Vitamin D status, vitamin D receptor polymorphisms, and risk of type 2 diabetes: A prospective cohort study.

CONTEXT: Vitamin D status has been associated with risk of type 2 diabetes (T2D), but evidence is scarce regarding whether such relation differs by glycemic status. OBJECTIVE: To prospectively investigate the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of incident T2D across the glycemic spectrum and the modification effect of genetic variants in vitamin D receptor (VDR). METHODS: This prospective study included 379,699 participants without T2D at baseline from the UK Biobank. Analyses were performed according to glycemic status and HbA1c levels. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs. RESULTS: During a median of 14.1 years of follow-up, 6,315 participants with normoglycemia and 9,085 prediabetes patients developed T2D. Compared to individuals with 25(OH)D <25 nmol/L, the multivariable-adjusted hazard ratios (95% CIs) of incident T2D for those with 25(OH)D ≥75 nmol/L was 0.62 (0.56, 0.70) among the normoglycemia and 0.64 (0.58, 0.70) among the prediabetes. A significant interaction was observed between 25(OH)D and VDR polymorphisms among participants with prediabetes (Pinteraction=0.017), whereby the reduced HR of T2D associated with higher 25(OH)D was more prominent in those carrying T allele of rs1544410. Triglycerides levels mediated 26% and 34% of the association between serum 25(OH)D and incident T2D among participants with normoglycemia and prediabetes. CONCLUSIONS: Higher serum 25(OH)D concentrations were associated with lower T2D risk across the glycemic spectrum below the threshold for diabetes, and the relations in prediabetes were modified by VDR polymorphisms. Improving lipid profile, mainly triglycerides, accounted for part of the favorable associations.

Assessing the impact of type 2 diabetes on mortality and life expectancy according to the number of risk factor targets achieved: an observational study.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of premature death. Whether multifactorial risk factor modification could attenuate T2D-related excess risk of death is unclear. We aimed to examine the association of risk factor target achievement with mortality and life expectancy among patients with T2D, compared with individuals without diabetes. METHODS: In this longitudinal cohort study, we included 316 995 participants (14 162 with T2D and 302 833 without T2D) free from cardiovascular disease (CVD) or cancer at baseline between 2006 and 2010 from the UK Biobank. Participants with T2D were categorised according to the number of risk factors within target range (non-smoking, being physically active, healthy diet, guideline-recommended levels of glycated haemoglobin, body mass index, blood pressure, and total cholesterol). Survival models were applied to calculate hazard ratios (HRs) for mortality and predict life expectancy differences. RESULTS: Over a median follow-up of 13.8 (IQR 13.1-14.4) years, deaths occurred among 2105 (14.9%) participants with T2D and 18 505 (6.1%) participants without T2D. Compared with participants without T2D (death rate per 1000 person-years 4.51 [95% CI 4.44 to 4.57]), the risk of all-cause mortality among those with T2D decreased stepwise with an increasing number of risk factors within target range (0-1 risk factor target achieved: absolute rate difference per 1000 person-years 7.34 [4.91 to 9.78], HR 2.70 [2.25 to 3.25]; 6-7 risk factors target achieved: absolute rate difference per 1000 person-years 0.68 [-0.62 to 1.99], HR 1.16 [0.93 to 1.43]). A similar pattern was observed for CVD and cancer mortality. The association between risk factors target achievement and all-cause mortality was more prominent among participants younger than 60 years than those 60 years or older (P for interaction = 0.012). At age 50 years, participants with T2D who had 0-1 and 6-7 risk factors within target range had an average 7.67 (95% CI 6.15 to 9.19) and 0.99 (-0.59 to 2.56) reduced years of life expectancy, respectively, compared with those without T2D. CONCLUSIONS: Individuals with T2D who achieved multiple risk factor targets had no significant excess mortality risk or reduction in life expectancy than those without diabetes. Early interventions aiming to promote risk factor modification could translate into improved long-term survival for patients with T2D.

Nonlinear relationship between body mass index and serum uric acid: An observational and Mendelian randomization study among Chinese adults.

