The final models were then evaluated using internal validation approaches. FINDINGS The PK results of 22 fully compliant patients were included in the population PK analysis. LDV and SOF were best described by a 1-compartment model with zero-order absorption and lag time, while the 2-compartment model with first-order absorption and lag time was the best-fitting model for the SOF metabolite. The internal validation approach confirmed the good predictive power of the selected models. The patients' weight explained the variability in the volume of distribution of LDV and the systemic clearance of SOF and LDV. The final SOF model also included a statistically significant covariate of steatosis stage on its volume of distribution, while the final GS-331007 model included mean corpuscular volume values on GS-331007 central compartment volume, packed cell volume, and direct bilirubin values on metabolite intercompartmental clearance. IMPLICATIONS The presence of ALL did not explain any variability in the developed population PK models for SOF, LDV, and GS-331007. Despite weight being a significant covariate in the final models suggesting that weight-based dosing of LDV/SOF is better than fixed dosing, the fixed dosing (45/200 mg LDV/SOF) is more practical in terms of simplicity in dosing children at home besides the proved efficacy and safety through both the clinical outcomes and PK exposure results. Weight-based dosing is still hindered due to the absence of exposure-response analysis, and the unavailability of dose-flexible formulas in the market. Future studies are required to support these findings. CLINICALTRIALS GOV IDENTIFIER NCT03903185.
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Affiliation(s)
- Aya M AbdelMagid
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Maggie M Abbassi
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Fatma S Ebeid
- Pediatric Hematology, Oncology and BMT Department, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Ain Shams University Research Institute - Clinical Research Center (MASRI-CRC), Cairo, Egypt
| | - Manal H El-Sayed
- Pediatric Hematology, Oncology and BMT Department, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Ain Shams University Research Institute - Clinical Research Center (MASRI-CRC), Cairo, Egypt
| | - Samar F Farid
- Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Tang S, Borlak J. A comparative genomic study across 396 liver biopsies provides deep insight into FGF21 mode of action as a therapeutic agent in metabolic dysfunction-associated steatotic liver disease. Clin Transl Med 2025; 15:e70218. [PMID: 39962359 PMCID: PMC11832436 DOI: 10.1002/ctm2.70218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/15/2025] [Accepted: 01/24/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease with insulin resistance at its core. It affects one-third of the world population. Fibroblast growth factor (FGF21)-based therapies are effective in lowering hepatic fat content and fibrosis resolution; yet, its molecular functions remain uncertain. To gain insight into FGF21 mode of action (MoA), we investigated the transcriptomes of MASLD liver biopsies in relation to FGF21 expression. METHODS We compared N = 66 healthy controls with 396 MASLD patients and considered clinical characteristics relative to NAS disease activity scores (steatosis, lobular inflammation and ballooning), fibrosis grades and sex. We performed comparative genomics to identify FGF21-responsive DEGs, utilised information from FGF21-transgenic and FGF21-knockout mice and evaluated DEGs following FGF21 treatment of MASLD animal models. Eventually, we explored 188 validated FGF21 targets, and for ≥10 patients showing the same changes, we constructed MASLD-associated networks to determine the effects of FGF21 in reverting metabolic dysfunction. RESULTS We identified patients with increased 30% (N = 117), decreased 40% (N = 159) or unchanged 30% (N = 120) FGF21 expression, and the differences are caused by changes in FGF21 transcriptional control with ATF4 functioning as a key regulator. Based on comparative genomics, we discovered molecular circuitries of FGF21 in MASLD, notably FGF21-dependent induction of autophagy and oxidative phosphorylation/mitochondrial respiration. Conversely, FGF21 repressed hepatic glycogen-storage, its glucose release and gluconeogenesis, and therefore reduced glucose flux in conditions of insulin resistance. Furthermore, FGF21 repressed lipid transporters, and acetyl-CoA carboxylase-β to attenuate hepatic lipid overload and lipogenesis. Strikingly, FGF21 dampened immune response by repressing complement factors, MARCO, CD163, MRC1/CD206, CD4, CD45 and pro-inflammatory cytokine receptors. It also reverted procoagulant imbalance in MASLD, stimulated extracellular matrix degradation, repressed TGFβ- and integrin-signalling and lessened liver sinusoidal endothelial cell defenestration in support of fibrosis resolution. CONCLUSIONS We gained deep insight into FGF21-MoA in MASLD. However, heterogeneity in FGF21 expression calls for molecular stratifications as to identify patients which likely benefit from FGF21-based therapies. KEY POINTS Performed comprehensive genomics across liver biopsies of 396 MASLD patients and identified patients with increased, decreased and unchanged FGF21 expression. Used genomic data from FGF21 transgenic, knock-out and animal MASLD models treated with synthetic FGF21 analogues to identify FGF21-mode-of-action and metabolic networks in human MASLD. Given the significant heterogeneity in FGF21 expression, not all patients will benefit from FGF21-based therapies.
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Affiliation(s)
- Shifang Tang
- Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
| | - Jürgen Borlak
- Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
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Cesaretti M, Izzo A, Pellegrino RA, Galli A, Mavrothalassitis O. Cold ischemia time in liver transplantation: An overview. World J Hepatol 2024; 16:883-890. [PMID: 38948435 PMCID: PMC11212655 DOI: 10.4254/wjh.v16.i6.883] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/26/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
The standard approach to organ preservation in liver transplantation is by static cold storage and the time between the cross-clamping of a graft in a donor and its reperfusion in the recipient is defined as cold ischemia time (CIT). This simple definition reveals a multifactorial time frame that depends on donor hepatectomy time, transit time, and recipient surgery time, and is one of the most important donor-related risk factors which may influence the graft and recipient's survival. Recently, the growing demand for the use of marginal liver grafts has prompted scientific exploration to analyze ischemia time factors and develop different organ preservation strategies. This review details the CIT definition and analyzes its different factors. It also explores the most recent strategies developed to implement each timestamp of CIT and to protect the graft from ischemic injury.
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Affiliation(s)
- Manuela Cesaretti
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari 09122, Italy
- Department of Nanophysic, Istituto Italiano di Tecnologia, Genova 16163, Italy.
| | - Alessandro Izzo
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari 09122, Italy
| | | | - Alessandro Galli
- Department of Critical Care Medicine and Anesthesia, ASST Papa Giovanni XXIII, Bergamo 24100, Italy
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, United States
| | - Orestes Mavrothalassitis
- Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, United States
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Swan J, Szabó Z, Peters J, Kummu O, Kemppi A, Rahtu-Korpela L, Konzack A, Hakkola J, Pasternack A, Ritvos O, Kerkelä R, Magga J. Inhibition of activin receptor 2 signalling ameliorates metabolic dysfunction-associated steatotic liver disease in western diet/L-NAME induced cardiometabolic disease. Biomed Pharmacother 2024; 175:116683. [PMID: 38705130 DOI: 10.1016/j.biopha.2024.116683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/19/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024] Open
Abstract
OBJECTIVE Blockade of activin 2 receptor (ACVR2) signaling has been shown to improve insulin sensitivity and aid in weight loss. Inhibition of ACVR2 signaling restores cardiac function in multiple heart failure models. However, its potential in the treatment of obesity-related cardiometabolic disease remains unknown. Here, we investigated targeting ACVR2 signaling in cardiometabolic disease manifested with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS Mice were fed a high-fat, high-sugar diet combined with the administration of nitric oxide synthase inhibitor L-NAME in drinking water, which causes hypertensive stress. For the last eight weeks, the mice were treated with the soluble ACVR2B decoy receptor (sACVR2B-Fc). RESULTS sACVR2B-Fc protected against the development of comorbidities associated with cardiometabolic disease. This was most pronounced in the liver where ACVR2 blockade attenuated the development of MASLD including cessation of pro-fibrotic activation. It also significantly reduced total plasma cholesterol levels, impeded brown adipose tissue whitening, and improved cardiac diastolic function. In vitro, ACVR2 ligands activin A, activin B and GDF11 induced profibrotic signaling and the proliferation of human cardiac fibroblasts. CONCLUSIONS Blockade of ACVR2B exerts broad beneficial effects for therapy of cardiometabolic disease. By reducing obesity, ameliorating cardiovascular deterioration and restraining MASLD, blockade of ACVR2B signaling proves a potential target in MASLD and its comorbidities.
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Affiliation(s)
- Julia Swan
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland.
| | - Zoltán Szabó
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Juliana Peters
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Outi Kummu
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Anna Kemppi
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Lea Rahtu-Korpela
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Anja Konzack
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Jukka Hakkola
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Arja Pasternack
- Department of Physiology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki 00014, Finland
| | - Olli Ritvos
- Department of Physiology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki 00014, Finland
| | - Risto Kerkelä
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, Oulu 90220, Finland
| | - Johanna Magga
- Research Unit of Biomedicine and Internal Medicine, University of Oulu, Aapistie 5, Oulu 90220, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, Oulu 90220, Finland.
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Singh S, Dwivedi S, Khan AA, Jain A, Dwivedi S, Yadav KK, Dubey I, Trivedi A, Trivedi SP, Kumar M. Oxidative stress, inflammation, and steatosis elucidate the complex dynamics of HgCl 2 induced liver damage in Channa punctata. Sci Rep 2024; 14:9161. [PMID: 38644412 PMCID: PMC11033285 DOI: 10.1038/s41598-024-59917-4] [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: 04/03/2024] [Accepted: 04/16/2024] [Indexed: 04/23/2024] Open
Abstract
Water bodies are highly pollution-prone areas in which mercury (Hg) is considered as a major menace to aquatic organisms. However, the information about the toxicity of mercuric chloride (HgCl2) in a vital organ such as the liver of fish is still inadequate. This study aimed to assess the impact of mercuric chloride (HgCl2) exposure on the liver of Channa punctata fish over 15, 30, and 45 days, at two different concentrations (0.039 mg/L and 0.078 mg/L). Mercury is known to be a significant threat to aquatic life, and yet, information regarding its effects on fish liver remains limited. The results of this study demonstrate that exposure to HgCl2 significantly increases oxidative stress markers, such as lipid peroxidation (LPO) and protein carbonyls (PC), as well as the levels of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in the fish. Additionally, the transcriptional and protein analysis of specific genes and molecules associated with necroptosis and inflammation, such as ABCG2, TNF α, Caspase 3, RIPK 3, IL-1β, Caspase-1, IL-18, and RIPK1, confirm the occurrence of necroptosis and inflammation in the liver. Histopathological and ultrastructural examinations of the liver tissue further reveal a significant presence of liver steatosis. Interestingly, the upregulation of PPARα suggests that the fish's body is actively responding to counteract the effects of liver steatosis. This study provides a comprehensive analysis of oxidative stress, biochemical changes, gene expression, protein profiles, and histological findings in the liver tissue of fish exposed to mercury pollution in freshwater environments.
