Association between influenza vaccination and one-year all-cause and cardiovascular mortality risk: A self-controlled case series and matched case-control study.

Debates surrounding the efficacy of influenza vaccination for survival benefits persist, and there is a lack of data regarding its duration of protection. A self-controlled case series (SCCS) and a 1:4 matched case-control study were conducted using the National Health Interview Survey (NHIS) and public-use mortality data from 2005 to 2018 in the United States. The SCCS study identified participants who received influenza vaccination within 12 months before the survey and subsequently died within 1 year of postvaccination. The matched case-control study paired participants who died during the influenza season at the time of survey with four survivors. Among 1167 participants in the SCCS study, there was a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality within 29-196 days of postvaccination. The greatest protection was observed during days 29-56 (all-cause mortality: RI: 0.19; 95% CI: 0.12-0.29; cardiovascular mortality: RI: 0.28; 95% CI: 0.14-0.56). Among 626 cases and 2504 controls included in the matched case-control study, influenza vaccination was associated with a reduction in all-cause mortality (OR: 0.74, 95% CI: 0.60-0.92) and cardiovascular mortality (OR: 0.64, 95% CI: 0.44-0.93) during the influenza season. This study highlights the importance of influenza vaccination in reducing the risks of all-cause and cardiovascular mortality, with effects lasting for approximately 6 months.

Protective effect of radiofrequency exposure against menadione-induced oxidative DNA damage in human neuroblastoma cells: The role of exposure duration and investigation on key molecular targets.

In our previous studies, we demonstrated that 20 h pre-exposure of SH-SY5Y human neuroblastoma cells to 1950 MHz, UMTS signal, at specific absorption rate of 0.3 and 1.25 W/kg, was able to reduce the oxidative DNA damage induced by a subsequent treatment with menadione in the alkaline comet assay while not inducing genotoxicity per se. In this study, the same cell model was used to test the same experimental conditions by setting different radiofrequency exposure duration and timing along the 72 h culture period. The results obtained in at least three independent experiments indicate that shorter exposure durations than 20 h, that is, 10, 3, and 1 h per day for 3 days, were still capable to exert the protective effect while not inducing DNA damage per se. In addition, to provide some hints into the mechanisms underpinning the observed phenomenon, thioredoxin-1, heat shock transcription factor 1, heat shock protein 70, and poly [ADP-ribose] polymerase 1, as key molecular players involved in the cellular stress response, were tested following 3 h of radiofrequency exposure in western blot and qRT-PCR experiments. No effect resulted from molecular analysis under the experimental conditions adopted.

Rhodobacter sphaeroides supplementation improves defense ability of Chinese mitten crab Eriocheir sinensis against Shewanella putrefaciens infection via intestinal flora and metabolism regulation.

Shewanella putrefaciens is a vital bacterial pathogen implicated in serious diseases in Chinese mitten crab Eriocheir sinensis. Yet the use of probiotics to improve the defense ability of E. sinensis against S. putrefaciens infection remains poorly understood. In the present study, the protective effect of dietary R. sphaeroides against S. putrefaciens infection in E. sinensis was evaluated through antioxidant capability, immune response, and survival under bacterial challenge assays, and its protective mechanism was further explored using a combination of intestinal flora and metabolome assays. Our results indicated that dietary R. sphaeroides could significantly improve immunity and antioxidant ability of Chinese mitten crabs, thereby strengthening their disease resistance with the relative percentage survival of 81.09% against S. putrefaciens. In addition, dietary R. sphaeroides could significantly alter the intestinal microbial composition and intestinal metabolism of crabs, causing not only the reduction of potential threatening pathogen load but also the increase of differential metabolites in tryptophan metabolism, pyrimidine metabolism, and glycerophospholipid metabolism. Furthermore, the regulation of differential metabolites such as N-Acetylserotonin positively correlated with beneficial Rhodobacter could be a potential protection strategy for Shewanella infection. To the best of our knowledge, this is the first study to illustrate the protective effect and mechanism of R. sphaeroides supplementation to protect E. sinensis against S. putrefaciens infection.

Hepatoprotective effects and mechanisms of l-theanine and epigallocatechin gallate combined intervention in alcoholic fatty liver rats.

