The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

Objective:To construct multimorbidity patterns among elderly individuals with chronic diseases and to explore the relationship between these patterns and frailty.Methods:A cross-sectional study was conducted involving 4, 706 elderly participants aged 60 years and older from selected prefecture-level cities in Shaanxi Province.Data were collected on general information, chronic diseases, and frailty status.The average age of the participants was 69.9±6.7 years, with males comprising 47.3%(2, 255 cases)and females comprising 52.7%(2, 481 cases)of the sample.Latent class analysis(LCA)was employed to identify multimorbidity patterns, while multivariate logistic regression analysis was utilized to examine the associations between these patterns and frailty.Results:The prevalence of multimorbidity within the study population was found to be 43.6%(2, 052 cases out of 4, 706 cases).The highest rates of multimorbidity were observed in anxiety and depression(100%, 23 cases out of 23 cases), dementia(100%, 6 cases out of 6 cases), and Parkinson's disease(100%, 11 cases out of 11 cases).Stroke followed closely with a rate of 96.8%(597 cases out of 617 cases), while rheumatoid arthritis exhibited the lowest rate of multimorbidity with other chronic diseases at 50%(4 cases out of 8 cases).Five distinct multimorbidity patterns were identified through LCA: the complex multimorbidity class(123 cases), the stroke-respiratory class(546 cases), the sleep disorders-osteoarticular class(488 cases), the cardiovascular-metabolic class(987 cases), and the relatively healthy class(2, 562 cases).When compared to the relatively healthy class, the complex multimorbidity class( OR=2.317, 95% CI: 1.573-3.412), stroke-respiratory class( OR=2.279, 95% CI: 1.862-2.788), sleep disorders-osteoarticular class( OR=1.370, 95% CI: 1.111-1.691), and cardiovascular-metabolic class( OR=1.185, 95% CI: 1.003-1.400)were all found to be significantly associated with frailty. Conclusions:The cardiovascular-metabolic class is the most prevalent among elderly individuals.Various patterns exhibit distinct associations with frailty, with the complex multimorbidity class and the stroke-respiratory class being the most significant, as they markedly elevate the risk of frailty.

Objective:To construct multimorbidity patterns among elderly individuals with chronic diseases and to explore the relationship between these patterns and frailty.Methods:A cross-sectional study was conducted involving 4, 706 elderly participants aged 60 years and older from selected prefecture-level cities in Shaanxi Province.Data were collected on general information, chronic diseases, and frailty status.The average age of the participants was 69.9±6.7 years, with males comprising 47.3%(2, 255 cases)and females comprising 52.7%(2, 481 cases)of the sample.Latent class analysis(LCA)was employed to identify multimorbidity patterns, while multivariate logistic regression analysis was utilized to examine the associations between these patterns and frailty.Results:The prevalence of multimorbidity within the study population was found to be 43.6%(2, 052 cases out of 4, 706 cases).The highest rates of multimorbidity were observed in anxiety and depression(100%, 23 cases out of 23 cases), dementia(100%, 6 cases out of 6 cases), and Parkinson's disease(100%, 11 cases out of 11 cases).Stroke followed closely with a rate of 96.8%(597 cases out of 617 cases), while rheumatoid arthritis exhibited the lowest rate of multimorbidity with other chronic diseases at 50%(4 cases out of 8 cases).Five distinct multimorbidity patterns were identified through LCA: the complex multimorbidity class(123 cases), the stroke-respiratory class(546 cases), the sleep disorders-osteoarticular class(488 cases), the cardiovascular-metabolic class(987 cases), and the relatively healthy class(2, 562 cases).When compared to the relatively healthy class, the complex multimorbidity class( OR=2.317, 95% CI: 1.573-3.412), stroke-respiratory class( OR=2.279, 95% CI: 1.862-2.788), sleep disorders-osteoarticular class( OR=1.370, 95% CI: 1.111-1.691), and cardiovascular-metabolic class( OR=1.185, 95% CI: 1.003-1.400)were all found to be significantly associated with frailty. Conclusions:The cardiovascular-metabolic class is the most prevalent among elderly individuals.Various patterns exhibit distinct associations with frailty, with the complex multimorbidity class and the stroke-respiratory class being the most significant, as they markedly elevate the risk of frailty.

Methamphetamine (METH) abuse is associated with significant neurotoxicity, high addiction potential, and behavioral abnormalities. Recent studies have identified a connection between the gut microbiota and METH-induced neurotoxicity and behavioral disorders. However, the underlying causal mechanisms linking the gut microbiota to METH pathophysiology remain largely unexplored. In this study, we employed fecal microbiota transplantation (FMT) and antibiotic (Abx) intervention to manipulate the gut microbiota in mice administered METH. Furthermore, we supplemented METH-treated mice with short-chain fatty acids (SCFAs) and pioglitazone (Pio) to determine the protective effects on gut microbiota metabolism. Finally, we assessed the underlying mechanisms of the gut-brain neural circuit in vagotomized mice. Our data provide compelling evidence that modulation of the gut microbiome through FMT or microbiome knockdown by Abx plays a crucial role in METH-induced neurotoxicity, behavioral disorders, gut microbiota disturbances, and intestinal barrier impairment. Furthermore, our findings highlight a novel prevention strategy for mitigating the risks to both the nervous and intestinal systems caused by METH, which involves supplementation with SCFAs or Pio.