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Affiliation(s)
- Shefalee Singh
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Shikha Dwivedi
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Adeel Ahmad Khan
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Anamika Jain
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Shraddha Dwivedi
- Department of Zoology, Government Degree College, Haripur-Nihastha, Raebareli, 229208, India
| | - Kamlesh Kumar Yadav
- Department of Zoology, Government Degree College, Bakkha Kheda, Unnao, 209801, India
| | - Indrani Dubey
- Department of Zoology, DBS College, Kanpur, Uttar Pradesh, 208006, India
| | - Abha Trivedi
- Department of Zoology, Mahatma Jyotiba Phule Rohilkhand University, Bareilly, Uttar Pradesh, 243006, India
| | - Sunil P Trivedi
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Manoj Kumar
- Environmental Toxicology and Bioremediation Laboratory (ETBL), Department of Zoology, University of Lucknow, Lucknow, 226007, India.
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Lonardo A. Association of NAFLD/NASH, and MAFLD/MASLD with chronic kidney disease: an updated narrative review. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) account for substantial financial burden worldwide. These alarming features call for enhanced efforts to prevent and manage the development and progression of CKD. Accumulating evidence supporting a causal role of NAFLD/MAFLD/MASLD-in CKD opens new horizons to achieve this aim. Recent epidemiological studies and meta-analyses exploring the association of NAFLD/MAFLD/MASLD with CKD and the characteristics of NAFLD/MAFLD/MASLD associated with the odds of incident CKD are discussed. The involved pathomechanisms, including the common soil hypothesis, genetics, gut dysbiosis, and portal hypertension, are examined in detail. Finally, lifestyle changes (diet and physical exercise), direct manipulation of gut microbiota, and drug approaches involving statins, renin-angiotensin-aldosterone system inhibitors, GLP-1 Receptor Agonists, Sodium-glucose cotransporter-2, pemafibrate, and vonafexor are examined within the context of prevention and management of CKD among those with NAFLD/MAFLD/MASLD. The evolving NAFLD/MAFLD/MASLD nomenclature may generate confusion among practicing clinicians and investigators. However, comparative studies investigating the pros and contra of different nomenclatures may identify the most useful definitions among NAFLD/MAFLD/MASLD and strategies to identify, prevent, and halt the onset and progression of CKD.
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Lambers L, Waschinsky N, Schleicher J, König M, Tautenhahn HM, Albadry M, Dahmen U, Ricken T. Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach. Biomech Model Mechanobiol 2024; 23:631-653. [PMID: 38402347 DOI: 10.1007/s10237-023-01797-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/22/2023] [Indexed: 02/26/2024]
Abstract
Metabolic zonation refers to the spatial separation of metabolic functions along the sinusoidal axes of the liver. This phenomenon forms the foundation for adjusting hepatic metabolism to physiological requirements in health and disease (e.g., metabolic dysfunction-associated steatotic liver disease/MASLD). Zonated metabolic functions are influenced by zonal morphological abnormalities in the liver, such as periportal fibrosis and pericentral steatosis. We aim to analyze the interplay between microperfusion, oxygen gradient, fat metabolism and resulting zonated fat accumulation in a liver lobule. Therefore we developed a continuum biomechanical, tri-phasic, bi-scale, and multicomponent in silico model, which allows to numerically simulate coupled perfusion-function-growth interactions two-dimensionally in liver lobules. The developed homogenized model has the following specifications: (i) thermodynamically consistent, (ii) tri-phase model (tissue, fat, blood), (iii) penta-substances (glycogen, glucose, lactate, FFA, and oxygen), and (iv) bi-scale approach (lobule, cell). Our presented in silico model accounts for the mutual coupling between spatial and time-dependent liver perfusion, metabolic pathways and fat accumulation. The model thus allows the prediction of fat development in the liver lobule, depending on perfusion, oxygen and plasma concentration of free fatty acids (FFA), oxidative processes, the synthesis and the secretion of triglycerides (TGs). The use of a bi-scale approach allows in addition to focus on scale bridging processes. Thus, we will investigate how changes at the cellular scale affect perfusion at the lobular scale and vice versa. This allows to predict the zonation of fat distribution (periportal or pericentral) depending on initial conditions, as well as external and internal boundary value conditions.
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Affiliation(s)
- Lena Lambers
- Institute of Structural Mechanics and Dynamics, Faculty of Aerospace Engineering and Geodesy, University of Stuttgart, Pfaffenwaldring 27, Stuttgart, 70191, Germany
| | - Navina Waschinsky
- Institute of Structural Mechanics and Dynamics, Faculty of Aerospace Engineering and Geodesy, University of Stuttgart, Pfaffenwaldring 27, Stuttgart, 70191, Germany
| | - Jana Schleicher
- Friedrich-Schiller-Universität Jena, Fürstengraben 27, Jena, 07743, Germany
| | - Matthias König
- Systems Medicine of Liver, Institute for Theoretical Biology, Institute for Biology, Humboldt-University Berlin, Philippstraße 13, 10115 Berlin, Germany
| | - Hans-Michael Tautenhahn
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany
| | - Mohamed Albadry
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Drackendorfer Straße 1, Jena, 07747, Germany
- Department of Pathology, Faculty of Veterinary Medicine, Menoufia University, Shebin Elkom, Menoufia, Egypt
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Drackendorfer Straße 1, Jena, 07747, Germany
| | - Tim Ricken
- Institute of Structural Mechanics and Dynamics, Faculty of Aerospace Engineering and Geodesy, University of Stuttgart, Pfaffenwaldring 27, Stuttgart, 70191, Germany.
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10
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Qian Y, Wong VWS, Wang YX, Hou J, Jiang B, Zhang X, Wong GLH, Chan Q, Yu SCH, Chu WCW, Chen W. Dynamic Glucose-Enhanced Imaging of the Liver Using Breath-Hold Black Blood Quantitative T 1ρ MRI at 3.0 T. J Magn Reson Imaging 2024; 59:1107-1109. [PMID: 37317614 DOI: 10.1002/jmri.28829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 06/16/2023] Open
Abstract
Evidence Level1Technical Efficacy Stage3
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Affiliation(s)
- Yurui Qian
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent W S Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Yi-Xiang Wang
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Jian Hou
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Baiyan Jiang
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
- Illuminatio Medical Technology Limited, Hong Kong, China
| | - Xinrong Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace L H Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | | | - Simon C H Yu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Winnie C W Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Weitian Chen
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
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11
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Minciuna I, Taru MG, Procopet B, Stefanescu H. The Interplay between Liver Sinusoidal Endothelial Cells, Platelets, and Neutrophil Extracellular Traps in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease. J Clin Med 2024; 13:1406. [PMID: 38592258 PMCID: PMC10932189 DOI: 10.3390/jcm13051406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 04/10/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a societal burden due to the lack of effective treatment and incomplete pathophysiology understanding. This review explores the intricate connections among liver sinusoidal endothelial cells (LSECs), platelets, neutrophil extracellular traps (NETs), and coagulation disruptions in MASLD pathogenesis. In MASLD's early stages, LSECs undergo capillarization and dysfunction due to excessive dietary macronutrients and gut-derived products. Capillarization leads to ischemic changes in hepatocytes, triggering pro-inflammatory responses in Kupffer cells (KCs) and activating hepatic stellate cells (HSCs). Capillarized LSECs show a pro-inflammatory phenotype through adhesion molecule overexpression, autophagy loss, and increased cytokines production. Platelet interaction favors leucocyte recruitment, NETs formation, and liver inflammatory foci. Liver fibrosis is facilitated by reduced nitric oxide, HSC activation, profibrogenic mediators, and increased angiogenesis. Moreover, platelet attachment, activation, α-granule cargo release, and NETs formation contribute to MASLD progression. Platelets foster fibrosis and microthrombosis, leading to parenchymal extinction and fibrotic healing. Additionally, platelets promote tumor growth, epithelial-mesenchymal transition, and tumor cell metastasis. MASLD's prothrombotic features are exacerbated by insulin resistance, diabetes, and obesity, manifesting as increased von Willebrand factor, platelet hyperaggregability, hypo-fibrinolysis, and a prothrombotic fibrin clot structure. Improving LSEC health and using antiplatelet treatment appear promising for preventing MASLD development and progression.
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Affiliation(s)
- Iulia Minciuna
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Madalina Gabriela Taru
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Bogdan Procopet
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
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12
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Ito Y, Yoshioka K, Hayashi K, Shimizu Y, Fujimoto R, Yamane R, Yoshizaki M, Kajikawa G, Mizutani T, Goto H. Prevalence of Non-alcoholic Fatty Liver Disease Detected by Computed Tomography in the General Population Compared with Ultrasonography. Intern Med 2024; 63:159-167. [PMID: 37225482 PMCID: PMC10864065 DOI: 10.2169/internalmedicine.1861-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/09/2023] [Indexed: 05/26/2023] Open
Abstract
Objective To assess the prevalence and clinical correlates of non-alcoholic fatty liver disease (NAFLD) identified by computed tomography (CT) in the general population compared with ultrasonography (US). Methods Four hundred and fifty-eight subjects who received health checkups at Meijo Hospital in 2021 and underwent CT within a year of US in the past decade were analyzed. The mean age was 52.3±10.1 years old, and 304 were men. Results NAFLD was diagnosed in 20.3% by CT and in 40.4% by the US. The NAFLD prevalence in men was considerably greater in subjects 40-59 years old than in those ≤39 years old and in those ≥60 years old by both CT and US. The NAFLD prevalence in women was substantially higher in the subjects 50-59 years old than in those ≤49 years old or those ≥60 years old on US, while no significant differences were observed on CT. The abdominal circumference, hemoglobin value, high-density lipoprotein cholesterol level, albumin level, and diabetes mellitus were independent predictors of NAFLD diagnosed by CT. The body mass index, abdominal circumference, and triglyceride level were independent predictors of NAFLD diagnosed by the US. Conclusion NAFLD was found in 20.3% of CT cases and 40.4% of US cases among recipients of health checkups. An "inverted U curve" in which the NAFLD prevalence rose with age and dropped in late adulthood was reported. NAFLD was associated with obesity, the lipid profile, diabetes mellitus, hemoglobin values, and albumin levels. Our research is the first in the world to compare the NAFLD prevalence in the general population simultaneously by CT and US.
