Metabolism: clinical and experimental最新文献

Metabolism of Branched-chain amino acids (BCAAs) is essential for the nutrient necessities in mammals. Catalytic enzymes serve to direct the whole-body BCAAs oxidation which involve in the development of various metabolic disorders. The reprogrammed metabolic elements are also responsible for malignant oncogenic processes, and favor the formation of distinctive immunosuppressive microenvironment surrounding different cancers. The impotent immune surveillance related to BCAAs dysfunction is a novel topic to investigate. Here we focus on the BCAA catalysts that contribute to metabolic changes and dysregulated immune reactions in cancer progression. We summarize the current knowledge of BCAA catalyzation, highlighting the interesting roles of BCAA metabolism in the treatment of cancers.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it the leading etiology of chronic liver diseases and a prime cause of liver-related mortality. MASLD can progress into steatohepatitis (termed MASH), fibrosis, cirrhosis, and ultimately cancer. MASLD is associated with increased risks of hepatocellular carcinoma (HCC) and also extrahepatic malignancies, which can develop in both cirrhotic and non-cirrhotic patients, emphasizing the importance of identifying patients with MASLD at risk of developing MASLD-associated malignancies. However, the optimal screening, diagnostic, and risk stratification strategies for patients with MASLD at risk of cancer are still under debate. Individuals with MASH-associated cirrhosis are recommended to undergo surveillance for HCC (e.g. by ultrasound and biomarkers) every six months. No specific screening approaches for MASLD-related malignancies in non-cirrhotic cases are established to date. The rapidly developing omics technologies, including genetics, metabolomics, and proteomics, show great potential for discovering non-invasive markers to fulfill this unmet need. This review provides an overview on the incidence and mortality of MASLD-associated malignancies, current strategies for HCC screening, surveillance and diagnosis in patients with MASLD, and the evolving role of omics technologies in the discovery of non-invasive markers for the prediction and risk stratification of MASLD-associated HCC.

Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern with significant implications for oncogenesis. This review synthesizes current evidence on the association between MASLD and cancer risk, highlighting its role as a risk factor for both intrahepatic and extrahepatic malignancies. MASLD is increasingly recognized as a major cause of hepatocellular carcinoma (HCC), with its incidence rising in parallel with the prevalence of metabolic dysfunction. Furthermore, MASLD is associated with an elevated risk of various gastrointestinal cancers, including colorectal, esophageal, stomach, and pancreatic cancers. Beyond the digestive tract, evidence suggests that MASLD may also contribute to an increased risk of other cancers such as breast, prostate, thyroid, gynecological, renal and lung cancers. Understanding the mechanisms underlying these associations and the impact of MASLD on cancer risk is crucial for developing targeted screening and prevention strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant and ever-increasing health and economic burden worldwide. Substantial epidemiological evidence shows that MASLD is a multisystem disease that is associated not only with liver-related complications but is also associated with an increased risk of developing cardiometabolic comorbidities and extrahepatic cancers (principally gastrointestinal [GI] cancers). GI cancers account for a quarter of the global cancer incidence and a third of cancer-related deaths. In this narrative review, we provide an overview of the literature on (a) the epidemiological data on the risk of non-liver GI cancers in MASLD, (b) the putative mechanisms by which MASLD (and factors linked with MASLD) may increase this risk, and (c) the possible pharmacotherapies beneficially affecting both MASLD and extrahepatic GI cancer risk. There are multiple potential pathophysiological mechanisms by which MASLD may increase extrahepatic GI cancer risk. Although further studies are needed, the current evidence supports a possible extrahepatic carcinogenic role for MASLD, regardless of obesity and diabetes status, thus highlighting the potential role of tailoring cancer screening for individuals with MASLD. Although there are conflicting data in the literature, aspirin, statins and metformin appear to exert some chemo-preventive effects against GI cancer.

Objective

This study tested the hypothesis that administration of the KCa channel activator SKA-31 restores endothelium-dependent vasodilation in vivo in Type 2 Diabetic (T2D) rats.

Background

Acute treatment of isolated resistance arteries from T2D rats and humans with SKA-31 significantly improved endothelium-dependent vasodilation. However, it is unknown whether these in situ actions translate to intact vascular beds in vivo.

