A Novel Perspective on PCSK9 in Alzheimer's Disease: A Focus on Amyloid Beta.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) belongs to a member of the proprotein convertase (PC) family, which is mainly secreted by the liver and plays a central role in lipid metabolism. Furthermore, PCSK9 plays a multifunctional role in promoting the inflammatory response, inducing cell apoptosis and pyroptosis and affecting tumor homeostasis. The brain is the organ with the richest lipid content. Incidentally, PCSK9 increased in many brain diseases, including brain injury and Alzheimer's disease (AD). Consequently, the relationship between PCSK9 and brain diseases has attracted increasing research interest. Amyloid beta (Aß) accumulation is the central and initial event in the pathogenesis of AD. This study focuses on the effects of PCSK9 on Aß accumulation in the brain via multiple modalities to explore the potential role of PCSK9 in AD, which is characterized by progressive loss of brain cells by increasing Aß accumulation. The study also explores the new mechanism by which PCSK9 is involved in the pathogenesis of AD, providing interesting and innovative guidance for the future of PCSK9-targeted therapy for AD.

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

Non-oxidative modified low-density lipoproteins: The underappreciated risk factors for atherosclerosis.

Atherosclerosis, the pathological basis of most cardiovascular diseases, is a main risk factor causing about 20 million deaths each year worldwide. Oxidized low-density lipoprotein is recognized as the most important and independent risk factor in initiating and promoting atherosclerosis. Numerous antioxidants are extensively used in clinical practice, but they have no significant effect on reducing the morbidity and mortality of cardiovascular diseases. This finding suggests that researchers should pay more attention to the important role of non-oxidative modified low-density lipoprotein in atherosclerosis with a focus on oxidized low-density lipoprotein. This review briefly summarizes several important non-oxidative modified low-density lipoproteins associated with atherosclerosis, introduces the pathways through which these non-oxidative modified low-density lipoproteins induce the development of atherosclerosis in vivo, and discusses the mechanism of atherogenesis induced by these non-oxidative modified low-density lipoproteins. New therapeutic strategies and potential drug targets are provided for the prevention and treatment of atherosclerotic cardiovascular diseases.

Transcriptional analysis of the dimorphic fungus Umbilicaria muehlenbergii reveals the molecular mechanism of phenotypic transition.

The lichen-forming fungus Umbilicaria muehlenbergii undergoes a phenotypic transition from a yeast-like to a pseudohyphal form. However, it remains unknown if a common mechanism is involved in the phenotypic switch of U. muehlenbergii at the transcriptional level. Further, investigation of the phenotype switch molecular mechanism in U. muehlenbergii has been hindered by incomplete genomic sequencing data. Here, the phenotypic characteristics of U. muehlenbergii were investigated after cultivation on several carbon sources, revealing that oligotrophic conditions due to nutrient stress (reduced strength PDA (potato dextrose agar) media) exacerbated the pseudohyphal growth of U. muehlenbergii. Further, the addition of sorbitol, ribitol, and mannitol exacerbated the pseudohyphal growth of U. muehlenbergii regardless of PDA medium strength. Transcriptome analysis of U. muehlenbergii grown in normal and nutrient-stress conditions revealed the presence of several biological pathways with altered expression levels during nutrient stress and related to carbohydrate, protein, DNA/RNA and lipid metabolism. Further, the results demonstrated that altered biological pathways can cooperate during pseudohyphal growth, including pathways involved in the production of protectants, acquisition of other carbon sources, or adjustment of energy metabolism. Synergistic changes in the functioning of these pathways likely help U. muehlenbergii cope with dynamic stimuli. These results provide insights into the transcriptional response of U. muehlenbergii during pseudohyphal growth under oligotrophic conditions. Specifically, the transcriptomic analysis indicated that pseudohyphal growth is an adaptive mechanism of U. muehlenbergii that facilitates its use of alternative carbon sources to maintain survival.

