Unveiling Synergistic Potency: Exploring Butyrolactone I to Enhance Gentamicin Efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA) Strain USA300.

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.

Long-term ozone exposure is negatively associated with estimated glomerular filtration rate in Chinese middle-aged and elderly adults.

Chronic kidney disease (CKD) is an inflammatory disease characterized by the deterioration of renal function, which imposes a significant burden on the healthcare system. In the recent decades, the ageing of the population and the increase of ozone pollution have accelerated. However, epidemiological associations between long-term ozone exposure and renal function in susceptible populations are understudied. In this study, we aimed to investigate the association of 1 y ozone exposure with renal function among the older adults in Xiamen City, China. We recruited 6024 eligible participants with a median age of 65.00 years, estimated their ozone exposure data, and collected questionnaires on demographic status and lifestyle factors as well as information on healthcare access. A generalized linear model was used to assess the association. An increase of 10 µg/m3 of 1 y ozone exposure was negatively associated with the estimated glomerular filtration rate (eGFR) [-3.12 (95% CI: -4.76, -1.48)]. The associations were stronger in men, non-smokers, and those with hypertension or T2DM. Clinical indicators of high-density lipoprotein, low-density lipoprotein, triglycerides, and total cholesterol were the main mediators to regulate the ozone-renal function association. Our results suggested that long-term ozone exposure is a potential risk factor for renal function in Chinese middle-aged and elderly adults.

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 association between bilirubin and hypertension among a Chinese ageing cohort: a prospective follow-up study.

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.

Serum Irisin Levels and Clinical Implication in Elderly Patients With Type 2 Diabetes Mellitus.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.