BACKGROUND AND AIMS: Conflicting evidence exists on the relationship between body mass index (BMI) and serum uric acid (SUA), and importantly, the causal role of BMI in SUA remains unclear. We aimed to evaluate the BMI-SUA relationship and its causality among Chinese adults using observational and Mendelian randomization (MR) analyses. METHODS AND RESULTS: Study included 6641 adults from East China. A genetic risk score based on 14 BMI-associated East Asian variants was formulated. One-sample MR and non-linear MR analyses assessed the causal link between BMI_GRS and SUA levels. Mean BMI levels were 24.8 (SD 3.4) and 24.3 (SD 3.6) kg/m2 in men and women, respectively. Spline models revealed gender-specific BMI-SUA associations: a reverse J-shape for men and a J-shape for women (P-values for nonlinearity <0.05). In men, BMI showed a positive correlation with SUA levels when BMI was below 29.6 kg/m2 (beta coefficient 19.1 [95 % CI 15.1, 23.0] µmol/L per 1-SD increase in BMI), while in women, BMI exhibited a negative correlation with SUA levels when the BMI was less than 21.7 kg/m2 (beta coefficient -12.9 [95 % CI -21.6, -4.1] µmol/L) and a positive correlation when BMI exceeded 21.7 kg/m2 (beta coefficient 13.3 [95 % CI 10.9, 15.8] µmol/L). Furthermore, MR analysis suggested non-linear BMI-SUA link in women but not men. CONCLUSION: Our study indicates a non-linear correlation between BMI and SUA in both genders. It is noteworthy that in women, this correlation may have a causal nature. Nevertheless, further longitudinal investigations are required to authenticate our findings.

Recent Updates on the Antimicrobial Compounds from Marine-Derived Penicillium fungi.

In this review, 72 compounds isolated from marine-derived Penicillium fungi and their antimicrobial activities are reviewed from 2020 to 2023. According to their structures, these compounds can be divided into terpenoids, polyketides, alkaloids and other structural compounds, among which terpenoids and polyketides are relatively large in number. Some compounds have powerful inhibitory effects against different pathogenic bacteria and fungi. This review aims to provide more useful information and enlightenment for further efficient utilization of Penicillium spp. and their secondary metabolites.

High-free Fatty Acid Treatment Induced Anti-inflammatory Changes in a Natural Killer (NK) Cell Line.

Background: Natural killer (NK) cells play a role in the pathogenesis of various metabolic diseases related to obesity. While our initial findings have indicated a potential involvement of NK cells in the pathogenesis of type 2 diabetes mellitus, the precise mechanism underlying NK cell-mediated development of this form of diabetes remains inadequately comprehended. Objective: To investigate the impact and the underlying mechanism of high glucose and elevated levels of free fatty acids (FFAs) on immune and inflammatory responses and oxidative stress in NK92 cells. Methods: In this experiment, the CCK8 cytotoxicity assay was used to select the 44.4 mM and 1.5 mM concentrations of high glucose and high FFAs, respectively, to treat NK92 cells for 4 days. The concentrations of superoxide dismutase (SOD) and glutathione (GSH) were determined using a biochemical analyzer. Intracellular reactive oxygen species (ROS) levels, cytokines concentrations (TNF-α, IFN-γ, IL-6, and IL-10), and the expression levels of intracellular molecules (perforin and granzyme B) were assessed by flow cytometry. Results: The number of NK92 cell clumps was significantly reduced in the high-FFA (HF) group. In addition, the production of ROS and levels of cytokines (TNF-α, IFN-γ, IL-6, and IL-10) significantly decreased in the HF group but showed no significant change in the high-glucose (HG) group. This observation was consistent with the expression levels of perforin and granzyme B that decreased in the HF group. Conclusion: High FFAs induced morphological changes and serious damage to oxidative stress and inflammatory response in NK92 cells.

Marine Aspergillus: A Treasure Trove of Antimicrobial Compounds.

Secondary metabolites from marine organisms are diverse in structure and function. Marine Aspergillus is an important source of bioactive natural products. We reviewed the structures and antimicrobial activities of compounds isolated from different marine Aspergillus over the past two years (January 2021-March 2023). Ninety-eight compounds derived from Aspergillus species were described. The chemical diversity and antimicrobial activities of these metabolites will provide a large number of promising lead compounds for the development of antimicrobial agents.

Investigating the shared genetic architecture between schizophrenia and body mass index.