BACKGROUND: Chronic excessive alcohol consumption can lead to alcoholic fatty liver, posing substantial health risks. l-Theanine (LTA) and epigallocatechin gallate (EGCG) in tea exert antioxidant and hepatoprotective effects. However, the combined effects of LTA and EGCG on rats with alcoholic fatty liver, and the underlying mechanisms of such effects, remain unclear. In this study, Sprague Dawley (SD) rats were fed with alcohol for 6 weeks to induce alcoholic fatty liver. Subsequently, for another 6 weeks, the rats were administered LTA (200 mg kg-1 day-1), EGCG (200 mg kg-1 day-1), or a combination of LTA with EGCG (40 mg kg-1 day-1 l-Thea +160 mg kg-1 day-1 EGCG), respectively. RESULTS: The combined use of LTA and EGCG for alcoholic fatty liver disease had more significant effects than their individual administration. This combination reduced the activity of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as the levels of hepatic triglyceride (TG), malondialdehyde (MDA), and reactive oxygen species (ROS) in the rats. The combined intervention also increased hepatic superoxide dismutase (SOD) and glutathione peroxidase activity. Reductions in hepatic fat accumulation and inflammatory responses were observed. The mechanism underlying these effects primarily involved the inhibition of fatty acid synthesis and the alleviation of lipid peroxidation through the downregulation of the mRNA and protein expression of TNF-α, SREBP1c, and CYP2E1 and the upregulation of the mRNA and protein expression of ADH1, ALDH2, Lipin-1, PPARαPPARα, AMPK, and PGC-1α, thereby promoting the oxidative decomposition of fatty acids and reducing the synthesis of cholesterol and glucose. CONCLUSION: l-Theanine and EGCG appear to be able to alleviate alcoholic fatty liver by modulating lipid metabolism and ameliorating oxidative stress, indicating their potential as natural active ingredients in anti-alcoholic fatty liver food products. © 2024 Society of Chemical Industry.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

A Novel Donepezil-Caffeic Acid Hybrid: Synthesis, Biological Evaluation, and Molecular Docking Studies.

A novel donepezil-caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect were investigated by the IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry. DP-CA was highly active against acetylcholine esterase and inhibited it at the micromolar concentrations. Fluorescence and UV-Vis spectroscopy studies showed strong binding of DP-CA to DNA. Moreover, DP-CA exhibited protective effects against H2O2-induced toxicity in U-118 MG glioblastoma cells. Finally, molecular docking showed a high affinity of DP-CA in all concentrations, and the active 4EY7 site exhibited essential residues with polar and apolar contacts. Taken together, these findings indicate that DP-CA could be a prospective multifunctional agent for the treatment of neurodegenerative diseases.

Contralateral versus ipsilateral protective effect against muscle damage of the elbow flexors and knee extensors induced by maximal eccentric exercise.

The present study compared the ipsilateral repeated bout effect (IL-RBE) and contralateral repeated bout effect (CL-RBE) of the elbow flexors (EF) and knee flexors (KF) for the same interval between bouts to shed light on their mechanisms. Fifty-two healthy sedentary young (20-28 years) men were randomly assigned to the IL-EF, IL-KF, CL-EF, and CL-KF groups (n = 13/group). Thirty maximal eccentric contractions of the EF were performed in IL-EF and CL-EF, and 60 maximal eccentric contractions of the KF were performed in IL-KF and CL-KF, with a 2-week interval between bouts. Changes in muscle damage markers such as maximal voluntary contraction (MVC) torque, muscle soreness, and plasma creatine kinase activity, and proprioception measures before to 5 days post-exercise were compared between groups. Changes in all variables were greater (p < 0.05) after the first than second bout for all groups, and the changes were greater (p < 0.05) for the EF than KF. The changes in all variables after the second bout were greater (p < 0.05) for the CL than IL condition for both EF and KF. The magnitude of the average protective effect was similar between CL-EF (33%) and CL-KF (32%), but slightly greater (p < 0.05) for IL-EF (67%) than IL-KF (61%). These demonstrate that the magnitude of CL-RBE relative to IL-RBE was similar between the EF and KF (approximately 50%), regardless of the greater muscle damage for the EF than KF. It appears that the CL-RBE is more associated with neural adaptations at cerebrum, cerebellum, interhemispheric inhibition, and coricospinal tract, but the IL-RBE is induced by additional adaptations at muscles.