Circulating mid-regional proadrenomedullin is a predictor of mortality in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Although there is increasing understanding of the changes in the laboratory parameters of Coronavirus disease 2019 (COVID-19), the correlation between circulating Mid-regional Proadrenomedullin (MR-proADM) and mortality of patients with COVID-19 is not fully understood. In this study, we conducted a systematic review and meta-analysis to evaluate the prognostic value of MR-proADM in patients with COVID-19. METHODS: The PubMed, Embase, Web of Science, Cochrane Library, Wanfang, SinoMed and Chinese National Knowledge Infrastructure (CNKI) databases were searched from 1 January 2020 to 20 March 2022 for relevant literature. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess quality bias, STATA was employed to pool the effect size by a random effects model, and potential publication bias and sensitivity analyses were performed. RESULTS: 14 studies comprising 1822 patients with COVID-19 met the inclusion criteria, there were 1145 (62.8%) males and 677 (31.2%) females, and the mean age was 63.8 ± 16.1 years. The concentration of MR-proADM was compared between the survivors and non-survivors in 9 studies and the difference was significant (P < 0.01), I2 = 46%. The combined sensitivity was 0.86 [0.73-0.92], and the combined specificity was 0.78 [0.68-0.86]. We drew the summary receiver operating characteristic (SROC) curve and calculated the area under curve (AUC) = 0.90 [0.87-0.92]. An increase of 1 nmol/L of MR-proADM was independently associated with a more than threefold increase in mortality (odds ratio (OR) 3.03, 95% confidence interval (CI) 2.26-4.06, I2 = 0.0%, P = 0.633). The predictive value of MR-proADM for mortality was better than many other biomarkers. CONCLUSION: MR-proADM had a very good predictive value for the poor prognosis of COVID-19 patients. Increased levels of MR-proADM were independently associated with mortality in COVID-19 patients and may allow a better risk stratification.

A comparison of safety and efficacy between long-term DAPT and intensive statins combined with short-term DAPT for acute ischemic stroke.

OBJECTIVES: The current study compared the safety and efficacy of long-term dual antiplatelet therapy (DAPT, aspirin plus clopidogrel) and intensive rosuvastatin with short-term DAPT for acute ischemic stroke (AIS). METHODS: A total of 220 patients were enrolled 72 h after the onset of mild to moderate AIS, and divided into a control group treated with 21-day DAPT and a study group treated with intensive rosuvastatin with 7-day DAPT on a voluntary basis. The primary outcome was recurrent ischemic stroke and hemorrhage during a 90-day follow-up period in an intention-to-treat analysis. The secondary outcome was clinical efficacy with respect to alleviating existing focal nerve defect symptoms. A Cox proportional-hazards model was used to evaluate treatment differences. RESULTS: Clinical efficacy was evident in 87.3% of patients in the study group, compared with 84.3% in the control group (p = 0.042). Recurrent ischemic stroke occurred in 9 patients (7.6%) in the study group and in 9 (8.8%) in the control group (p = 0.767). Hemorrhage occurred in 6 patients (5.1%) in the study group and in 15 (14.7%) in the control group (p = 0.023). In comparisons of levels of ALT, AST, LDH, and CK in the two groups before and 2 weeks after therapy, only CK differed significantly (p < 0.001). CONCLUSIONS: Compared to long-term DAPT, intensive rosuvastatin with short-term DAPT was equivalent in reducing the risk of recurrent ischemic stroke. It alleviated symptoms more rapidly, and significantly reduced the risk of bleeding, without causing an increase in transaminase or muscle enzymes. CLINICAL TRIAL REGISTRATION: China Clinical Trial Registration Center (ChiCTR1800017809).

Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke.

OBJECTIVE: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). METHODS: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. RESULTS: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. CONCLUSIONS: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.

PCSK9: A emerging participant in heart failure.

