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Accacha S, Barillas-Cerritos J, Srivastava A, Ross F, Drewes W, Gulkarov S, De Leon J, Reiss AB. From Childhood Obesity to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Hyperlipidemia Through Oxidative Stress During Childhood. Metabolites 2025; 15:287. [PMID: 40422865 DOI: 10.3390/metabo15050287] [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: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND/OBJECTIVES Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia. METHODS This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers. RESULTS Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD. CONCLUSIONS Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels.
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Affiliation(s)
- Siham Accacha
- Department of Pediatrics, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Julia Barillas-Cerritos
- Department of Pediatrics, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Ankita Srivastava
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Frances Ross
- Department of Pediatrics, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Wendy Drewes
- Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Shelly Gulkarov
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Joshua De Leon
- Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
| | - Allison B Reiss
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
- Department of Medicine, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA
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Emmanuel OP, Sandrine MNY, Claude BD, Ronald BAG, Vicky AM, Désiré DDP, Pierre K, Aziz T, Alamri AS, Alsanie WF, Alhomrani M. Exploring the Effects of Pterocarpus Soyauxii Against Menopause-Related NAFLD Based on Network Pharmacology, Molecular Docking, and Experimental Validation. Chem Biodivers 2025:e202403384. [PMID: 39964816 DOI: 10.1002/cbdv.202403384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/12/2025] [Accepted: 02/18/2025] [Indexed: 02/20/2025]
Abstract
Pterocarpus soyauxii (P. soyauxii) is a Fabaceae family traditionally used to treat menopausal disorders. This study aims to investigate the effect of P. soyauxii on menopause-related non-alcoholic fatty liver disease (NAFLD) and to determine its mechanisms of action and signaling pathways. The pharmacokinetic and dynamic properties and the toxicological profile of P. soyauxii compounds were assessed using the SwissADME and Protox III databases. A pharmacology network was constructed to identify active compound targets and corresponding genes. Compound target and protein-protein interaction networks were created using Cytoscape software. Molecular docking studies were conducted to assess the binding affinity of P. soyauxii compounds with specific proteins. In vitro experiments evaluated the antioxidant properties of P. soyauxii. In vivo studies using ovariectomized (Ovx) rat models underlined pathways and effects of P. soyauxii on biochemical and histological features linked with NAFLD. Findings suggest that P. soyauxii compounds are readily absorbed through the intestine and exhibit a relatively low level of toxicity. Protein-protein interaction, compound-target networks, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed several pathways and target proteins of P. soyauxii compounds. Indeed, they target specific proteins such as estrogen receptor alpha/beta ERα/β, nicotinamide adenine dinucleotide phosphate oxidase (NADPH-O), epidermal growth factor receptor (EGFR), MAPK1, peroxisome proliferator-activated receptors alpha/gamma (PPARα/G), and HMG-CoA reductase. Molecular docking revealed that P. soyauxii compounds demonstrate high binding affinity to various proteins. In vitro, P. soyauxii inhibits the oxidative power of OH, H2O2, and NO. In vivo, P. soyauxii significantly (p < 0.01, p < 0.001, and p < 0.01, respectively) reduces ALAT (25.14%), hepatic cholesterol (15.27%), and malondialdehyde (MDA) (26.78%) levels at 200 mg/kg and prevents steatosis in the liver. These findings suggest that P. soyauxii may have a protective role against menopause-related NAFLD.
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Affiliation(s)
- Owona Pascal Emmanuel
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Mengue Ngadena Yolande Sandrine
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
- Neurosciences and Psychogerontology Axis, Laboratory of Development and Maldevelopment, Department of Psychology, Faculty of Arts, Letters, and Social Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Bilanda Danielle Claude
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Bidingha A Goufani Ronald
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Ama Moor Vicky
- Faculty of Medicine and Biomedical Sciences, Clinical Biochemistry Laboratory, University Hospital Centre, Yaoundé, Cameroon
| | - Dzeufiet Djomeni Paul Désiré
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Kamtchouing Pierre
- Department of Animal Biology and Physiology Laboratory of Animal Physiology, Faculty of Science, University of Yaoundé 1, Yaoundé, Cameroon
| | - Tariq Aziz
- Laboratory of Animal Health Food Hygiene and Quality, University of Ioannina, Arta, Greece
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan
| | - Abdulhakeem S Alamri
- Department of Clinical Laboratory Sciences, The faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Walaa F Alsanie
- Department of Clinical Laboratory Sciences, The faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Majid Alhomrani
- Department of Clinical Laboratory Sciences, The faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
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Kim JJ, Kurial SNT, Choksi PK, Nunez M, Lunow-Luke T, Bartel J, Driscoll J, Her CL, Dhillon S, Yue W, Murti A, Mao T, Ramos JN, Tiyaboonchai A, Grompe M, Mattis AN, Syed SM, Wang BM, Maher JJ, Roll GR, Willenbring H. AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion. Nat Biotechnol 2025:10.1038/s41587-024-02523-6. [PMID: 39881029 DOI: 10.1038/s41587-024-02523-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 12/02/2024] [Indexed: 01/31/2025]
Abstract
Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.
