SENP1-Mediated HSP90ab1 DeSUMOylation in Cardiomyocytes Prevents Myocardial Fibrosis by Paracrine Signaling.

Myocardial infarction (MI) triggers a poor ventricular remodeling response, but the underlying mechanisms remain unclear. Here, the authors show that sentrin-specific protease 1 (SENP1) is downregulated in post-MI mice and in patients with severe heart failure. By generating cardiomyocyte-specific SENP1 knockout and overexpression mice to assess cardiac function and ventricular remodeling responses under physiological and pathological conditions. Increased cardiac fibrosis in the cardiomyocyte-specific SENP1 deletion mice, associated with increased fibronectin (Fn) expression and secretion in cardiomyocytes, promotes fibroblast activation in response to myocardial injury. Mechanistically, SENP1 deletion in mouse cardiomyocytes increases heat shock protein 90 alpha family class B member 1 (HSP90ab1) SUMOylation with (STAT3) activation and Fn secretion after ventricular remodeling initiated. Overexpression of SENP1 or mutation of the HSP90ab1 Lys72 ameliorates adverse ventricular remodeling and dysfunction after MI. Taken together, this study identifies SENP1 as a positive regulator of cardiac repair and a potential drug target for the treatment of MI. Inhibition of HSP90ab1 SUMOylation stabilizes STAT3 to inhibit the adverse ventricular remodeling response.

Ultrafast dynamics of fluorene initiated by highly intense laser fields.

We present an investigation of the ultrafast dynamics of the polycyclic aromatic hydrocarbon fluorene initiated by an intense femtosecond near-infrared laser pulse (810 nm) and probed by a weak visible pulse (405 nm). Using a multichannel detection scheme (mass spectra, electron and ion velocity-map imaging), we provide a full disentanglement of the complex dynamics of the vibronically excited parent molecule, its excited ionic states, and fragments. We observed various channels resulting from the strong-field ionization regime. In particular, we observed the formation of the unstable tetracation of fluorene, above-threshold ionization features in the photoelectron spectra, and evidence of ubiquitous secondary fragmentation. We produced a global fit of all observed time-dependent photoelectron and photoion channels. This global fit includes four parent ions extracted from the mass spectra, 15 kinetic-energy-resolved ionic fragments extracted from ion velocity map imaging, and five photoelectron channels obtained from electron velocity map imaging. The fit allowed for the extraction of 60 lifetimes of various metastable photoinduced intermediates.

Role of S100ß in Unstable Angina Pectoris: Insights from Quantitative Flow Ratio.

BACKGROUND AND OBJECTIVE: Disturbed autonomic nervous system (ANS) may promote inflammatory, immune, and oxidative stress responses, which may increase the risk of acute coronary events. S100ß has been proposed as a biomarker of neuronal injury that would provide an insightful understanding of the crosstalk between the ANS, immune-inflammatory cells, and plaques that drive atherosclerosis. This study investigates the correlation between S100ß, and functional coronary stenosis as determined by quantitative flow ratio (QFR). METHODS: Patients with unstable angina pectoris (UAP) scheduled for coronary angiography and QFR were retrospectively enrolled. Serum S100ß levels were determined by enzyme-linked immunosorbent assay. The Gensini score was used to estimate the extent of atherosclerotic lesions and the cumulative sum of three-vessel QFR (3V-QFR) was calculated to estimate the total atherosclerotic burden. RESULTS: Two hundred thirty-three patients were included in this study. Receiver operator characteristic (ROC) curve indicated that S100ß>33.28 pg/mL predicted functional ischemia in patients with UAP. Multivariate logistic analyses showed that a higher level of S100ß was independently correlated with a functional ischemia-driven target vessel (QFR ≤0.8). This was also closely correlated with the severity of coronary lesions, as measured by the Gensini score (OR = 5.058, 95% CI: 2.912-8.793, p <0.001). According to 3V-QFR, S100ß is inversely associated with total atherosclerosis burden (B = -0.002, p <0.001). CONCLUSIONS: S100ß was elevated in the functional ischemia stages of UAP. It was independently associated with coronary lesion severity as assessed by Gensini score and total atherosclerosis burden as estimated by 3V-QFR in patients with UAP.

