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Abdelhady R, Arab HH, Fakhr Eldeen RR, Shalaby HN, Nawwar DA, Elhemely MA, Sayed RH. Unveiling the Therapeutic Potential of Dulaglutide in Mitigating Tacrolimus-Induced Nephrotoxicity Through Targeting the miR-22/HMGB-1/TLR4/MyD88/NF-κB Trajectory. Arch Pharm (Weinheim) 2025; 358:e3127. [PMID: 40205909 PMCID: PMC11983086 DOI: 10.1002/ardp.202500023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/23/2025] [Accepted: 03/22/2025] [Indexed: 04/11/2025]
Abstract
Tacrolimus (Tac) is an immunosuppressive drug used to reduce the risk of allograft rejection; however, it can induce renal injury. High mobility group box 1 (HMGB-1) protein, which induces inflammation through the aberrant stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response protein (MyD88)/nuclear factor kappa B (NF-κB) trajectory, could represent a molecular target for alleviating Tac-induced renal damage. The present study aimed to investigate the potential protective role of the GLP-1 agonist, dulaglutide (Dula), against Tac-induced nephrotoxicity in rats. Rats were administered Tac (5 mg/kg/day) and vehicle or Dula (0.2 mg/kg once a week) for 14 days. Treatment with Dula reduced serum creatinine plus blood urea nitrogen and attenuated Tac-induced renal histopathological changes. Dula treatment also hampered renal inflammation and restored redox homeostasis, as indicated by remarkably reduced tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), and NADPH oxidase 1 levels alongside marked replenishment in reduced glutathione (GSH) content. These effects were mediated through the upregulation of miR-22 expression and the consequent inhibition of the HMGB-1/TLR4/MyD88/NF-κB trajectory. Collectively, Dula has been demonstrated to protect rats against Tac-induced nephrotoxicity by reducing inflammation, restoring redox homeostasis, and modulation of the miR-22/HMGB-1/TLR4/MyD88/NF-κB trajectory. Dula may be beneficial clinically in preventing Tac-induced renal injury.
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Affiliation(s)
- Rasha Abdelhady
- Pharmacology and Toxicology Department, Faculty of PharmacyFayoum UniversityFayoumEgypt
- Pharmacology and Toxicology Department, Faculty of PharmacyEgyptian Chinese UniversityCairoEgypt
| | - Hany H. Arab
- Department of Pharmacology and Toxicology, College of PharmacyTaif UniversityTaifSaudi Arabia
| | - Rasha R. Fakhr Eldeen
- Biochemistry Department, College of Pharmaceutical Sciences and Drug ManufacturingMisr University for Science and Technology6th of October CityEgypt
| | - Heba Nasr Shalaby
- Pharmacology and Toxicology Department, Faculty of PharmacyCairo UniversityCairoEgypt
| | - Dalia A. Nawwar
- Pharmacology and Toxicology Department, Faculty of PharmacyCairo UniversityCairoEgypt
| | - Mai Abdallah Elhemely
- School of Medical Sciences, Faculty of Biology, Medicine and HealthThe University of ManchesterManchesterUK
- Department of Pharmacology and Toxicology, Faculty of PharmacyBeni‐Suef UniversityBeni‐SuefEgypt
| | - Rabab H. Sayed
- Pharmacology and Toxicology Department, Faculty of PharmacyCairo UniversityCairoEgypt
- School of PharmacyNewgiza UniversityGizaEgypt
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J C, Me C, Mt C. Renoprotective mechanisms of glucagon-like peptide-1 receptor agonists. DIABETES & METABOLISM 2025; 51:101641. [PMID: 40127835 DOI: 10.1016/j.diabet.2025.101641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/26/2025]
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin hormone, secreted from gut endocrine cells, which acts to potentiate nutrient-induced insulin secretion. Activation of its receptor, GLP-1R, decreases glucagon secretion and gastric emptying, thereby decreasing blood glucose and body weight. It is largely through these mechanisms that Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the treatment of type 2 diabetes. More recently, preclinical and clinical studies have reported that these agents have potent extra-pancreatic effects, exhibiting cardioprotective and renoprotective actions. The recent FLOW trial was the first multicentre clinical trial investigating the effect of GLP-1RAs on a primary renal outcome and reported robust evidence that GLP-1RAs are renoprotective. Studies in rodent models of renal injury have shown that gain and loss of GLP-1R signalling improves or deteriorates kidney function. However, the precise mechanisms responsible for renal benefits of GLP-1RAs are not yet fully understood. While prolonged activation of GLP-1 receptors (GLP-1R) has been shown to reverse diabetes-related disruptions in gene expression across various renal cell populations, GLP-1R expression in both rodent and human kidneys is thought to be primarily confined to certain vascular smooth muscle cells. This review discusses recent advances in our understanding of the effects of GLP-1 medicines on the kidney with a focus on indirect and direct mechanisms of action.