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Affiliation(s)
- Jae-Jun Kim
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Simone N T Kurial
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Pervinder K Choksi
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA, USA
| | - Miguel Nunez
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Tyler Lunow-Luke
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- School of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Jan Bartel
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Julia Driscoll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Chris L Her
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Pliant Therapeutics, South San Francisco, CA, USA
| | - Simaron Dhillon
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Stone Research Foundation, San Francisco, CA, USA
| | - William Yue
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Abhishek Murti
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Tin Mao
- Ambys Medicines, South San Francisco, CA, USA
- Genentech, South San Francisco, CA, USA
| | - Julian N Ramos
- Ambys Medicines, South San Francisco, CA, USA
- Adverum Biotechnologies, Redwood City, CA, USA
| | - Amita Tiyaboonchai
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
| | - Markus Grompe
- Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | - Aras N Mattis
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Shareef M Syed
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Bruce M Wang
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jacquelyn J Maher
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Garrett R Roll
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Holger Willenbring
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
- Liver Center, University of California, San Francisco, San Francisco, CA, USA.
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Cammisotto V, Valeriani E, Pignatelli P, Violi F. Nicotinamide Adenine Dinucleotide Phosphate Oxidases and Metabolic Dysfunction-Associated Steatotic Liver Disease. Antioxidants (Basel) 2025; 14:83. [PMID: 39857417 PMCID: PMC11763266 DOI: 10.3390/antiox14010083] [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: 11/08/2024] [Revised: 01/01/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD-MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD.
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Affiliation(s)
- Vittoria Cammisotto
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Emanuele Valeriani
- Department of General Surgery and Surgical Specialty, Sapienza University of Rome, 00185 Rome, Italy
- Department of Infectious Disease, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Francesco Violi
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
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Haewphet T, Parhira S, Chaisupasakul P, Wangteeraprasert A, Phoungpetchara I, Pekthong D, Kaewkong W, Jiang ZH, Bai LP, Somran J, Srisawang P. The dichloromethane fraction from Calotropis gigantea (L.) dryand. Stem bark extract prevents liver cancer in SDT rats with insulin-independent diabetes mellitus. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118516. [PMID: 38971341 DOI: 10.1016/j.jep.2024.118516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/19/2024] [Accepted: 07/01/2024] [Indexed: 07/08/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Calotropis gigantea (L.) Dryand. (C. gigantea) is a traditional medicinal plant, recognized for its effectiveness in managing diabetes, along with its notable antioxidant, anti-inflammatory, and anticancer properties. Type II diabetes mellitus (T2DM) is characterized by chronic metabolic disorders associated with an elevated risk of hepatocellular carcinoma (HCC) due to hyperglycemia and impaired insulin response. The scientific validation of C. gigantea's ethnopharmacological efficacy offers advantages in alleviating cancer progression in T2DM complications, enriching existing knowledge and potentially aiding future clinical cancer treatments. AIM This study aimed to investigate the preventive potential of the dichloromethane fraction of C. gigantea stem bark extract (CGDCM) against diethylnitrosamine (DEN)-induced HCC in T2DM rats, aiming to reduce cancer incidence associated with diabetes while validating C. gigantea's ethnopharmacological efficacy. MATERIALS AND METHODS Spontaneously Diabetic Torii (SDT) rats were administered DEN to induce HCC (SDT-DEN-VEH), followed by treatment with CGDCM. Metformin was used as a positive control (SDT-DEN-MET). All the treatments were administered for 10 weeks after the initial DEN injection. Diabetes-related parameters, including serum levels of glucose, insulin, and glycosylated hemoglobin (HbA1c), as well as liver function enzymes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase), were quantified. Serum inflammation biomarkers interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Liver tissue samples were analyzed for inflammation protein expression (IL-6, TNF-α, transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA)). Histopathological evaluation was performed to assess hepatic necrosis, inflammation, and fibrosis. Liver cell proliferation was determined using immunohistochemistry for Ki-67 expression. RESULTS Rats with SDT-DEN-induced HCC treated with CGDCM exhibited reduced serum glucose levels, elevated insulin levels, and decreased HbA1c levels. CGDCM treatment also reduced elevated hepatic IL-6, TNF-α, TGF-β1, and α-SMA levels in SDT-DEN-VEH rats. Additionally, CGDCM treatment prevented hepatocyte damage, fibrosis, and cell proliferation. No adverse effects on normal organs were observed with CGDCM treatment, suggesting its safety for the treatment of HCC complications associated with diabetes. Additionally, the absence of adverse effects in SD rats treated with CGDCM at 2.5 mg/kg further supports the notion of its safe usage. CONCLUSIONS These findings suggest that C. gigantea stem bark extract exerts preventive effects against the development of HCC complications in patients with T2DM, expanding the potential benefits of its ethnopharmacological advantages.
