Vascular stiffness, a hallmark of aging and cardiovascular disease, involves vascular smooth muscle cell (VSMC) senescence and extracellular matrix (ECM) dysregulation. This study investigates the role of fibulin-1 (Fbln1) in these processes. Plasma proteomic profiling identified dysregulated proteins in vascular stiffness pedigrees. Fbln1 knockout mice and dual vascular stiffness models (natural aging and chronic angiotensin II [Ang II] infusion) were established. Phenotypic assessments included pulse wave velocity (PWV), histology, and molecular markers. Mechanistic investigations integrating DNA pull-down assays, dual-luciferase reporter assays, and RNA sequencing (RNA-seq) were employed to dissect the transcriptional and signaling axis regulating Fbln1 expression and function. Elevated plasma Fbln1 correlated with hereditary vascular stiffness. Both aging and Ang II promote vascular stiffness, whereas Fbln1 knockdown ameliorates this phenotype by reducing PWV, reversing VSMC senescence, and attenuating collagen deposition. Zinc Finger Protein 384 (ZNF384) was identified as a transcriptional activator of Fbln1, which promoted VSMC senescence and collagen deposition via transforming growth factor-beta (TGF-β)/SMAD family member 3 (Smad3). Inhibiting TGF-β/Smad3 signaling abolished Fbln1-driven senescence and ECM remodeling. Fbln1 exacerbates vascular stiffness through ZNF384-mediated transcriptional activation and TGF-β/Smad3-dependent ECM/senescence pathways. Targeting Fbln1 or its regulators may offer therapeutic strategies for age-related vascular pathologies.

Sirtuin 6 (Sirt6) is a member of the Sirtuin family, exhibiting histone deacetylase and ADP-ribosyltransferase activity. This enzyme is involved in several pathways, such as epigenetic regulation and inflammation control. It is essential for preserving cardiac equilibrium and postponing the emergence of cardiovascular disorders. Recent findings reveal that Sirt6 affects glucose and lipid metabolism and regulates oxidative stress via the HIF-1α/NF-κB signaling pathway, thereby delaying cardiomyocyte senescence and diminishing DNA damage accumulation. Sirt6 mitigates oxidative damage in cardiomyocytes by deacetylation, suppresses cardiac fibrosis, and improves cardiomyocyte survival rates. Sirt6 exhibits anti-atherosclerotic properties by enhancing DNA repair in endothelial cells, reducing lipid accumulation in macrophages, and promoting cholesterol transport via ATP-Binding Cassette A1 (ABCA1). Sirt6 promotes the degradation of the critical autophagic component Charged Multivesicular Body Protein 2B (CHMP2B) through the FoxO1-Atrogin-1 pathway. This action supports the autophagic process and mitigates ischemia-reperfusion harm. The regulatory mechanisms of Sirt6 in ferroptosis remain controversial. This article explores the specific molecular mechanisms of Sirt6 in the heart and various cell death pathways, including apoptosis, autophagy, and pyroptosis, while also considering the potential for targeted therapeutic applications of Sirt6 in cardiovascular medicine.

Purpose This paper aims to review the research progress in repairing injury caused by acute myocardial infarction, focusing on myocardial regeneration, cardiomyocyte apoptosis, and fibrosis. The goal is to investigate the current research trends and challenges in the field of myocardial injury repair. Methods The review delves into the latest research on myocardial regeneration, cardiomyocyte apoptosis, and fibrosis following acute myocardial infarction. It highlights stem cell transplantation and gene therapy as key areas of current research focus, while emphasizing the significance of cardiomyocyte apoptosis and fibrosis in the myocardial injury repair process. Additionally, the review addresses the challenges and unresolved issues that require further investigation in the field of myocardial injury repair. Summary Acute myocardial infarction is a prevalent cardiovascular condition that results in myocardial damage necessitating repair. Myocardial regeneration plays a crucial role in repairing myocardial injury, with current research focusing on stem cell transplantation and gene therapy. Cardiomyocyte apoptosis and fibrosis are key factors in the repair process, significantly impacting the restoration of myocardial structure and function. Nonetheless, there remain numerous challenges and unresolved issues that warrant further investigation in the realm of myocardial injury repair.