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Affiliation(s)
- Chen J
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia
| | - Cooper Me
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia
| | - Coughlan Mt
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia; Baker Heart and Diabetes Institute, Melbourne, 3004, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, 381 Royal Parade, Parkville, 3052, Victoria, Australia.
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Hupa-Breier KL, Schenk H, Campos-Murguia A, Wellhöner F, Heidrich B, Dywicki J, Hartleben B, Böker C, Mall J, Terkamp C, Wilkens L, Becker F, Rudolph KL, Manns MP, Mederacke YS, Marhenke S, Redeker H, Lieber M, Iordanidis K, Taubert R, Wedemeyer H, Noyan F, Hardtke-Wolenski M, Jaeckel E. Novel translational mouse models of metabolic dysfunction-associated steatotic liver disease comparable to human MASLD with severe obesity. Mol Metab 2025; 93:102104. [PMID: 39855563 PMCID: PMC11815970 DOI: 10.1016/j.molmet.2025.102104] [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: 11/27/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome. METHODS TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin. RESULTS After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH. CONCLUSIONS Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.
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Affiliation(s)
- Katharina L Hupa-Breier
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Heiko Schenk
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Björn Hartleben
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Clara Böker
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Julian Mall
- Department of General, Visceral, Vascular and Bariatric Surgery, Klinikum Nordstadt, 30167, Hannover, Germany
| | - Christoph Terkamp
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ludwig Wilkens
- Department of Pathology, Nordstadt Hospital Hannover, 30167, Hannover, Germany
| | - Friedrich Becker
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Karl Lenhard Rudolph
- Research Group on Stem Cell and Metabolism Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Young-Seon Mederacke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hanna Redeker
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maren Lieber
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Ajmera Transplant Centre, Toronto General Hospital, United Health Network, University of Toronto, Toronto, Canada
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da Silva RS, de Paiva IHR, Mendonça IP, de Souza JRB, Lucena-Silva N, Peixoto CA. Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota-gut--brain axis in obese mice. Inflammopharmacology 2025; 33:845-864. [PMID: 39586940 DOI: 10.1007/s10787-024-01603-y] [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: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/27/2024]
Abstract
Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.
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Affiliation(s)
- Rodrigo Soares da Silva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Igor Henrique Rodrigues de Paiva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Ingrid Prata Mendonça
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | | | - Norma Lucena-Silva
- Laboratory of Immunogenetics, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil.
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Makri ES, Xanthopoulos K, Pettas S, Goulas A, Mavrommatis-Parasidis P, Makri E, Tsingotjidou A, Cheva A, Ntenti C, Zacharis CK, Ballaouri I, Gerou S, Polyzos SA. Limited preventive effects of empagliflozin against metabolic dysfunction-associated steatotic liver disease in a mouse model of fast food diet. Hormones (Athens) 2024:10.1007/s42000-024-00621-3. [PMID: 39699846 DOI: 10.1007/s42000-024-00621-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024]
Abstract
PURPOSE Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent disease with limited treatment options. The aim of this study was to evaluate the preventive effects of a sodium-glucose co-transporter (SGLT)-2 inhibitor, empagliflozin, on a dietary mouse model of MASLD. METHODS In total, 24 C57BL/6 J mice of both sexes were randomly allocated to three groups, as follows: the fast food diet (FFD) group (eight mice, receiving a high-fat, high-cholesterol, high-fructose diet, FFD), the EMPA group (eight mice, fed a FFD with 10 mg/kg/d empagliflozin), and the chow diet (eight mice, CD) group. The mice were weighed and blood samples were drawn every 4 weeks; after 25 weeks the mice were euthanized, at which point liver tissues were histologically evaluated. RESULTS After 25 weeks, there was no significant difference in body weight between the three groups, whereas liver-to-body weight ratio was greater in the EMPA compared to the CD group (p = 0.002). Hepatic fibrosis was marginally different between the three groups (p = 0.045). Fibrosis stage 1 was present in five mice on FFD (62.5%), in one mouse on EMPA (12.5%), and in one mouse on CD (12.5%). Lipogenic, inflammatory, and fibrogenic genes did not differ between the EMPA and FFD groups. Interestingly, mRNA encoding for SGLT-1 and SGLT-2 was detected in the mouse livers. CONCLUSIONS Empagliflozin treatment in mice on a FFD did not result in any significant effects on morphological, biochemical, or histological features or on expression of hepatic genes associated with MASLD compared to those fed a FFD without empagliflozin. The observed effects on mild hepatic fibrosis warrant validation, possibly via studies of longer duration.