The predictive value of cumulative atherogenic index of plasma (AIP) for cardiovascular outcomes: a prospective community-based cohort study.

BACKGROUND: Atherogenic index of plasma (AIP) has been reported as a critical predictor on the risks and clinical outcomes of cardiovascular diseases (CVDs), and we aimed to explore the potential predictive value of cumulative AIP on major adverse cardiac events (MACE), stroke, myocardial infarction (MI) and cardiovascular mortality. METHODS: A large-scale community-based prospective cohort was established from December 2011 to April 2012 and followed up in May to July 2014. The endpoint outcomes were obtained before December 31, 2021. AIP was calculated as the logarithmically transformed ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-c) and cumulative AIP was the average value of AIP in 2012 and 2014. RESULTS: An overall of 3820 participants (36.1% male) with mean (SD) age of 59.1 (8.7) years, were enrolled. Within a median follow-up of 7.5 years, a total of 371 (9.7%) participants were documented with MACE, 293 (7.7%) participants developed stroke, 68 (1.8%) suffered from MI and 65 (1.7%) experienced cardiovascular mortality. Multivariable Cox regression analysis revealed significant associations between cumulative AIP and the risk of MACE, stroke and MI. Regarding MACE, individuals with one higher unit of cumulative AIP were associated with 75% increment on the incidence of going through MACE in fully adjusted model, while categorizing participants into four groups, individuals in the highest cumulative AIP quartile were significantly associated with increased incidence of MACE (HR = 1.76, 95%CI: 1.27-2.44, p < 0.001 in fully adjusted model), stroke (HR = 1.69, 95%CI: 1.17-2.45, p = 0.005) and MI (HR = 2.82, 95%CI: 1.18-6.72, p = 0.019). But not a significant association was observed between cumulative AIP and cardiovascular mortality. In subgroup analysis, the association of cumulative AIP and the incidence of stroke was more pronounced in the elderly (HR: 0.89 vs. 2.41 for the age groups < 65 years and ≥ 65 years, p for interaction = 0.018). CONCLUSIONS: A higher cumulative AIP was significantly associated with an increased risk of MACE, stroke and MI independent of traditional cardiovascular risk factors in a community-based population, and the association of cumulative AIP and stroke was particularly pronounced in the elderly population.

