Military Medical Research最新文献

Background: The prevalence of circadian misalignment, particularly social jetlag (SJL), contributes significantly to the epidemic of metabolic disorders. However, the precise impact of SJL on the liver has remained poorly elucidated.

Methods: The rhythmicity of circulating prolactin (PRL) was evaluated in subjects with SJL and mice under SJL. The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and Prl^-/- mice. Luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL. RNA-seq on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism. The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared.

Results: SJL increases the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), mediated by the disruption of the rhythmicity of serum PRL. In particular, SJL inhibits the rhythmic transcription of PRL in the pituitary, leading to desynchronized PRL levels in circulation. Under jetlag conditions, the rhythmicity of the hepatic PRL signaling pathway was significantly dampened, which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions. Notably, PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration.

Conclusions: Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL, which was mediated through derailed serum PRL rhythm. Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver, providing new insight into treating MASLD.

Background: China accounts for one-quarter of the world's diabetes population, with significant subnational disparities. However, none of the available data have provided comprehensive estimates and projections at both regional and national levels in diabetes prevention and management. This study aimed to explore the temporal trends and geographical variations in the prevalence and non-fatal burden of diabetes by age and sex across China from 2005 to 2023, and to forecast diabetes prevalence through 2050.

Methods: We conducted a population-based study based on the nationally representative surveys, and literature reviews. Using the DisMod-MR model and Chinese-specific disease disability weights, we estimated the non-fatal burdens of diabetes, including prevalence and years lived with disability (YLDs), across sexes, age groups, and locations. The temporal trend change was measured as the average annual percent change. The effect of the Human Development Index on burdens was assessed by applying Spearman's rank correlation analysis. We further projected diabetes prevalence to 2050 under two scenarios, the natural trend and the effective intervention on body mass index (BMI).

Results: In 2023, an estimated 233 million individuals in China were living with diabetes. Compared to 2005, the age-standardized rate (ASR) of prevalence has increased by nearly 50%, from 7.53% (95% CI 7.00-8.10%) to 13.7% (95% CI 12.6-14.8%) in 2023. The ASR of YLDs was estimated at 19.1 per 1000 population (95% CI 18.6-19.5) in 2023, compared to 10.5 per 1000 population in 2005. The ASR of prevalence and YLDs was consistently higher in males than in females. The provinces with the highest diabetes prevalence and disease burden were Beijing, Tianjin, and Shanghai. Our forecast results suggest that if existing trends continue, the prevalence of obesity will reach 29.1% (95% CI 22.2-38.2%) nationally by 2050, with some provinces in the northern region observing a prevalence of over 40%. Conversely, if effective obesity interventions were implemented, the growth in diabetes prevalence could potentially be suppressed by nearly 50%.

Conclusions: The health burden and economic cost associated with diabetes are profound. There is an urgent need to scale up preventive efforts and improve population awareness to enhance disease management and achieve optimal treatment outcomes.

The treatment of chronic wounds presents significant challenges due to the necessity of accelerating healing within complex microenvironments characterized by persistent inflammation and biochemical imbalances. Factors such as bacterial infections, hyperglycemia, and oxidative stress disrupt cellular functions and impair angiogenesis, substantially delaying wound repair. Nanozymes, which are engineered nanoscale materials with enzyme-like activities, offer distinct advantages over conventional enzymes and traditional nanomaterials, making them promising candidates for chronic wound treatment. To enhance their clinical potential, nanozyme-based catalytic systems are currently being optimized through formulation advancements and preclinical studies assessing their biocompatibility, anti-oxidant activity, antibacterial efficacy, and tissue repair capabilities, ensuring their safety and clinical applicability. When integrated into multifunctional wound dressings, nanozymes modulate reactive oxygen species levels, promote tissue regeneration, and simultaneously combat infections and oxidative damage, extending beyond conventional enzyme-like catalysis in chronic wound treatment. The customizable architectures of nanozymes enable precise therapeutic applications, enhancing their effectiveness in managing complex wound conditions. This review provides a comprehensive analysis of the incorporation of nanozymes into wound dressings, detailing fabrication methods and emphasizing their transformative potential in chronic wound management. By identifying and addressing key limitations, we introduce strategic advancements to drive the development of nanozyme-driven dressings, paving the way for next-generation chronic wound treatments.