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Affiliation(s)
- Evangelia S Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.
| | - Konstantinos Xanthopoulos
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Institute of Applied Biosciences, Centre for Research and Technology, Thessaloniki, Greece
| | - Spyros Pettas
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Panagiotis Mavrommatis-Parasidis
- Laboratory of Anatomy, Histology & Embryology, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleftheria Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Anastasia Tsingotjidou
- Laboratory of Anatomy, Histology & Embryology, School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Angeliki Cheva
- Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Charikleia Ntenti
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
| | - Constantinos K Zacharis
- Laboratory of Pharmaceutical Analysis, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | | | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece
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Coll E, Cigarran S, Portolés J, Cases A. Gut Dysbiosis and Its Role in the Anemia of Chronic Kidney Disease. Toxins (Basel) 2024; 16:495. [PMID: 39591250 PMCID: PMC11598790 DOI: 10.3390/toxins16110495] [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: 09/30/2024] [Revised: 11/07/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
The gut dysbiosis present in chronic kidney disease (CKD) has been associated with anemia. Factors such as the accumulation of gut-derived uremic toxins, increased gut barrier permeability-induced inflammation, and a reduced intestinal production of short-chain fatty acids (SCFAs), all associated with changes in the intestinal microbiota composition in CKD, may lead to the development or worsening of anemia in renal patients. Understanding and addressing these mechanisms related to gut dysbiosis in CKD patients can help to delay the development of anemia and improve its control in this population. One approach is to avoid or reduce the use of drugs linked to gut dysbiosis in CKD, such as phosphate binders, oral iron supplementation, antibiotics, and others, unless they are indispensable. Another approach involves introducing dietary changes that promote a healthier microbiota and/or using prebiotics, probiotics, or symbiotics to improve gut dysbiosis in this setting. These measures can increase the presence of SCFA-producing saccharolytic bacteria and reduce proteolytic bacteria, thereby lowering the production of gut-derived uremic toxins and inflammation. By ameliorating CKD-related gut dysbiosis, these strategies can also improve the control of renal anemia and enhance the response to erythropoiesis-stimulating agents (ESAs) in ESA-resistant patients. In this review, we have explored the relationship between gut dysbiosis in CKD and renal anemia and propose feasible solutions, both those already known and potential future treatments.
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Affiliation(s)
- Elisabet Coll
- Servei de Nefrologia, Fundacio Puigvert, 08025 Barcelona, Spain
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
| | | | - Jose Portolés
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
- Ressearch Net RICORS 2030 Instituto de Salud Carlos III ISCIII, 28029 Madrid, Spain
- Nephrology Department, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain
- Medicine Department, Facultad de Medicina, Research Institute Puerta de Hierro Segovia de Arana (IDIPHISA), Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Aleix Cases
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
- Nephrology Unit, Hospital Clinic, 08036 Barcelona, Spain
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Gancheva S, Roden M, Castera L. Diabetes as a risk factor for MASH progression. Diabetes Res Clin Pract 2024; 217:111846. [PMID: 39245423 DOI: 10.1016/j.diabres.2024.111846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/10/2024]
Abstract
Non-alcoholic (now: metabolic) steatohepatitis (MASH) is the progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), which often coexists and mutually interacts with type 2 diabetes (T2D), resulting in worse hepatic and cardiovascular outcomes. Understanding the intricate mechanisms of diabetes-related MASH progression is crucial for effective therapeutic strategies. This review delineates the multifaceted pathways involved in this interplay and explores potential therapeutic implications. The synergy between adipose tissue, gut microbiota, and hepatic alterations plays a pivotal role in disease progression. Adipose tissue dysfunction, particularly in the visceral depot, coupled with dysbiosis in the gut microbiota, exacerbates hepatic injury and insulin resistance. Hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress further potentiate inflammation and fibrosis, contributing to disease severity. Dietary modification with weight reduction and exercise prove crucial in managing T2D-related MASH. Additionally, various well-known but also novel anti-hyperglycemic medications exhibit potential in reducing liver lipid content and, in some cases, improving MASH histology. Therapies targeting incretin receptors show promise in managing T2D-related MASH, while thyroid hormone receptor-β agonism has proven effective as a treatment of MASH and fibrosis.