Cynomorium songaricum: UHPLC/ESI-LTQ-Orbitrap-MS analysis and mechanistic study on insulin sensitivity of a flavonoid-enriched fraction.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, posing a significant global health concern due to its increasing prevalence. Insulin resistance (IR) plays a major role in the development of T2DM and is often linked to factors such as obesity, physical inactivity, and a sedentary lifestyle. Recently, there has been growing interest in exploring the potential of natural products for improving insulin sensitivity and glucose metabolism. Among these, Cynomorium songaricum Rupr., an edible parasitic plant, has shown promising antidiabetic effects. However, research on its beneficial effects on IR is still nascent. Therefore, this study aims to investigate the application of a Cynomorium songaricum flavonoid-enriched fraction (CSF) in the treatment of IR in T2DM, along with elucidating the chemical and biochemical mechanisms involved. METHOD: First, UHPLC/ESI-LTQ-Orbitrap-MS was utilized to perform a chemical profiling of CSF. Subsequently, glycogen synthesis, gluconeogenesis and glucose consumption assays were conducted on HepG2 cells with a high glucose high insulin-induced IR model to illustrate the favorable impacts of CSF on IR. Then, an innovative network pharmacology analysis was executed to predict the potential chemical components and hub genes contributing to CSF's protective effect against IR. To further elucidate molecular interactions, molecular docking studies were performed, focusing on the binding interactions between active constituents of CSF and crucial targets. Additionally, an RNA-sequencing assay was employed to uncover the underlying biochemical signaling pathway responsible for CSF's beneficial effects. To validate these findings, western blot and qPCR assays were employed to verify the pathways related to IR and the potential signaling cascades leading to the amelioration of IR. RESULTS: The UHPLC/ESI-LTQ-Orbitrap-MS analysis successfully identified a total of thirty-six flavonoids derived from CSF. Moreover, CSF was shown to significantly improve glycogen synthesis and glucose consumption as well as inhibit gluconeogenesis in HepG2 cells of IR. An innovative network pharmacology analysis unveiled key hub genes-AKT1 and PI3K-integral to metabolic syndrome-related signaling pathways, which contributed to the favorable impact of CSF against IR. Noteworthy active ingredients including quercetin, ellagic acid and naringenin were identified as potential contributors to these effects. The results of western blot and qPCR assays provided compelling evidence that CSF improved insulin sensitivity by modulating the PI3K-Akt signaling pathway. Subsequent RNA-sequencing analysis, in tandem with western blot assays, delved deeper into the potential mechanisms underlying CSF's advantageous effects against IR, potentially associated with the enhancement of endoplasmic reticulum (ER) proteostasis. CONCLUSION: CSF exhibited a remarkable ability to enhance insulin sensitivity in the IR model of HepG2 cells. This was evident through enhancements in glycogen synthesis and glucose consumption, along with its inhibitory impact on gluconeogenesis. Furthermore, CSF demonstrated an improvement in the insulin-mediated PI3K-Akt signaling pathway. The potential active constituents were identified as quercetin, ellagic acid and naringenin. The underlying biochemical mechanisms responsible for CSF's beneficial effects against IR were closely linked to its capacity to mitigate ER stress, thereby offering a comprehensive understanding of its protective action.

Association Between Serine Concentration and Coronary Heart Disease: A Case-Control Study.

Purpose: Early identification of new residual risk factors for coronary heart disease (CHD) is warranted. In this study, we aim to investigate the association between the serine concentration, an important amino acid in one-carbon metabolism, and CHD in Chinese hospitalized patients. Patients and Methods: This case-control study included 428 case-control pairs comprising patients with CHD with a maximum coronary artery stenosis degree of >70% and controls with stenosis of <30%. The individuals were matched by age, sex, and date of coronary angiography at Peking University First Hospital from January 1, 2016, to December 31, 2019. Conditional logistic regression was used to investigate the associations between the serine concentration and CHD. Results: Patients with CHD were aged 63.48 ± 10.38 years, and 43.73% were male. Compared with controls, patients with CHD had a slightly lower serine concentration (13.35 ± 4.20 vs 13.77 ± 4.08 µg/mL), but the difference was not significant. In the multivariable conditional logistic regression analysis, for every 1 µg/mL increase in serine concentration, the odds of CHD decreased by 6% (95% confidence interval [CI] 0.90-0.99; P = 0.010). Patients with a serine concentration of ≥13.41 µg/mL had a lower CHD risk than those with a serine concentration of <13.41 µg/mL (odds ratio [OR] 0.57, 95% CI 0.39-0.84; P = 0.004). Subgroup analyses showed that sex interacted with the relationship between serine concentration and CHD (P interaction = 0.039), which was more significant in males (OR 0.93, 95% CI 0.87-0.98; P = 0.013) than in females. Conclusion: This study observed an inverse association between the serine concentration and CHD prevalence in Chinese hospitalized patients, which revealed that serine might play a protective role in CHD.

Chemical Compositions of Lianqiao (Forsythia suspensa) Extracts and Their Potential Health Benefits.

