CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure.Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation.CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal.Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress.
The relationship between ozone (O3) exposure and blood pressure (BP) remains inconclusive. Given the scarcity of Chinese epidemiological data, more research on this association is of paramount importance, particularly among middle-aged and older Chinese populations. This study involved 10,875 participants (median age: 60.0 years) in Xiamen, China, from 2013 to 2019, with 34,939 repeated BP measurements. Air pollutant exposure data, including O3, particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide were derived from China High Air Pollutants and High-resolution Air Quality Reanalysis datasets using a k-nearest neighbor algorithm. The relationship between mixed air pollutant exposure and BP was evaluated using Bayesian kernel machine regression model. The effects of daily-specific O3 exposure on BP were assessed by distributed lag models integrated into a linear mixed-effects framework. The mediating role of total cholesterol (TC), serum total bilirubin (STB), triglyceride (TG), and low-density lipoprotein (LDL) were examined using multilevel mediation analysis with a fully adjusted model. Mixed air pollutant exposure was positively correlated with BP, with O3 being a predominant contributor exhibiting an inverse effect. O3 exposure had immediate effects on pulse pressure (PP), while systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) showed delayed responses, with 3-, 14-, and 8-day lags, respectively. During the study period of up to 30 days, each 10 μg/m3 increase in maximum daily 8-h average O3 concentration was associated with reductions in SBP (β = − 1.176 mm Hg), DBP (− 0.237 mm Hg), PP (β = − 0.973 mm Hg), and MAP (β = − 0.544 mm Hg). Stronger correlations were observed in the older participants (aged ≥ 65 years), overweight/obese individuals, smokers and alcohol consumers, and those with hypertension or type 2 diabetes mellitus. STB and LDL mediated these effects, while TC and TG played mitigating roles. Short-term O3 exposure is negatively associated with BP in middle-aged and older Chinese individuals. The findings provide preliminary evidence for the impact of O3 exposure on BP regulation and underscore the urgent need to reassess public health policies in response to O3 pollution.
Abstract Background Hypertension is highly prevalent and associated with the elevated risks of cardiovascular diseases, dementia, and physical disabilities among adults. Although the correlation between bilirubin and hypertension has been reported, the observation in quinquagenarian population is scarce. We aimed to examine bilirubin-hypertension association in Guankou Ageing Cohort Study. Methods Participants ≥ 55 years were recruited and their questionnaires and physical examination data were collected. Kaplan–Meier survival analysis and Cox proportional hazards regression were implemented to assess the hypertension risk. The non-liner dose–response relationships of bilirubin-hypertension were determined by restricted cubic spline (RCS) models. Receiver operating characteristic (ROC) curves and multiple factors analysis (MFA) were performed to evaluate the predictive abilities. Results 1881 eligible participants (male 43.75%, female 56.25%) with the median age of 61.00 (59.00–66.00) were included. The hazard ratio (HR, 95% CI ) of serum total bilirubin (STB) and unconjugated bilirubin (UCB) were 1.03 (1.01–1.05) and 1.05 (1.03–1.07), while conjugated bilirubin (CB) showed a weak protective effect with the HR of 0.96 (0.92–0.99), and the associations remained significant in all models. RCS analyses further indicated the similar bidirectional effects of STB and UCB with the cut-off of 12.17 μmol/L and 8.59 μmol/L, while CB exhibited inverse bidirectional dose–response relationship with a cut-off of 3.47 μmol/L. ROC curves and MFA showed baseline STB combined with age, BMI, and waist circumference could well discriminate the low and high of hypertension risk. Conclusions Our findings suggested the higher levels of total and unconjugated bilirubin were hazardous factors of hypertension, while an inverse effect presented when more bilirubin was conjugated.
Staphylococcus aureus, including MRSA strains, poses significant health risks, imposing a significant disease burden and mortality. We investigate butyrolactone I (BL-1), a marine-derived metabolite from Aspergillus terreus, enhancing aminoglycoside efficacy against MRSA. A promising synergy is observed with BL-1 and various aminoglycosides, marked by low fractional inhibitory concentration indexes (FICIs < 0.5). Comprehensive studies utilizing USA300 MRSA and gentamicin reveal a remarkable one-fourth reduction in minimum inhibitory concentration (MIC) with 20 μg/mL BL-1. A relative abundance assay indicates that BL-1 enhances gentamicin uptake while restraining extracellular presence, involving intricate transmembrane signaling and molecular interactions. RNA-Seq analysis yielded an unexpected revelation, unveiling a distinctive gene expression profile and distinguishing it from other treatment approaches. Furthermore, meticulous analyses validated the extensive perturbations induced by BL-1 exposure, affecting diverse biological functions, encompassing glycolysis, amino acid metabolisms, substance transmembrane transport, and virulence generation. These valuable insights inspired further confirmation of bacterial virulence and the modulation of membrane permeability resulting from BL-1 treatment. Phenotypic validations corroborated our observations, revealing reduced membrane permeability and hemolytic toxicity, albeit demanding a deeper comprehension of the intricate interplay underlying these actions. Our study contributes crucial mechanistic insights to the development of therapeutic strategies against this notorious pathogen and the judicious employment of aminoglycosides. Additionally, it elucidates marine-derived metabolites' ecological and functional roles, exemplified by fungal quorum sensing signals. These compounds could give producers a competitive edge, inhibiting microorganism proliferation and suggesting novel approaches for combating resistant pathogens.
The aim of this study is to evaluate the level and role of serum irisin in elderly patients with type 2 diabetes mellitus (T2DM) using case-control study.A total of 71 patients with T2DM were selected as the case group according to the inclusion criteria and exclusion criteria; and the ratio of 1:1 was calculated according to the inclusion rate of the residents. The cohort established in Guankou Town, Jimei District, Xiamen City, Fujian Province, China and the residents of this cohort were selected at the age of 60 and above. A total of 71 healthy subjects were included as the control group with the same gender and the age with a difference of ± 5 years old. The clinical data of the subjects were collected to determine their previous history, blood pressure, body mass index (BMI), hemoglobin (HB), liver function test, renal function test, fasting blood glucose and serum lipid. The irisin level in serum was measured by enzyme-linked immunosorbent assay (ELISA). The data were analyzed by using SPSS17.0 software. Single factor analysis using Chi-square test or t-test was performed to compare the differences between T2DM patients with the control group of the general data, clinical indicators and irisin level in serum. Logistic regression was used to analyze the protective factors and risk factors of diabetes mellitus.The results of single factor analysis showed that the level of irisin in T2DM group was significantly lower than that in the control group (703.37 ± 241.51 ng/mL and 800.22 ± 275.59 ng/mL, respectively). The levels of BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG) and fasting plasma glucose (FPG) in T2DM group were higher than those in control group, and differences were statistically significant. Logistic regression analysis indicated that irisin may be a protective factor for type 2 diabetes (odds ratio (OR) = 0.997, 95% confidence interval (CI): 0.994 - 0.999).The serum irisin level in T2DM group was significantly lower than that in control group, suggesting that irisin may be a protective factor for type 2 diabetes.
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