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Affiliation(s)
- Sofiya Gancheva
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), Partner Düsseldorf, München-Neuherberg, Germany.
| | - Laurent Castera
- Department of Hepatology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris-Cité, INSERM UMR 1149, Centre de Recherche sur l'Inflammation Paris, Montmartre, Paris, France.
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Caturano A, Vetrano E, Galiero R, Sardu C, Rinaldi L, Russo V, Monda M, Marfella R, Sasso FC. Advances in the Insulin-Heart Axis: Current Therapies and Future Directions. Int J Mol Sci 2024; 25:10173. [PMID: 39337658 PMCID: PMC11432093 DOI: 10.3390/ijms251810173] [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: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
The insulin-heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin-heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor-neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin-heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.
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Affiliation(s)
- Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Luca Rinaldi
- Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, 86100 Campobasso, Italy
| | - Vincenzo Russo
- Department of Biology, College of Science and Technology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
- Division of Cardiology, Department of Medical Translational Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Marcellino Monda
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
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Afsar B, Afsar RE, Lentine KL. The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review. J Diabetes Metab Disord 2024; 23:497-508. [PMID: 38932911 PMCID: PMC11196485 DOI: 10.1007/s40200-024-01435-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 04/10/2024] [Indexed: 06/28/2024]
Abstract
Studies consistently showed that sodium-glucose cotransporter inhibitors (SGLTi) have cardiovascular and renal benefits, independent of their glucose lowering effects. Recent studies showed that SGLTi might influence gut microbiota. We performed a narrative review of publications focusing on use of SGLTi and changes in gut microbiota. Most studies showed that use of SGLTi re-shapes gut microbiota. These studies are heterogeneous regarding in study designs, doses and types of drugs used (SGLT1i vs. SGLT2i, or SGLT1/2i in combination) and the methods used to determine gut microbiota. However, existing data showed that SGLTi might alter food fermentation and gut permeability, which might translate into clinical outcomes. Thus the objective of this review is to summarize and discuss the updated data regarding SGLTi and changes in gut microbiota for the first time and suggest further study points that needs to be discovered. Graphical Abstract
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Affiliation(s)
- Baris Afsar
- Suleyman Demirel University, School of Medicine, Department of Nephrology, Isparta, Turkey
| | - Rengin Elsurer Afsar
- Suleyman Demirel University, School of Medicine, Department of Nephrology, Isparta, Turkey
- Saint Louis University, School of Medicine, Division of Nephrology, St. Louis, MO USA
| | - Krista L. Lentine
- Saint Louis University, School of Medicine, Division of Nephrology, St. Louis, MO USA
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10
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Makri ES, Makri E, Goulas A, Xanthopoulos K, Polyzos SA. Animal studies of sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease. Ann Gastroenterol 2024; 37:280-290. [PMID: 38779641 PMCID: PMC11107411 DOI: 10.20524/aog.2024.0884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/10/2024] [Indexed: 05/25/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common chronic liver diseases. Modern lifestyle, characterized by increasing rates of obesity and type 2 diabetes mellitus (T2DM), has led to a "pandemic" of NAFLD that imposes a personal health and socioeconomic burden. Apart from overnutrition and insulin resistance, various metabolic aberrations, gut microbiota and genetic predispositions are involved in the pathogenesis of the disease. The multifactorial nature of NAFLD's pathogenesis makes the development of pharmacological therapies for patients with this disease challenging. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) are antidiabetic agents that reduce blood glucose mainly by increasing its renal excretion. As T2DM is one of the major contributors to NAFLD, SGLT-2i have emerged as promising agents for the management of NAFLD. In this review, we summarize the main animal studies on SGLT-2i in models of NAFLD.
