Linkage of CDC42 and T-helper cell ratio with anxiety, depression and quality of life in ST-elevation myocardial infarction.

Objective: To investigate the correlations between CDC42 and T-cell subsets concerning anxiety, depression and quality of life in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention. Methods: Sera from 156 participants were analyzed for CDC42 levels and Th1, Th2, Th17 and Treg cells. Results: CDC42 correlated with reduced Th1/Th2 and Th17/Treg ratios, lower anxiety and depression, and higher EuroQol visual analog scale (EQ-VAS) score. The Th17/Treg ratio correlated with elevated anxiety, depression, EuroQol-5 dimensions score and decreased EQ-VAS score. The Th1/Th2 ratio was positively related to the EQ-VAS score. Conclusion: CDC42 correlates with reduced Th1/Th2 and Th17/Treg ratios, reduced anxiety and depression, and improved quality of life in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention.

CDC42 is a protein that regulates immune cells and negative mood. This study enrolled 156 patients with ST-elevation myocardial infarction (a severe type of coronary artery disease) who had percutaneous coronary intervention (a treatment that improves coronary blood flow). Their blood was collected for detecting CDC42 and specific immune cells, including Th1, Th2, Th17 and Treg cells. Their feelings of anxiety, depression and quality of life (QoL) were assessed using relevant questionnaires. The results showed that if a patient presented with reduced CDC42, they would have a high probability of anxiety and depression and poor QoL, as well as increased Th1 and Th17 cells. The study also found that patients with increased Th17 cells or decreased Treg cells would have a high possibility of anxiety and depression, as well as bad QoL. In addition, if a patient had increased Th2 cells, they would have a high probability of poor QoL. In summary, the detection of CDC42 can help ST-elevation myocardial infarction patients who have percutaneous coronary intervention better observe anxiety and depression.

The ability and optimal cutoff value of serum cell division cycle 42 in estimating major adverse cardiac event in STEMI patients treated with percutaneous coronary intervention.

Cell division cycle 42 (CDC42) regulates cholesterol efflux, chronic inflammation, and reendothelialization in various atherosclerotic diseases. This study aimed to investigate the correlation of serum CDC42 with myocardial injury indicators and major adverse cardiac event (MACE) in ST-elevation myocardial infarction (STEMI) patients who were treated with percutaneous coronary intervention (PCI). In 250 STEMI patients about to receive PCI, serum samples were collected at enrollment before PCI treatment, and the serum samples were also obtained from 100 healthy controls (HCs) at enrollment. Serum CDC42 was detected by enzyme-linked immunosorbent assay. Serum CDC42 was decreased (versus HCs, P < 0.001) and negatively correlated with diabetes mellitus (P = 0.017), multivessel disease (P = 0.016), cardiac troponin I (P < 0.001), creatine kinase MB (P = 0.012), stent diameter ≥ 3.5 mm (P = 0.039), white blood cell (P < 0.001), low-density lipoprotein cholesterol (P = 0.049), and C-reactive protein (P < 0.001) in STEMI patients. Besides, 29 (11.6%) STEMI patients experienced MACE. The 1-year, 2-year, and 3-year accumulating MACE rates were 7.5%, 17.3%, and 19.3%, accordingly. Serum CDC42 was reduced in STEMI patients who experienced MACE compared to those who did not (P = 0.001). Serum CDC42 ≥ 250 pg/mL, ≥ 400 pg/mL, ≥ 700 pg/mL (cut by near integer value of 1/4th quartile, median, and 3/4th quartile) were associated with decreased accumulating MACE rates in STEMI patients (all P < 0.050). Notably, serum CDC42 ≥ 250 pg/mL (hazard ratio = 0.435, P = 0.031) was independently related to reduced accumulating MACE risk in STEMI patients. A serum CDC42 level of ≥ 250 pg/mL well predicts decreased MACE risk in STEMI patients who are treated with PCI.

Linkage of Blood MALT1 with CD4+ T Cell Subset, Inflammation, Lipid, and Its Potency as a Biomarker for Predicting Major Adverse Cardiovascular Events in Coronary Heart Disease Patients.