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Affiliation(s)
- Thaiyawat Haewphet
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Supawadee Parhira
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand; Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence for Environmental Health and Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Pattaraporn Chaisupasakul
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand.
| | | | - Ittipon Phoungpetchara
- Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Dumrongsak Pekthong
- Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence for Environmental Health and Toxicology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand; Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Worasak Kaewkong
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Zhi-Hong Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, China.
| | - Li-Ping Bai
- State Key Laboratory of Quality Research in Chinese Medicine, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, China.
| | - Julintorn Somran
- Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Piyarat Srisawang
- Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand; Center of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand.
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Zhang M, Zhao W, Zhang Z, He M, Zhang Y, Song B, Liu J, Zhang H. FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c. BMC Endocr Disord 2024; 24:164. [PMID: 39210356 PMCID: PMC11360499 DOI: 10.1186/s12902-024-01705-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice. METHODS KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected. RESULTS Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue. CONCLUSION Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.
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Affiliation(s)
- Mengshu Zhang
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Wanwan Zhao
- Department of Nephrology, The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhen Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mengting He
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ya Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Bing Song
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jinlei Liu
- The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
| | - Haoqiang Zhang
- Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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Wang L, Gong WH. Predictive model using four ferroptosis-related genes accurately predicts gastric cancer prognosis. World J Gastrointest Oncol 2024; 16:2018-2037. [PMID: 38764813 PMCID: PMC11099433 DOI: 10.4251/wjgo.v16.i5.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/31/2024] [Accepted: 03/08/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis. AIM To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability. METHODS Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator-Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues. RESULTS Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner. CONCLUSION In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.
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Affiliation(s)
- Li Wang
- Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Hua Gong
- Department of Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
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Amadio P, Sandrini L, Zarà M, Barbieri SS, Ieraci A. NADPH-oxidases as potential pharmacological targets for thrombosis and depression comorbidity. Redox Biol 2024; 70:103060. [PMID: 38310682 PMCID: PMC10848036 DOI: 10.1016/j.redox.2024.103060] [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: 12/08/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/06/2024] Open
Abstract
There is a complex interrelationship between the nervous system and the cardiovascular system. Comorbidities of cardiovascular diseases (CVD) with mental disorders, and vice versa, are prevalent. Adults with mental disorders such as anxiety and depression have a higher risk of developing CVD, and people with CVD have an increased risk of being diagnosed with mental disorders. Oxidative stress is one of the many pathways associated with the pathophysiology of brain and cardiovascular disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is one of the major generators of reactive oxygen species (ROS) in mammalian cells, as it is the enzyme that specifically produces superoxide. This review summarizes recent findings on the consequences of NOX activation in thrombosis and depression. It also discusses the therapeutic effects and pharmacological strategies of NOX inhibitors in CVD and brain disorders. A better comprehension of these processes could facilitate the development of new therapeutic approaches for the prevention and treatment of the comorbidity of thrombosis and depression.
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Affiliation(s)
- Patrizia Amadio
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Leonardo Sandrini
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Marta Zarà
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Silvia S Barbieri
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy.
| | - Alessandro Ieraci
- Department of Theoretical and Applied Sciences, eCampus University, 22060, Novedrate (CO), Italy; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.
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9
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Mao J, Tan L, Tian C, Wang W, Zhang H, Zhu Z, Li Y. Research progress on rodent models and its mechanisms of liver injury. Life Sci 2024; 337:122343. [PMID: 38104860 DOI: 10.1016/j.lfs.2023.122343] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The liver is the most important organ for biological transformation in the body and is crucial for maintaining the body's vital activities. Liver injury is a serious pathological condition that is commonly found in many liver diseases. It has a high incidence rate, is difficult to cure, and is prone to recurrence. Liver injury can cause serious harm to the body, ranging from mild to severe fatty liver disease. If the condition continues to worsen, it can lead to liver fibrosis and cirrhosis, ultimately resulting in liver failure or liver cancer, which can seriously endanger human life and health. Therefore, establishing an rodent model that mimics the pathogenesis and severity of clinical liver injury is of great significance for better understanding the pathogenesis of liver injury patients and developing more effective clinical treatment methods. The author of this article summarizes common chemical liver injury models, immune liver injury models, alcoholic liver injury models, drug-induced liver injury models, and systematically elaborates on the modeling methods, mechanisms of action, pathways of action, and advantages or disadvantages of each type of model. The aim of this study is to establish reliable rodent models for researchers to use in exploring anti-liver injury and hepatoprotective drugs. By creating more accurate theoretical frameworks, we hope to provide new insights into the treatment of clinical liver injury diseases.
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Affiliation(s)
- Jingxin Mao
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Cheng Tian
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Wenxiang Wang
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Hao Zhang
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Zhaojing Zhu
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China
| | - Yan Li
- Chongqing Medical and Pharmaceutical College, Chongqing 400030, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing 400030, China.