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Affiliation(s)
- Evangelia S. Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Eleftheria Makri
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
| | - Konstantinos Xanthopoulos
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki (Konstantinos Xanthopoulos)
- Institute of Applied Biosciences, Centre for Research and Technology, Thessaloniki (Konstantinos Xanthopoulos), Greece
| | - Stergios A. Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki (Evangelia S. Makri, Eleftheria Makri, Antonis Goulas, Stergios A. Polyzos)
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11
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Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
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Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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12
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Noah AA, El-Mezayen NS, El-Ganainy SO, Darwish IE, Afify EA. Reversal of fibrosis and portal hypertension by Empagliflozin treatment of CCl 4-induced liver fibrosis: Emphasis on gal-1/NRP-1/TGF-β and gal-1/NRP-1/VEGFR2 pathways. Eur J Pharmacol 2023; 959:176066. [PMID: 37769984 DOI: 10.1016/j.ejphar.2023.176066] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 10/03/2023]
Abstract
To date, liver fibrosis has no clinically approved treatment. Empagliflozin (EMPA), a highly selective sodium-glucose-cotransporter-2 (SGLT2) inhibitor, has shown ameliorative potential in liver diseases without revealing its full mechanisms. Neuropilin-1 (NRP-1) is a novel regulator of profibrogenic signaling pathways related to hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) that modulates intrahepatic profibrogenic and angiogenic pathways. Herein, EMPA's antifibrotic potentials and effects on galactin-1 (Gal-1)/NRP-1 signaling pathways have been evaluated in an experimental liver fibrosis rat model by testing different EMPA dose regimens. EMPA treatment brought a dose-dependent decrease in Gal-1/NRP-1 hepatic expression. This was coupled with suppression of major HSCs pro-fibrotic pathways; transforming growth factor-β (TGF-β)/TGF-βRI/Smad2 and platelet-derived growth factor-beta (PDGF-β) with a diminution of hepatic Col 1A1 level. In addition, EMPA prompted a protuberant suppression of the angiogenic pathway; vascular endothelial growth factor (VEGF)/VEGF-receptor-2 (VEGFR-2)/SH2-Domain Containing Adaptor Protein-B (Shb), and reversal of altered portal hypertension (PHT) markers; endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS). The amelioration of liver fibrosis was coupled with a remarkable improvement in liver aminotransferases and histologic hepatic fibrosis Ishak scores. The highest EMPA dose showed a good safety profile with minimal changes in renal function and glycemic control. Thus, the current study brought about novel findings for a potential liver fibrosis treatment modality via targeting NRP-1 signaling pathways by EMPA.
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Affiliation(s)
- Ashraf A Noah
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Clinical Research Administration, Alexandria Directorate of Health Affairs, Egyptian Ministry of Health and Population, Alexandria, Egypt
| | - Nesrine S El-Mezayen
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.
| | - Samar O El-Ganainy
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Inas E Darwish
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt; Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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13
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Demir M, Bornstein SR, Mantzoros CS, Perakakis N. Liver fat as risk factor of hepatic and cardiometabolic diseases. Obes Rev 2023; 24:e13612. [PMID: 37553237 DOI: 10.1111/obr.13612] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 06/26/2023] [Accepted: 07/10/2023] [Indexed: 08/10/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies.
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Affiliation(s)
- Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Stefan R Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Diabetes and Nutritional Sciences, King's College London, London, UK
| | - Christos S Mantzoros
- Division of Endocrinology, Boston VA Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215, USA
| | - Nikolaos Perakakis
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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14
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Shamardl HAMA, Ibrahim NA, Merzeban DH, Elamir AM, Golam RM, Elsayed AM. Resveratrol and Dulaglutide ameliorate adiposity and liver dysfunction in rats with diet-induced metabolic syndrome: Role of SIRT-1 / adipokines / PPARγ and IGF-1. Daru 2023:10.1007/s40199-023-00458-y. [PMID: 36991247 DOI: 10.1007/s40199-023-00458-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 03/05/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Adiposity and non-alcoholic fatty liver disease (NAFLD) are common characteristics of metabolic syndrome (MS). Understanding the underlying pathogenesis is crucial for the development of new remedies. Resveratrol controls obesity and glycemic disorders in patients with MS. OBJECTIVES This study aimed to evaluate the effect of resveratrol and dulaglutide on adipose tissues and liver in rats with MS, declaring their possible mechanisms. METHODS Rats allocated as Control, MS (induced by a high fat/ high sucrose diet for eight weeks), MS + Resveratrol (30 mg/kg/day orally), and MS + Dulaglutide (0.6 mg/kg twice weekly SC); drugs administration was in the last four weeks. Serum biochemical measurements were done. Liver and visceral fat were processed for biochemistry, histopathology, and immunohistochemistry. RESULTS MS results demonstrated significantly increased systolic and diastolic blood pressure, anthropometric measurements, serum levels of alanine aminotransferase (ALT), glycemic indices, and lipids with decreased HDL-C. Tissue levels of leptin, malondialdehyde (MDA), and TNF-α reactivity significantly increased. Expression of adiponectin, PPARγ, and insulin growth factor-1 (IGF-1) decreased. Also, Western blotting mRNA gene expression of liver SIRT-1 was down-regulated. Resveratrol and dulaglutide significantly and effectively reversed MS complexity, ameliorating all findings, particularly NAFLD and adiposity-induced inflammation. Resveratrol significantly appears superior to dulaglutide regarding the effects on hemodynamics, lipids, adipokines, IGF-1 levels, and adipocyte size. Parallel, dulaglutide has more influence on glycemic control. CONCLUSION Protective effects of the drugs may be through correlations between SIRT-1/adipokines/IGF-1 and PPARγ, improving the cross-talk between insulin resistance, obesity markers, liver dysfunction, and TNF-α. Promising multi-beneficial therapies of resveratrol or dulaglutide in MS are recommended clinically for this purpose. Showing the Experimental Design.