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Affiliation(s)
- Yuki Ito
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Kentaro Yoshioka
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Yuko Shimizu
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Ryo Fujimoto
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Ryosuke Yamane
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Michiyo Yoshizaki
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Go Kajikawa
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Taro Mizutani
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Federation of National Public Service Personnel Mutual Aid Associations Meijo Hospital, Japan
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13
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Manandhar S, Gaddam RR, Chambers S, Bhatia M. Kupffer Cell Inactivation Alters Endothelial Cell Adhesion Molecules in Cecal Ligation and Puncture-Induced Sepsis. Biomolecules 2024; 14:84. [PMID: 38254684 PMCID: PMC10813064 DOI: 10.3390/biom14010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/01/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
The activation of Kupffer cells, resident macrophages in the liver, is closely associated with the inflammatory response during sepsis, which leads to multiple-organ failure. However, how Kupffer cell activation affects adhesion molecules (ICAM-1 and VCAM-1) in sepsis has not been determined. This study investigated Kupffer cell inactivation's (by gadolinium chloride; GdCl3) effects on adhesion molecule expression in CLP-induced sepsis. The induction of sepsis resulted in increased expression of liver and lung ICAM-1 and VCAM-1. GdCl3 pretreatment significantly decreased liver ICAM-1 expression but had no effect on VCAM-1 expression. In contrast, GdCl3 pretreatment had no effect on sepsis-induced increased adhesion molecule expression in the lungs. Similarly, the immunoreactivity of ICAM-1 was decreased in liver sinusoidal endothelial cells but increased in pulmonary endothelial cells in septic mice pretreated with GdCl3. Further, GdCl3 pretreatment had no effect on the immunoreactivity of VCAM-1 in endothelial cells of the liver and lungs. Hence, the findings of this study demonstrate the differential effects of Kupffer cell inactivation on liver and lung adhesion molecules and suggest the complexity of their involvement in the pathophysiology of sepsis.
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Affiliation(s)
| | | | | | - Madhav Bhatia
- Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand; (S.M.); (R.R.G.); (S.C.)
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14
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Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Zamboni WC, Charlab R, Burckart GJ, Stewart CF. Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents. J Clin Pharmacol 2023; 63 Suppl 2:S85-S102. [PMID: 37942904 DOI: 10.1002/jcph.2326] [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: 05/01/2023] [Accepted: 07/12/2023] [Indexed: 11/10/2023]
Abstract
An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.
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Affiliation(s)
- William C Zamboni
- UNC Eshelman School of Pharmacy, UNC Lineberger Comprehensive Cancer Center, Caroline Institute of Nanomedicine, University of North Carolina, Chapel Hill, NC, USA
| | - Rosane Charlab
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Gilbert J Burckart
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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16
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Pan X, Wang L, Liu J, Earp JC, Yang Y, Yu J, Li F, Bi Y, Bhattaram A, Zhu H. Model-Informed Approaches to Support Drug Development for Patients With Obesity: A Regulatory Perspective. J Clin Pharmacol 2023; 63 Suppl 2:S65-S77. [PMID: 37942906 DOI: 10.1002/jcph.2349] [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: 07/10/2023] [Accepted: 09/13/2023] [Indexed: 11/10/2023]
Abstract
Obesity, which is defined as having a body mass index of 30 kg/m2 or greater, has been recognized as a serious health problem that increases the risk of many comorbidities (eg, heart disease, stroke, and diabetes) and mortality. The high prevalence of individuals who are classified as obese calls for additional considerations in clinical trial design. Nevertheless, gaining a comprehensive understanding of how obesity affects the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of drugs proves challenging, primarily as obese patients are seldom selected for enrollment at the early stages of drug development. Over the past decade, model-informed drug development (MIDD) approaches have been increasingly used in drug development programs for obesity and its related diseases as they use and integrate all available sources and knowledge to inform and facilitate clinical drug development. This review summarizes the impact of obesity on PK, PD, and the efficacy of drugs and, more importantly, provides an overview of the use of MIDD approaches in drug development and regulatory decision making for patients with obesity: estimating PK, PD, and efficacy in specific dosing scenarios, optimizing dose regimen, and providing evidence for seeking new indication(s). Recent review cases using MIDD approaches to support dose selection and provide confirmatory evidence for effectiveness for patients with obesity, including pediatric patients, are discussed. These examples demonstrate the promise of MIDD as a valuable tool in supporting clinical trial design during drug development and facilitating regulatory decision-making processes for the benefit of patients with obesity.
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Affiliation(s)
- Xiaolei Pan
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Li Wang
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Jiang Liu
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Justin C Earp
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Yuching Yang
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Jingyu Yu
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Fang Li
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Youwei Bi
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Atul Bhattaram
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Hao Zhu
- Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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Abstract
The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.
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Affiliation(s)
- Joseph L Dempsey
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System Seattle, Washington
| | - Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
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18
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Li D, Janmey PA, Wells RG. Local fat content determines global and local stiffness in livers with simple steatosis. FASEB Bioadv 2023; 5:251-261. [PMID: 37287868 PMCID: PMC10242205 DOI: 10.1096/fba.2022-00134] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/09/2023] [Accepted: 04/04/2023] [Indexed: 06/09/2023] Open
Abstract
Fat accumulation during liver steatosis precedes inflammation and fibrosis in fatty liver diseases, and is associated with disease progression. Despite a large body of evidence that liver mechanics play a major role in liver disease progression, the effect of fat accumulation by itself on liver mechanics remains unclear. Thus, we conducted ex vivo studies of liver mechanics in rodent models of simple steatosis to isolate and examine the mechanical effects of intrahepatic fat accumulation, and found that fat accumulation softens the liver. Using a novel adaptation of microindentation to permit association of local mechanics with microarchitectural features, we found evidence that the softening of fatty liver results from local softening of fatty regions rather than uniform softening of the liver. These results suggest that fat accumulation itself exerts a softening effect on liver tissue. This, along with the localized heterogeneity of softening within the liver, has implications in what mechanical mechanisms are involved in the progression of liver steatosis to more severe pathologies and disease. Finally, the ability to examine and associate local mechanics with microarchitectural features is potentially applicable to the study of the role of heterogeneous mechanical microenvironments in both other liver pathologies and other organ systems.
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Affiliation(s)
- David Li
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Paul A. Janmey
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Medicine and EngineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of PhysiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Rebecca G. Wells
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- NSF Science and Technology Center for Engineering MechanoBiologyUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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19
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Gomes SV, Dias BV, Júnior PAM, Pereira RR, de Souza DMS, Breguez GS, de Lima WG, Magalhães CLDB, Cangussú SD, Talvani A, Queiroz KB, Calsavara AJC, Costa DC. High-fat diet increases mortality and intensifies immunometabolic changes in septic mice. J Nutr Biochem 2023; 116:109315. [PMID: 36921735 DOI: 10.1016/j.jnutbio.2023.109315] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/21/2023] [Accepted: 03/07/2023] [Indexed: 03/16/2023]
Abstract
Immunometabolic changes in the liver and white adipose tissue (WAT) caused by high-fat (HF) diet intake may worse metabolic adaptation and protection against pathogens in sepsis. We investigate the effect of chronic HF diet (15 weeks) on mortality and immunometabolic responses in female mice after sepsis induced by cecum ligation and perforation (CLP). At week 14, animals were divided into four groups: sham C diet (C-Sh), sepsis C diet (C-Sp), sham HF diet (HF-Sh) and sepsis HF diet (HF-Sp). The surviving animals were euthanised on the 7th day. The HF diet decreased survival rate (58.3% vs 76.2% C-Sp group), increased serum cytokine storm (IL-6 (1.41 ×; vs HF-Sh), IL-1β (1.37 ×; vs C-Sp), TNF (1.34 ×; vs C-Sp and 1.72 ×; vs HF-Sh), IL-17 (1.44 ×; vs HF-Sh), IL-10 (1.55 ×; vs C-Sp and 1.41 ×; HF-Sh), WAT inflammation (IL-6 (8.7 ×; vs C-Sp and 2.4 ×; vs HF-Sh), TNF (5 ×; vs C-Sp and 1.7 ×;vs HF-Sh), IL-17 (1.7 ×; vs C-Sp), IL-10 (7.4 ×; vs C-Sp and 1.3 ×; vs HF-Sh), and modulated lipid metabolism in septic mice. In the HF-Sp group liver's, we observed hepatomegaly, hydropic degeneration, necrosis, an increase in oxidative stress (reduction of CAT activity (-81.7%; vs HF-Sh); increase MDA levels (82.8%; vs HF-Sh), and hepatic IL-6 (1.9 ×; vs HF-Sh), and TNF (1.3 × %;vs HF-Sh) production. Furthermore, we found a decrease in the total number of inflammatory, mononuclear cells, and in the regenerative processes, and binucleated hepatocytes in a HF-Sp group liver's. Our results suggested that the organism under metabolic stress of a HF diet during sepsis may worsen the inflammatory landscape and hepatocellular injury and may harm the liver regenerative process.
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Affiliation(s)
- Sttefany Viana Gomes
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Bruna Vidal Dias
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Pedro Alves Machado Júnior
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Renata Rebeca Pereira
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Débora Maria Soares de Souza
- Laboratory of Immunobiology of Inflammation, Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Gustavo Silveira Breguez
- Multiuser Research Laboratory, School of Nutrition, School of Nutrition, Postgraduate Program in Health and Nutrition, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Wanderson Geraldo de Lima
- Morphopathology Laboratory, Department of Biological Sciences (DECBI), Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Cintia Lopes de Brito Magalhães
- Laboratory of Biology and Technology of Microorganisms (LBTM), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Silvia Dantas Cangussú
- Laboratory of Experimental Pathophysiology (LAFEx), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - André Talvani
- Laboratory of Immunobiology of Inflammation, Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Karina Barbosa Queiroz
- Laboratory of Experimental Nutrition (LABNEx), Department of Food, Postgraduate Program in Health and Nutrition, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Allan Jefferson Cruz Calsavara
- Laboratory of Cognition and Health (LACOS), School of Medicine, Department of Pediatric and Adult Clinics (DECPA), Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil
| | - Daniela Caldeira Costa
- Laboratory of Metabolic Biochemistry (LBM), Department of Biological Sciences (DECBI), Graduate Program in Health and Nutrition, Graduate Program in Biological Sciences, Federal University of Ouro Preto (UFOP), Ouro Preto, Minas Gerais, Brazil.
