International Journal of Medical Sciences最新文献

Adeno-associated virus (AAV) unequivocally emerges as one of the most powerful and promising delivery vectors for gene therapy targeting hereditary hearing loss. Following AAV transduction in the inner ear, varying degrees of natural immune responses are triggered, primarily characterized by macrophage activation and the secretion of pro-inflammatory factors. Additionally, the production of neutralizing antibodies may affect the efficacy of gene therapy. To evaluate immune dynamics, we injected AAV1 and AAV-ie (capsids with distinct transfection efficiencies) into murine cochleae and analyzed temporal transcriptomic profiles. Our results demonstrate that both capsids induce immune activity but with critical temporal and intensity differences that AAV1 elicits significantly later and milder immune reactions compared to AAV-ie. These findings establish that dynamic cochlear gene expression profiles directly inform the selection of immunologically optimized AAV vectors to minimize adverse responses in future hereditary hearing loss gene therapies.

Background : Growing evidence has highlighted the critical role of oxidative stress in the pathogenesis of sleep problems. The Composite Dietary Antioxidant Index (CDAI), a holistic metric designed to assess the cumulative antioxidant capacity of dietary components, may be intricately linked to sleep quality. This study aimed to investigate the association between CDAI and sleep parameters using data from the National Health and Nutrition Examination Survey (NHANES). Methods : Participants with complete data on CDAI, sleep parameters, and other essential covariates were included in this study. Weighted multivariable linear or logistic regression models were employed to examine the association between CDAI and sleep parameters (sleep duration, sleep trouble, and sleep disorder). Subgroup analyses, smooth curve fitting, threshold/saturation effect analyses, and sensitivity analyses were conducted to characterize the association's features. Results : A total of 10,491 participants were finally included in the analysis. After adjusting for all potential covariates, higher CDAI levels were associated with increased sleep duration (CDAI_T3 vs. CDAI_T1, β=0.16, 95% CI: 0.08-0.24), while exhibiting no significant correlation with sleep trouble (CDAI_T3 vs. CDAI_T1, OR=1.03, 95% CI: 0.88-1.20) or sleep disorder (CDAI_T3 vs. CDAI_T1, OR=1.01, 95% CI: 0.79-1.28). Subgroup analyses and interaction tests indicated a more pronounced association among individuals with depression (P interaction<0.0001) and those taking sleep-modulating medications (P interaction=0.0014). Smooth curve fitting analyses identified an inverted "L"-shaped association between CDAI and sleep duration, with the inflection point of CDAI determined to be 3.2. Within this threshold, each 1-unit increase in CDAI was associated with a 0.04-hour (95% CI: 0.02-0.05) increase in sleep duration, whereas no association was observed beyond this point. Finally, sensitivity analyses, which excluded individuals with extreme energy intakes or depression, confirmed a consistent and robust association between CDAI and sleep duration. Conclusion : The association between CDAI and sleep duration exhibits a positive, inverted "L"-shaped pattern with a saturation effect. Further prospective or longitudinal cohort studies with larger sample sizes and longer follow-up periods are needed to evaluate its practical value for clinical interventions.

Background: Betel-quid use is linked to cancer and other adverse health effects. However, its potential impact on depression has not been well studied. Objective: To investigate the association between betel-quid use and depression. Methods: We analyzed the data of 43,636 men from the Taiwan Biobank. Participants were divided into two groups on the basis of betel-quid use: never-user and ever-user groups. Depression was defined according to self-reported medical history in the questionnaire. Logistic regression was used to assess the association between betel-quid use and depression. Results: The average age of the participants was 49.89 ± 11.36 years. Among them, 16.31% were ever-users of betel quids. In the never-user group (n = 36,521), 828 participants (2.27%) reported a history of depression. However, 75 of 2,592 participants in the ever-user group (2.89%) reported a similar history. The adjusted odds ratio for depression in the ever-user group compared with the never-user group was 1.265, indicating its association with depression. Daily consumption of 11-30 betel quids was associated with depression compared with consumption of ≤10 betel quids. However, no association was found for those consuming more than 30 betel quids daily. Conclusions: Betel-quid use is associated with depression. The association between betel-quid use and depression may not be linear, suggesting a complex dose-response effect.