Heart failure (HF) is a complex clinical syndrome caused by various cardiovascular diseases. Its main pathogenesis includes cardiomyocyte loss, myocardial energy metabolism disorder, and activation of cardiac inflammation. Due to the clinically unsatisfactory treatment of heart failure, different mechanisms need to be explored to provide new targets for the treatment of this disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene mainly related to familial hypercholesterolemia, was discovered in 2003. Aside from regulating lipid metabolism, PCSK9 may be involved in other biological processes such as apoptosis, autophagy, pyroptosis, inflammation, and tumor immunity and related to diabetes and neurodegenerative diseases. Recently, clinical data have shown that the circulating PCSK9 level is significantly increased in patients with heart failure, and it is related to the prognosis for heart failure. Furthermore, in animal models and patients with myocardial infarction, PCSK9 in the infarct margin area was also found to be significantly increased, which further suggested that PCSK9 might be closely related to heart failure. However, the specific mechanism of how PCSK9 participates in heart failure remains to be further explored. The purpose of this review is to summarize the potential mechanism of PCSK9's involvement in heart failure, thereby providing a new treatment strategy for heart failure.

Safety and efficacy of short-term dual antiplatelet therapy combined with intensive rosuvastatin in acute ischemic stroke

Abstract Objective: To investigate the safety and efficacy of short-term (7-day) Dual Antiplatelet Therapy (DAPT) with intensive rosuvastatin in Acute Ischemic Stroke (AIS). Methods: In this study, patients with AIS in the emergency department of the hospital from October 2016 to December 2019 were registered and divided into the control group (Single Antiplatelet Therapy [SAPT] + rosuvastatin) and the study group (7-day DAPT + intensive rosuvastatin) according to the therapy regimens. The generalized linear model was used to compare the National Institute of Health Stroke Scale (NIHSS) scores between the two groups during the 21-day treatment. A Cox regression model was used to compare recurrent ischemic stroke, bleeding events, Statin-Induced Liver Injury (SILI), and Statin-Associated Myopathy (SAM) between the two groups during the 90-day follow-up. Results: Comparison of NIHSS scores after 21-day treatment: NIHSS scores in the study group decreased significantly, 0.273-times as much as that in the control group (Odds Ratio [OR] 0.273; 95% Confidence Interval [95% CI] 0.208-0.359; p < 0.001). Comparison of recurrent ischemic stroke during the 90-day follow-up: The therapy of the study group reduced the risk of recurrent stroke by 65% (7.76% vs. 22.82%, Hazard Ratio [HR] 0.350; 95% CI 0.167-0.730; p = 0.005). Comparison of bleeding events: There was no statistical difference between the two groups (7.79% vs. 6.71%, HR = 1.076; 95% CI 0.424-2.732; p = 0.878). No cases of SILI and SAM were found. Conclusions: Short-term DAPT with intensive rosuvastatin effectively relieved the clinical symptoms and significantly reduced the recurrent stroke for patients with mild-to-moderate AIS within 90 days, without increasing bleeding events, SILI and SAM.

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction.

GTPase-activating SH3 domain-binding protein 2 (G3BP2) is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases. However, no studies have examined the contribution of G3BP2 in the oscillatory shear stress (OSS)-induced endothelial dysfunction. Here we assessed the effects of G3BP2 in endothelial cells (ECs) function and investigated the underlying mechanism. Using shear stress apparatus and partial ligation model, we identified that stress granule-related genes in ECs could be induced by OSS with RNA-seq, and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions. G3bp2 -/- Apoe -/- mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function, decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels. Furthermore, loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation. These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

Development of hydrogen sulfide donors for anti-atherosclerosis therapeutics research: Challenges and future priorities.