Evidence for reciprocal comorbidity of schizophrenia (SCZ) and body mass index (BMI) has grown in recent years. However, little is known regarding the shared genetic architecture or causality underlying the phenotypic association between SCZ and BMI. Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) on each trait, we investigated the genetic overlap and causal associations of SCZ with BMI. Our study demonstrated a genetic correlation between SCZ and BMI, and the correlation was more evident in local genomic regions. The cross-trait meta-analysis identified 27 significant SNPs shared between SCZ and BMI, most of which had the same direction of influence on both diseases. Mendelian randomization analysis showed the causal association of SCZ with BMI, but not vice versa. Combining the gene expression information, we found that the genetic correlation between SCZ and BMI is enriched in six regions of brain, led by the brain frontal cortex. Additionally, 34 functional genes and 18 specific cell types were found to have an impact on both SCZ and BMI within these regions. Taken together, our comprehensive genome-wide cross-trait analysis suggests a shared genetic basis including pleiotropic loci, tissue enrichment, and shared function genes between SCZ and BMI. This work provides novel insights into the intrinsic genetic overlap of SCZ and BMI, and highlights new opportunities and avenues for future investigation.

Nomogram based on ultrasound radiomics score and clinical variables for predicting histologic subtypes of epithelial ovarian cancer.

OBJECTIVE: Ovarian cancer is one of the most common causes of death in gynecological tumors, and its most common type is epithelial ovarian cancer (EOC). This study aimed to establish a radiomics signature based on ultrasound images to predict the histopathological types of EOC. METHODS: Overall, 265 patients with EOC who underwent preoperative ultrasonography and surgery were eligible. They were randomly sorted into two cohorts (training cohort: test cohort = 7:3). We outlined the region of interest of the tumor on the ultrasound images of the lesion. Then, the radiomics features were extracted. Clinical, Rad-score and combined models were constructed based on the least absolute shrinkage, selection operator, and logistic regression analysis. The performance of the models was evaluated using receiver operating characteristic curves and decision curve analysis (DCA). A nomogram was formulated based on the combined prediction model. RESULTS: The combined model had good performance in predicting EOC histopathological types, with an AUC of 0.83 (95% CI: 0.77-0.90) and 0.82 (95% CI: 0.71-0.93) in the training and test cohorts, respectively. The calibration curves showed that the nomogram estimation was consistent with the actual observations. DCA also verified the clinical value of the combined model. CONCLUSIONS: The combined model containing clinical and ultrasound radiomics features showed an excellent performance in predicting type I and type II EOC. ADVANCES IN KNOWLEDGE: This study presents the first application of ultrasound radiomics features to distinguish EOC histopathological types. The proposed clinical-radiomics nomogram could help gynecologists non-invasively identify EOC types before surgery.

Comparative study of PM10-bound heavy metals and PAHs during six years in a Chinese megacity: Compositions, sources, and source-specific risks.

To comparatively analyze source-specific risks of atmospheric particulate matter (PM), PM10-bound polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) were synchronously detected in a megacity (Chengdu, China) from 2009 to 2016. Non-cancer risk (assessed by hazard quotient, HQ) of PAHs and HMs was within the acceptable level, while cancer risk (assessed by incremental life cancer risk (ILCR), R) of PAHs and HMs were 1.01 × 10-4 and 9.40 × 10-5 in DP and WP, which showed low risk. HMs dominated cancer (92.12%) and non-cancer (99.99%) risks. An advanced method named as joint source-specific risk assessment of HMs and PAHs (HP-SRA model) was developed to assess comprehensive source-specific risks. Gasoline combustion (contributed 9.6% of PM10, 0.3% of HQ and 10.0% of R), diesel combustion (6.2% of PM10, 0.2% of HQ and 10.7% of R), coal combustion (17.5% of PM10, 1.8% of HQ and 13.4% of R), industrial source (9.1% of PM10, 80.7% of HQ and 35.0% of R), crustal dust (28.1% of PM10, 9.0% of HQ and 1.6% of R), nitrate (7.5% of PM10, 1.1% of HQ and 6.2% of R) and sulphate & secondary organic carbon & adsorption (SSA, 19.6% of PM10, 6.9% of HQ and 23.1% of R) were identified as main sources. For cancer risk, industrial sources and SSA posed the highest proportion. Higher levels of Co and Ni generated from industrial sources and Cr (Ⅵ), Cd and Ni absorbed in the SSA can result in high-risk contributions. Thus, controlling HMs levels in industrial emissions is essential to protecting human health.

Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43.

