Unlocking therapeutic potential of amlexanox in MASH with insights into bile acid metabolism and microbiome DOI Creative Commons
Wenjing You, Jianfei Ji,

Danwan Wen

et al.

npj gut and liver., Journal Year: 2025, Volume and Issue: 2(1)

Published: Feb. 1, 2025

Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health issue associated with obesity and diabetes. It is becoming leading cause of end-stage liver diseases such as cirrhosis hepatocellular carcinoma (HCC). Despite its increasing prevalence, effective pharmacotherapies for MASH remain limited, underscoring the urgent need novel interventions. Amlexanox, an inhibitor noncanonical IκB kinases, demonstrated potential in restoring insulin sensitivity glucose homeostasis obese mice human patients, shown our earlier studies. Here, we aimed to assess therapeutic amlexanox dyslipidemia-associated diseases, particularly HCC, elucidate underlying mechanism. We employed GAN diet-fed Ldlr−/− mice, which simultaneously develop obesity, MASH, atherosclerosis, recapitulate metabolic syndrome complications. Amlexanox was administrated orally these after disease onset examine efficacy. Our study demonstrates that even low dose significantly reversed nearly completely prevented progression from HCC. Both phenotypic transcriptomic studies revealed markedly improved MASH-related dyslipidemia, hepatic steatosis, inflammation, injury, fibrosis. Furthermore, multi-omics analysis enhances bile acid synthesis promotes fecal excretion. Notably, reprogrammed gut microbiota, robustly abundance Akkermansia muciniphila, probiotic known improve dysfunction. These findings uncover multifaceted treating atherosclerosis by targeting metabolism, highlights promising candidate clinical applications.

Language: Английский

Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal DOI Creative Commons
Li Chen, Tingying Jiao, Weiwei Liu

et al.

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(9), P. 1366 - 1381.e9

Published: Sept. 1, 2022

Language: Английский

Citations

99
Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets DOI Creative Commons
Joshua S. Fleishman, Sunil Kumar

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 25, 2024

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. acid signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, neoplastic conditions, strongly influencing health disease. No curative treatment exists for any bile influenced disease, while most promising well-developed therapeutic was recently rejected by FDA. Here, we provide bottom-up approach on mechanistically explaining their biochemistry, physiology, pharmacology at canonical non-canonical receptors. Using this mechanistic model explain how abnormal physiology drives disease pathogenesis, emphasizing ceramide synthesis may serve unifying pathogenic feature cardiometabolic diseases. We an in-depth summary pre-existing receptor modulators, shortcomings, propose solutions they be remedied. Lastly, rationalize novel targets further translational drug discovery future perspectives. Rather than dismissing therapeutics due to recent setbacks, believe that there is immense clinical potential high likelihood success therapeutics.

Language: Английский

Citations

72
The role of the gut microbiota in health and cardiovascular diseases DOI Creative Commons
Lu Wang, Shiqi Wang, Qing Zhang

et al.

Molecular Biomedicine, Journal Year: 2022, Volume and Issue: 3(1)

Published: Oct. 11, 2022

Abstract The gut microbiota is critical to human health, such as digesting nutrients, forming the intestinal epithelial barrier, regulating immune function, producing vitamins and hormones, metabolites interact with host. Meanwhile, increasing evidence indicates that has a strong correlation occurrence, progression treatment of cardiovascular diseases (CVDs). In patients CVDs corresponding risk factors, composition ratio have significant differences compared their healthy counterparts. Therefore, dysbiosis, microbiota-generated metabolites, related signaling pathway may serve explanations for some mechanisms about occurrence development CVDs. Several studies also demonstrated many traditional latest therapeutic treatments are associated its generated pathways. Given information, we summarized advances in current research regarding effect on main CVDs, highlighted roles several introduced promising microbiota. this review mainly focuses exploring role potential which eventually provide better solutions well prevention

Language: Английский

Citations

67
Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis DOI Open Access
Yuxin Yao, Yujie Yu, Shu Dai