This study evaluated the fruits of Forsythia suspensa (Lianqiao), an important economic crop, for the chemical components of its water and ethanol extracts, inhibitory effects on SARS-CoV-2 virus spike protein binding to ACE2, inhibition of ACE2 activity, and capacity to scavenge free radicals. A total of 42 compounds were tentatively identified in the extracts via HPLC-MS/MS analysis. The water extract showed a greater ACE2 inhibition but a weaker inhibition on SARS-CoV-2 spike protein binding to ACE2 than the ethanol extract on a per-botanical-weight-concentration basis. The phenolic content was found to be greater in the water extract at 45.19 mg GAE/g dry botanical weight than in the ethanol extract (6.89 mg GAE/g dry botanical). Furthermore, the water extract had greater scavenging capacities against HO●, DPPH●, and ABTS●+ at 448.48, 66.36, and 121.29 µmol TE/g dry botanical, respectively, as compared to that of the ethanol extract (154.04, 3.55, and 33.83 µmol TE/g dry botanical, respectively). These results warrant further research into, and the development of, the potential COVID-19-preventive applications of Lianqiao and its extracts.

Environmentally relevant estrogens impaired spermatogenesis and sexual behaviors in male and female zebrafish.

Environmental estrogens (EEs) are found extensively in natural waters and negatively affect fish reproduction. Research on the reproductive toxicity of EEs mixtures in fish at environmentally relevant concentrations is scarce. In this study, adult male zebrafish were exposed for 60 days to EES (a mixture of EEs), EE2-low (5.55 ng/L, with an estrogenic potency equal to EES), and EE2-high (11.1 ng/L). After exposure, the expression levels of vtg1, vtg3, and esr1 in the livers in EES-treated fish remained unaltered, whereas they were significantly increased in EE2-treated fish. Both EE2-high and EES exposures notably reduced the gonad somatic index and sperm count. A disrupted spermatogenesis was also observed in the testes of EE2-high- and EES-exposed fish, along with an alteration in the expression of genes associated with spermatogonial proliferation (pcna, nanog), cell cycle transition (cyclinb1, cyclind1), and meiosis (aldh1a2, cyp26a1, sycp3). Both EE2 and EES significantly lowered plasma 11-ketotestosterone levels in males, likely by inhibiting the expression level of genes for its synthesis (scc, cyp17a1 and cyp11b2), and increased 17ß-estradiol (E2) levels, possibly through upregulating the expression of cyp19a1a. A significant increase in tnfrsf1a expression and the tnfrsf1a/tnfrsf1b ratio in EE2-high and EES-treated males also suggests increased apoptosis via the extrinsic pathway. Further investigation showed that both EE2-high and EES diminished the sexual behavior of male fish, accompanied with reduced E2 levels in the brain and the expression of genes in the kisspeptin/gonadotropin-releasing hormone system. Interestingly, the sexual behavior of unexposed females paired with treated males was also reduced, indicating a synergistic effect. This study suggests that EES have a more severe impact on reproduction than EE2-low, and EEs could interfere not only with spermatogenesis in fish, but also with the sexual behaviors of both exposed males and their female partners, thereby leading to a more significant disruption in fish reproduction.

Serum tumor marker and CT body composition scoring system predicts outcomes in colorectal cancer surgical patients.

OBJECTIVE: To investigate the prognostic value of preoperative body composition and serum tumor markers (STM) in patients undergoing surgical treatment for colorectal cancer (CRC) and to establish the prognostic score for patients with CRC. METHODS: This study enrolled 365 patients (training set 245, validation set 120) with CRC who underwent surgical resection. The predictive value of various body composition features and STM for determining CRC prognosis were compared. A novel index score based on the independent risk factors from Cox regression for CRC patients was established and evaluated for its usefulness. RESULTS: Multivariate Cox regression showed that low skeletal muscle radiodensity (SMD) (p = 0.020), low subcutaneous fat area (SFA) (p = 0.029), high carcinoembryonic antigen (CEA) (p = 0.008), and high alpha-fetoprotein (AFP) (p = 0.039) were all independent prognostic factors for poor overall survival (OS). The multifactorial analysis indicated that high intermuscular fat area (IMFA) (p = 0.033) and high CEA (p = 0.009) were independent prognostic factors for poor disease-free survival (DFS). Based on these findings, two scoring systems for OS and DFS were established in the training datasets. CRC patients who scored higher on the new scoring systems had lower OS and DFS (both p < 0.001) as shown in the Kaplan-Meier survival curves in the training and validation datasets. CONCLUSION: In predicting the prognosis of CRC patients, SFA and SMD are superior to other body composition measurements. A scoring system based on body composition and STM can have prognostic value and clinical applicability. CLINICAL RELEVANCE STATEMENT: This scoring system, combining body composition and serum tumor markers, may help predict postoperative survival of CRC patients and help clinicians make well-informed decisions regarding the treatment of patients. KEY POINTS: Colorectal cancer prognosis can be related to body composition. High intermuscular fat area and CEA were independent prognostic factors for poor disease-free survival. This scoring system, based on body composition and tumor markers, can prognosticate for colorectal cancer patients.