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10
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LeFort KR, Rungratanawanich W, Song BJ. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction. Cell Mol Life Sci 2024; 81:34. [PMID: 38214802 PMCID: PMC10786752 DOI: 10.1007/s00018-023-05061-7] [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: 09/08/2023] [Revised: 11/16/2023] [Accepted: 11/22/2023] [Indexed: 01/13/2024]
Abstract
This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.
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Affiliation(s)
- Karli R LeFort
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
| | - Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
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11
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Pansa CC, Molica LR, de Oliveira Júnior FC, Santello LC, Moraes KCM. Cellular and molecular effects of fipronil in lipid metabolism of HepG2 and its possible connection to non-alcoholic fatty liver disease. J Biochem Mol Toxicol 2024; 38:e23595. [PMID: 38050659 DOI: 10.1002/jbt.23595] [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: 02/10/2023] [Revised: 11/05/2023] [Accepted: 11/20/2023] [Indexed: 12/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global public health problem that affects more than a quarter of the population. The development of this disease is correlated with metabolic dysfunctions that lead to lipid accumulation in the liver. Pesticides are one of etiologies that support NAFLD establishment. Therefore, the effects of the insecticide fipronil on the lipid metabolism of the human hepatic cell line, HepG2, was investigated, considering its widespread use in field crops and even to control domestic pests. To address the goals of the study, biochemical, cellular, and molecular analyses of different concentrations of fipronil in cell cultures were investigated, after 24 h of incubation. Relevant metabolites such as triglycerides, glucose levels, β-oxidation processes, and gene expression of relevant elements correlated with lipid and metabolism of xenobiotics were investigated. The results suggested that at 20 μM, the pesticide increased the accumulation of triglycerides and neutral lipids by reducing fatty acid oxidation and increasing de novo lipogenesis. In addition, changes were observed in genes that control oxidative stress and the xenobiotic metabolism. Together, the results suggest that the metabolic changes caused by the insecticide fipronil may be deleterious if persistent, favoring the establishment of hepatic steatosis.
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Affiliation(s)
- Camila C Pansa
- Laboratório Sinalização Celular e Expressão Gênica, DBGA, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Letícia R Molica
- Laboratório Sinalização Celular e Expressão Gênica, DBGA, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Fabiano C de Oliveira Júnior
- Laboratório Sinalização Celular e Expressão Gênica, DBGA, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Lara C Santello
- Laboratório de Microbiologia Ambiental, DBGA, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
| | - Karen C M Moraes
- Laboratório Sinalização Celular e Expressão Gênica, DBGA, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Rio Claro, SP, Brazil
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12
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Moon DO. NADPH Dynamics: Linking Insulin Resistance and β-Cells Ferroptosis in Diabetes Mellitus. Int J Mol Sci 2023; 25:342. [PMID: 38203517 PMCID: PMC10779351 DOI: 10.3390/ijms25010342] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/20/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
This review offers an in-depth exploration of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) in metabolic health. It delves into how NADPH affects insulin secretion, influences insulin resistance, and plays a role in ferroptosis. NADPH, a critical cofactor in cellular antioxidant systems and lipid synthesis, plays a central role in maintaining metabolic homeostasis. In adipocytes and skeletal muscle, NADPH influences the pathophysiology of insulin resistance, a hallmark of metabolic disorders such as type 2 diabetes and obesity. The review explores the mechanisms by which NADPH contributes to or mitigates insulin resistance, including its role in lipid and reactive oxygen species (ROS) metabolism. Parallelly, the paper investigates the dual nature of NADPH in the context of pancreatic β-cell health, particularly in its relation to ferroptosis, an iron-dependent form of programmed cell death. While NADPH's antioxidative properties are crucial for preventing oxidative damage in β-cells, its involvement in lipid metabolism can potentiate ferroptotic pathways under certain pathological conditions. This complex relationship underscores the delicate balance of NADPH homeostasis in pancreatic health and diabetes pathogenesis. By integrating findings from recent studies, this review aims to illuminate the nuanced roles of NADPH in different tissues and its potential as a therapeutic target. Understanding these dynamics offers vital insights into the development of more effective strategies for managing insulin resistance and preserving pancreatic β-cell function, thereby advancing the treatment of metabolic diseases.