Protective Effect of Cannabidiol on Hydrogen Peroxide-Induced Oxidative Damage in Human Umbilical Vein Endothelial Cells (HUVECs).

Natural antioxidants play an important role in promoting good health because of their prevention for oxidative damage. The work aimed to explore the antioxidant mechanism and activity of cannabidiol (CBD) at the cellular level. The human umbilical vein endothelial cell (HUVEC) with oxidative damage was employed as the model to study the protective capability of CBD. The results showed that CBD pre-treatment before the cells were exposed to hydrogen peroxide (H2 O2 ) resulted in an obvious increase of cell viability (about 100 %) and antioxidant related enzymes activity, and a decline of malondialdehyde (MDA) level. Besides, CBD could alleviate the increase of intracellular reactive oxygen species (ROS) content, the contraction of nucleus, and condensation of chromatin. The changes showed a dose-dependent effect. Additionally, the free radicals scavenging capacity of CBD was comparable to that of typical natural antioxidant, anthocyanidins. In summary, CBD could be employed as a potent antioxidant source for avoiding the oxidative damage. These results could provide the foundation for the development of CBD antioxidant products.

Neutralization of iron oxide magnetic nanoparticle aquatoxicity on Oncorhynchus mykiss via supplementation with ulexite.

Nowadays, the unique features of nanoparticles (NPs) have encouraged new applications in different areas including biology, medicine, agriculture, and electronics. Their quick joining into daily life not only enhances the uses of NPs in a wide range of modern technologies but also their release into the aquatic environment causes inevitable environmental concerns. On the other hand boron exhibits key physiological effects on biological systems. This research was designed for evaluating the toxicity of magnetite nanoparticles (Fe3O4-MNPs) on aquatic organisms and obtaining data for the information gap in this area. In this study, Rainbow trout (Oncorhynchus mykiss) was considered as an aquatic indicator, and trials were designed as Ulexite (a boron mineral, UX) treatment against exposure to Fe3O4-MNPs. Synthesized and characterized Fe3O4-MNPs were exposed to rainbow trouts in wide spectrum concentrations (0.005-0.08 mL/L) to analyze its lethal dose (LC50) and cytoprotective properties by UX treatment were assessed against Fe3O4-MNPs applications for 96 h. For the initial toxicity analysis, hematological parameters (blood cell counts) were examined in experimental groups and micronucleus (MN) assay was performed to monitor nuclear abnormalities after exposure to NPs. Biochemical analyzes in both blood and liver samples were utilized to assess antioxidant/oxidative stress and inflammatory parameters. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG) assay was used to investigate oxidative DNA lesions and Caspase-3 analysis was performed on both blood and liver tissues to monitor apoptotic cell death occurrence. When antioxidant enzymes in blood and liver tissue were examined, time-dependent decreases in activity were determined in SOD, CAT, GPx, and GSH enzymes, while increased levels of MDA and MPO parameters were observed in respect to Fe3O4-MNPs exposure. It was found that TNF-α, Il-6 levels were enhanced against Fe3O4-MNPs treatment, but Nrf-2 levels were decreased at the 46th and 96th h. In the 96th application results, all parameters were statistically significant (p < 0.05) in blood and liver tissue, except for the IL-6 results. It was determined that the frequency of MN, the level of 8-OHdG and caspase-3 activity increased in respect to Fe3O4-MNPs exposure over time. Treatment with UX alleviated Fe3O4-MNPs-induced hematotoxic and hepatotoxic alterations as well as oxidative and genetic damages. Our findings offer strong evidence for the use of UX as promising, safe and natural protective agents against environmental toxicity of magnetite nanoparticles.

Vitamin B complex blocks the dust fall PM2 .5 -induced acute lung injury through DNA methylation in rats.