Endometriosis (EMs) is a common gynecological disorder. According to the most widely recognized theory of retrograde menstruation, endometrial cells require completion of three key steps during ectopic implantation: adhesion, invasion, and angiogenesis. Although kisspeptin exerts anti-invasive and anti-angiogenic effects in multiple tumors, its potential inhibitory effects mediated through the KISS1 receptor (KISS1R) on EMs-related invasion and angiogenesis remain uncharacterized. This study aimed to identify regulatory genes in EMs pathogenesis via RNA sequencing and elucidate underlying molecular mechanisms. We performed a comparative transcriptomic analysis of ectopic endometrium (EC) and eutopic endometrium (EU) in 5 patients with EMs and control endometrium in 3 women without EMs. Then, we screened for genes that showed significant differences between EU and group, and even more pronounced differences between EC and EU, indicating a progressive change. Moreover, we identified the top 20 progressively altered genes during EMs development, including KISS1R. Furthermore, KEGG pathway analysis revealed that these progressively altered DEGs were mainly enriched in the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. Previous studies suggest that the PI3K/AKT signaling pathway may mediate cell invasion and angiogenesis in EMs. Additionally, substantial evidence indicates that cAMP-response element binding protein (CREB5), a transcriptional regulator, can regulate the PI3K/AKT pathway. However, the mechanism of functional changes of CREB5 and PI3K/AKT in EMs is unclear. Our study validated the functional role of KISS1/KISS1R in EMs through animal experiments and cell experiments. It may suppress the cell invasion and angiogenesis of endometrial cells by reducing the phosphorylation levels of PI3K and AKT mediated by increasing CREB5. This mechanistic insight provides novel pathogenic explanations for EMs.

Background: Kidney stone disease (KSD) is a growing global health issue, while hyperuricemia has been linked to various health conditions. This study aimed to explore the association between hyperuricemia and KSD. Methods: This study analyzed the data of 118,963 generally healthy participants aged 30-70 years from the Taiwan Biobank. KSD was defined based on self-reported diagnoses, and hyperuricemia was defined as a serum uric acid level > 7 mg/dL in men and > 6 mg/dL in women. Key variables including age, sex, body mass index, lifestyle factors, presence of hypertension, diabetes, and chronic kidney disease were recorded. Statistical analysis was conducted using descriptive statistics and logistic regression to evaluate the association between hyperuricemia and KSD. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were reported, with statistical significance set at p < 0.05. An additional causal mediation analysis was performed to assess the mediating role of gout. Results: Among the 118,963 participants, 23,094 (19.4%) had hyperuricemia. Those with hyperuricemia were older, had a higher body mass index, and were more likely to smoke, consume alcohol, and have elevated blood pressure. They also had higher rates of comorbidities such as hypertension, diabetes, metabolic syndrome, chronic kidney disease, and gout, along with worse laboratory profiles. Multivariable analysis revealed that hyperuricemia was significantly associated with an increased risk of KSD (OR: 1.155, 95% CI: 1.089-1.224, p < 0.001). When stratified into four exposure groups, the prevalence of KSD was 5.4% in participants without hyperuricemia or gout, 8.5% in those with hyperuricemia alone, 17.0% in those with gout alone, and 15.7% in those with both conditions; the adjusted ORs were 1.178, 1.522, and 1.505, respectively, compared with the reference group. The risk was more pronounced in females, particularly those in higher uric acid quartiles, whereas in males, the association was weaker and became nonsignificant after full adjustments. Mediation analysis further indicated that gout explained approximately 24% of the association between hyperuricemia and KSD, while the direct effect of hyperuricemia on KSD remained significant. Conclusion: Hyperuricemia was an independent risk factor for KSD in this large Taiwanese cohort study, with a stronger association observed in females. Gout partially mediates this relationship, suggesting overlapping yet distinct pathways linking hyperuricemia to kidney stone formation. These findings underscore the importance of sex-specific management strategies for KSD. Routine monitoring of serum uric acid levels is recommended to mitigate KSD risk, especially among high-risk individuals. Future research should focus on elucidating the long-term impact of hyperuricemia on KSD and tailoring prevention strategies to regional and population-specific needs.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 10% of middle-aged women worldwide. The main clinical features of PCOS include hirsutism, anovulation, irregular menstruation, and polycystic ovaries. However, the exact etiology and underlying mechanisms of PCOS remain incompletely understood. Increasing evidence suggests that a variety of factors-including environmental toxins, chronic low-grade inflammation, oxidative stress, and dysregulated insulin secretion-are involved in the onset and progression of PCOS. Additionally, abnormalities in neurotransmitter metabolism play a significant role in the pathophysiology of PCOS, particularly in relation to weight gain, hyperandrogenemia, and mood disorders. Patients with PCOS often exhibit neuroendocrine system dysfunction, characterized by altered levels of neurotransmitters such as serotonin, norepinephrine, and dopamine. These changes are closely associated with clinical symptoms such as anxiety, depression, obesity, and metabolic disturbances. Current treatment strategies for PCOS primarily focus on lifestyle modifications and pharmacological interventions. These include dietary changes, nutritional supplementation, physical activity, and ovulation induction, all aimed at alleviating symptoms and improving quality of life. Notably, interventions targeting neurotransmitter metabolism are emerging as a novel area of research. The use of antidepressants, anxiolytics, and insulin-sensitizing agents has shown potential in alleviating symptoms and regulating neuroendocrine function. Furthermore, PCOS is significantly associated with metabolic dysfunction, particularly in hormone metabolism, lipid metabolism, and glucose metabolism, which exacerbates the risk of obesity, hyperandrogenemia, and type 2 diabetes. Therefore, understanding alterations in neurotransmitter metabolism and developing new therapeutic strategies may offer novel perspectives and intervention approaches for the diagnosis and treatment of PCOS.