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Affiliation(s)
- Dong-Oh Moon
- Department of Biology Education, Daegu University, 201 Daegudae-ro, Gyeongsan-si 38453, Gyeongsangbuk-do, Republic of Korea
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13
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García-Roche M, Talmón D, Cañibe G, Astessiano AL, Mendoza A, Cassina A, Quijano C, Carriquiry M. Hepatic metabolism of grazing cows of two Holstein strains under two feeding strategies with different levels of pasture inclusion. PLoS One 2023; 18:e0290551. [PMID: 37883506 PMCID: PMC10602316 DOI: 10.1371/journal.pone.0290551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/09/2023] [Indexed: 10/28/2023] Open
Abstract
The objective of the study was to characterize adaptations of hepatic metabolism of dairy cows of two Holstein strains with varying proportions of grazing in the feeding strategy. Multiparous autumn calving Holstein cows of New Zealand (NZH) and North American (NAH) strains were assigned to a randomized complete block design with a 2 x 2 factorial arrangement with two feeding strategies that varied in the proportions of pasture and supplementation: maximum pasture and supplementation with a pelleted concentrate (MaxP) or fixed pasture and supplementation with a total mixed ration (FixP) from May through November of 2018. Hepatic biopsies were taken at - 45 ± 17, 21 ± 7, 100 ± 23 and 180 ± 23 days in milk (DIM), representing prepartum, early lactation, early mid-lactation and late mid-lactation. The effects of DIM, feeding strategy (FS), strain and their interactions were analyzed with mixed models using repeated measures. Cows of both strains had similar triglyceride levels, mitochondrial function and carnitine palmitoyltransferase activity in liver during lactation. However, there was an effect of DIM and FS as liver triglyceride was higher for the MaxP strategy at 21 DIM and both mitochondrial function and carnitine palmitoyltransferase activity in liver were lower for the MaxP strategy at 21 DIM. Hepatic mitochondrial function and acetylation levels were affected by the interaction between strain and feeding strategy as both variables were higher for NAH cows in the MaxP strategy. Mid-lactation hepatic gene expression of enzymes related to fatty acid metabolism and nuclear receptors was higher for NZH than NAH cows. This work confirms the association between liver triglyceride, decreased hepatic mitochondrial function and greater mitochondrial acetylation levels in cows with a higher inclusion of pasture and suggests differential adaptative mechanisms between NAH and NZH cows to strategies with varying proportions of grazing in the feeding strategy.
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Affiliation(s)
- Mercedes García-Roche
- Facultad de Agronomía, Departamento de Producción Animal y Pasturas, Universidad de la República, Montevideo, Uruguay
- Facultad de Medicina, Centro de Investigaciones Biomédicas (CEINBIO) and Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay
| | - Daniel Talmón
- Facultad de Agronomía, Departamento de Producción Animal y Pasturas, Universidad de la República, Montevideo, Uruguay
| | - Guillermo Cañibe
- Facultad de Agronomía, Departamento de Producción Animal y Pasturas, Universidad de la República, Montevideo, Uruguay
| | - Ana Laura Astessiano
- Facultad de Agronomía, Departamento de Producción Animal y Pasturas, Universidad de la República, Montevideo, Uruguay
| | - Alejandro Mendoza
- Instituto Nacional de Investigación Agropecuaria, Programa Nacional de Producción de Leche, Ruta, Semillero, Uruguay
| | - Adriana Cassina
- Facultad de Medicina, Centro de Investigaciones Biomédicas (CEINBIO) and Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay
| | - Celia Quijano
- Facultad de Medicina, Centro de Investigaciones Biomédicas (CEINBIO) and Departamento de Bioquímica, Universidad de la República, Montevideo, Uruguay
| | - Mariana Carriquiry
- Facultad de Agronomía, Departamento de Producción Animal y Pasturas, Universidad de la República, Montevideo, Uruguay
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14
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Tan X, Yang X, Xu X, Peng Y, Li X, Deng Y, Zhang X, Qiu W, Wu D, Ruan Y, Zhi C. Investigation of anti-diabetic effect of a novel coenzyme Q10 derivative. Front Chem 2023; 11:1280999. [PMID: 37927560 PMCID: PMC10620959 DOI: 10.3389/fchem.2023.1280999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/04/2023] [Indexed: 11/07/2023] Open
Abstract
Introduction: The rising incidence of type 2 diabetes has seriously affected international public health. The search for more drugs that can effectively treat diabetes has become a cutting-edge trend in research. Coenzyme Q10 (CoQ10) has attracted much attention in the last decade due to its wide range of biological activities. Many researchers have explored the clinical effects of CoQ10 in patients with type 2 diabetes. However, CoQ10 has low bio-availability due to its high lipophilicity. Therefore, we have structurally optimized CoQ10 in an attempt to exploit the potential of its pharmacological activity. Methods: A novel coenzyme Q10 derivative (L-50) was designed and synthesized by introducing a group containing bromine atom and hydroxyl at the terminal of coenzyme Q10 (CoQ10), and the antidiabetic effect of L-50 was investigated by cellular assays and animal experiments. Results: Cytotoxicity results showed that L-50 was comparatively low toxicity to HepG2 cells. Hypoglycemic assays indicated that L-50 could increase glucose uptake in IR-HepG2 cells, with significantly enhanced hypoglycemic capacity compared to the CoQ10. In addition, L-50 improved cellular utilization of glucose through reduction of reactive oxygen species (ROS) accumulated in insulin-resistant HepG2 cells (IR-HepG2) and regulation of JNK/AKT/GSK3β signaling pathway, resulting in hypoglycemic effects. Furthermore, the animal experiments demonstrated that L-50 could restore the body weight of HFD/STZ mice. Notably, the findings suggested that L-50 could improve glycemic and lipid metabolism in HFD/STZ mice. Moreover, L-50 could increase fasting insulin levels (FINS) in HFD/STZ mice, leading to a decrease in fasting blood glucose (FBG) and hepatic glycogen. Furthermore, L-50 could recover triglycerides (TG), total cholesterol (T-CHO), lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels in HFD/STZ mice. Discussion: The addition of a bromine atom and a hydroxyl group to CoQ10 could enhance its anti-diabetic activity. It is anticipated that L-50 could be a promising new agent for T2DM.