OBJECTIVE: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) promotes CD4+ T cell differentiation, vascular inflammation, and atherogenesis to engage in coronary heart disease (CHD) progression. This study intended to explore the correlation of blood MALT1 with clinical characteristics, CD4+ T cell subset and prognosis in CHD patients. METHODS: MALT1 in peripheral blood mononuclear cells of 258 CHD patients and 50 healthy controls (HCs) was determined by RT-qPCR. Additionally, blood T helper (Th)1, Th2, Th17, and regulatory T (Treg) cells were measured through flow cytometry; major adverse cardiovascular events (MACE) were recorded during the routine follow up in CHD patients. RESULTS: Blood MALT1 was elevated in CHD patients compared to HCs. Interestingly, blood MALT1 positively associated with hyperlipidemia, triglyceride, C-reactive protein, and Gensini score in CHD patients. It also negatively linked with Th2 cells, Treg cells, and positively related to Th17 cells but not Th1 cells in CHD patients. More importantly, MACE-free survival was shortened in CHD patients with high blood MALT1 compared to those with low blood MALT1 (cut off by the median) while less significance was observed when cut off by quartiles. Separately, blood MALT1 was elevated in CHD patients occurred MACE within 1-year, 2-year, 3-year, and 4-year duration compared to those who did not. CONCLUSION: Blood MALT1 links with unbalanced CD4+ T-cell subset, elevated inflammation, and coronary-artery stenosis serving as a candidate biomarker for predicting MACE risk in CHD patients.

ASIC1a promotes hepatic stellate cell activation through the exosomal miR-301a-3p/BTG1 pathway.

Activation of hepatic stellate cells (HSCs) is a key cause of liver fibrosis. However, the mechanisms leading to the activation of HSCs are not fully understood. In the pathological process, acid-sensing ion channel 1a (ASIC1a) is widely involved in the development of inflammatory diseases, suggesting that ASIC1a may play an important role in liver fibrosis. We found that in an acidic environment, ASIC1a leads to HSC-T6 cell activation. Meanwhile, exosomes produced by activated HSC-T6 cells (HSC-EXOs) can be reabsorbed by quiescent HSC-T6 cells to promote their activation. Exosomes mainly carry miRNAs involved in intercellular information exchange. We performed exosome miRNA whole transcriptome sequencing. The results indicated that the acidic environment could alter the miRNA expression profile in the exosomes of HSC-T6 cells. Further studies revealed that ASIC1a promotes the activation of HSCs by regulating miR-301a-3p targeting B-cell translocation gene 1 (BTG1). In conclusion, our study found that ASIC1a may affect HSC activation through the exosomal miR-301a-3p/BTG1 axis, and inhibiting ASIC1a may be a promising treatment strategy for liver fibrosis.

CaM/CaMKII mediates activation and proliferation of hepatic stellate cells regulated by ASIC1a.

The activation of hepatic stellate cells (HSCs) is closely related to hepatic fibrosis and plays a key role in its occurrence and development. In the damaged liver, inhibition of the activation, proliferation, and clearance of HSCs is an important therapeutic strategy. However, the mechanism underlying the activation of HSCs is not completely clear. Acid-sensitive ion channel 1a (ASIC1a) is a cation channel activated by extracellular acid, which is responsible for the transport of Ca2+ and Na+ and participates in the activation of HSCs and the occurrence and development of many inflammatory diseases, suggesting that ASIC1a plays an important role in liver fibrosis. A previous study by the project team found that when the membrane channel protein ASIC1a was opened, intracellular Ca2+ levels increased, the expression of CaM/CaMKII in HSCs was high, and HSC was activated and proliferated. Therefore, we established an SD rat model of hepatic fibrosis and induced HSC-T6 activation by stimulating ASIC1a with acid in vitro. In vivo, CCl4 was used to induce liver fibrosis in rats, and different doses of KN93 (0.5, 1, and 2 mg/kg/d) and colchicine (0.1 mg/kg/d) were administered. Eight weeks later, the activities of ALT and AST in serum were measured and hematoxylin-eosin and Masson staining in liver tissue, and immunohistochemistry analysis were performed in SD rats. The expressions of ASIC1a, α-SMA, Collagen-1, CaM, and CaMKII were detected. In vitro, we activated HSC-T6 cells by stimulating ASIC1a with acid. The results showed that inhibition of ASIC1a could improve acid-induced HSCs activation. In addition, CaM/CaMKII was expressed in HSC of rats with hepatic fibrosis regulated by ASIC1a. After blocking or silencing the expression of CaMKII, the fibrosis marker protein can be down-regulated. KN93 also reduced inflammation and improved the activation, proliferation and fibrosis of HSC. In summary, we concluded that CaM/CaMKII participates in ASIC1a regulation of the proliferation and activation of HSC and promotes the occurrence of liver fibrosis.