Applications of physical and chemical treatments in plant-based gels for food 3D printing.

Extrusion-based three-dimensional (3D) printing has been extensively studied in the food manufacturing industry. This technology places particular emphasis on the rheological properties of the printing ink. Gel system is the most suitable ink system and benefits from the composition of plant raw materials and gel properties of multiple components; green, healthy aspects of the advantages of the development of plant-based gel system has achieved a great deal of attention. However, the relevant treatment technologies are still only at the laboratory stage. With a view toward encouraging further optimization of ink printing performance and advances in this field, in this review, we present a comprehensive overview of the application of diverse plant-based gel systems in 3D food printing and emphasize the utilization of different treatment methods to enhance the printability of these gel systems. The treatment technologies described in this review are categorized into three distinct groups, physical, chemical, and physicochemical synergistic treatments. We comprehensively assess the specific application of these technologies in various plant-based gel 3D printing systems and present valuable insights regarding the challenges and opportunities for further advances in this field.

Cinnamaldehyde Regulates the Migration and Apoptosis of Gastric Cancer Cells by Inhibiting the Jak2/Stat3 Pathway.

OBJECTIVE: Gastric cancer is a malignant tumor with high morbidity and mortality all around the world. Because of its poor prognosis and low survival rate, the treatment of gastric cancer has received extensive attention. Cinnamaldehyde (CA) is the main single active component of the Chinese herbal medicine cinnamon, which has a variety of pharmacological effects. The inhibitory effect of CA on the growth of some tumor cells has been proven, but its therapeutic effect on gastric cancer has rarely been reported. METHODS: Through network pharmacology, bioinformatics methods, and molecular docking technology, we predicted the interaction targets of CA and gastric cancer. Moreover, we found that apoptosis is an important mode of action of CA on gastric cancer cells. Subsequently, we validated it in gastric cancer cell lines cultured in vitro. RESULTS: The results showed that in the presence of CA, the Jak2/Stat3 pathway was inhibited, the ratio of Bcl-2/Bax decreased, and the apoptosis of gastric cancer cells was promoted in a concentration-dependent. CONCLUSION: In conclusion, CA can promote the apoptosis of gastric cancer cells by inhibiting the activity of the Jak2/Stat3 pathway, which may achieve the effect of treating gastric cancer.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

The association between the triglyceride-glucose index and in-stent restenosis in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Insulin resistance (IR) can lead to cellular metabolic disorders, activation of oxidative stress, and endothelial dysfunction, contributing to in-stent restenosis (ISR). The triglyceride-glucose index (TyG index), a new indicator reflecting IR, is extensively researched in the cardiovascular field. This study, through a meta-analysis, aimed to utilize a larger combined sample size and thereby enhance the overall test efficacy to explore the TyG index-ISR relationship. METHODS: A thorough search was conducted in the PubMed, EMBASE, Web of Science, and Cochrane Library databases to find original papers and their references published between 1990 and January 2024. This search included both prospective and retrospective studies detailing the correlation between the TyG index and ISR in individuals with coronary heart disease (CHD). OUTCOMES: The five included articles comprised 3,912 participants, and the odds ratio (OR) extracted from each study was combined using the Inverse Variance method. Results showed that, in the context of CHD patients, each incremental unit in the TyG index, when treated as a continuous variable, corresponded to a 42% elevation in ISR risk (95% CI 1.26-1.59, I²=13%, p < 0.005). When analyzing the TyG index categorically, the results revealed a higher ISR risk in the highest TyG index group compared to the lowest group (OR: 1.69, 95% CI 1.32-2.17, I²=0). Additionally, in patients with chronic coronary syndrome (CCS), each unit increase in the TyG index, the risk of ISR in patients increased by 37% (95% CI 1.19-1.57, I²=0%, p < 0.005). This correlation was also observable in acute coronary syndrome (ACS) patients (OR:1.48, 95% CI 1.19-1.85, I²=0, p < 0.005). CONCLUSIONS: The TyG index, an economical and precise surrogate for IR, is significantly linked with ISR. Furthermore, this correlation is unaffected by the type of coronary heart disease.

