Diabetes-related cognitive impairment (DCI) is a severe complication of type 2 diabetes mellitus (T2DM), with limited understanding of its molecular mechanisms hindering effective therapeutic development. This study identified SERPINA3 as a potential therapeutic target for DCI through integrated machine learning and molecular docking analyses. Transcriptomic data from cortical neuronal samples of T2DM patients were analysed using support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression, revealing SERPINA3 as a significantly upregulated gene in DCI. Experimental validation via Western blot confirmed elevated SERPINA3 protein levels in DCI patient plasma. Molecular docking demonstrated the stable binding of sulfonylurea hypoglycaemic agents, such as gliclazide and glimepiride, to SERPINA3, with binding energies of -6.8 and -6.6 kcal/mol, respectively. These findings suggest that SERPINA3 plays a pivotal role in DCI pathogenesis and that sulfonylurea drugs may exert neuroprotective effects through SERPINA3-mediated pathways. This study provides novel insights into the molecular mechanisms of DCI and highlights the potential of SERPINA3-targeted therapies for early intervention and treatment. Further research is warranted to validate these findings in larger cohorts and explore their clinical applicability.

Maternal exercise can improve the metabolic health of the offspring. However, the molecular mechanisms underlying the beneficial effects of maternal exercise on the offspring remain unclear. Here, we show that maternal exercise during pregnancy alleviates high-fat diet (HFD)-induced adipose inflammation and glucose intolerance in offspring mice, accompanied by upregulation of the adipokine serine protease inhibitor A3C (SERPINA3C) both in maternal adipose tissues and the fetal circulation. Adipose SERPINA3C knockdown impairs, but its overexpression in dams mimics, maternal exercise-mediated metabolic benefits in HFD-fed offspring. Maternal SERPINA3C is transported into the fetal circulation and promotes Krüppel-like factor 4 (Klf4) gene promoter demethylation in fetal preadipocytes to increase KLF4 expression, which inhibits adipose inflammation in HFD-fed offspring mice. The SERPINA3C-cathepsin G-integrin β1 axis activates phosphatidylinositol 3-kinase signalling in preadipocytes. This promotes nuclear translocation of the p110β subunit to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the nucleus. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase then binds to PIP3 to promote ten-eleven translocation methylcytosine dioxygenase 1 (TET1) O-GlcNAcylation, thereby enhancing TET1 activity to facilitate Klf4 gene promoter demethylation. These results provide mechanistic insights into maternal exercise-mediated improvement of offspring metabolism.

UpToDate, no drugs have been approved to treat nonalcoholic steatohepatitis, the advanced stage of the most prevalent liver disease, non-alcoholic fatty liver disease. The present study was conducted to explore the potential influences of L-carnitine on the pathomechanisms of hepatic injury that mediate progression to non-alcoholic steatohepatitis in dexamethasone-toxified rats.

Male Wistar rats were allocated as follows: dexamethasone group, rats received dexamethasone (8 mg/kg/day, intraperitoneally) for 6 days; DEXA-LCAR300, DEXA-LCAR500, and DEXA-MET groups, rats administered L-carnitine (300 or 500 mg/kg/day, IP) or metformin (500 mg/kg/day, orally) one week prior to dexamethasone injection (8 mg/kg/day, IP) and other six days alongside dexamethasone administration. Two groups of age-matched normal rats received either the drug vehicle (the control group) or the higher dose of L-carnitine (the drug-control group). At the end of the experiment, sets of biochemical, histological, and immunohistochemical examinations were performed.

L-carnitine (mainly at the dose of 500 mg/kg/day) markedly abolished dexamethasone-induced alterations in glucose tolerance, hepatic histological features, and serum parameters of hepatic function and lipid profile. Moreover, it significantly ameliorated dexamethasone-induced elevations of hepatic oxidative stress, SREBP-1 and p-MLKL protein levels, and nuclear FOXO1, LC3, P62, and caspase-3 immunohistochemical expression. Furthermore, it markedly diminished dexamethasone-induced suppression of hepatic Akt phosphorylation and Bcl2 immunohistochemical expression. The effects of L-carnitine (500 mg/kg/day) were comparable to those of metformin in most assessments and better than its corresponding lower dose.

These findings introduce L-carnitine as a potential protective drug that may mitigate the rate of disease progression in non-alcoholic fatty liver disease patients with early stages or those at the highest risks.