Colorectal cancer (CRC) is one of the most prevalent malignancies globally and poses a substantial threat to human health. The current understanding of the biological significance of Splicing Factor 3a Subunit 2(SF3A2) in CRC remains limited. In this study, the upregulation of SF3A2 in CRC was identified through TMT-based quantitative proteomic screening of surgically resected paired primary cancer and normal epithelial tissues. Patients with elevated SF3A2 expression exhibited reduced survival compared to those with lower expression levels. Knockdown of SF3A2 significantly decreased cell proliferation, migration, and invasive properties both in vivo and in vitro. Bioinformatics enrichment analysis revealed that SF3A2 was involved in alternative splicing and functioned as an oncogene by modulating the expression of genes associated with critical tumorigenesis pathways and functions. Furthermore, immune infiltration analysis using multiple algorithms (including TIMER, EPIC, QUANTISEQ, and MCPCOUNTER) indicated an inverse relationship between SF3A2 expression levels and the presence of various immune cell types. Concurrently, predictions derived from the TIDE algorithm corroborated that patients exhibiting elevated SF3A2 expression were likely to experience a diminished response to immunotherapy. In summary, SF3A2 emerged as a promising therapeutic target for CRC and served as a novel biomarker for forecasting responses to immunotherapeutic interventions.

Background: Preterm birth is associated with impairments in executive functions (EFs), particularly in cognitive flexibility, which is essential for adaptive and goal-directed behavior. While acute exercise has been shown to transiently enhance cognitive flexibility in children born full-term, its effects in preterm children remain poorly understood. This study aimed to examine the effects of acute aerobic exercise on cognitive flexibility and its underlying neural mechanisms in preterm children, and to determine whether these effects are comparable to those observed in full-term peers. Methods: Children aged between 10 and 16 years were assigned based on gestational age to either the preterm group (n = 20; born before 37 weeks of gestation) or the full-term group (n = 22; born at or after 37 weeks) to complete two sessions, including a 30-minute aerobic exercise (AE) session and a seated control (CON) session. Cognitive flexibility was assessed immediately after each session using a task-switching paradigm, with concurrent electroencephalographic recording to measure P3b event-related potentials (ERPs). Results: Across both groups, participants exhibited shorter response times in the global and local switch conditions and higher accuracy in the local switch condition following AE compared with CON, although switching costs did not differ significantly between sessions. ERP analyses showed increased P3b amplitudes after AE in both switch conditions, indicating enhanced allocation of attentional resources. No significant group differences were observed, suggesting comparable behavioral and neural patterns between preterm and full-term children. Conclusion: These findings indicate that a single session of moderate-intensity aerobic exercise may transiently enhance cognitive processing in both preterm and full-term children. Although behavioral improvements were not observed in the core index of cognitive flexibility (i.e., switching cost), the ERP results suggest a short-term modulation of neural efficiency following acute exercise.