Overexpression of connexin 43 (Cx43) was related to dysfunction of vascular smooth muscle cells (VSMCs). Our previous study reported that rutaecarpine, an active ingredient of herbal medicine Evodia, modulated connexins expression in human umbilical vein endothelial cells. This study aims to explore the effects of rutaecarpine on Cx43 expression and VSMCs dysfunction induced by oxidized low-density lipoprotein (ox-LDL). In cultured rat thoracic aortic VSMCs, ox-LDL upregulated the level of Cx43 in a time- and dose-dependent manner, which were abolished by the NF-κB inhibitor BAY11-7082 and PDTC. Furthermore, exposure to ox-LDL for 4 h induced the nuclear translocation of the NF-κB p65 in VMSCs. Ox-LDL (50 mg/l,48 h) induced dysfunction of VSMCs, demonstrated as excessive proliferation, migration, and phenotype switch of cells, which were attenuated by treatment with Cx43 gap junction blocker Gap26(100 µM)) or rutaecarpine (1, 3, and 10 µM). Rutaecarpine inhibited ox-LDL-induced upregulation of Cx43, prevented nuclear translocation of the NF-κB p65, and increased intracellular calcium level in VSMCs. These effects were abolished by pretreatment with transient receptor potential vanilloid subtype 1 (TRPV1) antagonist capsazepine, intracellular calcium chelator BAPTA-AM or CaM antagonist W-7. In conclusion, this study demonstrated that rutaecarpine inhibited Cx43 overexpression through TRPV1/[Ca2+]i/CaM/NF-κB signal pathway, thereby preventing VSMCs dysfunction induced by ox-LDL. Our study provides a novel mechanism by which rutaecarpine modulate Cx43 expression and VSMC function.

Source contributions to water-soluble organic carbon and water-insoluble organic carbon in PM2.5 during Spring Festival, heating and non-heating seasons.

To investigate the influences of anthropogenic activities on carbon aerosols, especially on water-soluble organic carbon (WSOC), PM2.5 samples were collected at an urban site in a northern city of China during Spring Festival (SF), heating season (HS), and non-heating season (NHS). Carbonaceous species and ions (Ca2+, SO42-, NO3-, etc.) were analyzed. Mass concentrations of WSOC and WSIC exhibited higher levels in SF and HS, and high WSOC/OC ratios (67.4%) on average were found. Stronger correlations between WSOC and K+, Cl- occurred in SF, which might due to contributions of firework emissions. Six major sources of PM2.5 were quantified by PMF model, which contributed in aerosol mass differently in different periods: biomass & firework burning exhibited higher contribution (11.2%) in SF; crustal dust accounted for 19.4% during NHS; secondary particles contributed most (41.0%) in HS; during SF and HS, coal combustion devoted more to aerosol mass. Contributions to WSOC were in the order of vehicular exhaust (41.0% of WSOC) > coal combustion (29.3%) > secondary formation (17.0%) > biomass & firework burning (12.7%). The 82.0% of WIOC were from coal combustion and the rest were devoted by vehicular exhaust. Obvious peaks of firework burning contributions to WSOC were observed on SF's Eve and Lantern Festival. Coal combustion contributed to organic carbons highly in SF and HS. Results implied that anthropogenic activities contributions, like firework burning and coal combustion, significantly influenced the levels of PM2.5 and WSOC.

Seasonal and regional variations of source contributions for PM10 and PM2.5 in urban environment.

To characterize the sources of to PM10 and PM2.5, a long-term, speciate and simultaneous dataset was sampled in a megacity in China during the period of 2006-2014. The PM concentrations and PM2.5/PM10 were higher in the winter. Higher percentages of Al, Si, Ca and Fe were observed in the summer, and higher concentrations of OC, NO3(-) and SO4(2-) occurred in the winter. Then, the sources were quantified by an advanced three-way model (defined as an ABB three-way model), which estimates different profiles for different sizes. A higher percentage of cement and crustal dust was present in the summer; higher fractions of coal combustion and nitrate+SOC were observed in the winter. Crustal and cement contributed larger portion to coarse part of PM10, whereas vehicular and secondary source categories were enriched in PM2.5. Finally, potential source contribution function (PSCF) and source regional apportionment (SRA) methods were combined with the three-way model to estimate geographical origins. During the sampling period, the southeast region (R4) was an important region for most source categories (0.6%-11.5%); the R1 (centre region) also played a vital role (0.3-6.9%).

