Biomechanics-mediated endocytosis in atherosclerosis.

Biomechanical forces, including vascular shear stress, cyclic stretching, and extracellular matrix stiffness, which influence mechanosensitive channels in the plasma membrane, determine cell function in atherosclerosis. Being highly associated with the formation of atherosclerotic plaques, endocytosis is the key point in molecule and macromolecule trafficking, which plays an important role in lipid transportation. The process of endocytosis relies on the mobility and tension of the plasma membrane, which is sensitive to biomechanical forces. Several studies have advanced the signal transduction between endocytosis and biomechanics to elaborate the developmental role of atherosclerosis. Meanwhile, increased plaque growth also results in changes in the structure, composition and morphology of the coronary artery that contribute to the alteration of arterial biomechanics. These cross-links of biomechanics and endocytosis in atherosclerotic plaques play an important role in cell function, such as cell phenotype switching, foam cell formation, and lipoprotein transportation. We propose that biomechanical force activates the endocytosis of vascular cells and plays an important role in the development of atherosclerosis.

Prognosis of patients with familial hypertrophic cardiomyopathy: A single-center cohort study with ten-year follow-up by propensity score matching analysis.

Objectives: Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy. However, few studies have investigated the prognosis of familial HCM (FHCM) through clinical data. The purpose of this study was to compare the clinical outcomes of FHCM and non-FHCM through propensity score matching analysis. Methods and results: The cohort study included 1243 patients with HCM between 1996 and 2013 in Fuwai Hospital, Chinese Academy of Medical Sciences, among whom 125 patients had FHCM. During a mean follow-up of 7.6 ± 3.8 years (interquartile range: (IQR) 5.0-10.0 years), 217 (16.57%) of the 1243 patients had died, including 3 patients who underwent cardiac transplantation. Using 30 demographic and clinical variables, a 4:1 propensity score matched cohort for FHCM was established. The stepwise variable selection procedure for the Cox proportional hazards model was performed to identify the factors associated with mortality and competing risk regression analysis was performed to analyze the competitive risk of cardiovascular and non-cardiovascular mortality. The results showed that FHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation (log-rank χ2 = 6.8, P = 0.0084) and an increased tendency of sudden cardiac death (SCD) (log-rank χ2 = 3.2, P = 0.074) compared with non-FHCM patients, but there was no difference in all-cause mortality (log-rank χ2 = 2.7, P = 0.1) between the two groups. Moreover, the Cox model showed that FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients. Conclusion: FHCM patients had a higher risk of cardiovascular mortality/cardiac transplantation and a higher tendency of SCD than non-FHCM patients, but there was no difference in all-cause mortality. Moreover, FHCM was an independent prognostic predictor for cardiovascular mortality/cardiac transplantation in HCM patients.

Alteration of gut microbiota after heat acclimation may reduce organ damage by regulating immune factors during heat stress.

Introduction: Heat-related illnesses can lead to morbidity, which are anticipated to increase frequency with predictions of increased global surface temperatures and extreme weather events. Although heat acclimation training (HAT) could prevent heat-related diseases, the mechanisms underlying HAT-promoting beneficial changes in organ function, immunity, and gut microbes remain unclear. Methods: In the current study, we recruited 32 healthy young soldiers and randomly divided them into 4 teams to conduct HATs for 10 days: the equipment-assisted training team at high temperature (HE); the equipment-assisted training team under normal hot weather (NE); the high-intensity interval training team at high temperature (HIIT), and the control team without training. A standard heat tolerance test (HTT) was conducted before (HTT-1st) and after (HTT-2nd) the training to judge whether the participants met the heat acclimation (HA) criteria. Results: We found that the participants in both HE and NE teams had significantly higher acclimation rates (HA/total population) than whom in the HIIT team. The effects of HAT on the participants of the HE team outperformed that of the NE team. In the HA group, the differences of physiological indicators and plasma organ damage biomarkers (ALT, ALP, creatinine, LDH, α-HBDH and cholinesterase) before and after HTT-2nd were significantly reduced to those during HTT-1st, but the differences of immune factors (IL-10, IL-6, CXCL2, CCL4, CCL5, and CCL11) elevated. The composition, metabolism, and pathogenicity of gut microbes changed significantly, with a decreased proportion of potentially pathogenic bacteria (Escherichia-Shigella and Lactococcus) and increased probiotics (Dorea, Blautia, and Lactobacillus) in the HA group. Training for a longer time in a high temperature and humidity showed beneficial effects for intestinal probiotics. Conclusion: These findings revealed that pathogenic gut bacteria decrease while probiotics increase following HA, with elevated immune factors and reduced organ damage during heat stress, thereby improving the body's heat adaption.