Objective:To explore the impact of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) on the risk of cardiovascular diseases (CVD) recurrence.Methods:This study is a prospective cohort study based on the China Health and Retirement Longitudinal Study (CHARLS) database. The inclusion criteria were participants who underwent the national baseline survey in 2011. The exclusion criteria were as follows: ① female participants; ② participants without BPH/LUTS information at baseline; ③ participants who had not experienced CVD at baseline. The basic characteristics of BPH/LUTS patients and non-BPH/LUTS patients was compared. The Cox proportional hazards model was used to analyze whether BPH/LUTS is a risk factor for CVD recurrence.Results:A total of 903 male patients with stroke or heart disease were finally included, among which there were 324 (36.9%) cases of BPH/LUTS and 579 (64.1%) cases without BPH/LUTS. Patients with BPH/LUTS had a higher proportion of comorbidities such as hypertension [186 cases (57.4%) vs. 165 cases (28.5%), P=0.014], dyslipidemia [100 cases (31.2%) vs. 104 cases (18.2%), P<0.001], diabetes [55 cases (17.2%) vs. 57 cases (9.8%), P=0.002], chronic kidney disease [71 cases (22.2%) vs. 56 cases (9.8%), P<0.001], and chronic lung disease [87 cases (26.9%) vs. 117 cases (20.3%), P=0.029] compared to those without BPH/LUTS. During the 7-year follow-up, there were 341 (37.8%) cases of CVD recurrence, including 319 (35.3%) cases of heart disease recurrence and 38 (4.2%) cases of stroke recurrence. In the multifactorial adjusted Cox regression model, BPH/LUTS was a risk factor for CVD recurrence ( HR=1.41, 95% CI 1.12-1.77, P=0.003) and heart disease recurrence ( HR=1.40, 95% CI 1.10-1.77, P=0.005), while BPH/LUTS was not a risk factor for stroke recurrence ( HR=2.05, 95% CI 0.97-4.32, P=0.058). When stratified by age, in the population aged ≤65 years, BPH/LUTS was a risk factor for CVD ( HR=1.43, 95% CI 1.07-1.91, P=0.002) and heart disease recurrence ( HR=1.40, 95% CI 1.03-1.90, P=0.006), but not for stroke recurrence ( HR=2.16, 95% CI 0.98-6.09, P=0.053). In patients aged >65 years, BPH/LUTS was not a risk factor for CVD ( P=0.110), heart disease ( P=0.096), or stroke recurrence ( P=0.830). Conclusions:BPH/LUTS is closely related to an increased risk of CVD recurrence, especially for CVD patients aged ≤65 years old. Therefore, for elderly male CVD patients aged ≤65 years, preventing and actively treating BPH/LUTS may have significant implications.

Objective:To explore the impact of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) on the risk of cardiovascular diseases (CVD) recurrence.Methods:This study is a prospective cohort study based on the China Health and Retirement Longitudinal Study (CHARLS) database. The inclusion criteria were participants who underwent the national baseline survey in 2011. The exclusion criteria were as follows: ① female participants; ② participants without BPH/LUTS information at baseline; ③ participants who had not experienced CVD at baseline. The basic characteristics of BPH/LUTS patients and non-BPH/LUTS patients was compared. The Cox proportional hazards model was used to analyze whether BPH/LUTS is a risk factor for CVD recurrence.Results:A total of 903 male patients with stroke or heart disease were finally included, among which there were 324 (36.9%) cases of BPH/LUTS and 579 (64.1%) cases without BPH/LUTS. Patients with BPH/LUTS had a higher proportion of comorbidities such as hypertension [186 cases (57.4%) vs. 165 cases (28.5%), P=0.014], dyslipidemia [100 cases (31.2%) vs. 104 cases (18.2%), P<0.001], diabetes [55 cases (17.2%) vs. 57 cases (9.8%), P=0.002], chronic kidney disease [71 cases (22.2%) vs. 56 cases (9.8%), P<0.001], and chronic lung disease [87 cases (26.9%) vs. 117 cases (20.3%), P=0.029] compared to those without BPH/LUTS. During the 7-year follow-up, there were 341 (37.8%) cases of CVD recurrence, including 319 (35.3%) cases of heart disease recurrence and 38 (4.2%) cases of stroke recurrence. In the multifactorial adjusted Cox regression model, BPH/LUTS was a risk factor for CVD recurrence ( HR=1.41, 95% CI 1.12-1.77, P=0.003) and heart disease recurrence ( HR=1.40, 95% CI 1.10-1.77, P=0.005), while BPH/LUTS was not a risk factor for stroke recurrence ( HR=2.05, 95% CI 0.97-4.32, P=0.058). When stratified by age, in the population aged ≤65 years, BPH/LUTS was a risk factor for CVD ( HR=1.43, 95% CI 1.07-1.91, P=0.002) and heart disease recurrence ( HR=1.40, 95% CI 1.03-1.90, P=0.006), but not for stroke recurrence ( HR=2.16, 95% CI 0.98-6.09, P=0.053). In patients aged >65 years, BPH/LUTS was not a risk factor for CVD ( P=0.110), heart disease ( P=0.096), or stroke recurrence ( P=0.830). Conclusions:BPH/LUTS is closely related to an increased risk of CVD recurrence, especially for CVD patients aged ≤65 years old. Therefore, for elderly male CVD patients aged ≤65 years, preventing and actively treating BPH/LUTS may have significant implications.