This study aimed to explore whether vitamin B complex (folic acid, B6 , and B12 ) could avert DNA methylation changes associated with inflammation induced by acute PM2.5 exposure. Sprague-Dawley rats were administered by gavage with different concentrations of vitamin B complex once a day for 28 days, and then by intratracheal instillation with saline or PM2.5 once every 2 days for three times. Vitamin B continued to be taken during the PM2.5 exposure. Rats were sacrificed 24 h after the last exposure. The results showed that vitamin B complex could block the pathological changes and injury in lungs induced by PM2.5 . Meanwhile, vitamin B complex could prevent the abnormal DNA methylation of IL-4 and IFN-γ to antagonize the imbalance of IL-4/IFN-γ associated with inflammation. It was further found that vitamin B complex could regulate DNA methyltransferases (DNMTs) and increase the S-adenosylmethionine (SAM)/S-Adenosyl-L-homocysteine (SAH) ratio to reverse the hypomethylation of genomic DNA and the abnormal DNA methylation of IL-4 and IFN-γ. In conclusion, vitamin B complex has a protective effect on acute lung injury by attenuating abnormal DNA methylation induced by PM2.5 in rats. This study may provide a new insight into the physiological function of vitamin B to prevent the health effects induced by PM2.5 .

Brain DNA damaging effects of volatile anesthetics and 1 and 2 Gy gamma irradiation in vivo: Preliminary results.

Although both can cause DNA damage, the combined impact of volatile anesthetics halothane/sevoflurane/isoflurane and radiotherapeutic exposure on sensitive brain cells in vivo has not been previously analyzed. Healthy Swiss albino male mice (240 in total, 48 groups) were exposed to either halothane/sevoflurane/isoflurane therapeutic doses alone (2 h); 1 or 2 gray of gamma radiation alone; or combined exposure. Frontal lobe brain samples from five animals were taken immediately and 2, 6, and 24 h after exposure. DNA damage and cellular repair index were analyzed using the alkaline comet assay and the tail intensity parameter. Elevated tail intensity levels for sevoflurane/halothane were the highest at 6 h and returned to baseline within 24 h for sevoflurane, but not for halothane, while isoflurane treatment caused lower tail intensity than control values. Combined exposure demonstrated a slightly halothane/sevoflurane protective and isoflurane protective effect, which was stronger for 2 than for 1 gray. Cellular repair indices and tail intensity histograms indicated different modes of action in DNA damage creation. Isoflurane/sevoflurane/halothane preconditioning demonstrated protective effects in sensitive brain cells in vivo. Owing to the constant increases in the combined use of radiotherapy and volatile anesthetics, further studies should explore the mechanisms behind these effects, including longer and multiple exposure treatments and in vivo brain tumor models.

Antioxidant Iron Oxide Nanoparticles: Their Biocompatibility and Bioactive Properties.

A lot of nanomaterials have been applied to various nano-biotechnological fields, such as contrast agents, drug or gene delivery systems, cosmetics, and so on. Despite the expanding usage of nanomaterials, concerns persist regarding their potential toxicity. To address this issue, many scientists have tried to develop biocompatible nanomaterials containing phytochemicals as a promising solution. In this study, we synthesized biocompatible nanomaterials by using gallic acid (GA), which is a phytochemical, and coating it onto the surface of iron oxide nanoparticles (IONPs). Importantly, the GA-modified iron oxide nanoparticles (GA-IONPs) were successfully prepared through environmentally friendly methods, avoiding the use of harmful reagents and extreme conditions. The presence of GA on the surface of IONPs improved their stability and bioactive properties. In addition, cell viability assays proved that GA-IONPs possessed excellent biocompatibility in human dermal papilla cells (HDPCs). Additionally, GA-IONPs showed antioxidant activity, which reduced intracellular reactive oxygen species (ROS) levels in an oxidative stress model induced by hydrogen peroxide (H2O2). To investigate the impact of GA-IONPs on exosome secretions from oxidative stress-induced cells, we analyzed the number and characteristics of exosomes in the culture media of HDPCs after H2O2 stimulation or GA-IONP treatment. Our analysis revealed that both the number and proportions of tetraspanins (CD9, CD81, and CD63) in exosomes were similar in the control group and the GA-IONP-treated groups. In contrast, exosome secretion was increased, and the proportion of tetraspanin was changed in the H2O2-treated group compared to the control group. It demonstrated that treatment with GA-IONPs effectively attenuated exosome secretion induced by H2O2-induced oxidative stress. Therefore, this GA-IONP exhibited outstanding promise for applications in the field of nanobiotechnology.

Prenatal Sex Hormone Exposure Is Associated with the Development of Autism Spectrum Disorder.