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20
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Yang H, Wang Q, Zhang P, Cheng K, Li H, Wang H, Cai M, Ming Y, Zhao Y. Preliminary mechanism of inhibitor of SGLT2 in fatty liver cold ischemia injury. Biochem Biophys Res Commun 2023; 646:96-102. [PMID: 36708596 DOI: 10.1016/j.bbrc.2022.12.055] [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: 12/01/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/31/2022]
Abstract
With rapid development of liver transplantation technology, the demand for transplants have reached beyond the supply of organs, and thus development of effective strategies to reduce cold ischemia injury in fatty liver is important. Here, we explored the potential effect of SGLT-2 inhibitor in cold ischemia injury, fatty livers from 2 weeks methionine and choline deficient diet (MCD) rats were administered. After one week of intragastric administration of Sodium-dependent glucose transporters (SGLT-2) inhibitor empagliflozin (EMPA) or NaCI, liver were stored for 24 h. The results showed that EMPA could significantly reduce the cold ischemic injury in the mitochondria of fatty liver. To explore the mechanism, signal transducers and activators of transcription 3(STAT3) inhibitor AG490 group was used in a similar manner. We detected the changes in p-signal transducers and activators of transcription 3 (P-STAT3), alcohol-dehydrogenase 2 (ALDH2) and degree of apoptosis in three distinct groups. The results suggested that the protein expression of P-STAT3 and ALDH2 was higher in the EMPA group than in other two groups, whereas extent of apoptosis in the EMPA group was lower than other two groups. The data suggested that SGLT2 inhibitors could alleviate cold ischemia damage of mitochondria in fatty liver, which may be related to the inhibition of apoptosis and the activation of P-STAT3 and ALDH2.
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Affiliation(s)
- Hanwen Yang
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Qiang Wang
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Pengpeng Zhang
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Ke Cheng
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Hao Li
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Huan Wang
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Mingxin Cai
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Yingzi Ming
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China
| | - Yujun Zhao
- Engineering and Technology Research Center for Transplantation Medicine of National Health Comission, Third Xiangya Hospital, Central South University, Changsha, 410006, China.
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21
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Gao J, Zapata I, Chen J, Erpelding TN, Adamson C, Park D. Quantitative Ultrasound Biomarkers to Assess Nonalcoholic Fatty Liver Disease. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2023. [PMID: 36744595 DOI: 10.1002/jum.16185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 06/18/2023]
Abstract
PURPOSE To assess diagnostic performance of quantitative ultrasound (QUS) biomarkers in assessing hepatic steatosis. METHODS We prospectively recruited 125 participants (mean age 54 years) who underwent liver QUS, magnetic resonance imaging (MRI), and laboratory tests within 30 days in this IRB approved study. Based on MRI-proton density fat fraction (MRI-PDFF) and MRE, we divided 125 participants into normal liver, nonalcoholic fatty liver (NAFL) and liver fibrosis (≥F1) groups. We examined diagnostic performance of ultrasound attenuation coefficient (AC), normalized local variance (NLV), superb microvascular imaging-based vascularity index (SMI-VI), and shear wave velocity (SWV) for determining hepatic steatosis and fibrosis using area under receiver operating characteristic curve (AUC). We also analyzed correlations of QUS biomarkers to MRI using Spearman correlation coefficient. RESULTS We observed significant differences in AC, NLV, and SMI-VI among the three groups (22 participants with normal liver, 78 with NAFL, and 25 with liver fibrosis). AUC of AC, NLV, and SMI-VI for determining ≥ mild steatotic livers (MRI-PDFF ≥5%) was 0.95, 0.90, and 0.92, respectively. AUC of SWV for determining ≥ F1 liver fibrosis was 0.93. The correlation of MRI-PDFF was positive to AC (r = 0.91) and negative to NLV (r = -0.74), SMI-VI (r = -0.8) in NAFL group. There was a significant difference in regression slope of AC to MRI-PDFF in livers with and without ≥F1 (0.84 vs 0.91, P = .02). CONCLUSIONS QUS biomarkers have high sensitivity and specificity to determine and grade hepatic steatosis and detect liver fibrosis. The effect of liver fibrosis on the performance of QUS biomarkers in quantifying liver fat content warrants further investigation.
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Affiliation(s)
- Jing Gao
- Rocky Vista University, Ivins, Utah, USA
- Weill Cornell Medicine, Cornell University, New York, New York, USA
| | | | - Johnson Chen
- Weill Cornell Medicine, Cornell University, New York, New York, USA
| | | | | | - David Park
- Rocky Vista University, Ivins, Utah, USA
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22
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Laitman JT, Smith HF. The Anatomical Record digests new findings on the twists and turns and surprises of the gastrointestinal system in a new Special Issue. Anat Rec (Hoboken) 2023; 306:937-940. [PMID: 36734640 DOI: 10.1002/ar.25156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 01/04/2023] [Indexed: 02/04/2023]
Affiliation(s)
- Jeffrey T Laitman
- Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Heather F Smith
- Department of Anatomy, Midwestern University, Glendale, Arizona, USA.,School of Human Evolution and Social Change, Arizona State University, Tempe, Arizona, USA
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23
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Kotlyarov S. Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease. World J Gastroenterol 2023; 29:597-615. [PMID: 36742172 PMCID: PMC9896611 DOI: 10.3748/wjg.v29.i4.597] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/28/2022] [Accepted: 11/07/2022] [Indexed: 01/20/2023] Open
Abstract
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, Ryazan 390026, Russia
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24
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Thimotheo Batista JP, Santos Marzano LA, Menezes Silva RA, de Sá Rodrigues KE, Simões E Silva AC. Chemotherapy and Anticancer Drugs Adjustment in Obesity: A Narrative Review. Curr Med Chem 2023; 30:1003-1028. [PMID: 35946096 DOI: 10.2174/0929867329666220806140204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/08/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Obese individuals have higher rates of cancer incidence and cancer- related mortality. The worse chemotherapy outcomes observed in this subset of patients are multifactorial, including the altered physiology in obesity and its impact on pharmacokinetics, the possible increased risk of underdosing, and treatment-related toxicity. AIMS The present review aimed to discuss recent data on physiology, providing just an overall perspective and pharmacokinetic alterations in obesity concerning chemotherapy. We also reviewed the controversies of dosing adjustment strategies in adult and pediatric patients, mainly addressing the use of actual total body weight and ideal body weight. METHODS This narrative review tried to provide the best evidence to support antineoplastic drug dosing strategies in children, adolescents, and adults. RESULTS Cardiovascular, hepatic, and renal alterations of obesity can affect the distribution, metabolism, and clearance of drugs. Anticancer drugs have a narrow therapeutic range, and variations in dosing may result in either toxicity or underdosing. Obese patients are underrepresented in clinical trials that focus on determining recommendations for chemotherapy dosing and administration in clinical practice. After considering associated comorbidities, the guidelines recommend that chemotherapy should be dosed according to body surface area (BSA) calculated with actual total body weight, not an estimate or ideal weight, especially when the intention of therapy is the cure. CONCLUSION The actual total body weight dosing appears to be a better approach to dosing anticancer drugs in both adults and children when aiming for curative results, showing no difference in toxicity and no limitation in treatment outcomes compared to adjusted doses.
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Affiliation(s)
- João Pedro Thimotheo Batista
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Lucas Alexandre Santos Marzano
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Renata Aguiar Menezes Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Karla Emília de Sá Rodrigues
- Departmento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efgênia, Belo Horizonte, MG, Brazil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil.,Departmento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efgênia, Belo Horizonte, MG, Brazil
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25
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Eriksen PL, Thomsen KL, Hamilton-Dutoit S, Vilstrup DMSH, Sørensen M. Experimental non-alcoholic fatty liver disease causes regional liver functional deficits as measured by the capacity for galactose metabolism while whole liver function is preserved. BMC Gastroenterol 2022; 22:541. [PMID: 36575375 PMCID: PMC9793673 DOI: 10.1186/s12876-022-02574-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 11/09/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Increasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function. AIMS To investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model. METHODS Male Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[18F]fluoro-2-deoxy-D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification. RESULTS Early NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002). CONCLUSION Regional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.
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Affiliation(s)
- Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200, Aarhus N, Denmark. .,Department of Internal Medicine, Randers Regional Hospital, Skovlyvej 15, 8930, Randers, Denmark.
| | - Karen Louise Thomsen
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Stephen Hamilton-Dutoit
- grid.154185.c0000 0004 0512 597XDepartment of Pathology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - DMSc Hendrik Vilstrup
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark
| | - Michael Sørensen
- grid.154185.c0000 0004 0512 597XDepartment of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark ,grid.154185.c0000 0004 0512 597XDepartment of Nuclear Medicine & PET, Aarhus University Hospital, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark ,grid.416838.00000 0004 0646 9184Department of Internal Medicine, Viborg Regional Hospital, Heibergs Alle 5A, 8800 Viborg, Denmark
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26
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Nasiri-Ansari N, Androutsakos T, Flessa CM, Kyrou I, Siasos G, Randeva HS, Kassi E, Papavassiliou AG. Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review. Cells 2022; 11:2511. [PMID: 36010588 PMCID: PMC9407007 DOI: 10.3390/cells11162511] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/07/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.