Female ; Infant, Newborn ; Humans ; Pregnancy ; Premature Birth ; Retrospective Studies ; Risk Factors ; Cerclage, Cervical ; Cervix Uteri

Methamphetamine (Meth) abuse can cause serious mental disorders, including anxiety and depression. The gut microbiota is a crucial contributor to maintaining host mental health. Here, we aim to investigate if microbiota participate in Meth-induced mental disorders, and the potential mechanisms involved. Here, 15 mg/kg Meth resulted in anxiety- and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor (SIGMAR1)/BDNF/TRKB pathway in the hippocampus. Meanwhile, Meth impaired gut homeostasis by arousing the Toll-like receptor 4 (TLR4)-related colonic inflammation, disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids (SCFAs). Moreover, fecal microbiota from Meth-administrated mice mediated the colonic inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1^-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated the anti-anxiety and -depression effects of SCFAs. The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety- and depression-like behaviors. Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis, and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner. This study confirms the crucial role of microbiota in Meth-related mental disorders and provides a potential preemptive therapy.

Objective:To develop an ex vivo normothermic mechanical perfusion(NMP)and compare the effect of air-oxygenated NMP versus oxygen-oxygenated NMP on reducing renal injury from donor after cardiac death(DCD).Methods:All kidneys from DCD rats were subjected to 30 min in situ warm ischemia after cardiac attest.And harvested kidneys were stored for 8h under static cold preservation after NMP for 2h.In experimental groups, kidneys were subjected to either air-oxygenated NMP(group A, n=6)or oxygen-oxygenated NMP(group O, n=6). Sham operation(group C, n=6)and DCD kidneys under static cold preservation without NMP(group SCS, n=6)were employed as controls.The evaluation parameters included creatinine(Cr), aspartate amino transferase(AST)and lactate dehydrogenase(LDH)in perfusate, pathological changes by hematoxylin-eosin(HE)staining, histological criteria, expressions of myeloperoxidase and intercellular adhesion molecular-1(ICAM-1)by immunohistochemistry and Western blot, tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6)by enzyme-linked immunoadsorbent assay and level of malondialdehyde(MDA)by thiobarbital method and activity of superoxide dismutase(SOD)by WST-8 in renal tissues.Differences between two groups were analyzed by two-tailed unpaired Student's test and differences among more than two groups by one-way ANOVA.Results:Renal arterial oxygen tensions in NMP perfusate were(576.3±68.2)mmHg with oxygen-oxygenation and(137.0±39.1)mmHg with air-oxygenation.There was significant difference( P<0.05). The pathological injury scores in groups SCS, O and A by HE staining were(7.0±0.1), (5.0±0.9)and(2.5±0.5); injury scores and the expressions of renal proximal tubular epithelial cell vacuolar degeneration in groups O and A were lower than those in group SCS( P<0.05)and injury score in group A was lower than group O( P<0.05). In perfusate, the levels of △Cr, △AST and △LDH in groups O and A were(43.9±52.8)μmol/L and(12.6±3.5)μmol/L, (532.3±52.8)U/L and(49.1±50.4)U/L and(9998.0±2014.4)U/L and(1477.0±810.4)U/L.There were significant differences( P<0.05). In perfused kidneys, the MDA level and SOD activity in groups O and A were(0.192±0.018)mmol/g, (0.162±0.023)mmol/g, (0.6±0.3)×10 3 U/g, (1.7±0.4)×10 3 U/g; TNF-α and IL-6 levels in groups O and A were(124.376±19.635)and(89.331±13.123)ng/g, and(4.038±1.026)×10 3 and(1.774±0.518)×10 3 ng/g.After air-oxygenated NMP, lower renal damage indices were characterized by a lower MDA level and a higher SOD activity, the lower levels of TNF-α and IL-6 and the lower expressions of MPO and ICAM-1 than those in oxygen-oxygenated NMP( P<0.05). Conclusions:NMP with air-oxygenation mimics renal perfusion under physiological conditions and decreases oxidative stress and inflammation injury.It may confer a better retrieval in DCD kidney against warm ischemia injury.

Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The