Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

Pharmacological Reviews, Год журнала: 2024, Номер 76(3), С. 454 - 499

Опубликована: Янв. 30, 2024

Steatotic liver disease (SLD) displays a dynamic and complex phenotype. Consequently, the metabolic dysfunction-associated steatotic (MASLD)/metabolic steatohepatitis (MASH) therapeutic pipeline is expanding rapidly in multiple directions. In parallel, non-invasive tools for diagnosing monitoring responses to interventions are being studied, clinically feasible findings explored as primary outcomes interventional trials. The realization that distinct subgroups exist under umbrella of SLD should guide more precise personalized treatment recommendations facilitate advancements pharmacotherapeutics. This review summarizes recent updates pathophysiology-based nomenclature outlines both effective pharmacotherapeutics those MASLD/MASH, detailing their mode action current status phase 2 3 clinical Of extensive arsenal MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, shown only marginal benefits now tested part combination therapies, yet others still development monotherapies. Although successful drug candidate (or combinations) remains elusive, such approaches will ideally target MASH fibrosis while improving cardiometabolic risk factors. Due urgent need novel strategies potential availability safety tolerability data, repurposing existing approved drugs an appealing option. Finally, it essential highlight and, by extension, MASLD be recognized approached systemic affecting organs, with vigorous implementation interdisciplinary coordinated plans. Significance Statement SLD, including, among others, MASH, considered most prevalent chronic condition than one-fourth global population. aims provide information regarding pathophysiology, diagnosis, management line guidelines Collectively, hoped provided furthers understanding state direct implications stimulates additional research initiatives.

Язык: Английский

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Sarcopenia, sarcopenic obesity and nonalcoholic fatty liver disease

Metabolism, Год журнала: 2023, Номер 147, С. 155676 - 155676

Опубликована: Авг. 4, 2023

Язык: Английский

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Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies

Archives of Pharmacal Research, Год журнала: 2024, Номер 47(4), С. 301 - 324

Опубликована: Апрель 1, 2024

Язык: Английский

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Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Янв. 19, 2024

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, connection between chronic complications has been revealed. However, effects non-steroidal anti-inflammatory drug celecoxib on remains unclear. Materials Methods: The streptozotocin (streptozotocin)-induced model was established. Rotarod test grip strength were used assess function. Hematoxylin eosin immunofluorescence staining performed evaluate inflammatory infiltration morphology motor endplates muscles. Succinate dehydrogenase (SDH) determine number succinate dehydrogenase-positive fibers. Dihydroethidium levels reactive oxygen species (ROS). Western blot measure proteins involved inflammation, oxidative stress, endoplasmic reticulum ubiquitination, autophagic-lysosomal pathway. Transmission electron microscopy mitophagy. Results: Celecoxib significantly ameliorated atrophy, improving function preserving mice. also decreased cell, reduced IL-6 TNF-α, suppressed activation NF-κB, Stat3, NLRP3 inflammasome pathways levels, downregulated Nox2 Nox4, upregulated GPX1 Nrf2, further stress by inhibiting Perk-EIF-2α-ATF4-Chop inhibited Foxo3a, Fbx32 MuRF1 ubiquitin-proteasome system, as well BNIP3, Beclin1, ATG7, LC3Ⅱ protected mitochondria promoted mitochondrial biogenesis elevating SIRT1 PGC1-α, increased SDH-positive fibers Conclusion: improved protecting mitochondria, subsequently suppressing proteolytic systems. study provides evidences molecular mechanism treatment sarcopenia, broaden way new use

Язык: Английский

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High-fat diet induces sarcopenic obesity in natural aging rats through the gut–trimethylamine N-oxide–muscle axis