AimsThis research aimed to study the changes in platelet function and their underlying mechanisms in iron deficiency anemia.Main methodsInitially, we evaluated platelet function in an IDA mice model. Due to the inability to accurately reduce intracellular Fe2+ concentrations, we investigated the impact of Fe2+ on platelet function by introducing varying concentrations of Fe2+. To probe the underlying mechanism, we simultaneously examined the dynamics of calcium in the cytosol, and integrin αIIbβ3 activation in Fe2+-treated platelets. Ferroptosis inhibitors Lip-1 and Fer-1 were applied to determine whether ferroptosis was involved in this process.Key findingsOur study revealed that platelet function was suppressed in IDA mice. Fe2+ concentration-dependently facilitated platelet activation and function in vitro. Mechanistically, Fe2+ promoted calcium mobilization, integrin αIIbβ3 activation, and its downstream outside-in signaling. Additionally, we also demonstrated that ferroptosis might play a role in this process.SignificanceOur data suggest an association between iron and platelet activation, with iron deficiency resulting in impaired platelet function, while high concentrations of Fe2+ contribute to platelet activation and function by promoting calcium mobilization, αIIbβ3 activation, and ferroptosis.

The farnesoid X receptor (FXR) has been recognized as a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). FXR agonists benefit NAFLD by modulating bile acid synthesis and transport, lipid metabolism, inflammation, and fibrosis pathways. However, there are still great challenges involved in developing safe and effective FXR agonists. To investigate the critical factors contributing to their activity on the FXR, 3D-QSAR molecular modeling was applied to a series of isoxazole derivatives, using comparative molecular field analysis (CoMFA (q2 = 0.664, r2 = 0.960, r2pred = 0.872)) and comparative molecular similarity indices analysis (CoMSIA (q2 = 0.706, r2 = 0.969, r2pred = 0.866)) models, which demonstrated strong predictive ability in our study. The contour maps generated from molecular modeling showed that the presence of hydrophobicity at the R2 group and electronegativity group at the R3 group in these compounds is crucial to their agonistic activity. A molecular dynamics (MD) simulation was carried out to further understand the binding modes and interactions between the FXR and its agonists in preclinical or clinical studies. The conformational motions of loops L: H1/H2 and L: H5/H6 in FXR–ligand binding domain (LBD) were crucial to the protein stability and agonistic activity of ligands. Hydrophobic interactions were formed between residues (such as LEU287, MET290, ALA291, HIS294, and VAL297) in helix H3 and ligands. In particular, our study found that residue ARG331 participated in salt bridges, and HIS447 participated in salt bridges and hydrogen bonds with ligands; these interactions were significant to protein–ligand binding. Eight new potent FXR agonists were designed according to our results, and their activities were predicted to be better than that of the first synthetic FXR agonist, GW4064.

Senescent cells that accumulate are regarded as promising therapeutic targets. However, senolytic therapy failed to achieve satisfactory results. We previously discovered that young human plasma improved vascular endothelial cell senescence, and UNC5B might be a novel intervention target. Netrin-1, as a natural ligand of UNC5B, plays roles in multiple age-related vascular disorders, but its involvement in aging is still unclear. Here, we observed a significant decrease in plasma Netrin-1 levels in old healthy subjects compared to the young. In vivo, adeno-associated-virus-mediated delivery of Netrin-1 into aged mice significantly improved functional recovery in a model of hindlimb ischemia, promoted angiogenesis in ischemic tissues, and activated the endothelial nitric oxide synthase. Furthermore, we revealed that low-dose Netrin-1 recombinant protein significantly reduced senescence-associated-β-galactosidase-positive cells, inhibited the P53 pathway, promoted cell migration, increased tubule formation, and elevated nitric oxide production in senescent endothelial cells. However, UNC5B inhibition blocked the pro-angiogenesis effect of low-dose Netrin-1 on senescent cells or aortic rings. In summary, this study depicts that modulating Netrin-1 signaling can result in improved vascular health and Netrin-1 may have therapeutic potential for age-related ischemic diseases.