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Affiliation(s)
- Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Gerasimos Siasos
- Third Department of Cardiology, ‘Sotiria’ Thoracic Diseases General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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27
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New Insights of OLFM2 and OLFM4 in Gut-Liver Axis and Their Potential Involvement in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23137442. [PMID: 35806447 PMCID: PMC9267292 DOI: 10.3390/ijms23137442] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/29/2022] [Accepted: 07/03/2022] [Indexed: 02/01/2023] Open
Abstract
Olfactomedins (OLFMs) are a family of glycoproteins that play a relevant role in embryonic development and in some pathological processes. Although OLFM2 is involved in the regulation of the energy metabolism and OLFM4 is an important player in inflammation, innate immunity and cancer, the role of OLFMs in NAFLD-related intestinal dysbiosis remains unknown. In this study, we analysed the hepatic mRNA expression of OLFM2 and the jejunal expression of OLFM4 in a well-established cohort of women with morbid obesity (MO), classified according to their hepatic histology into normal liver (n = 27), simple steatosis (n = 26) and nonalcoholic steatohepatitis (NASH, n = 16). Our results showed that OLFM2 hepatic mRNA was higher in NASH, in advanced degrees of steatosis and in the presence of lobular inflammation. Additionally, we obtained positive correlations between hepatic OLFM2 and glucose, cholesterol, trimethylamine N-oxide and deoxycholic acid levels and hepatic fatty acid synthase, and negative associations with weight and jejunal Toll-like receptors (TLR4) and TLR5 expression. Regarding jejunal OLFM4, we observed positive correlations with circulating interleukin (IL)-8, IL-10, IL-17 and jejunal TLR9. In conclusion, OLFM2 in the liver seems to play a relevant role in NAFLD progression, while OLFM4 in the jejunum could be involved in gut dysbiosis-related inflammatory events.
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28
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Individualized Contrast Media Application Based on Body Weight and Contrast Enhancement in Computed Tomography of Livers without Steatosis. Diagnostics (Basel) 2022; 12:diagnostics12071551. [PMID: 35885457 PMCID: PMC9322492 DOI: 10.3390/diagnostics12071551] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 11/16/2022] Open
Abstract
This study analyzes the homogeneity in liver attenuation of a body-weight-based protocol compared to a semi-fixed protocol. Patients undergoing abdominal multiphase computed tomography received 0.500 g of iodine (gI) per kilogram of body weight. Liver attenuation and enhancement were determined using regions of interest on scans in the pre-contrast and portal venous phases. The outcomes were analyzed for interpatient uniformity in weight groups. The subjective image quality was scored using a four-point Likert scale (excellent, good, moderate, and nondiagnostic). A total of 80 patients were included (56.3% male, 64 years, 78.0 kg) and were compared to 80 propensity-score-matched patients (62.5% male, 63 years, 81.7 kg). The liver attenuation values for different weight groups of the TBW-based protocol were not significantly different (p = 0.331): 109.1 ± 13.8 HU (≤70 kg), 104.6 ± 9.70 HU (70−90 kg), and 105.1 ± 11.6 HU (≥90 kg). For the semi-fixed protocol, there was a significant difference between the weight groups (p < 0.001): 121.1 ± 12.1 HU (≤70 kg), 108.9 ± 11.0 HU (70−90 kg), and 105.0 ± 9.8 HU (≥90 kg). For the TBW-based protocol, the enhancement was not significantly different between the weight groups (p = 0.064): 46.2 ± 15.1 HU (≤70 kg), 59.3 ± 6.8 HU (70−90 kg), and 52.1 ± 11.7 HU (≥90 kg). Additionally, for the semi-fixed protocol, the enhancement was not significantly different between the weight groups (p = 0.069): 59.4 ± 11.0 HU (≤70 kg), 53.0 ± 10.3 HU (70−90 kg), and 52.4 ± 7.5 HU (≥90 kg). The mean administered amount of iodine per kilogram was less for the TBW-based protocol compared to the semi-fixed protocol: 0.499 ± 0.012 and 0.528 ± 0.079, respectively (p = 0.002). Of the TBW-based protocol, 17.5% of the scans scored excellent enhancement quality, 76.3% good, and 6.3% moderate. Of the semi-fixed protocol, 70.0% scored excellent quality, 21.3% scored good, and 8.8% scored moderate. In conclusion, the TBW-based protocol increased the interpatient uniformity of liver attenuation but not the enhancement in the portal venous phase compared to the semi-fixed protocol, using an overall lower amount of contrast media and maintaining good subjective image quality.
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29
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Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology. Biomedicines 2022; 10:biomedicines10061315. [PMID: 35740337 PMCID: PMC9219880 DOI: 10.3390/biomedicines10061315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/24/2022] [Accepted: 06/01/2022] [Indexed: 12/10/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease; nevertheless, no definitive diagnostic method exists yet, apart from invasive liver biopsy, and nor is there a specific approved treatment. Runt-related transcription factor 1 (RUNX1) plays a major role in angiogenesis and inflammation; however, its link with NAFLD is unclear as controversial results have been reported. Thus, the objective of this work was to determine the proteins involved in the molecular mechanisms between RUNX1 and NAFLD, by means of systems biology. First, a mathematical model that simulates NAFLD pathophysiology was generated by analyzing Anaxomics databases and reviewing available scientific literature. Artificial neural networks established NAFLD pathophysiological processes functionally related to RUNX1: hepatic insulin resistance, lipotoxicity, and hepatic injury-liver fibrosis. Our study indicated that RUNX1 might have a high relationship with hepatic injury-liver fibrosis, and a medium relationship with lipotoxicity and insulin resistance motives. Additionally, we found five RUNX1-regulated proteins with a direct involvement in NAFLD motives, which were NFκB1, NFκB2, TNF, ADIPOQ, and IL-6. In conclusion, we suggested a relationship between RUNX1 and NAFLD since RUNX1 seems to regulate NAFLD molecular pathways, posing it as a potential therapeutic target of NAFLD, although more studies in this field are needed.
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30
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Rajapaksha IG, Gunarathne LS, Asadi K, Laybutt R, Andrikopoulous S, Alexander IE, Watt MJ, Angus PW, Herath CB. Angiotensin Converting Enzyme-2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver. Hepatol Commun 2022; 6:1056-1072. [PMID: 34951153 PMCID: PMC9035567 DOI: 10.1002/hep4.1884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/29/2021] [Accepted: 12/04/2021] [Indexed: 12/26/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is frequently associated with type 2 diabetes. However, there is no specific medical therapy to treat this condition. Angiotensin-converting enzyme 2 (ACE2) of the protective renin angiotensin system generates the antifibrotic peptide angiotensin-(1-7) from profibrotic angiotensin II peptide. In this study, we investigated the therapeutic potential of ACE2 in diabetic NAFLD mice fed a high-fat (20%), high-cholesterol (2%) diet for 40 weeks. Mice were given a single intraperitoneal injection of ACE2 using an adeno-associated viral vector at 30 weeks of high-fat, high-cholesterol diet (15 weeks after induction of diabetes) and sacrificed 10 weeks later. ACE2 significantly reduced liver injury and fibrosis in diabetic NAFLD mice compared with the control vector injected mice. This was accompanied by reductions in proinflammatory cytokine expressions, hepatic stellate cell activation, and collagen 1 expression. Moreover, ACE2 therapy significantly increased islet numbers, leading to an increased insulin protein content in β-cells and plasma insulin levels with subsequent reduction in plasma glucose levels compared with controls. Conclusion: We conclude that ACE2 gene therapy reduces liver fibrosis and hyperglycemia in diabetic NAFLD mice and has potential as a therapy for patients with NAFLD with diabetes.
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Affiliation(s)
- Indu G Rajapaksha
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | - Lakmie S Gunarathne
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | | | - Ross Laybutt
- Garvan Institute of Medical ResearchSydneyNSWAustralia.,St. Vincent's Clinical SchoolUniversity of New South WalesSydneyNSWAustralia
| | - Sof Andrikopoulous
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia
| | - Ian E Alexander
- School of MedicineUniversity of SydneyChildren's Medical Research InstituteSydneyNSWAustralia
| | - Mathew J Watt
- Department Anatomy and PhysiologyThe University of MelbourneMelbourneVICAustralia
| | - Peter W Angus
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia.,Department GastroenterologyAustin HealthHeidelbergVICAustralia
| | - Chandana B Herath
- Department of MedicineThe University of MelbourneAustin HealthHeidelbergVICAustralia.,South Western Sydney Clinical SchoolFaculty of MedicineUniversity of New South WalesSydneyNSWAustralia.,Ingham Institute for Applied Medical ResearchLiverpoolNSWAustralia
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31
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Micó-Carnero M, Casillas-Ramírez A, Sánchez-González A, Rojano-Alfonso C, Peralta C. The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors. Biomedicines 2022; 10:biomedicines10050978. [PMID: 35625715 PMCID: PMC9138382 DOI: 10.3390/biomedicines10050978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/29/2022] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
Background. Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). Methods: NRG1 pathways were characterized after surgery. Results: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. Conclusions: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD.
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Affiliation(s)
- Marc Micó-Carnero
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (C.R.-A.)
| | - Araní Casillas-Ramírez
- Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico; (A.C.-R.); (A.S.-G.)
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico
| | - Alfredo Sánchez-González
- Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico; (A.C.-R.); (A.S.-G.)
| | - Carlos Rojano-Alfonso
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (C.R.-A.)
| | - Carmen Peralta
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.M.-C.); (C.R.-A.)
- Correspondence: ; Tel.: +34-932-275-400
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Scorletti E, Carr RM. A new perspective on NAFLD: Focusing on lipid droplets. J Hepatol 2022; 76:934-945. [PMID: 34793866 DOI: 10.1016/j.jhep.2021.11.009] [Citation(s) in RCA: 174] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/13/2021] [Accepted: 11/06/2021] [Indexed: 02/07/2023]
Abstract
Lipid droplets (LDs) are complex and metabolically active organelles. They are composed of a neutral lipid core surrounded by a monolayer of phospholipids and proteins. LD accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease (NAFLD), which is a chronic, heterogeneous liver condition that can progress to liver fibrosis and hepatocellular carcinoma. Though recent research has improved our understanding of the mechanisms linking LD accumulation to NAFLD progression, numerous aspects of LD biology are either poorly understood or unknown. In this review, we provide a description of several key mechanisms that contribute to LD accumulation in hepatocytes, favouring NAFLD progression. First, we highlight the importance of LD architecture and describe how the dysregulation of LD biogenesis leads to endoplasmic reticulum stress and inflammation. This is followed by an analysis of the causal nexus that exists between LD proteome composition and LD degradation. Finally, we describe how the increase in size of LDs causes activation of hepatic stellate cells, leading to liver fibrosis and hepatocellular carcinoma. We conclude that acquiring a more sophisticated understanding of LD biology will provide crucial insights into the heterogeneity of NAFLD and assist in the development of therapeutic approaches for this liver disease.