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Affiliation(s)
- Xiaojun Tan
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xinyi Yang
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xun Xu
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Yuwei Peng
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xin Li
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Yongxing Deng
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Xueyang Zhang
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Wenlong Qiu
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Dudu Wu
- School of Pharmacy, Guangdong Medical University, Dongguan, China
| | - Yongdui Ruan
- The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, China
| | - Chen Zhi
- School of Pharmacy, Guangdong Medical University, Dongguan, China
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15
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Montemayor S, García S, Monserrat-Mesquida M, Tur JA, Bouzas C. Dietary Patterns, Foods, and Nutrients to Ameliorate Non-Alcoholic Fatty Liver Disease: A Scoping Review. Nutrients 2023; 15:3987. [PMID: 37764771 PMCID: PMC10534915 DOI: 10.3390/nu15183987] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/11/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease without pharmacological treatment yet. There is also a lack of specific dietary recommendations and strategies to treat the negative health impacts derived from NAFLD. OBJECTIVE This scoping review aimed to compile dietary patterns, foods, and nutrients to ameliorate NAFLD. METHODS A literature search was performed through MEDLINE, Scopus, Web of Science, and Google Scholar. RESULTS Several guidelines are available through the literature. Hypocaloric Mediterranean diet is the most accepted dietary pattern to tackle NAFLD. Coffee consumption (sugar free) may have a protective effect for NAFLD. Microbiota also plays a role in NAFLD; hence, fibre intake should be guaranteed. CONCLUSIONS A high-quality diet could improve liver steatosis. Weight loss through hypocaloric diet together with physical activity and limited sugar intake are good strategies for managing NAFLD. Specific dietary recommendations and a Mediterranean plate have been proposed to ameliorate NAFLD.
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Affiliation(s)
- Sofía Montemayor
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
| | - Silvia García
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Margalida Monserrat-Mesquida
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Josep A. Tur
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Cristina Bouzas
- Research Group on Community Nutrition & Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma, Spain (C.B.)
- Health Research Institute of Balearic Islands (IdISBa), 07120 Palma, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029 Madrid, Spain
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16
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Morawietz H, Brendel H, Diaba-Nuhoho P, Catar R, Perakakis N, Wolfrum C, Bornstein SR. Cross-Talk of NADPH Oxidases and Inflammation in Obesity. Antioxidants (Basel) 2023; 12:1589. [PMID: 37627585 PMCID: PMC10451527 DOI: 10.3390/antiox12081589] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.
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Affiliation(s)
- Henning Morawietz
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
| | - Heike Brendel
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
| | - Patrick Diaba-Nuhoho
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
- Department of Paediatric and Adolescent Medicine, Paediatric Haematology and Oncology, University Hospital Münster, 48149 Münster, Germany
| | - Rusan Catar
- Department of Nephrology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Nikolaos Perakakis
- Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (N.P.); (S.R.B.)
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
| | - Christian Wolfrum
- Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse, 8603 Schwerzenbach, Switzerland;
| | - Stefan R. Bornstein
- Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (N.P.); (S.R.B.)
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
- Diabetes and Nutritional Sciences, King’s College London, Strand, London WC2R 2LS, UK
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17
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Blas-García A, Apostolova N. Novel Therapeutic Approaches to Liver Fibrosis Based on Targeting Oxidative Stress. Antioxidants (Basel) 2023; 12:1567. [PMID: 37627562 PMCID: PMC10451738 DOI: 10.3390/antiox12081567] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Chronic liver disease (CLD) constitutes a growing global health issue, with no effective treatments currently available. Oxidative stress closely interacts with other cellular and molecular processes to trigger stress pathways in different hepatic cells and fuel the development of liver fibrosis. Therefore, inhibition of reactive oxygen species (ROS)-mediated effects and modulation of major antioxidant responses to counteract oxidative stress-induced damage have emerged as interesting targets to prevent or ameliorate liver injury. Although many preclinical studies have shown that dietary supplements with antioxidant properties can significantly prevent CLD progression in animal models, this strategy has not proved effective to significantly reduce fibrosis when translated into clinical trials. Novel and more specific therapeutic approaches are thus required to alleviate oxidative stress and reduce liver fibrosis. We have reviewed the relevant literature concerning the crucial role of alterations in redox homeostasis in different hepatic cell types during the progression of CLD and discussed current pharmacological approaches to ameliorate fibrosis by reducing oxidative stress focusing on selective modulation of enzymatic oxidant sources, antioxidant systems and ROS-mediated pathogenic processes.