eDNA reveals spatial homogenization of fish diversity in a mountain river affected by a reservoir cascade.

One of the main reasons for the decline in global freshwater biodiversity can be attributed to alterations in hydrological conditions resulting from dam construction. However, the majority of current research has focused on single or limited numbers of dams. Here, we carried out a seasonal fish survey, using environmental DNA (eDNA) method, on the Wujiang River mainstream (Tributaries of the Yangtze River, China) to investigate the impact of large-scale cascade hydropower development on changes in fish diversity patterns. eDNA survey revealed that native fish species have decreased in contrast to alien fish. There was also a shift in fish community structure, with declines of the dominant rheophilic fish species, an increase of the small-size fish species, and homogenization of species composition across reservoirs. Additionally, environmental factors, such as temperature, dissolved oxygen and reservoir age, had a significant effect on fish community diversity. This study provides basic information for the evaluation of the impact of cascade developments on fish diversity patterns.

Cytochemical localization and synthesis mechanism of the glucomannan in pseudobulbs of Bletilla striata Reichb. f.

The dried pseudobulbs of Bletilla striata, an important traditional Chinese medicine named BaiJi, have an extraordinary polysaccharide content and excellent prospects for medicinal effects. However, the distribution and molecular mechanism underlying biosynthesis are poorly understood. In this study, chemical and immunologic analyses were performed in representative tissues of B. striata, and the results showed that what are conventionally termed Bletilla striata polysaccharides (BSPs) are water-soluble polysaccharides deposited only in pseudobulbs. The structural component of BSPs is glucomannan, with a mannose:glucose mass ratio of ~3:2. BSPs are present in the parenchyma of the pseudobulbs in cells known as glucomannan idioblasts and distributed in the cytoplasm within cellular membranes, but are not contained in the vacuole. Comparative transcriptomics and bioinformatics analyses mapped the pathway from sucrose to BSP and identified BsGPI, BsmanA, and BsCSLAs as the key genes of BSP biosynthesis, suggesting that the functional differentiation of the cellulose synthase-like family A (CSLA) may be critical for the flow of glucomannan to the BSP or cell wall. Subsequently, virus-mediated gene silencing showed that silencing of two CSLAs (Bs03G11846 and Bs03G11849) led to a decrease in BSP content, and yeast two-hybrid and luciferase complementation experiments confirmed that four CSLAs (Bs03G11846, Bs03G11847, Bs03G11848, and Bs03G11849) can form homo- or heterodimers, suggesting that multiple CSLAs may form a large complex that functions in BSP synthesis. Our results provide cytological evidence of BSP and describe the isolation and characterization of candidate genes involved in BSP synthesis, laying a solid foundation for further research on its regulation mechanisms and the genetic engineering breeding of B. striata.

Chemical Composition of Turmeric (Curcuma longa L.) Ethanol Extract and Its Antimicrobial Activities and Free Radical Scavenging Capacities.