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Affiliation(s)
- Eleonora Scorletti
- Division of Translational Medicine and Human Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Rotonya M Carr
- Division of Gastroenterology, University of Washington, Seattle, WA 98195-6424, United States.
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Gao J, King J, Chatterji M, Miller BR, Siddoway RL. Superb Microvascular Imaging-Based Vascular Index to Assess Adult Hepatic Steatosis: A Feasibility Study. ULTRASOUND IN MEDICINE & BIOLOGY 2022; 48:480-487. [PMID: 34872787 DOI: 10.1016/j.ultrasmedbio.2021.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/28/2021] [Accepted: 11/01/2021] [Indexed: 06/13/2023]
Abstract
The aim of the study was to assess the feasibility of using a superb microvascular imaging-based vascular index (SMI-VI) for evaluating adult hepatic steatosis. We prospectively compared liver parenchyma SMI-VI (color pixels/total pixels in the region of interest), portal vein velocity, hepatic artery Doppler parameters (peak systolic velocity, end diastolic velocity, resistive index) and serum lipid and alanine aminotransferase (ALT) levels between 16 normal livers and 34 steatotic livers using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) as the reference. On the basis of a two-tailed t-test, differences in SMI-VI, portal vein velocity, MRI-PDFF and ALT between normal (MRI-PDFF <5%) and steatotic (MRI-PDFF ≥5%) livers were statistically significant (p < 0.02), whereas hepatic artery Doppler parameters and triglyceride levels were not (p > 0.05). We observed an inverse correlation of SMI-VI with MRI-PDFF (r = -0.88). With 0.19 as the best cutoff value, the area under the receiver operating characteristic curve, sensitivity and specificity of SMI-VI for determining ≥mild (MRI-PDFF ≥5%) non-alcoholic fatty liver disease (NAFLD) were 0.95, 96% and 94%, respectively. Our results indicate the feasibility of using SMI-VI to assess adult hepatic steatosis. SMI-VI is a potential surrogate marker in the screening for NAFLD.
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Affiliation(s)
- Jing Gao
- Rocky Vista University, Ivins, Utah, USA; Department of Radiology, Weill Cornell Medicine, New York, New York, USA.
| | - Jacob King
- Rocky Vista University, Ivins, Utah, USA
| | - Manjil Chatterji
- Department of Radiology, Weill Cornell Medicine, New York, New York, USA
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Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress. Nutrients 2022; 14:nu14030716. [PMID: 35277075 PMCID: PMC8838100 DOI: 10.3390/nu14030716] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/12/2022] Open
Abstract
Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.
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Wang S, Zeng X, Yang Y, Li S, Wang Y, Ye Q, Fan X. Hypothermic oxygenated perfusion ameliorates ischemia-reperfusion injury of fatty liver in mice via Brg1/Nrf2/HO-1 axis. Artif Organs 2022; 46:229-238. [PMID: 34570898 DOI: 10.1111/aor.14076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 08/05/2021] [Accepted: 09/14/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND After cold storage (CS) and subsequent transplantation, fatty liver is more inclined to develop liver dysfunction and serious postoperative complications in contrast to healthy liver. Hypothermic oxygenated perfusion (HOPE) is a safe and efficacious system, which can repair fatty liver and reduce ischemia-reperfusion injury. The aim of this research is to investigate the function of Brg1/Nrf2/HO-1 signaling pathway in the protective effect of HOPE on ischemia-reperfusion injury of fatty liver. METHODS The mouse fatty liver model was successfully established and verified by hematoxylin-eosin (HE) staining and oil red O staining. The animals were divided into Control group, CS group and HOPE group. The levels of liver enzyme and lactate in the perfusate were used to measure liver function and cellular metabolism. HE staining and TUNEL staining were utilized to assess the tissue structure and apoptosis, respectively. The levels of superoxide dismutase, malondialdehyde and reactive oxygen species in liver tissue were measured to quantitatively analyze the degree of oxidative stress, and the expressions of protein Brg1, Nrf2 and HO-1 were detected by means of the western blot. Double-labeling immunofluorescence was to explore the colocalization of Brg1 and Nrf2. RESULTS The injury of the liver in the CS group was more serious than that in the control group. However, HOPE could significantly reduce the injury, which was manifested by the improvement of liver function and cellular metabolism, and the lower degrees of apoptosis, necrosis and oxidative stress. Furthermore, the expressions of Brg1, Nrf2 and HO-1 in the HOPE group were significantly increased than those in the CS group. CONCLUSIONS One-hour HOPE treatment before reperfusion can obviously improve the injury of fatty liver in mice. The underlying mechanism may be that the interaction of Brg1 and Nrf2 can selectively activate the transcription of HO-1.
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Affiliation(s)
- Shengjie Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Xianpeng Zeng
- Department of Urology, Union Hospital, Affiliated TongJi Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yunying Yang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Shiyi Li
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Yanfeng Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
| | - Qifa Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
- Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha, China
| | - Xiaoli Fan
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China
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van Cooten VV, de Jong DJ, Wessels FJ, de Jong PA, Kok M. Liver Enhancement on Computed Tomography Is Suboptimal in Patients with Liver Steatosis. J Pers Med 2021; 11:1255. [PMID: 34945727 PMCID: PMC8707755 DOI: 10.3390/jpm11121255] [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: 09/22/2021] [Revised: 11/15/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
This study's aim was twofold. Firstly, to assess liver enhancement quantitatively and qualitatively in steatotic livers compared to non-steatotic livers on portal venous computed tomography (CT). Secondly, to determine the injection volume of contrast medium in patients with severe hepatic steatosis to improve the image quality of the portal venous phase. We retrospectively included patients with non-steatotic (n = 70), the control group, and steatotic livers (n = 35) who underwent multiphase computed tomography between March 2016 and September 2020. Liver enhancement was determined by the difference in attenuation in Hounsfield units (HU) between the pre-contrast and the portal venous phase, using region of interests during in three different segments. Liver steatosis was determined by a mean attenuation of ≤40 HU on unenhanced CT. Adequate enhancement was objectively defined as ≥50 ΔHU and subjectively using a three-point Likert scale. Enhancement of non-steatotic and steatotic livers were compared and associations between enhancement and patient- and scan characteristics were analysed. Enhancement was significantly higher among the control group (mean 51.9 ± standard deviation 11.5 HU) compared to the steatosis group (40.6 ± 8.4 HU p for difference < 0.001). Qualitative analysis indicated less adequate enhancement in the steatosis group: 65.7% of the control group was rated as good vs. 8.6% of the steatosis group. We observed a significant correlation between enhancement, and presence/absence of steatosis and grams of iodine per total body weight (TBW) (p < 0.001; adjusted R2 = 0.303). Deduced from this correlation, theoretical contrast dosing in grams of Iodine (g I) can be calculated: g I = 0.502 × TBW for non-steatotic livers and g I = 0.658 × TBW for steatotic livers. Objective and subjective enhancement during CT portal phase were significantly lower in steatotic livers compared to non-steatotic livers, which may have consequences for detectability and contrast dosing.
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Affiliation(s)
| | | | | | | | - Madeleine Kok
- Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (V.V.v.C.); (D.J.d.J.); (F.J.W.); (P.A.d.J.)
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Akkurt G, Birben B, Akçay FK, Altay ÇM, Başkan S, Yildiz BD. Effects of different intraabdominal pressures on internal jugular vein, liver and kidney functions in obese patients undergoing laparoscopic sleeve gastrectomy. Acta Chir Belg 2021; 123:244-250. [PMID: 34474644 DOI: 10.1080/00015458.2021.1976473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE The aim of this study was to investigate whether there was a difference in laparoscopic sleeve gastrectomy (LSG) performed with either 10 mmHg or 13 mmHg intraabdominal pressures. Effects of these pressures on the internal jugular vein (IJV) diameter and flow along with the liver and kidney function tests were evaluated. MATERIALS AND METHODS The patients were divided into two groups with respect to the intraabdominal pressure performed during LSG (either 10 or 13 mmHg). The patients' age, comorbidities, surgical history, height, weight, body mass index, family history, duration of surgery, length of hospital stay, serum liver and kidney function tests (Urea, creatinine, Aspartate transaminase, Alanine transaminase, Gamma-glutamyltransferase, Alkaline phosphatase, bilirubin) and the right IJV diameter and flow measured by Duplex ultrasound before intubation (t1), 10 min after insufflation (t2), and at the end of insufflation (t3) were recorded. RESULTS Preoperative and postoperative kidney and liver function values of the patients in both groups were within the reference range. In both groups, there was a significant decrease in the IJV diameter and flow measurement values at t2 compared to t1, and a significant increase was observed at t3 compared to t2 (p < 0.05). The mean IJV diameter and flow were significantly higher in the 10 mmHg pressure group compared to the 13 mmHg group (p < 0.05). CONCLUSION Neither of the peak pressures performed intraabdominal during LSG caused an adverse effect on liver or kidney functions. Our study emphasizes that low insufflation pressure does not have an advantage in terms of liver and kidney functions. But laparoscopic sleeve gastrectomy with low intra-abdominal pressure may be beneficial especially in patients who require central vein catheterization during the operation. We consider that LSG performed with CO2 pneumoperitoneum at 10 mmHg is a safe, effective and feasible method that can facilitate the insertion of the intraoperative central venous catheter due to lesser charges in the IJV diameter and flow compared to the standard technique.
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Affiliation(s)
- Gökhan Akkurt
- Surgical Oncology Department, Ankara City Hospital, Ankara, Turkey
| | - Birkan Birben
- General Surgery Department, Ankara City Hospital, Ankara, Turkey
| | | | - Çetin Murat Altay
- Radiology Department, Dr. Ersin Arslan Research and Training Hospital, Gaziantep, Turkey
| | - Semih Başkan
- Anesthesiology and Reanimation Department, Ankara City Hospital, Ankara, Turkey
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Große-Segerath L, Lammert E. Role of vasodilation in liver regeneration and health. Biol Chem 2021; 402:1009-1019. [PMID: 33908220 DOI: 10.1515/hsz-2021-0155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
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Affiliation(s)
- Linda Große-Segerath
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
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Goddi A, Schroedl L, Brey EM, Cohen RN. Laminins in metabolic tissues. Metabolism 2021; 120:154775. [PMID: 33857525 DOI: 10.1016/j.metabol.2021.154775] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/13/2021] [Accepted: 04/08/2021] [Indexed: 12/16/2022]
Abstract
Laminins are extracellular matrix proteins that reside in the basement membrane and provide structural support in addition to promoting cellular adhesion and migration. Through interactions with cell surface receptors, laminins stimulate intracellular signaling cascades which direct specific survival and differentiation outcomes. In metabolic tissues such as the pancreas, adipose, muscle, and liver, laminin isoforms are expressed in discrete temporal and spatial patterns suggesting that certain isoforms may support the development and function of particular metabolic cell types. This review focuses on the research to date detailing the expression of laminin isoforms, their potential function, as well as known pathways involved in laminin signaling in metabolic tissues. We will also discuss the current biomedical therapies involving laminins in these tissues in addition to prospective applications, with the goal being to encourage future investigation of laminins in the context of metabolic disease.
