​Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the treatment of coronary heart disease and myocardial infarction.

BACKGROUND: Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions. METHODS: A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins. RESULTS: Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13-1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21-1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59-0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54-0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins. CONCLUSIONS: This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.

Intramolecular Palladium(II)-Catalyzed Regioselective 6-endo or 6-exo C-H Benzannulation: An Approach for the Diversity-Oriented Synthesis of Quinolinone Derivatives from Pyridones.

Herein, a new intramolecular palladium(II)-catalyzed regioselective 6-endo-trig or 6-exo-trig annulation through direct C-H activation is presented as a method for the diversity-oriented synthesis of highly substituted quinolinones from pyridones. The reaction occurs under mild conditions and exhibits excellent regioselectivity, good functional group tolerance, and broad applications. This innovative approach has been successfully utilized in the synthesis of Glycopentanolone A and an intermediate of (R)-(+)-Tipifarnib.

Hypertensive patients with periodontitis as predictors of cardiovascular and all-cause mortality: a long-term cohort study.

OBJECTIVES: The aim of this study is to examine the potential correlation between periodontitis and the risk of cardiovascular mortality and all-cause mortality in individuals diagnosed with hypertension, despite the established association between periodontitis and hypertension. METHODS: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2014 involving hypertensive individuals. Following the criteria proposed by Eke et al., periodontitis was classified. Survival estimates were calculated using Kaplan Meier analyses and a Kaplan Meier curve was generated. Weighted multivariate cox regression were employed to assess the association between periodontitis and all-cause mortality, as well as cardiovascular mortality. RESULTS: Of the 21,645 individuals, 6,904 individuals were diagnosed with periodontitis. The Kaplan-Meier survival analysis revealed significantly higher rates of all-cause mortality (34.766% vs. 14.739%) and cardiovascular mortality (12.469% vs. 3.736%) in the periodontitis group compared to the non-periodontitis group. Hazard ratios (HRs) for all-cause mortality were 3.19 (95% CI 2.88-3.53) and for cardiovascular mortality were 3.80 (95% CI 3.13-4.61) in individuals with periodontitis compared to those without periodontitis. CONCLUSION: Periodontitis is a risk factor for mortality in patient with hypertension, especially if it is moderate to severe. Improving periodontal health could lead to better outcomes for these patients.

Cryo-EM structure of a eukaryotic zinc transporter at a low pH suggests its Zn2+-releasing mechanism.

Zinc transporter 8 (ZnT8) is mainly expressed in pancreatic islet ß cells and is responsible for H+-coupled uptake (antiport) of Zn2+ into the lumen of insulin secretory granules. Structures of human ZnT8 and its prokaryotic homolog YiiP have provided structural basis for constructing a plausible transport cycle for Zn2+. However, the mechanistic role that protons play in the transport process remains unclear. Here we present a lumen-facing cryo-EM structure of ZnT8 from Xenopus tropicalis (xtZnT8) in the presence of Zn2+ at a luminal pH (5.5). Compared to a Zn2+-bound xtZnT8 structure at a cytosolic pH (7.5), the low-pH structure displays an empty transmembrane Zn2+-binding site with a disrupted coordination geometry. Combined with a Zn2+-binding assay our data suggest that protons may disrupt Zn2+ coordination at the transmembrane Zn2+-binding site in the lumen-facing state, thus facilitating Zn2+ release from ZnT8 into the lumen.

Regioselective [2 + 1] photocycloaddition of 2-pyridones with diazo compounds.

Herein, we report a novel regioselective [2 + 1] cyclization reaction of 2-pyridones with carbenes generated in situ via visible light irradiation, without the requirement for catalysts or additives. The diverse functional groups of 2-pyridones and diazo compounds exhibit good tolerance, enabling the rapid synthesis of highly valuable cyclopropanated dihydro-2-pyridone scaffolds with exceptional regio- and stereoselectivity. Furthermore, DFT calculations provide a comprehensive explanation for the regio- and stereoselectivity observed in the reaction.

Forgetfulness as the primary presenting symptom of type A acute aortic dissection.