Turmeric (Curcuma longa L.) is a perennial tuberous plant from the genus Curcuma (Zingiberaceae) and has been widely used in foods for thousands of years. The present study examined the ethanol extract of turmeric for its chemical composition, antimicrobial activity, and free radical scavenging properties. UHPLC-MS/MS analysis tentatively identified eight compounds in the turmeric extract. Potential antimicrobial effects of 0.1, 1.0, and 10 mg turmeric equivalents (TE)/mL were evaluated in vitro against a variety of Gram-negative bacteria (i.e., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas sp.) and Gram-positive bacteria (i.e., Enterococcus faecalis, Listeria innocua, and Staphylococcus aureus). Concentrations of 0.1 and 1.0 mg TE/mL inhibited the growth of S. aureus and significantly suppressed that of Pseudomonas sp., E. faecalis, and L. innocua. The growth of all strains, including E. coli, was inhibited by 10 mg TE/mL. Moreover, free radical scavenging capacities were determined using HO●, ABTS●+, and DPPH● (HOSC, ABTS, and RDSC, respectively) radicals. The turmeric ethanol extract had a TPC value of 27.12 mg GAE/g, together with HOSC, RDSC, and ABTS values of 1524.59, 56.38, and 1.70 µmol TE/g, respectively. Our results suggest that turmeric extract has potential applications for use in functional foods to reduce microbial burdens and oxidative stress-related health problems.

Inter-leg systolic blood pressure difference has been associated with all-cause and cardiovascular mortality: analysis of NHANES 1999-2004.

BACKGROUND: Inter-leg systolic blood pressure difference (ILSBPD) has emerged as a novel cardiovascular risk factor. This study aims to investigate the predictive value of ILSBPD on all-cause and cardiovascular mortality in general population. METHODS: We combined three cycles (1999-2004) of the National Health and Nutrition Examination Survey (NHANES) data. Levels of ILSBPD were calculated and divided into four groups based on three cut-off values of 5, 10 and 15mmHg. Time-to-event curves were estimated with the use of the Kaplan-Meier method, and two multivariable Cox proportional hazards regression models were conducted to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cardiovascular mortality associated with ILSBPD. RESULTS: A total of 6 842 subjects were included, with the mean (SD) age of 59.5 (12.8) years. By December 31, 2019, 2 544 and 648 participants were identified all-cause and cardiovascular mortality respectively during a median follow-up of 16.6 years. Time-to-event analyses suggested that higher ILSBPD was associated with increased all-cause and cardiovascular mortality (logrank, p < 0.001). Every 5mmHg increment of ILSBPD brings about 5% and 7% increased risk of all-cause and cardiovascular mortality, and individuals with an ILSBPD ≥ 15mmHg were significantly associated with higher incidence of all-cause mortality (HR 1.43, 95%CI 1.18-1.52, p < 0.001) and cardiovascular mortality (HR 1.73, 95%CI 1.36-2.20, p < 0.001) when multiple confounding factors were adjusted. Subgroup and sensitivity analysis confirmed the relationship. CONCLUSIONS: Our findings suggest that the increment of ILSBPD was significantly associated with higher risk of all-cause and cardiovascular mortality in general population.

B(a)P induces ovarian granulosa cell apoptosis via TRAF2-NFκB-Caspase1 axis during early pregnancy.

Benzo(a)pyrene [B(a)P] is an environmental endocrine disruptor with reproductive toxicity. The corpus luteum (CL) of the ovary plays an important role in embryo implantation and pregnancy maintenance. Our previous studies have shown that B(a)P exposure affects embryo implantation and endometrial decidualization in mouse, but its effects and mechanisms on CL function remain unclear. In this study, we explore the mechanism of ovarian toxicity of B(a)P using a pregnant mouse model and an in vitro model of human ovarian granulosa cells (GCs) KGN. Pregnant mice were gavaged with corn oil or 0.2 mg/kg.bw B(a)P from pregnant day 1 (D1) to D7, while KGN cells were treated with DMSO, 1.0IU/mL hCG, or 1.0IU/mL hCG plus benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a B(a)P metabolite. Our findings revealed that B(a)P exposure damaged embryo implantation and reduced estrogen and progesterone levels in early pregnant mice. Additionally, in vitro, BPDE impaired luteinization in KGN cells. We observed that B(a)P/BPDE promoted oxidative stress (OS) and inflammation, leading to apoptosis rather than pyroptosis in ovaries and luteinized KGN cells. This apoptotic response was mediated by the activation of inflammatory Caspase1 through the cleavage of BID. Furthermore, B(a)P/BPDE inhibited TRAF2 expression and suppressed NFκB signaling pathway activation. The administration of VX-765 to inhibit the Caspase1 activation, over-expression of TRAF2 using TRAF2-pcDNA3.1 (+) plasmid, and BetA-induced activation of NFκB signaling pathway successfully alleviated BPDE-induced apoptosis and cellular dysfunction in luteinized KGN cells. These findings were further confirmed in the KGN cell treated with H2O2 and NAC. In conclusion, this study elucidated that B(a)P/BPDE induces apoptosis rather than pyroptosis in GCs via TRAF2-NFκB-Caspase1 during early pregnancy, and highlighting OS as the primary contributor to B(a)P/BPDE-induced ovarian toxicity. Our results unveil a novel role of TRAF2-NFκB-Caspase1 in B(a)P-induced apoptosis and broaden the understanding of mechanisms underlying unexplained luteal phase deficiency.