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116694 - 116694

Published: May 6, 2024

The incidence of metabolic diseases has progressively increased, which a negative impact on human health and life safety globally. Due to the good efficacy limited side effects, there is growing interest in developing effective drugs treat from natural compounds. Kaempferol (KMP), an important flavonoid, exists many vegetables, fruits, traditional medicinal plants. Recently, KMP received widespread attention worldwide due its potential treatment diseases. To promote basic research clinical application KMP, this review provides timely comprehensive summary pharmacological advances four molecular mechanisms action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), atherosclerosis. According research, shows remarkable therapeutic effects by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, ER stress. In addition, most recent literature KMP's source, pharmacokinetics studies, well toxicity are also discussed review, thus providing foundation evidence for further studies develop novel Collectively, our manuscript strongly suggested that could be promising candidate

Language: Английский

Citations

15
A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development DOI Open Access

Tang Yu-hong,

Yujuan Fan, Yiming Wang

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116658 - 116658

Published: May 2, 2024

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. incidence NAFLD-induced cirrhosis is rapidly rising and become the leading indicator for transplantation in US. However, there are currently no US Food Drug Administration-approved drugs NAFLD. Increasing evidence underscores close association between NAFLD bile acid metabolism disorder, highlighting feasibility targeting signaling pathway treatment. farnesoid X receptor (FXR) endogenous acids that exhibits favorable effects ameliorating metabolic imbalance acids, lipid disorders, disruption intestinal homeostasis, all which key characteristics NAFLD, making FXR a promising therapeutic target present review provides comprehensive overview diverse mechanisms through improves particular emphasis on its involvement regulating homeostasis recent advancements drug development

Language: Английский

Citations

11
The Janus of a disease: Diabetes and metabolic dysfunction-associated fatty liver disease DOI Creative Commons
Francisco Barrera, Javier Uribe,

Nixa Olvares

et al.

Annals of Hepatology, Journal Year: 2024, Volume and Issue: 29(4), P. 101501 - 101501

Published: April 15, 2024

Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist synergistically contribute to the progression of each other. Several pathophysiological pathways involved in association, including insulin resistance, inflammation, lipotoxicity, providing a foundation for understanding complex interrelationships between these conditions. The presence MASLD has significant impact on diabetes risk development microvascular macrovascular complications, significantly contributes an increased liver fibrosis hepatocellular carcinoma. Moreover, both pathologies have synergistic effect cardiovascular events mortality. Therapeutic interventions targeting discussed, considering lifestyle modifications, pharmacological agents, emerging treatment modalities. review also addresses challenges managing comorbidities, such as need personalized approaches potential health. insights gleaned from this analysis can inform clinicians, researchers, policymakers developing integrated strategies preventing, diagnosing, disorders.

Language: Английский

Citations

9
Biomarkers for Health Functional Foods in Metabolic Dysfunction-Associated Steatotic Liver Disorder (MASLD) Prevention: An Integrative Analysis of Network Pharmacology, Gut Microbiota, and Multi-Omics DOI Open Access

Heng Yuan,

Eun-Soo Jung,

Soo-Wan Chae

et al.

Nutrients, Journal Year: 2024, Volume and Issue: 16(18), P. 3061 - 3061

Published: Sept. 11, 2024

Metabolic dysfunction-associated steatotic liver disorder (MASLD) is increasingly prevalent globally, highlighting the need for preventive strategies and early interventions. This comprehensive review explores potential of health functional foods (HFFs) to maintain healthy function prevent MASLD through an integrative analysis network pharmacology, gut microbiota, multi-omics approaches. We first examined biomarkers associated with MASLD, emphasizing complex interplay genetic, environmental, lifestyle factors. then applied pharmacology identify food components beneficial effects on metabolic function, elucidating their action mechanisms. identifies evaluates halting or reversing development disease in stages, as well that can evaluate success failure such strategies. The crucial role microbiota its metabolites prevention homeostasis discussed. also cover state-of-the-art omics approaches, including transcriptomics, metabolomics, integrated analyses, research preventing MASLD. These advanced technologies provide deeper insights into physiological mechanisms HFF development. concludes by proposing approach developing HFFs targeting prevention, considering Korean regulatory framework. outline future directions bridge gap between basic science practical applications narrative provides a foundation researchers industry professionals interested support health. Emphasis placed maintaining balance focusing early-stage intervention