Sexual differentiation is a major developmental process. Sex differences resulting from sexual differentiation have attracted the attention of researchers. Unraveling what contributes to and underlies sex differences will provide valuable insights into the development of neurodevelopmental disorders that exhibit sex biases. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual's social interaction and communication abilities, and its male preponderance has been consistently reported in clinical studies. The etiology of male preponderance remains unclear, but progress has been made in studying prenatal sex hormone exposure. The present review examined studies that focused on the association between prenatal testosterone exposure and ASD development, as well as sex-specific behaviors in individuals with ASD. This review also included studies on maternal immune activation-induced developmental abnormalities that also showed striking sex differences in offspring and discussed its possible interacting roles in ASD so as to present a potential approach for future studies on sex biases in ASD.

In vitro chemo-protective effect of Eisenia foetida coelomic fluid against histone deacetylase inhibitor-induced oxidative toxicity in breast cancer cells.

Developing new drugs from natural products is important for therapeutic effects to minimise tissue toxicity of drugs used in cancer treatment. Eisenia foetida is a worm with a double transport system consisting of coelomic fluid (ECF) that can be used as alternative medicine. It is important to eliminate or reduce the high cytotoxicity of sodium butyrate (NaBu), a chemotherapeutic agent used in breast cancer treatment, for both neoplastic and normal cells. We aimed to evaluate the effect of ECF on the oxidative toxicity induced by NaBu in MCF-7 cells, changes in ROS production levels and expression of cell death and ROS-related genes. It was determined that the expression levels of Bax and Bcl-2 genes remained unchanged, while the amount of ROS decreased significantly in MCF-7 cells exposed to NaBu with ECF. Thus, ECF may be a potential therapeutic molecule with fewer side effects in cancer treatment in the future.

[Research Progress in the Role of Tamoxifen in Nervous System and Cognitive Function].

Neurological diseases include a variety of neurodegenerative diseases and other brain damage diseases.The treatment schemes for neurological diseases are still in research.The existing clinical and basic studies have confirmed that traditional estrogen therapy has certain protective effect on the nervous system,while it increases the risk of breast or endometrial cancer.The emergence of the selective estrogen receptor modulators (SERMs) can avoid the above mentioned problems.The available studies have confirmed the protective effect of tamoxifen as a SERM on the nervous system.This paper reviews the role and functioning mechanisms of tamoxifen in the nervous system and cognitive function,aiming to provide guidance for the future application of tamoxifen in the treatment of neurological diseases and the improvement of cognitive function.

[Acacetin protects rats from cerebral ischemia-reperfusion injury by regulating TLR4/NLRP3 signaling pathway].

This study aims to investigate the mechanism of acacetin in protecting rats from cerebral ischemia-reperfusion injury via the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. Wistar rats were randomized into sham, model, low-and high-dose acacetin, and nimodipine groups, with 10 rats in each group. The rat model of middle cerebral artery occlusion(MCAO) was established with the improved suture method in other groups except the sham group. The neurological deficit score and cerebral infarction volume of each group were evaluated 24 h after modeling. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1ß(IL-1ß), IL-6, tumor necrosis factor-α(TNF-α), malondialdehyde(MDA), supe-roxide dismutase(SOD), and glutathione(GSH). Western blot was employed to determine the expression levels of B-cell lymphonoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and TLR4/NLRP3 signaling pathway-related proteins(TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß) in the rat brain tissue. Hematoxylin-eosin(HE) staining was employed to reveal the histopathological changes in the ischemic area. Compared with the sham group, the modeling of MCAO increased the neurological deficit score and cerebral infarction volume, elevated the IL-1ß, IL-6, TNF-α, and MDA levels and lowered the SOD and GSH levels in the brain tissue(P<0.05). Compared with the MCAO model group, low-and high-dose acacetin and nimodipine decreased the neurological deficit score and cerebral infarction volume, lowered the IL-1ß, IL-6, TNF-α, and MDA levels and elevated the SOD and GSH levels in the brain tissue(P<0.05). Compared with the sham group, the model group showed up-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß and down-regulated protein level of Bcl-2 in the brain tissue(P<0.05). Compared with the MCAO model group, the acacetin and nimodipine groups showed down-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß and up-regulated protein level of Bcl-2 in the brain tissue(P<0.05). In conclusion, acacetin regulates the TLR4/NLRP3 signaling pathway to inhibit neuroinflammatory response and oxidative stress, thus exerting the protective effect on cerebral ischemia-reperfusion injury in rats.