Aim and Background: The aim of this study was to evaluate the association between inflammatory markers, Red Blood Cell to Platelet Ratio (RPR) and the Red Cell Distribution Width (RDW%) with intracranial artery calcification subtypes and the severity of ischemic stroke. Methods: A total of 118 patients with a mean age of 67.3±12.5 years, of whom 49% were female, with ischemic stroke were prospectively enrolled. The study was conducted at a single center. Intracranial artery calcification was evaluated using a standardized methodology, differentiating mainly intimal from mainly medial, mixed type (medial and intimal calcification), and lack of arterial calcification. In addition, a new categorical variable representing stroke outcome was created based on the change in modified Rankin Scale (mRS) scores between admission and discharge. Inflammatory markers were assessed based on CBC results collected from each patient with ischemic stroke. Results: Patients with a predominantly intimal type of intracranial artery calcification had significantly higher RPR levels compared to those with predominantly medial or mixed-type calcification. In a multinomial logistic regression analysis adjusted for age, sex, diabetes, dyslipidemia, hypertension, smoking status, NIHSS at admission, and mRS at discharge, each standard deviation (SD) increase in RPR was associated with a higher likelihood of having intimal versus medial calcification (OR = 1.53; 95% CI: 1.06-2.11; p = 0.022), and intimal versus mixed-type calcification (OR = 1.34; 95% CI: 1.03-1.75; p = 0.027). Moreover, higher RPR levels were independently associated with worse functional outcomes after stroke (OR = 1.43; 95% CI: 1.09-1.88; p = 0.009). Conclusion: We found that higher RPR were significantly correlated with intracranial intimal artery calcification and worse functional outcomes in patients with ischemic stroke, as indicated by increased modified mRS scores at discharge.

Background: Colorectal cancer (CRC) ranks as the third most common cancer globally and is characterized by a poor prognosis. Abnormal glycosylation, a hallmark of cancer development, influences multiple signaling pathways and contributes to CRC progression. Identifying key glycosyltransferase genes associated with CRC prognosis could provide novel therapeutic targets and improve patient outcomes. Methods: We utilized datasets from The Cancer Genome Atlas (TCGA) to analyze the expression of glycosyltransferase genes in CRC tissues. Lasso regression and COX regression models were employed to identify key glycosyltransferase genes associated with patient prognosis. Angiogenesis assays were performed utilizing tumor-conditioned medium to assess the influence of GDP-fucose protein O-fucosyltransferase 2 (POFUT2) in cancer cells on human umbilical vein endothelial cells (HUVECs).Flag-Immunoprecipitation combining mass spectrometry detection was employed to identify potential interacting proteins with POFUT2.Western blot, immunoprecipitation, and immunohistochemistry were used to assess the interaction between POFUT2 and Junction Plakoglobin (JUP), as well as the correlation between the expression of Vascular endothelial growth factor A (VEGFA) and Platelet Endothelial Cell Adhesion Molecule-1 (CD31). Results: Our analysis revealed that POFUT2 is significantly upregulated in CRC tissues and correlates with poor prognosis. Elevated POFUT2 expression in CRC cells enhances proliferation, invasion, and angiogenic capabilities of HUVECs. Among POFUT2 potential interacting proteins, three proteins were found to be involved in angiogenesis: JUP, HSBP1 (Heat Shock Factor Binding Protein 1), and AGO2 (Argonaute RISC Catalytic Component 2). Specifically, HSBP1 negatively regulates angiogenesis, whereas JUP and AGO2 positively regulate angiogenesis. Our results demonstrated that POFUT2 promotes the protein expression of JUP but does not affect the expression of AGO2. Further investigations revealed that POFUT2 interacts with JUP, upregulates its expression through fucosylation, and subsequently regulates VEGFA levels, thereby enhancing angiogenesis. A significant positive correlation was observed between POFUT2 and the expression levels of JUP, VEGFA, and CD31 in CRC tissues. Conclusions: POFUT2 is identified as a critical glycosyltransferase gene in CRC, closely associated with angiogenic phenotypes and poor prognosis. High POFUT2 expression in CRC regulates JUP fucosylation, increasing JUP and VEGFA levels, which promotes angiogenesis. These findings suggest POFUT2 could serve as a prognostic marker for colorectal cancer, and targeting it may inhibit angiogenesis and aid in treatment.