Acute aortic dissection (AAD) is the most common lethal disease affecting the aorta. Neurological symptoms have been linked to AAD in some patients. Although aortic dissection patients have previously been shown to present with neurological symptoms, AAD with forgetfulness as the first manifestation is extremely rare. To increase the awareness of AAD among clinicians, we report the first case of a male Chinese patient with AD presenting with forgetfulness as the initial symptom. A 53-year-old man presented to the emergency department with forgetfulness. Based on the concept that "time is brain," stroke was initially considered in the differential diagnosis. The patient underwent emergency coronary angiography and was diagnosed with acute myocardial infarction. After contrast-enhanced computed tomography angiography, the patient was finally diagnosed with AAD. Because valuable time was lost in diagnosis rather than treatment, optimal timing for surgery missed. The patient died following an aortic dissection rupture while waiting for emergency surgery. When forgetfulness cannot be completely accounted for in patients presenting with acute myocardial infarction, AAD should be considered. We believe that this case report contains a worthwhile clinical lesson for clinicians.

Crystal structures of LeuT reveal conformational dynamics in the outward-facing states.

The neurotransmitter:sodium symporter (NSS) homolog LeuT from Aquifex aeolicus has proven to be a valuable model for studying the transport mechanism of the NSS family. Crystal structures have captured LeuT in key conformations visited during the transport cycle, allowing for the construction of a nearly complete model of transport, with much of the conformational dynamics studied by computational simulations. Here, we report crystal structures of LeuT representing new intermediate conformations between the outward-facing open and occluded states. These structures, combined with binding and accessibility studies, reveal details of conformational dynamics that can follow substrate binding at the central substrate binding site (S1) of LeuT in outward-facing states, suggesting a potential competition for direction between the outward-open and outward-occluded states at this stage during substrate transport. Our structures further support an intimate interplay between the protonation state of Glu290 and binding of Na1 that may ultimately regulate the outward-open-to-occluded transition.

Torsade de pointes caused by citalopram during the pacemaker battery-depletion phase: A case report.

Drug-induced QT prolongation, primarily antiarrhythmic drugs, is a common cause of torsade de pointes (TdP). Although there have been previous reports of drug-induced TdP in patients, it has not been well documented when caused by citalopram during the pacemaker battery-depletion phase. To improve delirium recognition, we report a case of citalopram-induced TdP during the pacemaker battery-depletion phase. An 84-year-old Chinese female was brought to the hospital presenting recurrent syncope. She lost consciousness and was admitted after her syncope TdP was documented. Her pacemaker was inspected and found to be operating in an extremely ineffective manner. Although she had prolonged QT interval after the pacemaker was replaced, she did not suffer another syncope attack, and ECG monitoring revealed no cardiac arrhythmia or TdP. During her admission, she was treated with citalopram for depression. Citalopram was discontinued when the QT interval shortened progressively. In this study, we described a case of citalopram-induced TdP during the depletion phase of a pacemaker battery. This case should serve as a cautionary lesson to clinicians to avoid using citalopram during the pacemaker battery-depletion phase.

[Screening of differentially expressed genes for colorectal cancer and prediction of potential traditional Chinese medicine: based on bioinformatics].

This study screened and analyzed the differentially expressed genes(DEGs) between colorectal cancer(CRC) tissues and normal tissues with bioinformatics techniques to predict biomarkers and Chinese medicinals for the diagnosis and treatment of CRC. The microarray data sets GSE21815, GSE106582, and GSE41657 were downloaded from the Gene Expression Omnibus(GEO), and the DEGs were screened by GEO2 R, followed by the Gene Ontology(GO) tern enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the DEGs based on DAVID. The protein-protein interaction network was constructed by STRING, and MCODE and Cytohubba plug-ins were used to screen the significant modules and hub genes in the network. UCSC, cBioPortal, and Oncomine were employed for hierarchical clustering, survival analysis, Oncomine analysis, and correlation analysis of clinical data. Coremine Medical was applied to predict the Chinese medicinals acting on hub genes. A total of 284 DEGs were screened out, with 146 up-regulated and 138 down-regulated. The up-regulated genes were mainly involved in cell cycle, NLRs pathway, and TNF signaling pathway, and the down-regulated genes were related to mineral absorption, nitrogen metabolism, and bicarbonate reabsorption in proximal tubules. The 15 hub genes were CDK1, CDC20, AURKA, MELK, TOP2 A, PTTG1, BUB1, CDCA5, CDC45, TPX2, NEK2, CEP55, CENPN, TRIP13, and GINS2, among which CDK1 and CDC20 were regarded as core genes. The high expression of CDK1 and CDC20 suggested poor prognosis, and they significantly expressed in many cancers, especially breast cancer, lung cancer, and CRC. The expression of CDK1 and CDC20 was correlated with gender, tumor type, TNM stage, and KRAS gene mutation. The potential effective medicinals against CRC were Scutellariae Radix, Scutellariae Barbatae Herba, Arnebiae Radix, etc. The significant expression of CDK1 and CDC20 can help distinguish tumor tissues from normal tissues, and is related to survival prognosis. Thus, the two can be used as biomarkers for the diagnosis and treatment of CRC. This study provides a reference for related drug development.

Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion.

Identification of protective loss-of-function (LoF) mutations holds great promise for devising novel therapeutic interventions, although it faces challenges due to the scarcity of protective LoF alleles in the human genome. Exploiting the detailed mechanistic characterization of animal models of validated disease mutations offers an alternative. Here, we provide insights into protective-variant biology based on our characterization of a model of the 22q11.2 deletion, a strong genetic risk factor for schizophrenia (SCZ). Postnatal brain up-regulation of Mirta22/Emc10, an inhibitor of neuronal maturation, represents the major transcriptional effect of the 22q11.2-associated microRNA dysregulation. Here, we demonstrate that mice in which the Df(16)A deficiency is combined with a LoF Mirta22 allele show rescue of key SCZ-related deficits, namely prepulse inhibition decrease, working memory impairment, and social memory deficits, as well as synaptic and structural plasticity abnormalities in the prefrontal cortex. Additional analysis of homozygous Mirta22 knockout mice, in which no alteration is observed in the above-mentioned SCZ-related phenotypes, highlights the deleterious effects of Mirta22 up-regulation. Our results support a causal link between dysregulation of a miRNA target and SCZ-related deficits and provide key insights into beneficial LoF mutations and potential new treatments.

Sertad1 promotes prostate cancer progression through binding androgen receptor ligand binding domain.

Androgen receptor (AR) signaling is involved in the initiation and progression of prostate cancer (PCa), which is the most frequently diagnosed nonskin cancer and remains a leading cause of cancer-related death in men. Further investigation of the involvement of AR signaling in PCa progression is urgently needed. In the present study, we performed a yeast two-hybrid screen and demonstrated that SERTA domain-containing protein 1 (Sertad1) is a novel AR-binding protein that binds to the AR ligand binding domain (LBD). The binding between AR-LBD and Sertad1 was confirmed by glutathione S-transferase (GST) pull-down assays and immunoprecipitation (IP) and confocal immunofluorescence co-localization experiments. Furthermore, we demonstrated that DHT inhibited Sertad1 protein degradation in prostate cancer cell lines and that Sertad1 knockdown inhibited the proliferation of prostate cancer cells in vitro. In human PCa tumor tissues, Sertad1 expression is positively correlated with AR expression and the Gleason score. Taken together, this report is the first to show that Sertad1 is a novel AR-LBD-binding protein, and DHT-liganded AR-LBD inhibits Sertad1 degradation. Thus, Sertad1 may represent a novel therapeutic target for the treatment of AR-positive PCa.

Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.

Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit Kv1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of Kv1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.SIGNIFICANCE STATEMENT Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes, DISC1, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.

Hydrogen peroxide displacing DNA from nanoceria: mechanism and detection of glucose in serum.

Hydrogen peroxide (H2O2) is a key molecule in biology. As a byproduct of many enzymatic reactions, H2O2 is also a popular biosensor target. Recently, interfacing H2O2 with inorganic nanoparticles has produced a number of nanozymes showing peroxidase or catalase activities. CeO2 nanoparticle (nanoceria) is a classical nanozyme. Herein, a fluorescently labeled DNA is used as a probe, and H2O2 can readily displace adsorbed DNA from nanoceria, resulting in over 20-fold fluorescence enhancement. The displacement mechanism instead of oxidative DNA cleavage is confirmed by denaturing gel electrophoresis and surface group pKa measurement. This system can sensitively detect H2O2 down to 130 nM (4.4 parts-per-billion). When coupled with glucose oxidase, glucose is detected down to 8.9 µM in buffer. Detection in serum is also achieved with results comparable with that from a commercial glucose meter. With an understanding of the ligand role of H2O2, new applications in rational materials design, sensor development, and drug delivery can be further exploited.

Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Insight into binding of endogenous neurosteroid ligands to the sigma-1 receptor.

The sigma-1 receptor (σ1R) is a non-opioid membrane receptor, which responds to a diverse array of synthetic ligands to exert various pharmacological effects. Meanwhile, candidates for endogenous ligands of σ1R have also been identified. However, how endogenous ligands bind to σ1R remains unknown. Here, we present crystal structures of σ1R from Xenopus laevis (xlσ1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09 Å resolutions. Both neurosteroids bind to a similar location in xlσ1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xlσ1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xlσ1R-neurosteroid complex structures. Furthermore, molecular dynamics simulations and structural data reveal a potential water entry pathway. Our results provide insight into binding of two endogenous neurosteroid ligands to σ1R.

Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding.

Vesicular monoamine transporter 2 (VMAT2) belongs to the major facilitator superfamily (MFS), and mediates cytoplasmic monoamine packaging into presynaptic vesicles. Here, we present two cryo-EM structures of VMAT2, with a frog VMAT2 adopting a canonical MFS fold and an engineered sheep VMAT2 adopting a non-canonical fold. Both VMAT2 proteins mediate uptake of a selective fluorescent VMAT2 substrate into cells. Molecular docking, substrate binding and transport analysis reveal potential substrate binding mechanism in VMAT2. Meanwhile, caution is advised when interpreting engineered membrane protein structures.

Nanoplastics increase algal absorption and toxicity of Cd through alterations in cell wall structure and composition.

Nanoplastics (NPs) may act as carriers of heavy metals and cause complex toxicity to aquatic organisms, while the exact role of NPs in the joint toxicity remains unclear. Here, we investigated the joint toxicity of polystyrene NPs (PS-NPs) and Cd to freshwater algae (Chlorella vulgaris). It was found that PS-NPs (1 mg L-1) could hardly enter algal cells and slightly inhibit algal growth (p < 0.01). The effect of PS-NPs as carriers on the joint toxicity of PS-NPs and heavy metals could be neglected because of the limited adsorption of Cd by PS-NPs, while the PS-NPs altered the cell wall structure and composition, which resulted in the increased algal absorption and toxicity of Cd. Compared to the low dose Cd (0.4 mg L-1) treatment alone, the extracellular and intracellular Cd contents in the cotreatment were significantly increased by 27.3 % and 18.0 %, respectively, due to the increased contents of cell wall polysaccharides (pectin and hemicellulose in particular) by the PS-NPs. Furthermore, after the high dose Cd (2 mg L-1) exposure, the inhibited polysaccharide biosynthesis and the loosen cell wall structure weakened the tolerance of cell wall to abiotic stress, facilitating the entry of PS-NPs into the algal cells and inducing the higher toxicity. These results elucidate the mechanism by which NPs enhance heavy metal toxicity to algae, providing a novel insight into environmental risks of NPs.

Protective effect of salvianolic acid B against myocardial ischemia/reperfusion injury: preclinical systematic evaluation and meta-analysis.

Background: Salvianolic acid B is the most abundant water-soluble component in the traditional Chinese medicine Danshen and can reduce myocardial ischemia-reperfusion (MI/R) injury through multiple targets and pathways. However, the role of SalB in protecting the myocardium from ischemia/reperfusion injury remains unclear. Purpose: To perform a preclinical systematic review and meta-analysis to assess the efficacy of Sal B in an animal model of myocardial infarction/reperfusion (MI/R) and to summarize the potential mechanisms of Sal B against MI/R. Methods: Studies published from inception to March 2024 were systematically searched in PubMed, Web of Science, Embase, China National Knowledge Infrastructure Wanfang, and VIP databases. The methodological quality was determined using the SYRCLE RoB tool. The R software was used to analyze the data. The potential mechanisms are categorized and summarized. Results: 32 studies containing 732 animals were included. The results of the meta-analysis showed that Sal B reduced myocardial infarct size (p < 0.01), and the cardiological indices of CK-MB (p < 0.01), CK (p < 0.01), LDH (p < 0.01), and cTnI (p < 0.01) compared to the control group. In addition, Sal B increased cardiac function indices, such as LVFS (p < 0.01), -dp/dt max (p < 0.01), +dp/dt max (p < 0.01), and cardiac output (p < 0.01). The protective effects of Sal B on the myocardium after I/R may be mediated by attenuating oxidative stress and inflammation, promoting neovascularization, regulating vascular function, and attenuating cardiac myocyte apoptosis. Publication bias was observed in all the included studies. Further studies are required to elucidate the extent of the cardioprotective effects of SalB and the safety of its use. Conclusion: To the best of our knowledge, this is the first meta-analysis of Sal B in the treatment of MI/R injury, and Sal B demonstrated a positive effect on MI/R injury through the modulation of key pathological indicators and multiple signaling pathways. Further studies are needed to elucidate the extent to which SalB exerts its cardioprotective effects and the safety of its use. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/.

Effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: The acute and long-term benefits of exercise training on cardiovascular health have been well established. The systematic review and meta-analysis aimed to systematically assess the effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women with elevated blood pressure. METHODS: A comprehensive search was conducted on PubMed, Embase, Web of Science, ProQuest, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov website from inception to September 30, 2023, to identify the randomized controlled trials (RCTs), which evaluated the effectiveness of exercise training on arterial stiffness and blood pressure in postmenopausal women. Standardized mean differences (SMD), weighted mean differences (WMD), and 95% confidence intervals (95% CIs) were calculated using random/fixed effects models. Quality assessment was performed using the modified Jadad scale and the Cochrane Risk of Bias Tool. Sensitivity analysis and subgroup analysis were conducted based on drug dosage, treatment duration, and age of administration to further explore potential heterogeneity. Funnel plots were performed to assess publication bias and Begg's regression test was carried out for funnel plot asymmetry. RESULTS: Twenty-two RCTs involving 1978 participants were included in the quantitative analysis. The mean quality of eligible studies was 4.2 out of 7 based on the modified Jadad scale. The results indicated that exercise training had a significant effect on reducing brachial-ankle pulse wave velocity [MD = - 0.69, 95%CI (- 1.11, - 0.27), P = 0.001], decreasing augmentation index (AIx) [MD = - 6.00, 95%CI (- 6.39, - 5.61), P < 0.00001] and AIx normalized to a heart rate of 75 beats per minute (AIx@75%) [MD = - 7.01, 95%CI - 7.91 to - 6.12, P < 0.00001], lowering systolic blood pressure [MD = - 6.19, 95%CI - 9.24 to - 3.15, P < 0.0001], diastolic blood pressure [MD = - 3.57, 95%CI (- 6.10, - 1.03), P = 0.006) and pulse pressure [MD = - 8.52, 95%CI (- 16.27, - 0.76), P = 0.03]. Subgroup analysis revealed that baseline blood pressure levels had a large impact on the effect of exercise training. CONCLUSIONS: The systematic review and meta-analysis suggested that exercise training may ameliorate arterial stiffness and reduce blood pressure in postmenopausal women with elevated blood pressure. However, the optimal mode of exercise training that improves arterial stiffness and blood pressure in this population requires further investigation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021211268.

Nanoplastics inhibit carbon fixation in algae: The effect of aging.

Despite the considerable efforts devoted to the toxicological assessment of nanoplastics, the effect of UV-irradiation induced aging, a realistic environmental process, on the toxicity of nanoplastics toward microalgae and its underlying mechanisms remain largely unknown. Herein, this study comparatively investigated the toxicities of polystyrene nanoplastics (nano-PS) and the UV-aged nano-PS on the eukaryotic alga Chlorella vulgaris, focusing on evaluating their inhibitory effects on carbon fixation. Exposure to environmentally relevant concentrations (0.1-10 mg/L) of nano-PS caused severe damage to chloroplast, inhibited the photosynthetic efficiency and electron transport, and suppressed the activities of carbon fixation related enzymes. Multi-omics results revealed that nano-PS interfered with energy supply by disrupting light reactions and TCA cycle and hindered the Calvin cycle, thereby inhibiting the photosynthetic carbon fixation of algae. The above alterations partially recovered after a recovery period. The aged nano-PS were less toxic than the pristine ones as evidenced by the mitigated inhibitory effect on algal growth and carbon fixation. The aging process introduced oxygen-containing functional groups on the surface of nano-PS, increased the hydrophilicity of nano-PS, limited their attachment on algal cells, and thus reduced the toxicity. The findings of this work highlight the potential threat of nanoplastics to the global carbon cycle.