Cell Biochemistry and Function最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 32.4% of the global population. It is expected to be the primary cause of end-stage liver disease and liver transplantation. Obesity is a major risk factor for MASLD. However, a subset of patients with MASLD does not exhibit obesity-related traits, and this group is frequently neglected in clinical workups. Therefore, these patients do not receive timely diagnosis and treatment. Research has shown that MASLD is a multisystemic disease that is linked not only to type 2 diabetes mellitus but also to end-stage liver disorders (cirrhosis, liver failure, and hepatocellular carcinoma), cardiovascular disease, and chronic kidney disease. Thus, lean patients with MASLD are likely to develop liver fibrosis and end-stage liver disease. They are also at a high risk of cardiovascular disease and mortality. In this review, we systematically summarized the epidemiological characteristics and pathophysiological mechanisms of lean MASLD to elucidate the clinical profile and molecular basis of this disease subtype while proposing targeted integrated management strategies. By addressing critical gaps in current clinical practice, including shortcomings in screening, incomplete risk assessment frameworks, and the lack of individualized treatment approaches, this review provides practical guidance for reducing the risk of end-stage liver disease and extrahepatic complications in this patient population.

CML is a myeloproliferative disease related to several cases of resistance and intolerance to treatments; therefore, the search for new therapeutic agents in natural products has become increasingly important. The chemical diversity and bioactive structures among fungal secondary metabolites (FSM) are enormous and still little explored as potential antileukemic drugs. Thus, the objective of this review is to provide information on articles in the literature that used FSM as agents against CML and to discuss them critically to direct new studies against this disease. We analyzed 26 scientific articles published in the last 20 years that identified or did not identify the main mechanism of action in the form of either an isolated compound or a complex extract in CML models. In vitro studies with the K562 cell line demonstrated that compounds such as nipecotic acid, nicotinic acid, neosetofomon B, greensporone A and C, and isosuilin induce apoptosis, promote cell cycle arrest, and modulate crucial signaling pathways, including PI3K/AKT/mTOR and NF-κB at promising concentrations. The action of these metabolites involves the regulation of pro- and antiapoptotic proteins, caspase activation, and DNA damage, highlighting their ability to interfere with processes essential for the survival of leukemic cells. Alkaloids and terpenoids were the most promising classes observed. Although there have been important advances, it is still necessary to identify the mechanism of action of several compounds and their possible association with conventional anti-CML agents. FSM represents a valuable and still little-explored source for the development of new strategies for CML.

Drinking behavior, especially binge drinking, has a debilitating impact on systemic health. In this study, we report that in the absence of any changes in hepatic lactate dehydrogenase activity, the cardiac glycogen level fluctuates following short-term binge drinking. The change in cardiac glycogen levels follows a sex specific pattern. Our work is first to demonstrate that early metabolic changes in the heart, specifically glycogen levels, can be an ideal readout for forthcoming hepatic and systemic complications following binge drinking at an earlier stage. Also, females demonstrate a robust change in cardiac glycogen levels in comparison to their binge drinking male counterparts following short-term exposure, hinting at an early cardiometabolic risk in females. This study prompts us to look at early metabolic changes in the heart as a marker for binge drinking-mediated injury.

Breast cancer remains the most commonly diagnosed cancer and a leading cause of cancer-related mortality among women worldwide. Despite advancements in treatment, resistance and toxicity issues highlight the urgent need for novel, effective, and safer therapeutic agents. Natural compounds are increasingly explored as promising sources of anticancer candidates due to their structural diversity and bioactivity. Among these, polyols, a class of sugar alcohols, have been reported to influence cancer cell behaviour by modulating oxidative stress, metabolic pathways and apoptosis, though their precise mechanisms and therapeutic potential remain underexplored. In this study, the anticancer potential of dulcitol, a naturally occurring polyol, was investigated in breast cancer cell lines with different molecular profiles. The cytotoxic effects of dulcitol were assessed using the MTT assay in MCF-7 (ER-positive), MDA-MB-231 (triple-negative), and MCF-10A (non-tumorigenic) breast cell lines. Mechanistic studies including flow cytometry-based cell cycle analysis, apoptosis detection (Annexin V-FITC), mitochondrial membrane potential assessment, caspase activation, and DNA damage analysis were performed on MDA-MB-231 cells. The expression levels of MMP-2 and MMP-9 genes were also evaluated using qRT-PCR. Dulcitol exhibited selective cytotoxicity against MDA-MB-231 cells at concentrations ≥ 7.5 mmol/L, while showing no significant effects on MCF-7 and MCF-10A cells. In MDA-MB-231 cells, dulcitol induced G0/G1 phase cell cycle arrest and promoted apoptosis in a dose-dependent manner. Additionally, increased caspase activity and mitochondrial depolarization were observed, indicating activation of the intrinsic apoptotic pathway. No significant DNA damage was detected; however, a significant downregulation of MMP-2 and MMP-9 expression suggested potential antimetastatic activity. Although the effective in vitro concentrations were relatively high, it should be noted that such levels are commonly required to reveal mechanistic effects in cell-based systems, and pharmacokinetic data on dulcitol are currently unavailable. Therefore, the present findings should be regarded as exploratory and hypothesis-generating, emphasizing the need for in vivo pharmacokinetic and efficacy studies to evaluate translational feasibility. In conclusion, our findings demonstrate that dulcitol selectively targets triple-negative breast cancer cells without affecting normal or ER-positive breast cells. Its ability to induce apoptosis and suppress metastatic gene expression highlights its promise as a potential natural therapeutic candidate for aggressive breast cancer subtypes.

This study investigates p16/p21 senescence marker heterogeneity in diabetes-related tissues using the p21-3MR mouse model, focusing on p16 and p21 as senescence markers. Type 2 diabetes, a common age-related disease, impacts multiple organs; the study examines the heterogeneous distribution of senescence markers in tissues including the pancreas, kidney, heart, adipose tissue, femur, spleen, thymus, liver, and lungs. The results reveal significant spatiotemporal heterogeneity in p16/p21 co-expression patterns across different organs during diabetes progression, with varying responses to senescent cell clearance treatments. Specifically, the combination of dasatinib and quercetin demonstrated superior reduction in p16/p21 dual-positive cells in several tissues compared to p21 intervention alone, while p21 intervention showed distinct effects on marker expression in adipose tissue and bone marrow. Immune organs displayed heterogeneity in p16-associated immunosenescence, and the liver and lungs showed greater p16/p21 expression in vascular niches. This is the first study to use the p21-3MR model to explore p16/p21 marker heterogeneity and differential clearance efficacy of senolytic treatments in diabetic tissues. The findings highlight the need for tissue-specific senolytic strategies, particularly targeting adipocytes and metabolic disorders. Future research should focus on understanding the mechanisms of p21^high cell persistence, offering insights for more senescence-targeted treatments.