Background: Fibrosis constitutes a significant pathophysiological mechanism in the clinical progression of benign prostatic hyperplasia (BPH) and represents a contributing factor to the ineffectiveness of prevailing pharmacological treatments. Emerging evidence suggests a close association between microbial presence and the development of fibrosis. Nonetheless, the potential involvement of microbes within prostatic tissue in the pathogenesis of BPH and prostatic fibrosis, along with the underlying mechanisms, remains unexplored.

Methods: Utilizing immunohistochemistry and microbial sequencing, we analyzed the microbes of prostate tissues from BPH patients with different degrees of prostate fibrosis and found that Salmonella enterica (S. enterica) was enriched in the high degree of prostate fibrosis. We developed prostate cell and animal models infected with the lipopolysaccharide of S. enterica (S.e-LPS) to assess its impact on prostate fibrosis. To elucidate the underlying functional mechanisms, we employed molecular biology techniques, including RNA degradation assays, N⁶-methyladenosine (m⁶A) dot blotting, RNA immunoprecipitation, and m⁶A immunoprecipitation.

Results: Microbial diversity differed between low- and high-fibrosis groups, with S. enterica showing the highest mean abundance among the four species that differed significantly. S.e-LPS was detected in S. enterica-rich prostate tissue and was found to significantly promote cell proliferation, cell contractility, lipid peroxidation, and the induction of ferroptosis. Animal experiments demonstrated that S.e-LPS infection led to pronounced hyperplasia of the prostatic epithelium, with epithelial thickness increasing to 1.57 times that of the sham group, and collagen fibrosis increasing to 2.84 times that of the sham group, thereby exacerbating prostatic tissue fibrosis in rats. In vitro experiments further revealed that S.e-LPS promoted prostate cell fibrosis by inducing ferroptosis. Mechanistically, it was determined that S.e-LPS regulates ferroptosis via AlkB homolog 5 (ALKBH5)-mediated m⁶A modification, which affects the stability of glutathione peroxidase 4 (GPX4) mRNA, thereby affecting prostatic fibrosis.

Conclusion: The findings of this study suggest that S. enterica promotes prostatic fibrosis through ALKBH5-m⁶A-GPX4-mediated ferroptosis. This research offers novel insights for the development of new therapeutic targets and personalized strategies for the prevention and treatment of BPH from the perspectives of microbes and epigenetics.

Background: Second primary malignancies (SPMs) account for over 30% of total deaths in head and neck cancer (HNC) patients. The increasing use of radiotherapy raises concerns about the elevated risk of radiation-associated SPMs. This study aimed to investigate the age-stratified association between radiotherapy and SPM risk in survivors of non-metastatic primary HNC.

Methods: Using data from the Surveillance, Epidemiology, and End Results program (2004-2015), incidence rate ratios (IRRs) and standardized incidence ratios (SIRs) were evaluated for solid and hematologic SPMs associated with radiotherapy within different age groups. Follow-up for hematologic and solid SPMs began 2 and 5 years, respectively, after the diagnosis of first primary HNC. The IRRs for SPMs were compared between radiotherapy-exposed and unexposed groups using multivariable modified Poisson regression. The SIRs were computed as the ratio of observed cancers in the cohort to expected cases derived from sex-, age-, and calendar year-matched general population incidence rates.

Results: The study included 75,209 2-year survivors, with 73.2% being male and a median age of 60 years. Of these, 58,063 had survived 5 years or more. Radiotherapy was associated with an increased risk of solid SPMs [IRR = 1.16, 95% confidence interval (CI) 1.08-1.24; P < 0.001]. The associations varied significantly among young (aged 15-39 years), middle-aged (aged 40 - 64 years), and elderly (aged 65-89 years) patients. Specifically, radiotherapy was associated with an increased risk of solid SPMs in middle-aged patients (IRR = 1.21, 95% CI 1.11-1.32; P < 0.001), and a decreased risk of hematologic SPMs in elderly patients (IRR = 0.77, 95% CI 0.60-0.99; P = 0.045). Compared with the general population, young patients had an elevated risk of radiotherapy-associated second primary non-Hodgkin lymphoma (SIR = 4.01, 95% CI 1.47-8.74). Middle-aged patients showed the highest SIR for SPMs in the bones/joints (SIR = 7.72, 95% CI 4.32-12.73), while elderly patients had the highest SIR for second primary esophageal malignancies (SIR = 3.87, 95% CI 2.91-5.05). Males were more likely to develop solid SPMs compared to females.

Conclusions: This study reveals an age-stratified association between radiotherapy and the risk of SPMs in HNC patients. These findings highlight the importance of considering patient age when making treatment decisions for HNC and suggest that long-term surveillance is necessary for high-risk groups.