The transcription factor sex-determining region Y-related high-mobility group-box gene 9 (SOX9) plays a critical role in organ development. Although SOX9 has been implicated in regulating lipid metabolism in vitro, its specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in MASH pathogenesis and explored the underlying mechanisms.

MASH models were established using mice fed either a methionine- and choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific SOX9 deletion or overexpression was performed. Lipidomic analyses were conducted to assess how SOX9 influences hepatic lipid metabolism. RNA sequencing was employed to identify pathways modulated by SOX9 during MASH progression. To elucidate the mechanism further, HepG2 cells were treated with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.

SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific SOX9 deletion exacerbated MCD-induced MASH, whereas overexpression of SOX9 mitigated high-fat, high-fructose-induced MASH. Lipidomic and RNA sequencing analyses revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, SOX9 deletion inhibited AMPK pathway activation, while SOX9 overexpression enhanced it. Notably, administration of an AMPK inhibitor negated the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.

Our findings demonstrate that SOX9 overexpression alleviates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target for treating MASH.

Peroxisome proliferator-activated receptors (PPARs) participate in the fatty acid oxidation, the homeostasis of lipid and glucose metabolism, the regulation of insulin sensitivity, and numerous metabolic processes, making them novel and important therapeutic targets for cancer treatment. However, PPARs manifest dual functions, wherein their activation and inhibition engender diverse outcomes in different types of tumors. The specificity of drugs for tumors is also a challenge when targeting PPARs. In recent years, proteolysis targeting chimeras (PROTACs) have gained significant attention in the field of cancer therapy, demonstrating potent therapeutic potential in both basic and clinical research. Furthermore, heterobifunctional molecules derived from PROTACs have ventured into domains that extend beyond protein degradation. Currently, there are no developed PPAR-targeting PROTACs. Therefore, our review delves into various aspects, including the dual roles of PPARs, known inhibitors, agonists, ligands, and co-crystal structures, and explores the feasibility and advantages of PPAR-targeting PROTACs and other heterobifunctional molecules in cancer therapy.

Waist circumference (WC) is closely associated with metabolic diseases, including diabetes mellitus (DM), metabolic syndrome, and mortality. However, the correlation between WC and mortality varies across populations and has rarely been examined specifically in patients with DM. In this study, we explored the relationships between WC and both all-cause and cardiovascular mortalities among individuals with DM.

Participants from the National Health and Nutrition Examination Survey 2003–2018 included 3,151 women and 3,473 men with DM who had baseline WC measurements. Survival data were collected from enrollment until December 31, 2019. Cox proportional hazard models were adjusted for demographic features and other confounders. Restricted cubic spline curves and threshold effect analyses were performed separately for men and women. Sensitivity analyses were conducted to minimize reverse causality.

Among 6,624 participants with DM, 621 women and 871 men died during median follow-ups of 6.8 and 6.3 years, respectively. WC demonstrated a U-shaped association with all-cause and cardiovascular mortalities in women, and a J-shaped trend in men. The optimal WC thresholds for minimizing mortality risk were 107.0 cm for women and 89.0 cm for men. For women, adjusted hazard ratios for all-cause mortality were 0.97 (95% confidence interval (CI): 0.96–0.98, P < 0.001) for WC below 107.0 cm and 1.04 (95% CI: 1.02–1.05, P < 0.001) for WC above 107.0 cm. In men, the corresponding ratios were 0.94 (95% CI: 0.90–0.97, P < 0.001) for WC below 89.0 cm and 1.03 (95% CI: 1.02–1.05, P < 0.001) for WC above 89.0 cm.

WC showed a U-shaped association with all-cause and cardiovascular mortalities in women and a J-shaped association in men among U.S. adults with DM from the National Health and Nutrition Examination Survey. Further research is needed to explore the underlying mechanisms rather than promoting preconceived notions about an optimal WC.