Hydrogen sulfide (H2S), a gas transmitter found in eukaryotic organisms, plays an essential role in several physiological processes. H2S is one of the three primary biological gas transmission signaling mediators, along with nitric oxide and carbon monoxide. Several animal and in vitro experiments have indicated that H2S can prevent coronary endothelial mesenchymal transition, reduce the expression of endothelial cell adhesion molecules, and stabilize intravascular plaques, suggesting its potential role in the treatment of atherosclerosis (AS). H2S donors are compounds that can release H2S under certain circumstances. Development of highly targeted H2S donors is a key imperative as these can allow for in-depth evaluation of the anti-atherosclerotic effects of exogenous H2S. More importantly, identification of an optimal H2S donor is critical for the creation of H2S anti-atherosclerotic prodrugs. In this review, we discuss a wide range of H2S donors with anti-AS potential along with their respective transport pathways and design-related limitations. We also discuss the utilization of nano-synthetic technologies to manufacture H2S donors. This innovative and effective design example sheds new light on the production of highly targeted H2S donors.

A promising field: regulating imbalance of EndMT in cardiovascular diseases.

Endothelial-mesenchymal transition (EndMT) is widely involved in the occurrence and development of cardiovascular diseases. Although there is no direct evidence, it is very promising as an effective target for the treatment of these diseases. Endothelial cells need to respond to the complex cardiovascular environment through EndMT, but sustained stimuli will cause the imbalance of EndMT. Blocking the signal transduction promoting EndMT is an effective method to control the imbalance of EndMT. In particular, we also discussed the potential role of endothelial cell apoptosis and autophagy in regulating the imbalance of EndMT. In addition, promoting mesenchymal-endothelial transformation (MEndT) is also a method to control the imbalance of EndMT. However, targeting EndMT to treat cardiovascular disease still faces many challenges. By reviewing the research progress of EndMT, we have put forward some insights and translated them into challenges and opportunities for new treatment strategies for cardiovascular diseases.

Effects of gut microbiota on atherosclerosis through hydrogen sulfide.

Cardiovascular diseases are the leading cause of death and morbidity worldwide. Atherosclerotic cardiovascular disease (ASCVD) is affected by both environmental and genetic factors. Microenvironmental disorders of the human gut flora are associated with a variety of health problems, not only gastrointestinal diseases, such as inflammatory bowel disease, but also extralintestinal organs. Hydrogen sulfide (H2S) is the third gas signaling molecule other than nitric oxide and carbon monoxide. In the cardiovascular system, H2S plays important roles in the regulation of blood pressure, angiogenesis, smooth muscle cell proliferation and apoptosis, anti-oxidative stress, cardiac functions. This review is aiming to explore the potential role of gut microbiota in the development of atherosclerosis through hydrogen sulfide production as a novel therapeutic direction for atherosclerosis.

PCSK9 mediates the oxidative low­density lipoprotein­induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway.

The present study aimed to explore the role and mechanisms of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the oxidized low­density lipoprotein (oxLDL)­induced pyroptosis of vascular endothelial cells. For this purpose, human umbilical vein endothelial cells (HUVECs) were incubated with oxLDL (100 µg/ml) for 24 h to induce pyroptosis, which was detected using PI/hoechst33342 double staining. The expression of pyroptosis­associated molecules was measured by western blot analysis and RT­qPCR. Reactive oxygen species (ROS) and membrane potential were examined through ROS probe and JC­1 staining, respectively. PCSK9 and mitochondrial ubiquinol­cytochrome c reductase core protein 1 (UQCRC1) protein were knocked down by small interfering RNA (siRNA). PCSK9 was overexpressed by lentivirus. The results revealed that oxLDL induced HUVEC injury, pyroptosis and inflammatory factor release, and upregulated the expression of PCSK9 protein in the HUVECs in a concentration­dependent manner. The silencing of PCSK9 expression with siRNA suppressed the oxLDL­induced damage to HUVECs, the release of inflammatory substances and the occurrence of pyroptosis. In addition, oxLDL inhibited UQCRC1 expression, promoted mitochondrial membrane potential collapse and damaged mitochondrial function; however, these processes were reversed by the silencing of PCSK9. PCSK9 overexpression induced the pyroptosis of HUVECs, the generation of ROS and the disorder of mitochondrial function by inhibiting UQCRC1. Therefore, PCSK9 mediates the oxLDL­induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway.

Melatonin inhibits vascular endothelial cell pyroptosis by improving mitochondrial function via up-regulation and demethylation of UQCRC1.