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Affiliation(s)
- Anna Goddi
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, 900 East 57th St, Chicago, IL 60637, USA
| | - Liesl Schroedl
- Pritzker School of Medicine, The University of Chicago, 924 E 57th St, Chicago, IL 60637, USA
| | - Eric M Brey
- Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
| | - Ronald N Cohen
- Committee on Molecular Metabolism and Nutrition, The University of Chicago, 900 East 57th St, Chicago, IL 60637, USA; Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 South Maryland Ave, Chicago, IL 60637, USA.
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40
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AlSaad AMS, Alasmari F, Abuohashish HM, Mohany M, Ahmed MM, Al-Rejaie SS. Renin angiotensin system blockage by losartan neutralize hypercholesterolemia-induced inflammatory and oxidative injuries. Redox Rep 2021; 25:51-58. [PMID: 32396454 PMCID: PMC7269056 DOI: 10.1080/13510002.2020.1763714] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Objectives: This study explores the protective role of losartan (LT) against oxidative and inflammatory damages in different physiological systems including heart, liver, and kidney tissue in hypercholesterolemic rats. Methods: After induction of hypercholesterolemia by high cholesterol diet for 6 weeks, LT was administered for 4 weeks. In serum, the levels of lipoproteins, aminotransferases, creatine kinases, urea, apoptosis, and inflammatory markers were measured. In cardiac, hepatic, and renal tissues, lipid peroxidation product and GSH as well as antioxidant enzymatic activities were assayed. Finally, histopathological assessment evaluated the structural damage in cardiac, hepatic, and renal tissues. Results: Serum markers of cardiac, hepatic, and renal toxicities including creatine kinases, aminotransferases, and urea were attenuated by LT in hypercholesterolemic animals. Moreover, LT markedly corrected the elevated levels of lipoproteins, apoptosis, and inflammatory biomarkers. Hypercholesterolemia-induced lipid peroxidation, low GSH levels, and diminished activities of antioxidant enzymes were prominently improved in LT treated animals. Histopathological alterations by hypercholesterolemia in heart, liver, and kidney tissues were ameliorated by LT. Conclusion: This study confirmed the pathological enrollment of renin–angiotensin system in hypercholesterolemia-associated metabolic alterations. LT had a significant cardiac, hepatic, and renal protective role against these impairments through down-regulation of oxidative damage, inflammation and necrosis.
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Affiliation(s)
- Abdulaziz M S AlSaad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hatem M Abuohashish
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohamed Mohany
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed M Ahmed
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Salim S Al-Rejaie
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Luo C, Lü D, Zheng L, Zhang F, Zhang X, Lü S, Zhang C, Jia X, Shu X, Li P, Li Z, Long M. Hepatic differentiation of human embryonic stem cells by coupling substrate stiffness and microtopography. Biomater Sci 2021; 9:3776-3790. [PMID: 33876166 DOI: 10.1039/d1bm00174d] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mechanical or physical cues are associated with the growth and differentiation of embryonic stem cells (ESCs). While the substrate stiffness or topography independently affects the differentiation of ESCs, their cooperative regulation on lineage-specific differentiation remains largely unknown. Here, four topographical configurations on stiff or soft polyacrylamide hydrogel were combined to direct hepatic differentiation of human H1 cells via a four-stage protocol, and the coupled impacts of stiffness and topography were quantified at distinct stages. Data indicated that the substrate stiffness is dominant in stemness maintenance on stiff gel and hepatic differentiation on soft gel while substrate topography assists the differentiation of hepatocyte-like cells in positive correlation with the circularity of H1 clones initially formed on the substrate. The differentiated cells exhibited liver-specific functions such as maintaining the capacities of CYP450 metabolism, glycogen synthesis, ICG engulfment, and repairing liver injury in CCl4-treated mice. These results implied that the coupling of substrate stiffness and topography, combined with the biochemical signals, is favorable to improve the efficiency and functionality of hepatic differentiation of human ESCs.
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Affiliation(s)
- Chunhua Luo
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
| | - Dongyuan Lü
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lu Zheng
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fan Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiao Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shouqin Lü
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chen Zhang
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
| | - Xiaohua Jia
- CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Xinyu Shu
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiwen Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
| | - Zhan Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China.
| | - Mian Long
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Science, University of Chinese Academy of Sciences, Beijing 100049, China
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Oldenburger A, Birk G, Schlepütz M, Broermann A, Stierstorfer B, Pullen SS, Rippmann JF. Modulation of vascular contraction via soluble guanylate cyclase signaling in a novel ex vivo method using rat precision-cut liver slices. Pharmacol Res Perspect 2021; 9:e00768. [PMID: 34014044 PMCID: PMC8135082 DOI: 10.1002/prp2.768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 01/05/2023] Open
Abstract
Fibrotic processes in the liver of non-alcoholic steatohepatitis (NASH) patients cause microcirculatory dysfunction in the organ which increases blood vessel resistance and causes portal hypertension. Assessing blood vessel function in the liver is challenging, necessitating the development of novel methods in normal and fibrotic tissue that allow for drug screening and translation toward pre-clinical settings. Cultures of precision cut liver slices (PCLS) from normal and fibrotic rat livers were used for blood vessel function analysis. Live recording of vessel diameter was used to assess the response to endothelin-1, serotonin and soluble guanylate cyclase (sGC) activation. A cascade of contraction and relaxation events in response to serotonin, endothelin-1, Ketanserin and sGC activity could be established using vessel diameter analysis of rat PCLS. Both the sGC activator BI 703704 and the sGC stimulator Riociguat prevented serotonin-induced contraction in PCLS from naive rats. By contrast, PCLS cultures from the rat CCl4 NASH model were only responsive to the sGC activator, thus establishing that the sGC enzyme is rendered non-responsive to nitric oxide under oxidative stress found in fibrotic livers. The role of the sGC pathway for vessel relaxation of fibrotic liver tissue was identified in our model. The obtained data shows that the inhibitory capacities on vessel contraction of sGC compounds can be translated to published preclinical data. Altogether, this novel ex vivo PCLS method allows for the differentiation of drug candidates and the translation of therapeutic approaches towards the clinical use.
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Affiliation(s)
- Anouk Oldenburger
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
| | - Gerald Birk
- Target Discovery SciencesBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Marco Schlepütz
- Immunology and Respiratory Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Andre Broermann
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
| | - Birgit Stierstorfer
- Target Discovery SciencesBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Steven S. Pullen
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharmaceuticals, IncRidgefieldCTUSA
| | - Jörg F. Rippmann
- Cancer Immunology+Immune ModulationBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
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Wáng YXJ. Observed paradoxical perfusion fraction elevation in steatotic liver: An example of intravoxel incoherent motion modeling of the perfusion component constrained by the diffusion component. NMR IN BIOMEDICINE 2021; 34:e4488. [PMID: 33559161 DOI: 10.1002/nbm.4488] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/20/2021] [Accepted: 01/24/2021] [Indexed: 06/12/2023]
Affiliation(s)
- Yì Xiáng J Wáng
- Department of Imaging and Interventional Radiology, Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong SAR
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44
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Role of Angiogenesis in the Pathogenesis of NAFLD. J Clin Med 2021; 10:jcm10071338. [PMID: 33804956 PMCID: PMC8037441 DOI: 10.3390/jcm10071338] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.
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Lupsor-Platon M, Serban T, Silion AI, Tirpe GR, Tirpe A, Florea M. Performance of Ultrasound Techniques and the Potential of Artificial Intelligence in the Evaluation of Hepatocellular Carcinoma and Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2021; 13:790. [PMID: 33672827 PMCID: PMC7918928 DOI: 10.3390/cancers13040790] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/14/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Global statistics show an increasing percentage of patients that develop non-alcoholic fatty liver disease (NAFLD) and NAFLD-related hepatocellular carcinoma (HCC), even in the absence of cirrhosis. In the present review, we analyzed the diagnostic performance of ultrasonography (US) in the non-invasive evaluation of NAFLD and NAFLD-related HCC, as well as possibilities of optimizing US diagnosis with the help of artificial intelligence (AI) assistance. To date, US is the first-line examination recommended in the screening of patients with clinical suspicion of NAFLD, as it is readily available and leads to a better disease-specific surveillance. However, the conventional US presents limitations that significantly hamper its applicability in quantifying NAFLD and accurately characterizing a given focal liver lesion (FLL). Ultrasound contrast agents (UCAs) are an essential add-on to the conventional B-mode US and to the Doppler US that further empower this method, allowing the evaluation of the enhancement properties and the vascular architecture of FLLs, in comparison to the background parenchyma. The current paper also explores the new universe of AI and the various implications of deep learning algorithms in the evaluation of NAFLD and NAFLD-related HCC through US methods, concluding that it could potentially be a game changer for patient care.