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

OBJECTIVE:This retrospective cohort study aimed to investigate the association of sleep characteristics measured by the Pittsburgh Sleep Quality Index (PSQI) with the vertigo outcome in vertiginous patients with comorbid cardiometabolic diseases.METHODS:Four hundred and thirteen patients with comorbid cardiometabolic diseases who consecutively visiting vertigo and dizziness clinic were enrolled between October 2018 and January 2020 in a tertiary teaching medical center. Regression analyses and stratified analyses were used to explore the relationship between PSQI and vertigo outcome, which was measured by the visual analogue scale (VAS) score.RESULTS:In the study sample, 73.8% (305/413) were defined as 'poor sleep' (PSQI>5). Participants with better recovery tended to have better baseline PSQI global score, PSQI sleep quality, PSQI sleep onset latency, PSQI daytime dysfunction, less severe baseline vertigo symptoms indicated by VAS, Vertigo Symptom Scale (VSS) and Dizziness Handicap Inventory (DHI) scores. Moreover, baseline PSQI global score and PSQI daytime dysfunction score were independently associated with the vertigo VAS scores at the last follow-up.CONCLUSION:The present results clearly indicated that poor sleep is common and inversely associated with vertigo outcome in vertiginous patients with co-morbid cardiometabolic diseases. Therefore, sleep deserves greater attention in the total medical care in specific subgroup of vertiginous patients.

Objective:To investigate the role and mechanisms of fibulin-1 in senescence-related calcification of rat vascular smooth muscle cells induced by high-concentrationphosphate treatment.Methods:From September 2020 to September 2021, rat primary vascular smooth muscle cells were extracted from the thoracic aorta and abdominal aorta of 10 male SD rats aged 6 to 8 weeks.Phosphate(2.5 mmol/L Pi)was used to stimulate the calcification of vascular smooth muscle cells(VSMCs)in a model of stress-induced senescence-related calcification.Cellular senescence was assessed by SA-β-gal staining.Cellular calcification was determined by alizarin red staining and quantification of calcium deposition.Phenotypic transformation indexes and the expression of fibulin-1 during the process of calcification were detected by Western blot.The expression of fibulin-1 in primary rat vascular smooth muscle cells was knocked down by siRNA, the expression of pSmad3 was detected by immunofluorescence, and the effects of fibulin-1 on phenotypic transformation indexes of smooth muscle cells were detected by Western blot.The cells were cultured with recombinant fibulin-1 while transforming growth factor beta(TGF-β)inhibitor A83-01 and pSmad3 inhibitor SIS3 were also added.The senescence and calcification indexes of smooth muscle cells were detected by Western blot.Results:In the stress-induced aging model with phosphate stimulation of calcification in rat VSMCs, the expression of fibulin-1 was up-regulated( t=11.20, P<0.01), the expressions of MHC and SM22α was down-regulated( t=7.97, P<0.01; t=10.27, P<0.01), and the expression of osteoblastic phenotype markers OPN and Bmp2 and senescence marker P53 was up-regulated( t=4.79, P<0.01; t=9.56, P<0.01; t=14.07, P<0.01). Knockdown of fibulin-1 attenuated the degree of senescence and calcium deposition in VSMCs( t=12.90, P<0.05)and decreased the expression of OPN, Bmp2 and P53( t=5.92, P<0.05; t=10.15, P<0.01; t=8.28, P<0.01), at the same time, and TGF-β and pSmad3 expression was inhibited( t=12.90, P<0.01; t=7.46, P<0.01). After the addition of TGF-β/ smad3 pathway inhibitors, the stimulatory effect of recombinant fibulin-1 on phenotypic transformation and senescence protein expression inVSMCs was significantly reduced( t=4.52, P<0.01; t=9.82, P<0.01; t=3.85, P<0.05). Conclusions:Fibulin-1 can promote aging-related calcification of vascular smooth muscle cells through the TGF-β/smad3 signaling pathway.