Prognosis for patients with apical hypertrophic cardiomyopathy: A multicenter cohort study based on propensity score matching.

BACKGROUND: Apical hypertrophic cardiomyopathy (AHCM) is a subtype of HCM, and few studies on the prognosis in AHCM are available. AIMS: This study aimed to explore the clinical prognosis for AHCM and non-AHCM patients through clinical data based on propensity score matching (PSM) in a large cohort of Chinese HCM patients. METHODS: The cohort study included 2268 HCM patients, 226 AHCM and 2042 non-AHCM patients from 13 tertiary hospitals, who were treated between 1996 and 2021. Fifteen demographic and clinical variables of 226 AHCM patients and 2042 non-AHCM patients were matched using 1:2 PSM. A Cox proportional hazard regression model was constructed to assess the effect of AHCM on mortality. RESULTS: During a median follow-up of 5.1 (2.4-8.4) years, 353 (15.6%) of the 2268 HCM patients died, of whom 205 died due to cardiovascular mortality/cardiac transplantation and 94 experienced sudden cardiac death (SCD). In the matched cohort, the ACHM patients had lower rates of all-cause mortality (P = 0.003), cardiovascular mortality/cardiac transplantation (P = 0.03), and SCD (P = 0.02) than the non-AHCM patients. Furthermore, the Cox proportional hazard regression model showed that AHCM was an independent prognostic predictor of all-cause HCM mortality (P = 0.004) and a univariable prognostic predictor of cardiovascular mortality/cardiac transplantation (P = 0.03) and for SCD (P = 0.03). However, AHCM was not significant in multivariable Cox regression models in relation to cardiovascular mortality/cardiac transplantation and SCD. CONCLUSION: AHCM had a favorable prognosis both before and after matching, with lower all-cause mortality, cardiovascular mortality/cardiac transplantation, and SCD than non-AHCM.

Correlation Between Non-insulin-Based Insulin Resistance Indices and Increased Arterial Stiffness Measured by the Cardio-Ankle Vascular Index in Non-hypertensive Chinese Subjects: A Cross-Sectional Study.

Data are limited on the relationship between the cardio-ankle vascular index (CAVI) and non-insulin-based insulin resistance (IR) indices, including the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), fasting triglyceride and glucose index (TyG), and metabolic score for IR (METS-IR). In this study, we explored the relationship between TG/HDL-C, TyG, METS-IR, and the risk of increased arterial stiffness (CAVI ≥ 8.0) and compared their ability to detect arterial stiffness in the non-hypertensive Chinese population. A total of 3,265 non-hypertensive subjects were included. Spearman's and partial correlation analyses were used to assess the relationship between non-insulin-based IR indices and CAVI. The correlation between these indices and the risk of a CAVI ≥ 8.0 was explored by multiple logistic regression analysis. The area under the receiver-operating characteristic curve was used to compare the ability of TG/HDL-C, TyG, and METS-IR to detect a CAVI ≥ 8.0. After adjustment for confounding factors, linear regression analysis showed that the CAVI changed by 0.092 [95% confidence interval (CI) 0.035-0.149] per standard deviation increase in TyG. While, this linear relationship was not found when analyzing TG/HDL-C and METS-IR. Multiple logistic regression analysis showed that the proportion of patients with CAVI ≥ 8.0 in the fourth quartile of TG/HDL-C [Q4 vs. Q1: odds ratio (OR) 2.434, 95% CI 1.489-3.975], TyG (Q4 vs. Q1: OR 2.346, 95% CI 1.413-3.896), and METS-IR (Q4 vs. Q1: OR 2.699, 95% CI 1.235-5.897) was significantly higher than that in the lowest quartile. The area under the curve that could discriminate CAVI ≥ 8.0 was 0.598 (95% CI 0.567-0.629) for TG/HDL-C, 0.636 (95% CI 0.606-0.667) for TyG, and 0.581 (95% CI 0.550-0.613) for METS-IR. In this study, we demonstrated a significant association between increased arterial stiffness and non-insulin-based IR indices. Among them, TyG showed better discriminatory ability than TG/HDL-C or METS-IR.

