Dysregulated bile acid homeostasis:unveiling its role in metabolic diseases

Maintaining bile acid homeostasis is essential for metabolic health.Bile acid homeostasis encompasses a complex interplay between biosynthesis,conjugation,secretion,and reabsorption.Beyond their vital role in digestion and absorption of lipid-soluble nutrients,bile acids are pivotal in systemic metabolic regulation.Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases,including obesity,type 2 diabetes melli-tus(T2DM),and metabolic dysfunction-associated steatotic liver disease(MASLD).Bile acids are essential signaling molecules that regulate many critical biological processes,including lipid metabolism,energy expenditure,insulin sensitivity,and glucose metabolism.Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms,hormonal dysregu-lation,interactions with the gut microbiota,and changes in the expression and function of bile acid transporters and receptors.This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity,T2DM,and MASLD.We aim to underscore the significance of bile acids as potential diag-nostic markers and therapeutic agents in the context of metabolic diseases,providing insights into their application in translational medicine.

Extracellular signal regulated kinase 5 promotes cell migration,invasion and lung metastasis in a FAK-dependent manner

This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma.We show that ERK5 expression is abundant in human lung cancer samples,and elevated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive potential.Importantly,we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site.Mechanistically,ERK5 increased the expression of the transcription factor USF1,which could transcriptionally upregulate FAK expression,resulting in FAK signaling activation to promote cell migration.We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2,and we then suggested a role for Ser910 in the control of cell motility.In addition,ERK5 had targets in addition to FAK that regulate epithelial-to-mesenchymal transition and cell motility in cancer cells.Taken together,our findings uncover a cancer metastasis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.

ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis

Owing to the increasing incidence and prevalence of inflammatory bowel disease(IBD)worldwide,effective and safe treatments for IBD are urgently needed.Hydrogen sulfide(H2S)is an endogenous gasotransmitter and plays an important role in inflammation.To date,H2S-releasing agents are viewed as potential anti-inflammatory drugs.The slow-releasing H_(2)S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione(ADT-OH),known as a potent therapeutic with chemopreventive and cytoprotective properties,has received attention recently.Here,we reported its anti-inflammatory effects on dextran sodium sulfate(DSS)-induced acute(7 days)and chronic(30 days)colitis.We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length.Moreover,ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway.In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels.In addition,ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter,Mucispirillum,Parasutterella,and Desulfovibrio.Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines.Collectively,ADT-OH is safe without any short-term(5 days)or long-term(30 days)toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.