Age-related cataract (ARC) is a common eye disease that occurs mostly in the elderly. Emerging evidence suggests that circular RNA (circRNA) plays an important role in disease development. However, there are few reports about the role of circRNA in cataract. Here, we investigated the function of circ_0060,144 in ARC. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of circ_0060,144, miR-23b-3p, and homeodomain interacting protein kinase 3 (HIPK3) mRNA. CCK-8 and flow cytometry analysis of cell proliferation and apoptosis. Western blot was performed to measure protein-associated proliferation and apoptosis. ELISA was used to detect cellular MDA and GSH-Px levels. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to investigate the association between miR-23b-3p and circ_0060,144 or HIPK3. Circ_0060,144 and HIPK3 mRNA expression were decreased in ARC tissues, and miR-23b-3p was increased. Circ_0060,144 overexpression promoted proliferation and inhibited apoptosis of SRA01/04 cells. And proliferation-related and apoptosis-related proteins also confirmed this conclusion. In addition, circ_0060,144 overexpression reduced MDA level and increased GSH-Px level. In terms of mechanism, circ_0060,144 inhibited HIPK3 expression via sponging miR-23b-3p. Circ_0060,144 promoted ARC development via regulation of miR-23b-3p/HIPK3 axis.

As one of classic Chinese kidney-tonifying herbal medicines, Taxillus chinensis (DC.) Danser is widely applied in Chinese folk medicine as herbal tea for nutraceutical purposes including nourishing kidney, strengthening muscle and bone to against weakness, etc. In the present study, we investigated the protective effect of aqueous extracts from Taxillus chinensis (AETCs) on the ovariectomy (OVX)-induced osteoporosis in rats. Results showed that AETC treatment at the dose of 12.0 g raw materials/kg for 12 weeks significantly enhanced the bone mineral densities of femur and tibia, improved the trabecular microarchitecture compared with OVX controls. The serum levels of osteogenic markers alkaline phosphatase and osteocalcin were increased, and the levels of bone resorption biomarkers tartrate-resistant acid phosphatase 5b and telopeptides of collagen type I were suppressed by AETCs. Moreover, 12.0 g raw materials/kg AETC treatment significantly reduced the OVX-induced up-regulation of cyclooxygenase (COX)-2 mRNA and protein expression in bone tissues. Data suggested that AETCs showed anti-osteoporotic effect in OVX rats, possibly via promoting bone formation and inhibiting bone absorption. The down-regulation of inflammatory COX-2 might be involved in the protection of AETCs against OVX ???induced osteoporosis.