Atherosclerosis (AS) is a chronic inflammatory disease that involves cell death and endothelial dysfunction. Melatonin is an endocrine hormone with anti-inflammatory and anti-AS effects. However, the underlying molecular mechanisms for the anti-AS effects of melatonin are unknown. A previous study has shown that pyroptosis plays a detrimental role in the development of AS, therefore, this study was designed to investigate the anti-pyroptotic effects and potential mechanisms of melatonin in atherosclerotic endothelium. Our results show that melatonin attenuated the expression of genes related to pyroptosis, including NLRP3, caspase-1, and IL-1ß, in human umbilical vein endothelial cells treated with oxidized low-density lipoprotein. Furthermore, melatonin up-regulated the expression of ten-eleven translocation 2 (TET2), inhibited the methylation of ubiquinol-cytochrome c reductase core protein 1 (UQCRC1), and reduced pyroptosis. The up-regulation of UQCRC1 by melatonin improved mitochondrial function, thereby inhibiting oxidative stress and endothelial cell pyroptosis. Collectively, our results indicate that melatonin prevents endothelial cell pyroptosis by up-regulating TET2 to inhibit the methylation of UQCRC1 and improving mitochondrial function.

Three Musketeers for Lowering Cholesterol: Statins, Ezetimibe and Evolocumab.

Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate the potential side effects of high statin dosages, and several patients also still do not reach their optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by targeting the Niemann-Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver's ability to remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9 monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipid-lowering effects by regulating the three key pathways in lipid metabolism. Combining any with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect. Whether the combination of the three musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be studied further in the future.

The Role of Ubiquitin E3 Ligase in Atherosclerosis.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

[Establishment and evaluation of clinical diagnostic scoring system for septic cardiomyopathy].

OBJECTIVE: To establish a clinical diagnostic scoring system for septic cardiomyopathy (SCM) and evaluate its diagnostic efficacy. METHODS: A prospective cohort study was performed. Patients with sepsis and septic shock admitted to the department of emergency of China Rehabilitation Research Center were enrolled from January 2019 to December 2020. The baseline information, medical history, heart rate (HR), mean arterial pressure (MAP), body temperature and respiratory rate (RR) on admission were recorded. Laboratory indexes such as white blood cell count (WBC), hypersensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and blood lactic acid (Lac) were measured. Transthoracic echocardiography was conducted within 24 hours and on the 7th after admission. Sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II), and nutritional risk screening 2002 scale (NRS2002) were also assessed. The patients were divided into two groups according to whether SCM occurred or not. The risk factors of SCM were screened by univariate and multivariate Logistic regression. The cut-off value of continuous index was determined by receiver operator characteristic curve (ROC curve) and discretized concerning clinical data. The regression coefficient ß was used to establish the corresponding score, and the clinical diagnostic score system of SCM was established. The diagnostic value of the model was evaluated by ROC curve. RESULTS: In total, 147 patients were enrolled in the study and the incidence of SCM was 28.6% (42/147). Univariate Logistic regression analysis showed the risk factors of SCM included: (1) continuous indicators: age, NT-proBNP, RR, MAP, Lac, NRS2002, SOFA, APACHE II; (2) discrete indicators: shock, use of vasoactive drugs, history of coronary heart disease, acute kidney injury (AKI). Multivariate Logistic regression analysis after discretization of above continuous index showed that age ≥ 87 years old, NT-proBNP ≥ 3 000 ng/L, RR ≥ 30 times/min, Lac ≥ 3 mmol/L and SOFA ≥ 10 points were independent risk factors for SCM [age ≥ 87 years: odds ratio (OR) = 3.491, 95% confidence interval (95%CI) was 1.371-8.893, P = 0.009; NT-proBNP ≥ 3 000 ng/L: OR = 2.708, 95%CI was 1.093-6.711, P = 0.031; RR ≥ 30 times/min: OR = 3.404, 95%CI was 1.356-8.541, P = 0.009; Lac ≥ 3 mmol/L: OR = 3.572, 95%CI was 1.460-8.739, P = 0.005; SOFA ≥ 10 points: OR = 8.693, 95%CI was 2.541-29.742, P = 0.001]. The clinical diagnostic score system of SCM was established successfully, which was composed of age ≥ 87 years old (1 point), NT-proBNP ≥ 3 000 ng/L (1 point), RR ≥ 30 times/min (1 point), Lac ≥ 3.0 mmol/L (1 point), SOFA ≥ 10 points (2 points), and the total score was 6 points. ROC curve analysis showed the cut-off value of the scoring system for diagnosing SCM was 3 points, the area under ROC curve (AUC) was 0.833, 95%CI was 0.755-0.910, P < 0.001, with the sensitivity of 71.4%, and specificity of 86.7%. CONCLUSIONS: The clinical diagnostic scoring system has good diagnostic efficacy for SCM and contributes to early identification of SCM for clinicians.