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory condition affecting the ileum, colon, and rectum, including ulcerative colitis and Crohn’s disease. Clinical symptoms include abdominal pain, diarrhea, and even bloody stools. The intestinal barrier is the first line of defense between the intestinal tract and the external environment, and maintaining its stability is essential for intestinal health. On one hand, it enables the digestion and absorption of water and nutrients; on the other, it plays a crucial role in reducing the absorption of toxins and the invasion of pathogens. Damage to the intestinal barrier has become one of the most important factors in the onset and progression of IBD. However, there is currently no literature that systematically reviews the mechanisms of the intestinal barrier in the pathogenesis of IBD and the factors influencing it. In this paper, we aimed to systematically elaborate on the role of the intestinal barrier in IBD through the perspectives of oxidative stress, intestinal flora, and cellular autophagy. Our goal was to explore the mechanisms of the intestinal barrier in IBD more deeply and to provide new insights for the diagnosis and treatment of IBD. This article will summarize the composition of the intestinal barrier, the factors affecting it, and strategies to protect it.

A growing body of literature has demonstrated improved quality of life in cancer patients who utilize web-based patient portals; however, no studies have investigated their impact on objective clinical measures. The study aimed to evaluate the impact of patient portal utilization on clinical outcomes in cancer care. Patient portal platforms provide patients with direct access to their providers through messaging, medication requests, and other tools. There is a knowledge gap in the literature regarding whether electronic patient portals enhance outcomes in cancer care.

This study is a retrospective analysis of 791 patients with multiple myeloma within the Scripps Health system. The effect of MyScripps electronic patient portal use on unplanned hospital visits and mortality was assessed. Outcomes were also evaluated in relation to the age-adjusted Charlson comorbidity index and chemotherapy use.

Results showed that older, male, Hispanic, and Spanish-speaking patients had lower portal utilization. Those with inactive portal status had higher rates of unplanned hospital visits and mortality. Inactive portal status was an independent predictor of unplanned hospital visits in two multivariable logistic regression analyses. A logistic regression model investigating the interaction between patient portal use and age-adjusted Charlson comorbidity index revealed that active portal status remained a predictor of unplanned hospital visits.

This study highlights the potential to improve clinical outcomes among patients with multiple myeloma, particularly in vulnerable communities, by increasing access to electronic patient portals.

The spatial heterogeneity of tumors has long been a subject of significant interest in oncology. Recent research has revealed that tumors and their microenvironments undergo dynamic changes over time, particularly in the form of periodic circadian rhythms. Disruptions to these rhythms have been recognized as a pivotal factor in the advancement of tumorigenesis. Such disruptions not only induce dysregulation of gene expression within tumor cells, influencing tumor growth, metabolism, the cell cycle, and vascular homeostasis but also facilitate metastasis. Furthermore, they mediate the remodeling of the tumor immune microenvironment, fostering the development of an immunosuppressive milieu. Additionally, the in vivo metabolism and therapeutic responsiveness of tumor treatments—including chemotherapy, targeted therapy, and immunotherapy—have been shown to be modulated by circadian rhythms. This suggests that time-specific drug administration may enhance treatment efficacy, offering novel insights for precision cancer therapy. In this review, we systematically update contemporary research on the impact of circadian rhythms on tumor biology, encompassing both tumor progression and the efficacy of drug therapies. Building upon these insights, we explore the potential for a synergistic approach that integrates the targeting of rhythmic genes with current tumor treatment modalities. We also discuss the feasibility of tailoring tumor therapy to the rhythmic alterations that define in vivo metabolism and the efficacy of specific therapeutic agents, highlighting the significance of rhythm-based strategies in the personalized treatment of tumors and the prevention of associated diseases.

The proto-oncogene c-Fos is known as a reliable marker of cell activation, which is immediately induced after a new stimulus in specific brain regions, depending on the nature of the stimulus applied. However, the expression of c-Fos is increased in Alzheimer’s disease (AD) and contributes to amyloid β-peptide-induced neurotoxicity. This review attempted to focus on the role of c-Fos in learning and memory in both healthy brain and AD, emphasizing on possible mechanisms. Comparing the available findings, regarding learning and memory, c-Fos expression leads to memory formation through ERK (extracellular signal-regulated kinase)/CREB (cAMP response element-binding protein) and long-term potentiation, while it is down regulated after the repetition and habituation of stimuli. However, its overexpression in neurons and glia of AD, contributes to cognitive deficits and neuronal loss, which represents a defect in its ability to habituate to repeated stimuli. Also, expression pattern in glial is associated with constitutive CREB activation following increasing amyloid beta (Aβ), activation transcription factor (ATF3), and cytochrome c in apoptosis pathways. Thus, two contradictory roles of c-Fos in the healthy brain and AD, reveal more complexity in c-Fos up and down stream signaling pathways, bioavailability, and sensitivity. Future studies focusing on c-Fos modulation, might offer promising strategies to mitigate cognitive decline in AD.