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Affiliation(s)
| | - Noha A Ibrahim
- Histology and Cell Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Dina H Merzeban
- Medical Physiology DepartmentFaculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Azza M Elamir
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Rehab M Golam
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
| | - Asmaa M Elsayed
- Histology and Cell Biology Department, Faculty of Medicine, Fayoum University, Fayoum, 19052, Egypt
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15
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Youssef ME, Yahya G, Popoviciu MS, Cavalu S, Abd-Eldayem MA, Saber S. Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control. Int J Mol Sci 2023; 24:ijms24076039. [PMID: 37047011 PMCID: PMC10094124 DOI: 10.3390/ijms24076039] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline.
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Affiliation(s)
- Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Al Sharqia 44519, Egypt
| | - Mihaela Simona Popoviciu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
| | - Marwa A Abd-Eldayem
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
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16
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Khanmohammadi S, Kuchay MS. Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease. Pharmacol Res 2022; 185:106507. [DOI: 10.1016/j.phrs.2022.106507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 10/31/2022]
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17
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Ni Y, Zheng L, Nan S, Ke L, Fu Z, Jin J. Enterorenal crosstalks in diabetic nephropathy and novel therapeutics targeting the gut microbiota. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1406-1420. [PMID: 36239349 PMCID: PMC9827797 DOI: 10.3724/abbs.2022140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/03/2022] [Indexed: 12/29/2022] Open
Abstract
The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics, probiotics, postbiotics, fecal microbial transplantation (FMT), and engineering bacteria and phages, are potential microbiota-based therapies for DN. Furthermore, novel diabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, may affect the progression of DN partly through gut microbiota. In the current review, we mainly summarize the evidence concerning the gut-kidney axis in the advancement of DN and discuss therapies targeting the gut microbiota, expecting to provide new insight into the clinical treatment of DN.
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Affiliation(s)
- Yinhua Ni
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Liujie Zheng
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Sujie Nan
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Lehui Ke
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Zhengwei Fu
- College of Biotechnology and BioengineeringZhejiang University of TechnologyHangzhou310032China
| | - Juan Jin
- Urology & Nephrology CenterDepartment of NephrologyZhejiang Provincial People’s Hospital (Affiliated People’s HospitalHangzhou Medical College)Hangzhou310014China
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18
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Khalifa O, H. Mroue K, Mall R, Ullah E, S. Al-Akl N, Arredouani A. Investigation of the Effect of Exendin-4 on Oleic Acid-Induced Steatosis in HepG2 Cells Using Fourier Transform Infrared Spectroscopy. Biomedicines 2022; 10:biomedicines10102652. [PMID: 36289914 PMCID: PMC9599706 DOI: 10.3390/biomedicines10102652] [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: 05/19/2022] [Revised: 07/10/2022] [Accepted: 07/13/2022] [Indexed: 12/04/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier transform infrared (FTIR) spectroscopy, we sought to investigate the biochemical changes in a steatosis cell model treated or not with the GLP-1R agonist Exendin-4 (Ex-4). HepG2 cells were made steatotic with 400 µM of oleic acid and then treated with 200 nM Ex-4 in order to reduce lipid accumulation. We quantified steatosis using the Oil Red O staining method. We investigated the biochemical alterations induced by steatosis and Ex-4 treatment using Fourier transform infrared (FTIR) spectroscopy and chemometric analyses. Analysis of the Oil Red O staining showed that Ex-4 significantly reduces steatosis. This reduction was confirmed by FTIR analysis, as the phospholipid band (C=O) at 1740 cm−1 in Ex-4 treated cells is significantly decreased compared to steatotic cells. The principal component analysis score plots for both the lipid and protein regions showed that the untreated and Ex-4-treated samples, while still separated, are clustered close to each other, far from the steatotic cells. The biochemical and structural changes induced by OA-induced lipotoxicity are at least partially reversed upon Ex-4 treatment. FTIR and chemometric analyses revealed that Ex-4 significantly reduces OA-induced lipid accumulation, and Ex-4 also restored the lipid and protein biochemical alterations caused by lipotoxicity-induced oxidative stress. In combination with chemometric analyses, FTIR spectroscopy may offer new approaches for investigating the mechanisms underpinning NAFLD.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Kamal H. Mroue