Methods

Male Sprague Dawley (SD) and T2D Goto-Kakizaki (GK) rats (26–32 weeks of age) were injected intraperitoneally with either drug vehicle or 10 mg/kg SKA-31. Doppler ultrasound imaging was used to record reactive hyperemia/flow-mediated dilation (FMD) in the femoral artery following release of an occlusion cuff on the distal hind limb, along with diameter changes in the left main coronary artery in response to inhaled isoflurane (2 % → 5 %).

Results

Vehicle treated SD rats exhibited a robust and reversible FMD response, the magnitude and time course of which did not differ in SD rats treated with SKA-31. In contrast, only a weak FMD response was observed in vehicle-treated T2D GK rats, whereas prior SKA-31 administration restored FMD to the level observed in control SD rats. Exposure of SD rats to 5 % isoflurane caused robust coronary artery dilation, which was not altered by prior treatment with SKA-31. In T2D GK rats, 5 % isoflurane inhalation alone did not increase coronary artery diameter, however, a strong vasodilatory response was observed following SKA-31 treatment. SKA-31 administration did not modify intrinsic heart rate responses in either protocol.

Conclusions

Enhancement of KCa channel activity in vivo restores endothelium-dependent vasodilation in T2D rats that exhibit peripheral endothelial dysfunction.

Background

Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex.

Methods

Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI).

Results

In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190–259] DALYs), whilst T2DM (75 million [95 % UI: 63–90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90–4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34–0.51]) and obesity (0.26 % [95 % UI: 0.17–0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (−0.30 % [95 % UI: −0.34 to −0.25]) and hypercholesterolemia (−0.33 % [95 % UI: −0.37 to −0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: −0.06 to 0.17]).

Conclusion

In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.

The rising prevalence of obesity-related illnesses, such as metabolic steatotic liver disease (MASLD), represents a significant global public health concern. This disease affects approximately 30 % of the adult population and is the result of metabolic abnormalities rather than alcohol consumption. Additionally, MASLD is associated with an increased risk of cardiovascular disease (CVD), chronic liver disease, and a variety of cancers, particularly gastrointestinal cancers. Clonal hematopoiesis (CH) is a biological state characterized by the expansion of a population of blood cells derived from a single mutated hematopoietic stem cell. The presence of CH in the absence of a diagnosed blood disorder or cytopenia is known as clonal hematopoiesis of indeterminate potential (CHIP), which itself increases the risk of hematological malignancies and CVD. Steatotic liver disease may also complicate the clinical course of cancer patients receiving antineoplastic agents, a condition referred to as chemotherapy induced steatohepatitis (CASH). This review will present an outline of the various aspects of MASLD, including complications. Furthermore, it will summarize the existing knowledge on the emerging association between CHIP and MASLD and present the available data on patient cases with concurrent MASLD and hematological neoplasms. Finally, it will provide a brief overview of the chemotherapeutic drugs associated with CASH, the underlying pathophysiologic mechanisms and their clinical implications.

Sarcopenia is a geriatric syndrome characterized by a functional decline in muscle. The prevalence of sarcopenia increases with natural aging, becoming a serious health problem among elderly individuals. Therefore, understanding the pathology of sarcopenia is critical for inhibiting age-related alterations and promoting health and longevity in elderly individuals.

The development of sarcopenia may be influenced by interactions between visceral and subcutaneous adipose tissue and skeletal muscle, particularly under conditions of chronic low-grade inflammation and metabolic dysfunction. This hypothesis is supported by the following observations: (i) accumulation of senescent cells in both adipose tissue and skeletal muscle with age; (ii) gut dysbiosis, characterized by an imbalance in gut microbial communities as the main trigger for inflammation, sarcopenia, and aged adipose tissue; and (iii) microbial dysbiosis, which could impact the onset or progression of a senescent state. Moreover, adipose tissue acts as an endocrine organ, releasing molecules that participate in intricate communication networks between organs. Our discussion focuses on novel adipokines and their role in regulating adipose tissue and muscle, particularly those influenced by aging and obesity, emphasizing their contributions to disease development. On the basis of these findings, we propose that age-related adipose tissue and sarcopenia are disorders characterized by chronic inflammation and metabolic dysregulation. Finally, we explore new potential therapeutic strategies involving specialized proresolving mediator (SPM) G protein-coupled receptor (GPCR) agonists, non-SPM GPCR agonists, transient receptor potential (TRP) channels, antidiabetic drugs in conjunction with probiotics and prebiotics, and compounds designed to target senescent cells and mitigate their pro-inflammatory activity.