Rutaecarpine Reverses the Altered Connexin Expression Pattern Induced by Oxidized Low-density Lipoprotein in Monocytes.

Adhesion of monocytes to the vascular endothelium is crucial in atherosclerosis development. Connexins (Cxs) which form hemichannels or gap junctions, modulate monocyte-endothelium interaction. We previously found that rutaecarpine, an active ingredient of the Chinese herbal medicine Evodia, reversed the altered Cx expression induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells, and consequently decreases the adhesive properties of endothelial cells to monocytes. This study further investigated the effect of rutaecarpine on Cx expression in monocytes exposed to ox-LDL. In cultured human monocytic cell line THP-1, ox-LDL rapidly reduced the level of atheroprotective Cx37 but enhanced that of atherogenic Cx43, thereby inhibiting adenosine triphosphate release through hemichannels. Pretreatment with rutaecarpine recovered the expression of Cx37 but inhibited the upregulation of Cx43 induced by ox-LDL, thereby improving adenosine triphosphate-dependent hemichannel activity and preventing monocyte adhesion. These effects of rutaecarpine were attenuated by capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. The antiadhesive effects of rutaecarpine were also attenuated by hemichannel blocker 18α-GA. This study provides additional evidence that rutaecarpine can modulate Cx expression through transient receptor potential vanilloid subtype 1 activation in monocytes, which contributes to the antiadhesive properties of rutaecarpine.

Source regional contributions to PM2.5 in a megacity in China using an advanced source regional apportionment method.

To quantify contributions of individual source categories from diverse regions to PM2.5, PM2.5 samples were collected in a megacity in China and analyzed through a newly developed source regional apportionment (SRA) method. Levels, compositions and seasonal variations of speciated PM2.5 dataset were investigated. Sources were determined by Multilinear Engine 2 (ME2) model, and results showed that the PM2.5 in Tianjin was mainly influenced by secondary sulphate & secondary organic carbon SOC (percent contribution of 26.2%), coal combustion (24.6%), crustal dust & cement dust (20.3%), secondary nitrate (14.9%) and traffic emissions (14.0%). The SRA method showed that northwest region R2 was the highest regional contributor to secondary sources, with percent contributions to PM2.5 being 9.7% for secondary sulphate & SOC and 6.0% for secondary nitrates; the highest coal combustion was from local region R1 (6.2%) and northwest R2 (8.0%); the maximum contributing region to crustal & cement dust was southeast region R4 (5.0%); and contributions of traffic emissions were relatively spatial homogeneous. The seasonal variation of regional source contributions was observed: in spring, the crustal and cement dust contributed a higher percentage and the R4 was an important contributor; the secondary process attributed an increase fraction in summer; the mixed coal combustion from southwest R5 enhanced in autumn.

Rutaecarpine prevented dysfunction of endothelial gap junction induced by Ox-LDL via activation of TRPV1.

Gap junctions, which is formed by connexins, has been proved to play an important role in the atherogenesis development. Rutaecarpine was reported to inhibited monocyte migration, which indicates its potential for anti-atherosclerosis activity. This study evaluated the effect of rutaecarpine on endothelial dysfunction, and focused on the regulation of connexin expression in endothelial cells by rutaecarpine. Endothelia damage was induced by exposing HUVEC-12 to Ox-LDL (100mg/l) for 24h, which decreased the expression of protective proteins Cx37 and Cx40, but induced atherogenic Cx43 expression, in both mRNA and protein levels, concomitant with the impaired propidium iodide diffusion through the gap junctions. Pretreatment with rutaecarpine effectively recovered the expression of Cx37 and Cx40, but inhibited Cx43 expression, thereby improving gap junction communication and significantly prevented the endothelial dysfunction. Consequently, the cell viability and nitric oxide production were increased, lactate dehydrogenase production was decreased and monocyte adhesion was inhibited. These protective effects of rutaecarpine were remarkably attenuated by pretreatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid subtype 1 (TRPV1). In summary, this study is the first to report that rutaecarpine prevents endothelial injury and gap junction dysfunction induced by Ox-LDL in vitro, which is related to regulation of connexin expression patterns via TRPV1 activation. These results suggest that rutaecarpine has the potential for use as an anti-atherosclerosis agent with a novel mechanism.