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Affiliation(s)
- Monica Lupsor-Platon
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Teodora Serban
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania; (T.S.); (A.I.S.)
| | - Alexandra Iulia Silion
- Medical Imaging Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania; (T.S.); (A.I.S.)
| | - George Razvan Tirpe
- County Emergency Hospital Cluj-Napoca, 3-5 Clinicilor Street, 400000 Cluj-Napoca, Romania;
| | - Alexandru Tirpe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337 Cluj-Napoca, Romania;
| | - Mira Florea
- Community Medicine Department, Iuliu Hatieganu University of Medicine and Pharmacy, 400001 Cluj-Napoca, Romania;
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Basavarajappa L, Baek J, Reddy S, Song J, Tai H, Rijal G, Parker KJ, Hoyt K. Multiparametric ultrasound imaging for the assessment of normal versus steatotic livers. Sci Rep 2021; 11:2655. [PMID: 33514796 PMCID: PMC7846566 DOI: 10.1038/s41598-021-82153-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/15/2021] [Indexed: 12/13/2022] Open
Abstract
Liver disease is increasing in prevalence across the globe. We present here a multiparametric ultrasound (mpUS) imaging approach for assessing nonalcoholic fatty liver disease (NALFD). This study was performed using rats (N = 21) that were fed either a control or methionine and choline deficient (MCD) diet. A mpUS imaging approach that includes H-scan ultrasound (US), shear wave elastography, and contrast-enhanced US measurements were then performed at 0 (baseline), 2, and 6 weeks. Thereafter, animals were euthanized and livers excised for histological processing. A support vector machine (SVM) was used to find a decision plane that classifies normal and fatty liver conditions. In vivo mpUS results from control and MCD diet fed animals reveal that all mpUS measures were different at week 6 (P < 0.05). Principal component analysis (PCA) showed that the H-scan US data contributed the highest percentage to the classification among the mpUS measurements. The SVM resulted in 100% accuracy for classification of normal and high fat livers and 92% accuracy for classification of normal, low fat, and high fat livers. Histology findings found considerable steatosis in the MCD diet fed animals. This study suggests that mpUS examinations have the potential to provide a comprehensive estimation of the main components of early stage NAFLD.
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Affiliation(s)
- Lokesh Basavarajappa
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Jihye Baek
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA
| | - Shreya Reddy
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Jane Song
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA
| | - Haowei Tai
- Department of Electrical and Computer Engineering, University of Texas at Dallas, Richardson, TX, USA
| | - Girdhari Rijal
- Department of Medical Laboratory Sciences, Tarleton State University, Forth Worth, TX, USA
| | - Kevin J Parker
- Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA
| | - Kenneth Hoyt
- Department of Bioengineering, University of Texas at Dallas, BSB 13.929, 800 W Campbell Rd, Richardson, TX, 75080, USA. .,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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47
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Li Z, Lee SH, Jeong HJ, Kang HE. Pharmacokinetic changes of clozapine and norclozapine in a rat model of non-alcoholic fatty liver disease induced by orotic acid. Xenobiotica 2020; 51:324-334. [PMID: 33185134 DOI: 10.1080/00498254.2020.1851070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Impaired in vitro oxidation of clozapine has been reported in steatotic rat liver due to downregulation of cytochrome P450 (CYP) 1A. Pharmacokinetic changes of clozapine and its major metabolite, norclozapine, were evaluated in a rat model of non-alcoholic fatty liver disease (NAFLD) induced by orotic acid. Significantly slower in vitro CLint for formation of norclozapine from clozapine was observed in NAFLD rats than in control rats as a result of the reduced protein expression and metabolic activity of CYP1A1/2. However, systemic exposures to clozapine in NAFLD rats were comparable to those in controls after intravenous (4 mg/kg) and oral (10 mg/kg) administration of clozapine. Of note, the AUC of the norclozapine and AUCnorclozapine/AUCclozapine ratio following intravenous and oral administration of clozapine rather increased significantly in NAFLD rats, as a result of the slowed subsequent metabolism of norclozapine via CYP1A1/2. Steady-state brain concentrations of both clozapine and norclozapine were significantly higher in NAFLD rats than those in control rats following intravenous infusion of clozapine. Increased systemic exposure to norclozapine and elevated brain concentrations of clozapine and norclozapine observed in NAFLD rats imply that further studies are warranted on the pharmacotherapy of clozapine in patients with pre-existing or drug-induced hepatic steatosis.
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Affiliation(s)
- Zhengri Li
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
| | - Song Hee Lee
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
| | - Hee Jin Jeong
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
| | - Hee Eun Kang
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea
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48
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Ding Q, Zhou Y, Zhang S, Liang M. Association between hemoglobin levels and non-alcoholic fatty liver disease in patients with young-onset type 2 diabetes mellitus. Endocr J 2020; 67:1139-1146. [PMID: 32684526 DOI: 10.1507/endocrj.ej20-0071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This retrospective study aimed to investigate the relationship between hemoglobin (Hb) levels and non-alcoholic fatty liver disease (NAFLD) in patients with young-onset type 2 diabetes mellitus (T2DM). Data were collected for 296 patients with young-onset T2DM admitted to the first Affiliated Hospital of Guangxi Medical University from May 2017 to January 2020. Subjects were divided into NAFLD (n = 186) and non-NAFLD groups (n = 110). Patients with NAFLD had significantly higher Hb levels (p = 0.001). According to logistic regression analysis, Hb levels were significantly correlated with NAFLD after adjusting for confounding factors [odds ratio (OR) = 1.024, 95% confidence interval = 1.003-1.046, p = 0.028]. Subjects were also grouped according to Hb quartiles. After adjusting for sex and body mass index (BMI), the OR (95%CI) for NAFLD significantly increased with increasing Hb levels (p for trend = 0.009). Patients were also divided into lean (BMI <25 kg/m2, n = 139) and overweight/obese groups (BMI ≥25 kg/m2, n = 157), with adjusted ORs (95%CI) for the highest quartiles of 1.797 (0.559-5.776) and 6.009 (1.328-27.181), respectively. Further quartile classification of Hb according to sex showed adjusted OR (95%CI) for the highest compared with the lowest quartile of 2.796 (1.148-6.814) for males and 2.945 (0.482-17.997) for females. In conclusion, high Hb levels were associated with the presence of NAFLD in patients with young-onset T2DM, especially in males and overweight/obese patients.
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Affiliation(s)
- Qinpei Ding
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yubo Zhou
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Shu Zhang
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Min Liang
- Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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49
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Barberá A, Raurell I, García-Lezana T, Torres-Arauz M, Bravo M, Hide D, Gil M, Salcedo MT, Genescà J, Martell M, Augustin S. Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model. Liver Int 2020; 40:2732-2743. [PMID: 32770818 DOI: 10.1111/liv.14632] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/10/2020] [Accepted: 08/02/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Portal hypertension (PH) can be present in pre-cirrhotic stages, even in absence of fibrosis in non-alcoholic steatohepatitis (NASH) patients. Liver endothelial dysfunction (ED) has been shown as responsible for this effect in short-term dietary animal models. We evaluated the persistence of PH and underlying mechanisms in a long-term rat model of NASH. METHODS Sprague-Dawley rats were fed 8 or 36 weeks with control diet or high-fat high-glucose/fructose diet. Metabolic parameters, histology, ED and haemodynamics were characterized. Structural characteristics of liver sections were analysed using image analysis. RESULTS Both interventions reproduced NASH histological hallmarks (with steatosis being particularly increased at 36 weeks), but neither induced fibrosis. The 36-week intervention induced a significant increase in portal pressure (PP) compared to controls (12.1 vs 8.7 mmHg, P < .001) and the 8-week model (10.7 mmHg, P = .006), but all features of ED were normalized at 36 weeks. Image analysis revealed that the increased steatosis at 36-week was associated to an increase in hepatocyte area and a significant decrease in the sinusoidal area, which was inversely correlated with PP. The analysis provided a critical sinusoidal area above which animals were protected from developing PH and below which sinusoidal flux was compromised and PP started to increase. CONCLUSION Liver steatosis per se (in absence of fibrosis) can induce PH through a decrease in the sinusoidal area secondary to the increase in hepatocyte area in a long-term diet-induced rat model of NASH. Image analysis of the sinusoidal area might predict the presence of PH.
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Affiliation(s)
- Aurora Barberá
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | - Imma Raurell
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | | | - Manuel Torres-Arauz
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | - Miren Bravo
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | - Diana Hide
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | - Mar Gil
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain
| | - María Teresa Salcedo
- Pathology Department, Hospital Universitari Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Joan Genescà
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain.,Centro De Investigación Biomédica En Red De Enfermedades Hepáticas y Digestivas, Instituto De Salud Carlos III, Madrid, Spain
| | - María Martell
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain.,Centro De Investigación Biomédica En Red De Enfermedades Hepáticas y Digestivas, Instituto De Salud Carlos III, Madrid, Spain
| | - Salvador Augustin
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain, Barcelona, Spain.,Centro De Investigación Biomédica En Red De Enfermedades Hepáticas y Digestivas, Instituto De Salud Carlos III, Madrid, Spain
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50
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Keller SB, Suo D, Wang YN, Kenerson H, Yeung RS, Averkiou MA. Image-Guided Treatment of Primary Liver Cancer in Mice Leads to Vascular Disruption and Increased Drug Penetration. Front Pharmacol 2020; 11:584344. [PMID: 33101038 PMCID: PMC7554611 DOI: 10.3389/fphar.2020.584344] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
Despite advances in interventional procedures and chemotherapeutic drug development, hepatocellular carcinoma (HCC) is still the fourth leading cause of cancer-related deaths worldwide with a <30% 5-year survival rate. This poor prognosis can be attributed to the fact that HCC most commonly occurs in patients with pre-existing liver conditions, rendering many treatment options too aggressive. Patient survival rates could be improved by a more targeted approach. Ultrasound-induced cavitation can provide a means for overcoming traditional barriers defining drug uptake. The goal of this work was to evaluate preclinical efficacy of image-guided, cavitation-enabled drug delivery with a clinical ultrasound scanner. To this end, ultrasound conditions (unique from those used in imaging) were designed and implemented on a Philips EPIQ and S5-1 phased array probe to produced focused ultrasound for cavitation treatment. Sonovue® microbubbles which are clinically approved as an ultrasound contrast agent were used for both imaging and cavitation treatment. A genetically engineered mouse model was bred and used as a physiologically relevant preclinical analog to human HCC. It was observed that image-guided and targeted microbubble cavitation resulted in selective disruption of the tumor blood flow and enhanced doxorubicin uptake and penetration. Histology results indicate that no gross morphological damage occurred as a result of this process. The combination of these effects may be exploited to treat HCC and other challenging malignancies and could be implemented with currently available ultrasound scanners and reagents.
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Affiliation(s)
- Sara B Keller
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Dingjie Suo
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Yak-Nam Wang
- Applied Physics Laboratory, University of Washington, Seattle, WA, United States
| | - Heidi Kenerson
- Department of Surgery, University of Washington, Seattle, WA, United States
| | - Raymond S Yeung
- Department of Surgery, University of Washington, Seattle, WA, United States
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