Journal of Advanced Research, Год журнала: 2024, Номер unknown

Опубликована: Май 1, 2024

The lack of suitable animal models for sarcopenic obesity (SO) limits in-depth research into the disease. Emerging studies have demonstrated that gut dysbiosis is involved in development SO. As importance microbial metabolites starting to unveil, it necessary comprehend specific associated with microbiota and We aimed investigate whether high-fat diet (HFD) causes SO natural aging are linking HFD Young rats received or control 80 weeks, obesity-related metabolic disorders sarcopenia were measured. 16S rRNA sequencing non-targeted targeted metabolomics methods used detect fecal serum metabolites. Gut barrier function was evaluated by intestinal integrity permeability. Trimethylamine N-oxide (TMAO) treatment further conducted verification. resulted body weight gain, dyslipidemia, impaired glucose tolerance, insulin resistance, systemic inflammation rats. also caused decreases muscle mass, strength, function, fiber cross-sectional area increase fatty infiltration nontargeted analysis indicated contributed dysbiosis, mainly characterized increases deleterious bacteria TMAO. destroyed increased permeability, as reducing levels colonic mucin-2, tight junction proteins, goblet cells elevating level fluorescein isothiocyanate-dextran 4. Correlation showed a positive association between TMAO In addition, aggravated HFD-fed aged through regulating ROS-AKT/mTOR signaling pathway. leads rats, partially gut-microbiota-TMAO-muscle axis.

Язык: Английский

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Adiponectin regulates proliferation and differentiation of chicken skeletal muscle satellite cells via ERK1/2 and p38 signaling pathways

Poultry Science, Год журнала: 2025, Номер 104(2), С. 104813 - 104813

Опубликована: Янв. 13, 2025

Skeletal muscle satellite cells (SMSCs) are critical for postnatal skeletal growth and regeneration. Adiponectin plays a pivotal role in regulating glucose uptake fatty acid metabolism. However, its function the proliferation differentiation of chicken SMSCs remains poorly understood. In this study, we investigated effects adiponectin on vitro cultured SMSCs. Our results demonstrated that promoted while inhibiting myogenic inducing adipogenic differentiation. RNA-seq analysis revealed enrichment MAPK signaling pathway, suggesting potential involvement regulation activity. Western blot activated ERK1/2 phosphorylation inhibited p38 during process inhibition Furthermore, suppression with U0126 or activation SSK1 reversed downregulated expression marker MyHC, MyOD1, MyOG induced by adiponectin. These findings validated impeded through pathways. Additionally, pathway reduced increased percentage EdU-positive Collectively, these impedes activating pathways, promoting pathway.

Язык: Английский

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Role of Inflammatory Biomarkers in Mediating Causal Effect of Life Course Body Composition on Hypertension

Hypertension, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

BACKGROUND: The mediating role of inflammatory biomarkers in the causal relationship between body composition and hypertension remains unclear requires further investigation. METHODS: This study used a combination retrospective observational analysis Mendelian randomization approaches. Observational data were derived from 4717 Chinese children adolescents aged 6 to 18 years who underwent dual-energy X-ray absorptiometry assess composition. analyses utilized summary statistics large-scale sets, including UK Biobank, deCODE2021, International Consortium Blood Pressure, FinnGen, other consortia. included leptin, insulin, adiponectin, osteocalcin, FGF23 (fibroblast growth factor 23), PTH (parathyroid hormone). RESULTS: revealed that increased fat mass positively influenced diastolic blood pressure through while fat-free had an inverse effect. Insulin mediated association systolic pressure, hypertension, with additional indirect effects observed for (all P <0.05). demonstrated childhood index by insulin (indirect effect: odds ratio, 0.87 [95% CI, 0.78–0.97]) adiponectin (odds 1.13 1.04–1.23]). Adiponectin 0.81 0.71–0.93]) 1.30 1.11–1.51]) on hypertension. Leptin, also CONCLUSIONS: These findings indicate influences distinct biomarkers. Targeting may provide tailored strategies managing

Язык: Английский

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Crosstalk between autophagy and insulin resistance: evidence from different tissues