Electric Insulating Irrigations Mitigates Esophageal Injury Caused by Button Battery Ingestion.

Objective: Accidental ingestion of button batteries (BB), usually occurred in children and infants, will rapidly erode the esophagus and result in severe complications, even death. It has been recommended that treatment of this emergent accident as soon as possible with drinking of pH-neutralizing viscous solutions such as honey and sucralfate before surgical removal can mitigate the esophageal injury. Recently, we reported that the electric insulating solutions such as edible oils could mitigate tissue damage in BB-exposed esophageal segments. In this study, we compared the protective effect of kitchen oil with honey or sucralfate, the recommended pH-neutralizing beverages, and with their mixture on esophageal injury caused by BB ingestion in pig esophageal segments and in living piglets. Methods: Effect of olive oil irrigations was compared to that of honey or sucralfate irrigations in the BB-damaged esophageal segments freshly collected from the local abattoir and in live Bama miniature piglets with the proximal esophagus exposed to BB for 60 min. Also, the effect of olive oil and honey mixture (MOH) irrigations was assessed in live animals. The BB voltage was recorded before insertion and after its removal. Gross and histological analysis of the esophageal injury was performed after BB exposure in segmented fresh esophagus and 7 days after BB exposure in live animals, respectively. Results: Olive oil irrigations demonstrated better protective effect against BB-induced esophageal damage, compared to honey or sucralfate for BB-induced esophageal damage in vitro. But in vivo study showed that olive oil alone exacerbated esophageal injury because all esophagi irrigated with olive oil perforated. Surprisingly, irrigations with the MOH showed considerable protective effect for BB-induced esophageal damage in live animals, significantly better than irrigations with honey alone. The MOH decreased BB discharge, reduced area of surface injury, attenuated injured depth of esophageal wall thickness, and downed the mucosal injury index in comparison to using honey alone. Conclusion: Irrigations with olive oil alone couldn't prevent the BB discharge and is harmful for BB ingestion before surgical removal. However, mixed with honey, olive oil very effectively prevents the BB discharging and produces better esophageal protection than honey.

Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes.

Pyroptosis is a kind of cell necrosis mediated by inflammasomes. The caspase 1-induced cleavage of gasdermin D (GSDMD) is a canonical pathway to cause membrane pores and eventually cell pyroptosis. Poly-l-lysine (PLL) is widely used to enhance cell adhesion during experiments. Human THP-1 cells are a typical cell line used to study pyroptosis due to their monocytic and macrophage-like characteristics. However, it was found that THP-1 cells seeded on the PLL-coated slides died. To figure out the reason, we observed the morphology of THP-1 cells on PLL-coated slides, which showed obvious pore forming on the cell membranes and cell swelling. The indicated pyroptosis-related protein expression was evaluated and it showed that the conventional caspase-1 pathway of pyroptosis was activated through the NLRP3 inflammasome in THP-1 monocytes on the PLL-coated slides. Hence, PLL-guided cell adhesion induces cell pyroptosis in THP-1 monocytes, which calls for THP-1 dominant studies of pyroptosis to avoid the use of PLL-coated slides or PLL-related drugs.

Correlation between non-insulin-based insulin resistance indexes and the risk of prehypertension: A cross-sectional study.