Because of the delicate structure of the adipose tissue, fat necrosis accounts for 43.7% of all complications after autologous fat grafting; however, its regulation remains unclear.

The purpose of this study was to examine the role of necroptosis in fat graft remodeling after grafting.

Clinical fat graft necrosis samples were collected, and the expression levels of the necroptosis marker phosphorylated(p)-MLKL were analyzed. Transcriptome analysis was performed on fat grafts before and 1 week after transplantation in C57BL/6 mouse fat grafting models. Additionally, the in vivo effects of RIPK1 inhibitor Nec-1s or RIPK3 inhibitor GSK'872 on the fat grafting complications, including fat necrosis and fibrosis, were investigated.

Necroptosis markers were observed and associated with higher occurrence of fibrosis in clinical fat graft necrosis samples compared to normal fat tissue. Amplification and RNA-Seq were conducted on RNA isolated from fat grafts before and after grafting. MLKL, RIPK1, and RIPK3's expression levels were significantly upregulated in comparison to controls. Higher expression levels of necroptotic RNAs were associated with higher levels of DAMPs, including Cxcl2, HMGB1, S100a8, S100a9, Nlrp3, and IL33, and activated proinflammatory signaling pathways, including the TNF, NF-kappa B, and chemokine signaling pathways. Necroptotic inhibitor Nec-1s and GSK'872 robustly suppressed the p-MLKL expression level and significantly inhibited necroptotic cell death, especially in adipocytes. Moreover, administration of Nec-1s and GSK'872 significantly alleviated fat necrosis and subsequent fibrosis in fat grafts.

Collectively, our study findings highlight the potential therapeutic applications of necroptosis inhibitors in preventing fat necrosis and fibrosis after grafting.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

Evidence indicates that chronic non-alcoholic fatty liver disease (NAFLD) can increase the risk of atherosclerosis (AS), but the underlying mechanism remains unclear.

This study is intended for confirming key genes shared between NAFLD and AS, and their clinical diagnostic value to establish a foundation for searching novel therapeutic targets.

We downloaded the Gene Expression Omnibus (GEO) datasets, GSE48452 and GSE89632 for NAFLD and GSE100927, GSE40231 and GSE28829 for AS. The progression of NAFLD co-expression gene modules were recognized via weighted gene co-expression network analysis (WGCNA). We screened for differentially expressed genes (DEGs) associated with AS and identified common genes associated with NAFLD and AS using Venn diagrams. We investigated the most significant core genes between NAFLD and AS using machine learning algorithms. We then constructed a diagnostic model by creating a nomogram and evaluating its performance using ROC curves. Furthermore, the CIBERSORT algorithm was utilized to explore the immune cell infiltration between the two diseases, and evaluate the relationship between diagnostic genes and immune cells.

The WGCNA findings associated 1,129 key genes with NAFLD, and the difference analysis results identified 625 DEGs in AS, and 47 genes that were common to both diseases. We screened the core RPS6KA1 and SERPINA3 genes associated with NAFLD and AS using three machine learning algorithms. A nomogram and ROC curves demonstrated that these genes had great clinical meaning. We found differential expression of RPS6KA1 in patients with steatosis and NASH, and of SERPINA3 only in those with NASH compared with normal individuals. Immune infiltration findings revealed that macrophage and mast cell infiltration play important roles in the development of NAFLD and AS. Notably, SERPINA3 correlated negatively, whereas RPS6KA1 correlated positively with macrophages and mast cells.

We identified RPS6KA1 and SERPINA3 as potential diagnostic markers for NAFLD and AS. The most promising marker for a diagnosis of NAFLD and AS might be RPS6KA1, whereas SERPINA3 is the most closely related gene for NASH and AS. We believe that further exploration of these core genes will reveal the etiology and a pathological relationship between NAFLD and AS.