[Research on the protective effect of hearing protective device for workers exposed to noise in a motor manufacturing enterprise].

Objective: To understand the current situation of noise hazard in a motor manufacturing enterprise, and to explore the protective effect of workers wearing hearing protective device and its possible influencing factors. Methods: In November 2021, a total of 179 noise workers wearing hearing protective devices in a motor manufacturing company in a city were selected as research objects. Personal attenuation rating (PAR) of workers wearing hearing protective devices was measured. Baseline PAR was analyzed for different subgroups of basic demographic information, noise exposure, and the use of hearing protective devices to evaluate the effect of the intervention. Baseline PAR was compared using nonparametric tests. Results: There were 179 workers from 35 positions in 4 types of work, and the over-standard noise rate was 51.2% (42/82), among which the noise exposure intensity of motor equipment debugging workers was the highest [94.4 dB (A) ]. Compared the baseline PAR of different characteristics, it was found that the baseline PAR of male workers, workers whose daily noise exposure time were <8 h, workers who had used the hearing protective devices for 10 to 14 years, and workers who thought the hearing protective devices were comfortable were all higher, and the differences were statistically significant (P<0.05). Baseline PAR passing rate was 43.0% (77/179), and PAR of 102 workers who did not pass baseline test increased from 0 (0, 3) dB before intervention to 14 (12, 16) dB after intervention, with statistical significance (P<0.05) . Conclusion: The noise hazard in this motor manufacturing enterprise is serious, and the protective effect of workers wearing hearing protective devices is not good. Gender, daily noise exposure time, years and comfort of wearing hearing protective device are the possible influencing factors of poor protective effect.

Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK-dependent mechanisms.

Metformin, a well-known AMPK agonist, has been widely used as the first-line drug for treating type 2 diabetes. There had been a significant concern regarding the use of metformin in people with cardiovascular diseases (CVDs) due to its potential lactic acidosis side effect. Currently growing clinical and preclinical evidence indicates that metformin can lower the incidence of cardiovascular events in diabetic patients or even non-diabetic patients beyond its hypoglycaemic effects. The underlying mechanisms of cardiovascular benefits of metformin largely involve the cellular energy sensor, AMPK, of which activation corrects endothelial dysfunction, reduces oxidative stress and improves inflammatory response. In this minireview, we summarized the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischaemic/reperfusion injury and arrhythmia, both in patients with or without diabetes. Meanwhile, we highlighted the potential AMPK-dependent mechanisms in in vitro and/or in vivo models.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Specific T Cells and Antibodies in Coronavirus Disease 2019 (COVID-19) Protection: A Prospective Study.

BACKGROUND: During the ongoing coronavirus disease 2019 (COVID-19) pandemic, many individuals were infected with and have cleared the virus, developing virus-specific antibodies and effector/memory T cells. An important unanswered question is what levels of T-cell and antibody responses are sufficient to protect from the infection. METHODS: In 5340 Moscow residents, we evaluated anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M (IgM)/immunoglobulin G (IgG) titers and frequencies of the T cells specific to the membrane, nucleocapsid, and spike proteins of SARS-CoV-2, using interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay. Additionally, we evaluated the fractions of virus-specific CD4+ and CD8+ T cells using intracellular staining of IFN-γ and interleukin 2 followed by flow cytometry. We analyzed the COVID-19 rates as a function of the assessed antibody and T-cell responses, using the Kaplan-Meier estimator method, for up to 300 days postinclusion. RESULTS: We showed that T-cell and antibody responses are closely interconnected and are commonly induced concurrently. Magnitudes of both responses inversely correlated with infection probability. Individuals positive for both responses demonstrated the highest levels of protectivity against the SARS-CoV-2 infection. A comparable level of protection was found in individuals with antibody response only, whereas the T-cell response by itself granted only intermediate protection. CONCLUSIONS: We found that the contribution of the virus-specific antibodies to protection against SARS-CoV-2 infection is more pronounced than that of the T cells. The data on the virus-specific IgG titers may be instructive for making decisions in personalized healthcare and public anti-COVID-19 policies. Clinical Trials Registration. NCT04898140.

Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.

While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.