- Qatar Environment and Energy Research Institute, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
| | - Raghvendra Mall
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA
| | - Ehsan Ullah
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Nayla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- Correspondence:
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19
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Hossain MF, Khan NA, Rahman A, Chowdhury MFI, Bari S, Khan MA, Masud UW, Zakia UB, Paul SP, Tasnim N. Empagliflozin Ameliorates Progression From Prediabetes to Diabetes and Improves Hepatic Lipid Metabolism: A Systematic Review. Cureus 2022; 14:e28367. [PMID: 36168335 PMCID: PMC9506669 DOI: 10.7759/cureus.28367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/05/2022] Open
Abstract
Diabetes mellitus (DM) and hepatic steatosis are two of the most common metabolic syndromes that affect the health of people globally. Empagliflozin (EMPA) is a promising drug of choice for the diabetic population. Recent studies have shown its beneficial effects not only on diabetic patients but also on patients suffering from cardiac, hepatic, neurological, or pancreatic anomalies. In this paper, we systematically searched electronic databases to compile literature that focuses on EMPA’s effect on the prediabetic population, diabetic population, and hepatic lipid metabolism. We focus on the mechanism of EMPA, specifically by which it increases insulin sensitivity and fat browning and reduces fat accumulation. Overall, we hypothesized that by its effect on weight loss and reducing inflammatory markers and insulin resistance (IR), EMPA decreases the rate of prediabetes to diabetes conversion. We concluded that by improving hepatic and serum triglyceride, decreasing visceral fat, and its positive impact on hepatic steatosis, the drug improves hepatic lipid metabolism. Further research should be done on this matter.
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20
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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21
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Kant R, Chandra L, Verma V, Nain P, Bello D, Patel S, Ala S, Chandra R, Antony MA. Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus. World J Methodol 2022; 12:246-257. [PMID: 36159100 PMCID: PMC9350729 DOI: 10.5662/wjm.v12.i4.246] [Citation(s) in RCA: 12] [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: 03/01/2022] [Revised: 05/03/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.
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Affiliation(s)
- Ravi Kant
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
| | - Lakshya Chandra
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Vipin Verma
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Internal Medicine, AnMed Health, Anderson, SC 29621, United States
| | - Priyanshu Nain
- Department of Graduate Medical Education, Maulana Azad Medical College, Delhi 110002, India
| | - Diego Bello
- Department of Surgery, AnMed Health, Anderson, SC 29621, United States
| | - Siddharth Patel
- Department of Internal Medicine, Decatur Morgan Hospital, Decatur, AL 35601, United States
| | - Subash Ala
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Rashmi Chandra
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
| | - Mc Anto Antony
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
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22
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Bendotti G, Montefusco L, Lunati ME, Usuelli V, Pastore I, Lazzaroni E, Assi E, Seelam AJ, El Essawy B, Jang Y, Loretelli C, D'Addio F, Berra C, Ben Nasr M, Zuccotti G, Fiorina P. The anti-inflammatory and immunological properties of GLP-1 Receptor Agonists. Pharmacol Res 2022; 182:106320. [PMID: 35738455 DOI: 10.1016/j.phrs.2022.106320] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 12/29/2022]
Abstract
In the last few years, a great interest has emerged in investigating the pleiotropic effects of Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs). While GLP-1RAs ability to lower plasma glucose and to induce weight loss has allowed them to be approved for the treatment of diabetes and obesity, consistent evidences from in vitro studies and preclinical models suggested that GLP-1RAs have anti-inflammatory properties and that may modulate the immune-system. Notably, such anti-inflammatory effects target different pathways in different tissues, underling the broad spectrum of GLP-1RAs actions. This review examines some of the currently proposed molecular mechanisms of GLP-1RAs actions and explores their potential benefits in reducing inflammatory responses, which may well suggest a future therapeutic use of GLP-1RAs in new indications.