Arterial stiffness forms the basis of cardiovascular diseases (CVD) and is also an independent predictor of CVD risk. Early detection and intervention of arterial stiffness are important for improving the global burden of CVD. Pulse wave velocity (PWV) is the gold standard for assessing arterial stiffness and the molecular mechanism of arterial stiffness remains to be studied. Extracellular matrix (ECM) remodeling is one of the major mechanisms of arterial stiffness. Partial quantitative changes of ECM proteins can be detected in plasma. Therefore, we examined the hypothesis that a discovery proteomic comparison of plasma proteins between high arterial stiffness (baPWV ≥ 1,400 cm/s) and normal arterial stiffness (baPWV < 1,400 cm/s) populations might identify relevant changed ECM proteins for arterial stiffness. Plasma samples were randomly selected from normal arterial stiffness (n = 6) and high arterial stiffness (n = 6) people. Isobaric tags for relative and absolute quantitation (iTRAQ) based quantitative proteomics technique was performed to find a total of 169 differentially expressed proteins (DEPs). Nine ECM proteins were included in all DEPs and were all up-regulated proteins. Fibulin-1 had the highest statistically fold-change (FC = 3.7, p < 0.0001) in the high arterial stiffness population compared with the control group during the nine ECM proteins. The expression of plasma fibulin-1 in normal arterial stiffness (n = 112) and high arterial stiffness (n = 72) populations was confirmed through enzyme-linked immunosorbent assay (ELISA). Similarly, ELISA results showed that plasma concentrations of fibulin-1 in the high arterial stiffness group were higher than those in the normal arterial stiffness group (12.69 ± 0.89 vs. 9.84 ± 0.71 μg/ml, p < 0.05). Univariate analysis of fibulin-1 with brachial-ankle pulse wave velocity (baPWV) indicated that fibulin-1 was positively correlated with baPWV in all participants (r = 0.32, p < 0.01) and a stronger positive correlation between baPWV and fibulin-1 in high arterial stiffness group (r = 0.64, p < 0.0001) was found. Multiple regression analysis of factors affecting baPWV showed that fibulin-1 was also a significant determinant of the increased ba-PWV (R 2 = 0.635, p = 0.001). Partial correlation analysis showed that baPWV increased with the growth of plasma fibulin-1(r = 0.267, p < 0.001). In conclusion, our results demonstrated that fibulin-1 is positively correlated with ba-PWV and an independent risk factor for arterial stiffness.

Pulmonary hypertension (PH) is a progressive and life-threatening chronic disease in which increased pulmonary artery pressure (PAP) and pulmonary vasculature remodeling are prevalent. Inhaled nitric oxide (NO) has been used in newborns to decrease PAP in the clinic; however, the effects of NO endogenous derivatives, S-nitrosothiols (SNO), on PH are still unknown. We have reported that S-nitroso-L-cysteine (CSNO), one of the endogenous derivatives of NO, inhibited RhoA activity through oxidative nitrosation of its C16/20 residues, which may be beneficial for both vasodilation and remodeling. In this study, we presented data to show that inhaled CSNO attenuated PAP in the monocrotaline- (MCT-) induced PH rats and, moreover, improved right ventricular (RV) hypertrophy and fibrosis induced by RV overloaded pressure. In addition, aerosolized CSNO significantly inhibited the hyperactivation of signal transducers and activators of transduction 3 (STAT3) and extracellular regulated protein kinases (ERK) pathways in the lung of MCT-induced rats. CSNO also regulated the expression of smooth muscle contractile protein and improved aberrant endoplasmic reticulum (ER) stress and mitophagy in lung tissues following MCT induction. On the other hand, CSNO inhibited reactive oxygen species (ROS) production in vitro, which is induced by angiotensin II (AngII) as well as interleukin 6 (IL-6). In addition, CSNO inhibited excessive ER stress and mitophagy induced by AngII and IL-6 in vitro; finally, STAT3 and ERK phosphorylation was inhibited by CSNO in a concentration-dependent manner. Taken together, CSNO led to pulmonary artery relaxation and regulated pulmonary circulation remodeling through anti-ROS and anti-inflammatory pathways and may be used as a therapeutic option for PH treatment.