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Affiliation(s)
- Ana Blas-García
- Departamento de Fisiología, Universitat de València, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Av. de Catalunya, 21, 46020 Valencia, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Instituto de Salud Carlos III, Monforte de Lemos, 3-5, 28029 Madrid, Spain
| | - Nadezda Apostolova
- FISABIO (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana), Av. de Catalunya, 21, 46020 Valencia, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Instituto de Salud Carlos III, Monforte de Lemos, 3-5, 28029 Madrid, Spain
- Departamento de Farmacología, Universitat de València, Av. Blasco Ibáñez, 15, 46010 Valencia, Spain
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18
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Memaj P, Ouzerara Z, Jornayvaz FR. Role of Oxidative Stress and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:11271. [PMID: 37511031 PMCID: PMC10379080 DOI: 10.3390/ijms241411271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify two main factors that play a crucial role in the pathophysiology of NAFLD: oxidative stress and the key role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.
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Affiliation(s)
- Plator Memaj
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Zayd Ouzerara
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - François R Jornayvaz
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, Geneva University, 1205 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Geneva University, 1205 Geneva, Switzerland
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19
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Bae SJ, Lee WY, Bak SB, Kim YE, Kim MJ, Kim YW. Unraveling the Antioxidant Capacity of Spatholobi caulis in Nonalcoholic Fatty Liver Disease: A Multiscale Network Approach Integrated with Experimental Validation. Antioxidants (Basel) 2023; 12:antiox12051097. [PMID: 37237962 DOI: 10.3390/antiox12051097] [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: 04/15/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is closely associated with obesity and metabolic syndrome. Spatholobi caulis (SC) is a herbal medicine with potential hepatoprotective effects; however, its active compounds and underlying mechanisms have not been fully explored. In this study, we combined a multiscale network-level approach with experimental validation to investigate SC's antioxidant properties and their impact on NAFLD. Data collection and network construction were performed, and active compounds and key mechanisms were identified through multi-scale network analysis. Validation was conducted using in vitro steatotic hepatocyte models and in vivo high-fat diet-induced NAFLD models. Our findings revealed that SC treatment improved NAFLD by modulating multiple proteins and signaling pathways, including AMPK signaling pathways. Subsequent experiments showed that SC treatment reduced lipid accumulation and oxidative stress. We also validated SC's effects on AMPK and its crosstalk pathways, emphasizing their role in hepatoprotection. We predicted procyanidin B2 to be an active compound of SC and validated it using a lipogenesis in vitro model. Histological and biochemical analyses confirmed that SC ameliorated liver steatosis and inflammation in mice. This study presents SC's potential use in NAFLD treatment and introduces a novel approach for identifying and validating active compounds in herbal medicine.
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Affiliation(s)
- Su-Jin Bae
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
| | - Won-Yung Lee
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
| | - Seon-Been Bak
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
| | - Young-Eun Kim
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
| | - Min-Jin Kim
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
| | - Young-Woo Kim
- School of Korean Medicine, Dongguk University, Gyeonju 38066, Republic of Korea
- Department of Computer Science and Engineering, Kyungpook National University, Daegu 41566, Republic of Korea
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20
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Oxidative Stress Modulation by ncRNAs and Their Emerging Role as Therapeutic Targets in Atherosclerosis and Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12020262. [PMID: 36829822 PMCID: PMC9952114 DOI: 10.3390/antiox12020262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are pathologies related to ectopic fat accumulation, both of which are continuously increasing in prevalence. These threats are prompting researchers to develop effective therapies for their clinical management. One of the common pathophysiological alterations that underlies both diseases is oxidative stress (OxS), which appears as a result of lipid deposition in affected tissues. However, the molecular mechanisms that lead to OxS generation are different in each disease. Non-coding RNAs (ncRNAs) are RNA transcripts that do not encode proteins and function by regulating gene expression. In recent years, the involvement of ncRNAs in OxS modulation has become more recognized. This review summarizes the most recent advances regarding ncRNA-mediated regulation of OxS in atherosclerosis and NAFLD. In both diseases, ncRNAs can exert pro-oxidant or antioxidant functions by regulating gene targets and even other ncRNAs, positioning them as potential therapeutic targets. Interestingly, both diseases have common altered ncRNAs, suggesting that the same molecule can be targeted simultaneously when both diseases coexist. Finally, since some ncRNAs have already been used as therapeutic agents, their roles as potential drugs for the clinical management of atherosclerosis and NAFLD are analyzed.