The authors aimed to characterize the relationships between non-insulin-based insulin resistance (IR) indexes and the risk of prehypertension, and to compare their abilities to identify prehypertension. The authors recruited 3274 adults who did not have hypertension and were not taking hypoglycemic or lipid-lowering medications. The triglyceride-to-high-density lipoprotein-cholesterol ratio (TG/HDL-C), fasting triglyceride and glucose index (TyG), and metabolic score for IR (METS-IR) were calculated. Bivariate Spearman's correlation analysis and multiple logistic analysis were used. The area under the receiver operating characteristic (ROC) curve was used to compare the ability of the three indexes to identify prehypertension. Systolic and diastolic blood pressure (BP) positively correlated with TG/HDL-C (r = .272, P < .001), TyG (r = .286, P < .001), and METS-IR (r = .340, P < .001) in the entire cohort. Multiple logistic analysis showed that the proportion of prehypertension in the third and fourth quartiles of the TG/HDL-C (Q3 vs. Q1: odds ratio (OR) = 1.527, 95% confidence interval (CI): 1.243-1.988; Q4 vs. Q1: OR = 1.580, 95% CI: 1.231-2.028), TyG (Q3 vs. Q1: OR = 1.519, 95% CI: 1.201-1.923; Q4 vs. Q1: OR = 1.658, 95% CI: 1.312-2.614), and METS-IR (Q3 vs. Q1: OR = 1.542, 95% CI: 1.138-2.090; Q4 vs. Q1:OR = 2.216, 95% CI: 1.474-3.331) were significantly higher than in the lowest quartiles. The areas under the curves and 95% CIs for the identification of prehypertension were .647 (.628-.667) for TG/HDL-C, .650 (.631-.669) for TyG, and .683 (.664-.702) for METS-IR, respectively. Thus, non-insulin-based IR indexes (TG/HDL-C, TyG, and METS-IR) are significantly associated with the risk of prehypertension. Furthermore, METS-IR is better able to identify prehypertension than TG/HDL-C and TyG. These non-insulin-based IR indexes might assist with the prevention of hypertension in primary care and areas with limited medical resources.

CD226 deficiency promotes glutaminolysis and alleviates mitochondria damage in vascular endothelial cells under hemorrhagic shock.

Hemorrhagic shock (HS) is common in clinical emergencies, leading to millions of deaths each year globally. CD226 is a costimulatory adhesion molecule expressed on both immune cells and endothelial cells (ECs) to regulate their metabolic activity and function. As endothelial dysfunction occurs after HS, the roles CD226 plays in vascular EC metabolism were investigated. CD226fl/fl Tekcre mice were adopted to achieve vascular EC-specific knockout of CD226, and subjected to HS modelling. Serum levels of crucial intermediate metabolites were evaluated through liquid chromatography-mass spectrometry analysis. Human umbilical vein ECs (HUVECs) were used to study the effects of CD226 under hypoxia in vitro. Seahorse analysis evaluated the cellular glycolysis and mitochondria bioenergetics. Results showed that CD226 deficiency in vascular ECs alleviated HS-induced intestinal damage and inflammatory response in mice. Animal studies indicated an improved energy metabolism when CD226 was knocked out in ECs after HS, as evidenced by enhanced glutamine-glutamate metabolism and decreased lactic acid levels. Glut-1 was upregulated in mouse vascular ECs after HS and HUVECs under hypoxia, combined with decreased CD226. Moreover, HUVECs with CD226 knockdown exhibited relieved mitochondrial damage and early apoptosis under hypoxia, whereas CD226 overexpression showed opposite effects. Seahorse analysis showed that downregulated CD226 significantly increased mitochondrial ATP production and glucose uptake in HUVECs under hypoxia. Additionally, Erk/PHD2 signaling-mediated HIF-1α/Glut-1 and HIF-2α/ASCT2 pathways were involved in CD226 regulation on HUVEC glutaminolysis after hypoxia. Hence, CD226 deficiency promotes bypass energy supply to vascular ECs under ischemic or hypoxic stress, to ameliorate the stress-mediated metabolic disturbance.

[IL-6, IL-1ß, and IL-10 levels in peripheral blood as indicators for early identification of gram-positive and gram-negative sepsis].

Objective To find out indicators for rapid identification of Gram-positive (G+) and Gram-negative (G-) bacteria through transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) and serum liquid-phase chip technology in early sepsis. Methods 35 eligible cases out of 182 sepsis patients in the emergency intensive care unit (EICU) were selected for retrospective analysis. They were divided into G+ group (12 cases) and G- group (23 cases) based on their blood culture results. General characteristics like patients' age, gender, sequential organ failure assessment (SOFA) scores, etc. and other laboratory indexes such as blood routine, IL-6, CRP, procalcitonin(PCT)of these two groups were analyzed. PBMCs were isolated through single density gradient centrifugation. Total RNA was extracted for transcriptome sequencing to find out differential genes. Serum liquid-phase chip technology was performed to detect serum granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, monocytes chemotactic protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) in two groups. Receiver operating characteristic (ROC) curve was drawn using bacteria types as a dependent variable and selected cytokines as test variables, to analyze the correlation between selected biomarkers and bacteria type. Results No significant difference in general characteristics, CRP, and PCT were found between the G+ and G- group. The serum level of IL-6 in G+ group was lower than that in the G- group. Transcriptome sequencing results revealed 30 immune-related genes that were differentially expressed in the PBMCs of two groups. Compared to the G+ group, the serum levels of IL-6 and IL-1ß in G- group significantly increased, while serum IL-10 was reduced. ROC curve analysis indicated that serum IL-6, IL-1ß, and IL-10 levels could identify the G- and G+ bacteria types. The combined diagnosis using these three indicators is highly applicable in distinguishing G- and G+ bacteria. Conclusion IL-6, IL-1ß and IL-10 levels can be used as indicators for early identification of sepsis induced by G+ or G- bacteria.

Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-ß1 signaling pathway.

Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-ß1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-ß1 (TGF-ß1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin ß receptor (LTßR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTßR and drove liver fibrosis in vitro. Blocking TGF-ß1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-ß1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT.

[The conditional knockout of CD226 gene reduces acute lung injury in mice with hemorrhagic shock].

Objective To investigate the effects on acute lung injury (ALI) of CD226 conditional knockout (CD226 CKO) in vascular endothelial cells were investigated in mice with hemorrhagic shock (HS) and its mechanism. Methods Male wild type (WT) and CD226 CKO mice were randomly divided into sham and HS groups: in the sham group, a heart puncture was performed but blood was not drawn; in the HS group, the heart was punctured and 30% of the total blood volume was drawn. To assess lung injury, lung lesions were observed by HE staining. Immunofluorescence histochemical staining was used to detect the expression and distribution of CD31, CD226 in lung tissue and CD3 and CD226 in spleen. In addition, a RNA interering (RNAi) was used to knockdown CD226 in human umbilical vein endothelial cells and a hypoxia model was established. Protein expression of Bcl2 in lung tissue and vascular endothelial cells was detected by Western blotting. Early apoptosis was detected by JC-1 mitochondrial membrane potential staining. Results In the HS groups, CD226 CKO mice showed significantly less ALI than WT mice, and the protein expression of Bcl2 in their lung tissues increased. Furthermore, in vitro cytological models revealed that protein expression of Bcl2 increased and apoptosis decreased in the siCD226 group relative to the siNC group under hypoxia. Conclusion CD226 CKO in vascular endothelial cells reduces ALI in mice with HS, and this effect is associated with increased expression of Bcl2 and decreased apoptosis.

Deficiency of platelet adhesion molecule CD226 causes megakaryocyte development and platelet hyperactivity.

This study used constitutive CD226 gene knockout (KO) mice as a model to investigate the functions and mechanisms of CD226 in megakaryocyte (MK) maturation and platelet activation. Although CD226 deficiency did not cause MK polyploidization or platelet granule abnormalities, increased MK counts were detected in the femora bone marrow (BM) and spleen of CD226 KO mice. Particularly, CD226 KO mice have a more extensive membrane system in MKs and platelets than wild-type (WT) mice. We also demonstrated that CD226 KO mice displayed increased platelet counts, shortened bleeding time, and enhanced platelet aggregation. CD226 KO platelets had an increased mature platelet ratio compared to the control platelets. In addition, the observed reduction in bleeding time may be due to decreased nitric oxide (NO) production in the platelets. Platelet-specific CD226-deficient mice showed similar increased MK counts, shortened bleeding time, enhanced platelet aggregation, and decreased NO production in platelets. Furthermore, we performed middle cerebral artery occlusion-reperfusion surgery on WT and CD226 KO mice to explore the potential effect of CD226 on acute ischemia-reperfusion injury; the results revealed that CD226 deficiency led to significantly increased infarct area. Thus, CD226 is a promising candidate for the treatment of thrombotic disorders.

Diabetic muscle infarction in a patient admitted to the cardiac ward.

Diabetic muscle infarction (DMI) is a rare complication of long-standing diabetes mellitus. This is the first case of DMI reported by cardiologists. A 49-year-old patient with a history of diabetes and hypertension for only two years was admitted to the cardiac ward due to pain in the left thigh with pitting edema in both lower extremities. Magnetic resonance imaging finally confirmed the presence of DMI in the left thigh, which was improved by treatment with anticoagulants, analgesics and rest. However, the typical clinical symptoms of DMI were unrecognizable at the start of treatment, which may be attributed to a lack of awareness of this rare condition among non-endocrinologist physicians.