European journal of medical research, Год журнала: 2023, Номер 28(1)

Опубликована: Окт. 25, 2023

Insulin is a critical hormone that promotes energy storage in various tissues, as well anabolic functions. resistance significantly reduces these responses, resulting pathological conditions, such obesity and type 2 diabetes mellitus (T2DM). The management of insulin requires better knowledge its pathophysiological mechanisms to prevent secondary complications, cardiovascular diseases (CVDs). Recent evidence regarding the etiological behind emphasizes role imbalance neurohormonal dysregulation, both which are closely regulated by autophagy. Autophagy conserved process maintains homeostasis cells. Accordingly, autophagy abnormalities have been linked variety metabolic disorders, including resistance, T2DM, obesity, CVDs. Thus, there may be link between resistance. Therefore, interaction function will examined this review, particularly insulin-responsive adipose tissue, liver, skeletal muscle.

Язык: Английский

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Mediating role of inflammatory biomarkers in the causal effect of body composition on glycaemic traits and type 2 diabetes

Diabetes Obesity and Metabolism, Год журнала: 2024, Номер 26(11), С. 5444 - 5454

Опубликована: Сен. 4, 2024

Abstract Objective The aim was to investigate the mediating role of inflammatory biomarkers in causal effect body composition on glycaemic traits and type 2 diabetes. Methods A retrospective observational study a Mendelian randomization (MR) were used. Observational analyses performed using data from 4717 Chinese children adolescents aged 6–18 years who underwent dual‐energy X‐ray absorptiometry for composition. MR based summary statistics UK Biobank, deCODE2021, Meta‐Analysis Glucose Insulin‐Related Traits Consortium (MAGIC) other large consortiums. Inflammatory included leptin, adiponectin, osteocalcin, fibroblast growth factor 23 (FGF23) parathyroid hormone (PTH). Results In study, increased fat mass had positive homeostasis model assessment insulin resistance (HOMA‐IR) pancreatic beta cell function (HOMA‐β) through FGF23, whereas fat‐free produced opposite effects. PTH osteocalcin played significant roles association with fasting glucose, HOMA‐IR (all p < 0.05). Mediation results indicated that childhood index affected leptin adiponectin. There existed diabetes via FGF23 (indirect effect: OR [odds ratio]: 1.14 [95% CI, confidence interval: 1.01–1.28]) adiponectin (OR: 0.85 CI: 0.77–0.93]). Leptin mediated β: −0.05 −0.07, −0.02]) (β: 0.03 0.01, 0.04]) glucose. Conclusions Our findings suggest different compositions have differential influences distinct biomarkers. may be helpful tailoring management statuses.

Язык: Английский

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Prognostic Impact of Sarcopenic Obesity on Postoperative Outcomes in Colorectal Cancer Patients Undergoing Surgery: A Systematic Review and Meta-Analysis

Nutrition and Cancer, Год журнала: 2025, Номер unknown, С. 1 - 12

Опубликована: Янв. 11, 2025

Sarcopenic obesity is a condition in which the coexistence of sarcopenia and may have unfavorable prognostic implications cancer. This meta-analysis aims to evaluate effects sarcopenic on postoperative outcomes patients undergoing colorectal cancer surgery. A systematic literature search was conducted Scopus, PubMed, Web Science databases for articles up February 8, 2024. The primary were overall major complications survival. random- or fixed-effects model used each case based heterogeneity, both subgroup sensitivity analyses performed. Twenty studies with 11,264 included. prevalence 14.5%. found be risk factor [pooled OR: 1.69 (95% CI: 1.26–2.26); p < 0.001] 1.64 1.06–2.55); = 0.028]. effect survival not significant HR: 1.24 0.98–1.56); 0.076], but significance varied some subgroups. Furthermore, associated an increased 30-day mortality, prolonged hospitalization. In conclusion, after surgery; therefore, it useful include diagnosis when formulating disease prognosis.

Язык: Английский

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