T lymphocytes play a pivotal role in resolving hepatitis B virus infection. This study aimed to investigate the dynamics of peripheral blood T lymphocyte subsets during peginterferon alpha (peg-IFN-α) therapy and their association with hepatitis B surface antigen (HBsAg) clearance in inactive HBsAg carriers (IHCs).

This prospective observational study enrolled 197 IHCs treated with peg-IFNα-2a/2b for 48 weeks and followed for 24 weeks (treatment group), and 221 IHCs who were regularly monitored for 72 weeks without treatment (IHC control group). Peripheral blood T lymphocyte subsets were evaluated using flow cytometry at baseline, and at 12, 24, 48, and 72 weeks in both groups. At 72 weeks, IHCs in the treatment group were categorized into an HBsAg clearance group and an HBsAg persistence group. Differences in T lymphocyte subsets among these groups were compared, and correlations between T lymphocyte subsets and HBsAg clearance were analyzed.

At 72 weeks, intention-to-treat analysis showed significantly higher HBsAg clearance (46.7%) and seroconversion rates (34.5%) in the treatment group compared to the IHC control group (HBsAg clearance rate of 1.4%, seroconversion rate of 0.9%; both p < 0.001). The median absolute counts of CD3+, CD4+, and CD8+ cells significantly decreased at 12, 24, and 48 weeks in both the HBsAg clearance and persistence groups, returning to baseline at 72 weeks (all p < 0.001). IHCs with HBsAg clearance had higher median percentages of CD3+ CD8+ cells and lower median percentages of CD3+ CD4+ cells and CD4+/CD8+ ratios at 12, 24, and 48 weeks compared to the HBsAg persistence and IHC control groups (all p < 0.001). Baseline HBsAg levels (below 2.0 log10 IU/mL) and hepatitis B virus DNA levels (below 20 IU/mL), alanine aminotransferase elevation at 12 weeks (greater than 2×upper limit of normal), and CD4+/CD8+ ratios (less than 1.5 at 12 weeks and below 1.4 at 24 weeks) were predictive of HBsAg clearance.

Peripheral blood CD4+/CD8+ ratios at 12 and 24 weeks may serve as predictive markers for HBsAg clearance in IHCs treated with peg-IFN-α.

Recent studies have highlighted a link between amyotrophic lateral sclerosis (ALS) and gut microbiota. This prospective study aimed to evaluate the effects of electroacupuncture combined with Chinese herbal medicine on gut microbiota and metabolomics in ALS patients.

Ten ALS patients were randomly assigned to either a treatment group (electroacupuncture with Chinese herbal medicine, n = 6) or a control group (waiting treatment, n = 4). Healthy controls (age- and sex-matched, n = 10) were also included. Data were collected after 12 sessions of electroacupuncture and follow-ups at three and six months. ALS functional rating scale scores were documented pre- and post-treatment. Stool samples were collected at two time points (T0 and T4 weeks) and analyzed, and metabolomic profiles from urine samples were analyzed post-treatment. Heatmap correlation analysis was used to explore relationships between microbiota, metabolomics, and clinical outcomes.

Treatment with electroacupuncture reduced Eisenbergiella abundance in the treatment group. A significant positive correlation was found between Lachnospiraceae and ALS functional rating scale scores (P < 0.005 and P < 0.001, respectively). Differential expression of purine metabolism was observed in ALS patients (P = 0.0017).

Imbalances in the gut microbiome and metabolic disorders have been found among patients with ALS. These imbalances appear to be partially mitigated by treatment with electroacupuncture combined with Chinese herbal medicine. Our research suggests that Eisenbergiella might be a diagnostic biomarker and a potential therapeutic target for ALS.