This study aimed to evaluate the possible ameliorative effects of saroglitazar (SAR) on aspects of hepatic injury in dexamethasone (DEX)-induced nonalcoholic steatohepatitis (NASH) in rats. Wistar rats received SAR (2 or 4 mg/kg/day, orally) or metformin (MET, 500 mg/kg/day, orally) for one week before and concurrently with DEX administration (8 mg/kg/day, i.p., for 6 days. Control and drug control groups received vehicle or the higher dose of SAR, respectively. At the end of the experiment, an oral glucose tolerance test (OGTT) was conducted, serum hepatic function parameters and lipid profile were assessed, and hepatic histological changes were evaluated. Moreover, hepatic p-Akt/Akt ratios, malondialdehyde (MDA) content, SREBP-1, FOXO1, LC3, cleaved caspase-3, and p-MLKL protein levels were determined. Furthermore, hepatic immunohistochemical expressions of FOXO1, caspase-3, Bcl-2, LC3, and P62 were examined. SAR (mainly at 4 mg/kg/day) significantly improved Area under the OGTT curve (P < 0.0001), hepatic function parameters, lipid profile, and hepatic histopathological features in DEX-administered rats. Moreover, SAR significantly attenuated DEX-induced increases in hepatic MDA content (P < 0.05), SREBP-1 levels (P < 0.0001), and nuclear FOXO1, caspase-3, LC3, P62, and p-MLKL protein expressions (P < 0.0001). Furthermore, SAR significantly enhanced hepatic p-Akt/Akt ratio and Bcl-2 protein expression in DEX-administered rats (P < 0.0001). The higher dose of SAR showed greater hepatoprotective effects compared to its corresponding lower dose and MET in most assessments, approaching levels similar to the control group. SAR mitigated hepatic injury associated with DEX-induced NASH in rats, suggesting it might be a potential hepatoprotective drug for patients with or at high risk of NASH.

Programmed cell death (PCD) is a comprehensive term that encompasses various forms of cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy, which play a crucial role in the pathogenesis of liver fibrosis. PCD facilitates the elimination of aberrant cells, particularly activated hepatic stellate cells (HSCs), which are the primary producers of extracellular matrix (ECM). The removal of HSCs may impede ECM synthesis, thereby mitigating liver fibrosis. As such, PCD has emerged as a promising therapeutic target for the development of novel drugs to treat liver fibrosis. Numerous studies have been conducted to investigate the underlying mechanisms of PCD in the elimination of activated HSCs and other aberrant liver cells in fibrotic liver tissue, including hepatocytes, hepatic sinusoid endothelial cells (LSECs), and Kupffer cells (KCs). The induction of PCD, the interplay between different forms of PCD, and the potential harm or benefit of PCD in liver fibrosis are topics of ongoing research. Evidences suggest that PCD is a complex process with dual effects on liver fibrosis. The purpose of this review is to summarize the most recent advances in PCD and liver fibrosis research.

Murine Serpina3c belongs to the family of serine protease inhibitors (Serpins), clade "A" and its human homologue is SerpinA3. Serpina3c is involved in some physiological processes, including insulin secretion and adipogenesis. In the pathophysiological process, the deletion of Serpina3c leads to more severe metabolic disorders, such as aggravated non-alcoholic fatty liver disease (NAFLD), insulin resistance and obesity. In addition, Serpina3c can improve atherosclerosis and regulate cardiac remodeling after myocardial infarction. Many of these processes are directly or indirectly mediated by its inhibition of serine protease activity. Although its function has not been fully revealed, recent studies have shown its potential research value. Here, we aimed to summarize recent studies to provide a clearer view of the biological roles and the underlying mechanisms of Serpina3c.

Necroptosis, a regulated form of cell death, is involved in the genesis and development of various life-threatening diseases, including cancer, neurological disorders, cardiac myopathy, and diabetes. Necroptosis initiates with the formation and activation of a necrosome complex, which consists of RIPK1, RIPK2, RIPK3, and MLKL. Emerging studies has demonstrated the regulation of the necroptosis cell death pathway through the implication of numerous post-translational modifications, namely ubiquitination, acetylation, methylation, SUMOylation, hydroxylation, and others. In addition, the negative regulation of the necroptosis pathway has been shown to interfere with brain homeostasis through the regulation of axonal degeneration, mitochondrial dynamics, lysosomal defects, and inflammatory response. Necroptosis is controlled by the activity and expression of signaling molecules, namely VEGF/VEGFR, PI3K/Akt/GSK-3β, c-Jun N-terminal kinases (JNK), ERK/MAPK, and Wnt/β-catenin. Herein, we briefly discussed the implication and potential of necrosome activation in the pathogenesis and progression of neurological manifestations, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and others. Further, we present a detailed picture of natural compounds, micro-RNAs, and chemical compounds as therapeutic agents for treating neurological manifestations.