Preclinical Pharmacokinetics and Pharmacology Study of RC98: A Programmed Cell Death Ligand 1 Monoclonal Antibody in Cynomolgus Monkeys.

INTRODUCTION: RC98 is the monoclonal antibody against Programmed Cell Death Ligand 1 (PD-L1). Relevant reports have confirmed that the influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined. OBJECTIVE: This study aimed to design a Pharmacokinetics/Pharmacology (PK/PD) study of RC98 in normal cynomolgus monkeys to research the effect on the immune system. METHODS: RC98 and vehicle were administered to cynomolgus monkeys at 15 mg/kg via intravenous infusion once a week for 4 weeks to evaluate the relationship between PK and PD. The pharmacodynamic activity was measured by the PD-L1 receptor occupancy (RO) in CD3+ T cells, A T-cell-dependent antibody response (TDAR), and the concentration of soluble PD-L1. RESULTS: The pharmacokinetic result showed that the exposure from the last administration was lower than that of the first administration, probably due to immunogenicity production. There was a strong correlation between systemic exposure and RO in CD3+ T cells but decreased RO levels after the last dose, which indirectly reflected the activation of T cells. The keyhole limpet hemocyanin (KLH)-induced TDAR in the RC98 group was higher than in the vehicle group. The concentration of soluble PD-L1 had increased feedback with RC98, and the concentration of soluble PD-L1 was maintained at a higher level after multiple doses than before dosing. CONCLUSION: These data indicate that the immune system was clearly activated. In addition, the non-clinical data could provide a basis for its efficacy evaluation in clinical trials.

Metal-Free Electron Donor-Acceptor Pair Enabled Long-Term Stability of Li-CO2 Battery.

The challenges of Lithium-carbon dioxide (Li-CO2) batteries for ensuring long-term cycling stability arise from the thermodynamically stable and electrically insulating discharge products (e.g., Li2CO3), which primarily rely on their interaction with the active materials. To achieve the optimized intermediates, the bifunctional electron donor-acceptor (D-A) pairs are proposed in cathode design to adjust such interactions in the case of B-O pairs. The inclusion of BC2O sites allows for the optimized redistribution of electrons via p-π conjugation. The as-obtained DO-AB pairs endow the enhanced interactions with Li+, CO2, and various intermediates, accompanied by the adjustable growth mode of Li2CO3. The shift from solvation-mediated mode into surface absorption mode in turn manipulates the morphology and decomposition kinetics of Li2CO3. Therefore, the corresponding Li-CO2 battery got twofold improved in both the capacity and reversibility. The cycling prolongs exceed 1300 h and well operates at a wide temperature range (20-50 °C) and different folding angles (0-180°). Such a strategy of introducing electron donor-acceptor pairs provides a distinct direction to optimize the lifetime of Li-CO2 battery from local structure regulation at the atomic scale, further inspiring in-depth understandings for developing electrochemical energy storage and carbon capture technologies.