AIMS:The imbalance of M1/M2 macrophage ratio promotes the occurrence of diabetic cardiomyopathy (DCM), but the precise mechanisms are not fully understood. The aim of this study was to investigate whether miR-471-3p/silent information regulator 1 (SIRT1) pathway is involved in the macrophage polarization during the development of DCM.METHODS:Immunohistochemical staining was used to detect M1 and M2 macrophages infiltration in the heart tissue. Flow cytometry was used to detect the proportion of M1 and M2 macrophages. Expression of miR-471-3p was quantified by real time quantitative-PCR. Transfection of miRNA inhibitor into RAW264.7 cells was performed to investigate the underlying mechanisms. Bioinformatics methods and western blotting were used to explore the target gene of miR-471-3p and further confirmed by dual luciferase reporter assay.KEY FINDINGS:We observed that M1 macrophages infiltration in the heart of tissue in DCM while M2 type was decreased. M1/M2 ratio was increased significantly in bone marrow-derived macrophages (BMDMs) from db/db mice and in RAW264.7 cells treated with advanced glycation end products (AGEs). Meanwhile, miR-471-3p was significantly upregulated in RAW264.7 cells induced by AGEs and inhibition of miR-471-3p could reduce the inflammatory polarization of macrophages. Bioinformatics analysis identified SIRT1 as a target of miR-471-3p. Both dual luciferase reporter assay and western blotting verified that miR-471-3p negatively regulated SIRT1 expression. SIRT1 agonist resveratrol could downregulate the increased proportion of M1 macrophages induced by AGEs.CONCLUSION:Our results indicated that the development of DCM was related to AGEs-induced macrophage polarized to M1 type through a mechanism involving the miR-471-3p/SIRT1 pathway.

目的 探讨伴有心血管代谢性疾病的眩晕/头晕患者的临床特征和近期结局影响因素.方法 本研究纳入了2018年10月至2020年1月之间连续就诊于武汉同济医院眩晕专科门诊的伴有心血管代谢性疾病的眩晕/头晕患者.随访时获得的患者眩晕/头晕症状视觉模拟量表(Visual analogue scale,VAS)评分作为结局指标并按其分为完全缓解组和未完全缓解组,以t检验、Mann-Whitney U检验和χ2检验比较组间差异,近期结局影响因素通过线性回归模型进行评估.结果 474名患者中女性多见(250名,60.5％).在此群体中最常见的共患病是高血压(215[52.1％]).在没有纳入单纯BPPV患者的前提下,诊断以前庭型偏头痛(vestibular migraine,VM)最为常见,确定VM为149人(36.1％),其完全缓解率显著低于可能VM和本研究中其他眩晕/头晕疾病(P=0.028).VAS评分从基线时的8分(四分位数间距:6-9分)下降至随访时的2分(四分位数间距:0-4分).相较于未完全缓解组,完全缓解组中男性更多,具有更好的教育背景,HADS-D得分较低,VSS和DHI评分表明眩晕或头晕症状较轻,睡眠质量较好.多因素回归分析表明,基线时眩晕症状量表得分和医院焦虑抑郁量表的抑郁得分与随访的VAS评分之间具有显著相关性.结论 伴有心血管代谢性疾病的眩晕/头晕患者的近期结局与就诊时症状严重程度和抑郁程度有独立相关性,医生有必要将情绪管理纳入综合治疗中.

Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated β-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.

Background: The association between fibroblast growth factor 21 (FGF21) and cardiovascular disease (CVD) risk remains unclear. We conducted this systematic review and meta-analysis to evaluate the association between FGF21 and CVDs, and relevant vascular parameters. Methods: PubMed and Web of Science databases were systematically searched to identify relevant studies published before March 2021. The FGF21 concentration was compared between individuals with and without CVDs. The effect of FGF21 on CVD risk was assessed by using hazard ratio (HR) and odds ratio (OR). The association between FGF21 and vascular parameters was assessed by Pearson's r . Study quality was assessed using Newcastle–Ottawa Scale and Joanna Briggs Institution Checklist. Results: A total of 29,156 individuals from 30 studies were included. Overall, the serum FGF21 concentration was significantly higher in CVD patients ( p < 0.001), especially for coronary artery disease (CAD) ( p < 0.001) and hypertension ( p < 0.001). The pooled OR ( p = 0.009) and HR ( p < 0.001) showed that the risk of CVDs increased with FGF21. The linear association between FGF21 and vascular parameters, including pulse wave velocity ( r = 0.32), carotid intima-media thickness ( r = 0.21), ankle-brachial index ( r = 0.33), systolic blood pressure ( r = 0.13), and diastolic blood pressure ( r = 0.05), was insignificant. The incidence of overall CVDs ( p = 0.03) was significantly higher in individuals with higher FGF21 levels. Conclusion: High-level serum FGF21 concentration is closely associated with an increased risk of CVDs, which may be independent of vascular parameters. A standard FGF21 classification threshold needs to be established before clinical use for CVD risk assessment. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241968 , identifier: CRD42021241968.