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21
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Pecchillo Cimmino T, Ammendola R, Cattaneo F, Esposito G. NOX Dependent ROS Generation and Cell Metabolism. Int J Mol Sci 2023; 24:ijms24032086. [PMID: 36768405 PMCID: PMC9916913 DOI: 10.3390/ijms24032086] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023] Open
Abstract
Reactive oxygen species (ROS) represent a group of high reactive molecules with dualistic natures since they can induce cytotoxicity or regulate cellular physiology. Among the ROS, the superoxide anion radical (O2·-) is a key redox signaling molecule prominently generated by the NADPH oxidase (NOX) enzyme family and by the mitochondrial electron transport chain. Notably, altered redox balance and deregulated redox signaling are recognized hallmarks of cancer and are involved in malignant progression and resistance to drugs treatment. Since oxidative stress and metabolism of cancer cells are strictly intertwined, in this review, we focus on the emerging roles of NOX enzymes as important modulators of metabolic reprogramming in cancer. The NOX family includes seven isoforms with different activation mechanisms, widely expressed in several tissues. In particular, we dissect the contribute of NOX1, NOX2, and NOX4 enzymes in the modulation of cellular metabolism and highlight their potential role as a new therapeutic target for tumor metabolism rewiring.
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Affiliation(s)
- Tiziana Pecchillo Cimmino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Rosario Ammendola
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Fabio Cattaneo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
- Correspondence: (F.C.); (G.E.)
| | - Gabriella Esposito
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore S.c.a.r.l., 80131 Naples, Italy
- Correspondence: (F.C.); (G.E.)
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22
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Shiragannavar VD, Sannappa Gowda NG, Puttahanumantharayappa LD, Karunakara SH, Bhat S, Prasad SK, Kumar DP, Santhekadur PK. The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator. Front Pharmacol 2023; 14:1135952. [PMID: 36909161 PMCID: PMC9995434 DOI: 10.3389/fphar.2023.1135952] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule. Methods: In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20 weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR. Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis. Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.
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Affiliation(s)
- Varsha D Shiragannavar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Nirmala G Sannappa Gowda
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Lakshana D Puttahanumantharayappa
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Shreyas H Karunakara
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Smitha Bhat
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
| | - Shashanka K Prasad
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.,Bioactive Compound Laboratory, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
| | - Divya P Kumar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Prasanna K Santhekadur
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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23
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Malnick SDH, Alin P, Somin M, Neuman MG. Fatty Liver Disease-Alcoholic and Non-Alcoholic: Similar but Different. Int J Mol Sci 2022; 23:16226. [PMID: 36555867 PMCID: PMC9783455 DOI: 10.3390/ijms232416226] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.
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Affiliation(s)
- Stephen D. H. Malnick
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Pavel Alin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Marina Somin
- Department of Internal Medicine, Kaplan Medical Center, Affiliated to Hebrew University, Rehovot 76100, Israel
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, Temerity Faculty of Medicine, University of Toronto, Toronto, ON M5G OA3, Canada
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24
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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25
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NAFLD: From Mechanisms to Therapeutic Approaches. Biomedicines 2022; 10:biomedicines10071747. [PMID: 35885052 PMCID: PMC9313291 DOI: 10.3390/biomedicines10071747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) now represents the most frequent chronic liver disease worldwide [...]
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26
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Memaj P, Jornayvaz FR. Non-alcoholic fatty liver disease in type 1 diabetes: Prevalence and pathophysiology. Front Endocrinol (Lausanne) 2022; 13:1031633. [PMID: 36531463 PMCID: PMC9752856 DOI: 10.3389/fendo.2022.1031633] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the general population with a global prevalence of 25%. It is often associated with metabolic syndrome and type 2 diabetes, as insulin resistance and hyperinsulinemia are known to be favoring factors. Recent studies have described growing incidence of NAFLD in type 1 diabetes (T1D) as well. Although increasing prevalence of metabolic syndrome in these patients seems to explain part of this increase in NAFLD, other underlying mechanisms may participate in the emergence of NAFLD. Notably, some genetic factors are more associated with fatty liver disease, but their prevalence in T1D has not been evaluated. Moreover, oxidative stress, poor glucose control and long-lasting hyperglycemia, as well as exogenous insulin administration play an important role in intrahepatic fat homeostasis. The main differential diagnosis of NAFLD in T1D is glycogenic hepatopathy, which needs to be considered mostly in T1D patients with poor glycemic control. This article aims to review the prevalence and pathophysiology of NAFLD in T1D and open perspectives for clinicians taking care of T1D patients with potential hepatopathy.
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Affiliation(s)
- Plator Memaj
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - François R. Jornayvaz
- Division of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland
- Diabetes Center, Faculty of Medicine, Geneva University, Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, Geneva University, Geneva, Switzerland
- *Correspondence: François R. Jornayvaz,
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