EndMT: Potential Target of H2S against Atherosclerosis.

Atherosclerosis is a chronic arterial wall illness that forms atherosclerotic plaques within the arteries. Plaque formation and endothelial dysfunction are atherosclerosis' characteristics. It is believed that the occurrence and development of atherosclerosis mainly include endothelial cell damage, lipoprotein deposition, inflammation and fibrous cap formation, but its molecular mechanism has not been elucidated. Therefore, protecting the vascular endothelium from damage is one of the key factors against atherosclerosis. The factors and processes involved in vascular endothelial injury are complex. Finding out the key factors and mechanisms of atherosclerosis caused by vascular endothelial injury is an important target for reversing and preventing atherosclerosis. Changes in cell adhesion are the early characteristics of EndMT, and cell adhesion is related to vascular endothelial injury and atherosclerosis. Recent researches have exhibited that endothelial-mesenchymal transition (EndMT) can urge atherosclerosis' progress, and it is expected that inhibition of EndMT will be an object for anti-atherosclerosis. We speculate whether inhibition of EndMT can become an effective target for reversing atherosclerosis by improving cell adhesion changes and vascular endothelial injury. Studies have shown that H2S has a strong cardiovascular protective effect. As H2S has anti- inflammatory, anti-oxidant, inhibiting foam cell formation, regulating ion channels and enhancing cell adhesion and endothelial functions, the current research on H2S in cardiovascular aspects is increasing, but anti-atherosclerosis's molecular mechanism and the function of H2S in EndMT have not been explicit. In order to explore the mechanism of H2S against atherosclerosis, to find an effective target to reverse atherosclerosis, we sum up the progress of EndMT promoting atherosclerosis, and Hydrogen sulfide's potential anti- EndMT effect is discussed in this review.

Role of oral microbiota in atherosclerosis.

Oral infections are common among individuals of all ages and can activate local and systemic inflammation. The inflammatory response plays an important role in atherosclerosis. An increasing number of studies have reported an association between oral pathogen infection and atherosclerotic coronary heart disease. For instance, epidemiological studies support the positive correlation between oral infections and atherosclerosis. The presence of oral pathogens in human atherosclerotic plaques has been detected by multiple methods, and oral infections promote atherosclerosis in animal experiments. Various mechanisms are involved in oral infections, thereby promoting atherosclerosis. First, oral infections can trigger the local and systemic inflammatory response, causing vascular endothelial damage. Oral-derived pathogens that enter atherosclerotic plaque can activate macrophages and cause an intra-plaque inflammatory response. Second, oral infections can promote intra-plaque macrophage cholesterol accumulation and foam cell formation. Third, oral infections can regulate plasma lipid levels, thereby increasing atherogenic lipid low-density lipoprotein and triglyceride levels. Although atherosclerosis caused by oral infections is currently studied, the precise mechanism remains to be further explored. The rise of gut microbiota research also makes the relationship between oral microbiota and disease, especially the relationship with coronary heart disease, worthy of attention and in-depth research.