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Affiliation(s)
- Giulia Bendotti
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Elisa Lazzaroni
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Basset El Essawy
- Transplantation Research Center, Nephrology Division, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Medicine, Al-Azhar University, Cairo, Egypt
| | - Yun Jang
- Institute of Organ Transplantation, Tongji Hospital and Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Cesare Berra
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS Multimedica, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - GianVincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano and Department of Pediatrics, Buzzi Children's Hospital, Milan, Italy
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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23
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Impact of the Gastrointestinal Tract Microbiota on Cardiovascular Health and Pathophysiology. J Cardiovasc Pharmacol 2022; 80:13-30. [PMID: 35384898 DOI: 10.1097/fjc.0000000000001273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/25/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT The microbiota of the gastrointestinal tract (GIT) is an extremely diverse community of microorganisms, and their collective genomes (microbiome) provide a vast arsenal of biological activities, in particular enzymatic ones, which are far from being fully elucidated. The study of the microbiota (and the microbiome) is receiving great interest from the biomedical community as it carries the potential to improve risk-prediction models, refine primary and secondary prevention efforts, and also design more appropriate and personalized therapies, including pharmacological ones. A growing body of evidence, though sometimes impaired by the limited number of subjects involved in the studies, suggests that GIT dysbiosis, i.e. the altered microbial composition, has an important role in causing and/or worsening cardiovascular disease (CVD). Bacterial translocation as well as the alteration of levels of microbe-derived metabolites can thus be important to monitor and modulate, because they may lead to initiation and progression of CVD, as well as to its establishment as chronic state. We hereby aim to provide readers with details on available resources and experimental approaches that are used in this fascinating field of biomedical research, and on some novelties on the impact of GIT microbiota on CVD.
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24
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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection. Int J Mol Sci 2022; 23:ijms23063107. [PMID: 35328527 PMCID: PMC8953901 DOI: 10.3390/ijms23063107] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/03/2022] [Accepted: 03/09/2022] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.
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25
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Yeung MHY, Leung KL, Choi LY, Yoo JS, Yung S, So PK, Wong CM. Lipidomic Analysis Reveals the Protection Mechanism of GLP-1 Analogue Dulaglutide on High-Fat Diet-Induced Chronic Kidney Disease in Mice. Front Pharmacol 2022; 12:777395. [PMID: 35299724 PMCID: PMC8921774 DOI: 10.3389/fphar.2021.777395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/23/2021] [Indexed: 12/31/2022] Open
Abstract
Many clinical studies have suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have renoprotective properties by ameliorating albuminuria and increasing glomerular filtration rate in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) by lowering ectopic lipid accumulation in the kidney. However, the mechanism of GLP-1RAs was hitherto unknown. Here, we conducted an unbiased lipidomic analysis using ultra-high-performance liquid chromatography/electrospray ionization-quadrupole time-of-flight mass spectrometry (UHPLC/ESI-Q-TOF-MS) and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to reveal the changes of lipid composition and distribution in the kidneys of high-fat diet-fed mice after treatment with a long-acting GLP-1RA dulaglutide for 4 weeks. Treatment of dulaglutide dramatically improved hyperglycemia and albuminuria, but there was no substantial improvement in dyslipidemia and ectopic lipid accumulation in the kidney as compared with controls. Intriguingly, treatment of dulaglutide increases the level of an essential phospholipid constituent of inner mitochondrial membrane cardiolipin at the cortex region of the kidneys by inducing the expression of key cardiolipin biosynthesis enzymes. Previous studies demonstrated that lowered renal cardiolipin level impairs kidney function via mitochondrial damage. Our untargeted lipidomic analysis presents evidence for a new mechanism of how GLP-1RAs stimulate mitochondrial bioenergetics via increasing cardiolipin level and provides new insights into the therapeutic potential of GLP-1RAs in mitochondrial-related diseases.
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Affiliation(s)
- Martin Ho Yin Yeung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Ka Long Leung
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Lai Yuen Choi
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Jung Sun Yoo
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Susan Yung
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Pui-Kin So
- University Research Facility in Life Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Chi-Ming Wong
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
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26
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Khalifa O, Al-Akl NS, Errafii K, Arredouani A. Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway. Sci Rep 2022; 12:2226. [PMID: 35140289 PMCID: PMC8828858 DOI: 10.1038/s41598-022-06143-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 01/24/2022] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar
| | - Neyla S Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar
| | - Khaoula Errafii
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar. .,College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
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27
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NASH and Systemic Complications: From Basic to Clinical Research. Biomedicines 2021; 9:biomedicines9121913. [PMID: 34944726 PMCID: PMC8698260 DOI: 10.3390/biomedicines9121913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022] Open
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28
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Perakakis N, Chrysafi P, Feigh M, Veidal SS, Mantzoros CS. Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH. Int J Mol Sci 2021; 22:6332. [PMID: 34199317 PMCID: PMC8232001 DOI: 10.3390/ijms22126332] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/02/2021] [Accepted: 06/09/2021] [Indexed: 12/19/2022] Open
Abstract
Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA; (N.P.); (P.C.)
| | - Pavlina Chrysafi
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA; (N.P.); (P.C.)
| | - Michael Feigh
- Gubra, Hørsholm Kongevej 11, B, 2970 Hørsholm, Denmark; (M.F.); (S.S.V.)
| | | | - Christos S. Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA; (N.P.); (P.C.)
- Department of Medicine, Boston VA Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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