Pulmonary hypertension (PH) is a progressive and life-threatening chronic disease in which increased pulmonary artery pressure (PAP) and pulmonary vasculature remodeling are prevalent. Inhaled nitric oxide (NO) has been used in newborns to decrease PAP in the clinic; however, the effects of NO endogenous derivatives, S-nitrosothiols (SNO), on PH are still unknown. We have reported that S-nitroso-L-cysteine (CSNO), one of the endogenous derivatives of NO, inhibited RhoA activity through oxidative nitrosation of its C16/20 residues, which may be beneficial for both vasodilation and remodeling. In this study, we presented data to show that inhaled CSNO attenuated PAP in the monocrotaline- (MCT-) induced PH rats and, moreover, improved right ventricular (RV) hypertrophy and fibrosis induced by RV overloaded pressure. In addition, aerosolized CSNO significantly inhibited the hyperactivation of signal transducers and activators of transduction 3 (STAT3) and extracellular regulated protein kinases (ERK) pathways in the lung of MCT-induced rats. CSNO also regulated the expression of smooth muscle contractile protein and improved aberrant endoplasmic reticulum (ER) stress and mitophagy in lung tissues following MCT induction. On the other hand, CSNO inhibited reactive oxygen species (ROS) production in vitro, which is induced by angiotensin II (AngII) as well as interleukin 6 (IL-6). In addition, CSNO inhibited excessive ER stress and mitophagy induced by AngII and IL-6 in vitro; finally, STAT3 and ERK phosphorylation was inhibited by CSNO in a concentration-dependent manner. Taken together, CSNO led to pulmonary artery relaxation and regulated pulmonary circulation remodeling through anti-ROS and anti-inflammatory pathways and may be used as a therapeutic option for PH treatment.

Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (PSTAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P < 0.01), down-regulated IL-6 levels (P < 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P < 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-alpha in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.

Considering the potential hazardous effects of disinfectant residues on environment, organisms and biodiversity, the sharp rise in use of disinfectants during COVID-19 pandemic has been considered highly likely to cause worldwide secondary disasters in ecosystems and human health. This questionnaire-based survey investigated the impact of COVID-19 outbreak on household disinfectant product consumption levels and behavior of 3667 Chinese residents. In particular, in the context that no strategy is currently available to minimize the disinfectant pollution, based on the similarities between disinfectants and pharmaceuticals, we proposed a perspective of ecopharmacovigilance (EPV), which is an effective measure to minimize the environmental risks posed by pharmaceuticals using drug administration protocols, for disinfectant environmental risk management. The public's environmental perceptions, attitudes and the related practices regarding household disinfectant consumption from an EPV perspective were also included in the study. The results showed that the COVID-19 outbreak caused a tremendous rise in the public's household disinfectant consumption and usage levels in China. After the COVID-19 outbreak, the chlorine-based and alcohol-based disinfectants were considered as the most preferred products for household disinfection and hand sanitization, respectively. Importantly, the Chinese public's environmental perceptions and practice on disinfectants were poor. Less than half respondents had positive attitudes toward the source control of disinfectant pollution. The population groups including females, the middle aged adults, those having healthcare professional background, as well as the higher-educated could be focused on to develop targeted efforts for the future control of disinfectant pollution in environment.