Language: Английский

Citations

9
Golden bile powder prevents drunkenness and alcohol-induced liver injury in mice via the gut microbiota and metabolic modulation DOI Creative Commons
Yarong Wang,

Zhenzhuang Zou,

Sihua Wang

et al.

Chinese Medicine, Journal Year: 2024, Volume and Issue: 19(1)

Published: March 2, 2024

Abstract Background Drunkenness and alcoholic liver disease (ALD) are critical public health issues associated with significant morbidity mortality due to chronic overconsumption of alcohol. Traditional remedies, such as bear bile powder, have been historically acclaimed for their hepatoprotective properties. This study assessed the efficacy a biotransformed powder known golden (GBP) in alleviating alcohol-induced drunkenness ALD. Methods A murine model was engineered simulate alcohol acute hepatic injury through administration 50% ethanol solution. Intervention GBP its effects on alcohol-related symptoms were scrutinized, by employing an integrative approach that encompasses serum metabolomics, network medicine, gut microbiota profiling elucidate protective mechanisms GBP. Results significantly delayed onset decreased duration ethanol-induced inebriation mice. Enhanced cell recovery indicated increased aldehyde dehydrogenase levels superoxide dismutase activity, along decreases alanine aminotransferase, aspartate alkaline phosphatase, triglyceride, total cholesterol ( P < 0.05). These biochemical alterations suggest diminished damage enhanced lipid homeostasis. Microbiota analysis via 16S rDNA sequencing revealed changes microbial diversity composition following exposure, these effectively reversed treatment. Metabolomic analyses demonstrated normalized perturbations phospholipids, fatty acids, acids. Correlation assessments linked distinct genera acid profiles, indicating may be attributable modulatory metabolism composition. Network medicine insights prominence two active agents addressing Conclusion is potent intervention pathology offers benefits, at least part, modulation related metabolic cascades.

Language: Английский

Citations

8
Supplementation of Silymarin Alone or in Combination with Salvianolic Acids B and Puerarin Regulates Gut Microbiota and Its Metabolism to Improve High-Fat Diet-Induced NAFLD in Mice DOI Open Access

Xin Wang,

Yufeng Jin,

Can Di

et al.

Nutrients, Journal Year: 2024, Volume and Issue: 16(8), P. 1169 - 1169

Published: April 14, 2024

Silymarin, salvianolic acids B, and puerarin were considered healthy food agents with tremendous potential to ameliorate non-alcoholic fatty liver disease (NAFLD). However, the mechanisms by which they interact gut microbiota exert benefits are largely unknown. After 8 weeks of NAFLD modeling, C57BL/6J mice randomly divided into five groups fed a normal diet, high-fat diet (HFD), or HFD supplemented medium high dose Silybum marianum extract contained silymarin polyherbal silymarin, for 16 weeks, respectively. The untargeted metabolomics 16S rRNA sequencing used molecular exploration. intervention significantly improved steatosis recovered function in mice, accompanied an increase probiotics like Akkermansia Blautia, suppressed Clostridium, related changes bile profile feces serum. Fecal microbiome transplantation confirmed that this alteration its metabolites responsible improvement NAFLD. present study substantiated alterations upon have beneficial effects on HFD-induced hepatic suggested pivotal role amelioration

Language: Английский

Citations

8
Dual GIP and GLP-1 receptor agonist tirzepatide alleviates hepatic steatosis and modulates gut microbiota and bile acid metabolism in diabetic mice DOI

Weiting Hu,

Wenyu Gong,

Fan Yang

et al.

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 147, P. 113937 - 113937

Published: Jan. 2, 2025

Language: Английский

Citations

1