Inhibition of ASIC1a-Mediated ERS Improves the Activation of HSCs and Copper Transport Under Copper Load.

Hepatolenticular degeneration (HLD) is an autosomal recessive genetic disease caused by the toxic accumulation of copper in the liver. Excessive copper will disrupt the redox balance in cells and tissues, causing ischemia, hypoxia, and inflammation. Acid-sensitive ion channel 1a is a cationic channel activated by extracellular acid and allowing Ca2+ and Na+ to flow into cells. Its expression appears in inflammation, arthritis, fibrotic tissue, and damaged environment, but its role in hepatolenticular degeneration has not been studied. This study established a Wistar rat model of high copper accumulation and used CuSO4 to induce the activation of HSC-T6 in an in vitro experiment. In vivo, Wistar rats were examined to determine the serum copper concentration, serum ALT and AST activities, and liver copper accumulation, and liver tissue HE staining and immunohistochemical analyses were conducted. The expression of ASIC1a, α-SMA, Collagen-Ι, GRP78, XBP1, ATP7B, and CCS were detected. Besides, immunofluorescence technology can detect the expression of the phosphorylated protein in vitro. It is suggested that ASIC1a is involved in the quality control of the endoplasmic reticulum, which degrades mutant ATP7B and increases the accumulation of copper. After blocking or silencing the expression of ASIC1a, ELISA can detect the level of inflammatory factors, the expression of endoplasmic reticulum stress-related factors, and ATP7B was improved in a higher copper environment reduction of copper deposition was observed in liver Timm's staining. Collectively, we conclude that ASIC1a is involved in the HSC activation induced by copper accumulation and promotes the occurrence of hepatolenticular fibrosis.

Ligustrazine Suppresses Platelet-Derived Growth Factor-BB-Induced Pulmonary Artery Smooth Muscle Cell Proliferation and Inflammation by Regulating the PI3K/AKT Signaling Pathway.

Pulmonary arterial hypertension (PAH) is a serious pulmonary vascular disease. Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role in the course of this disease. Ligustrazine is an alkaloid monomer extracted from the rhizome of the herb Ligusticum chuanxiong. It is often used to treat cardiovascular diseases, but its effect on PAH has rarely been reported. This study aims to explore the protective effect and mechanism of ligustrazine on PAH. In the in vivo experiment, monocrotaline (MCT) was used to induce PAH in rats, and then ligustrazine (40, 80, 160 mg/kg/day) or sildenafil (25 mg/kg/day) was administered. Four weeks later, hemodynamic changes, right ventricular hypertrophy index, lung morphological characteristics, inflammatory factors, phosphoinositide 3-kinase (PI3K), and AKT expression were evaluated. In addition, primary rat PASMCs were extracted by the tissue adhesion method, a proliferation model was established with platelet-derived growth factor-BB (PDGF-BB), and the cells were treated with ligustrazine to investigate its effects on cell proliferation, inflammation, and cell cycle distribution. The results indicate that ligustrazine can markedly alleviate right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling, and inflammation caused by MCT, and that it decreased PI3K and AKT phosphorylation expression. Moreover, ligustrazine can inhibit the proliferation and inflammation of PASMCs and arrest the progression of G0/G1 to S phase through the PI3K/AKT signaling pathway. Therefore, we conclude that ligustrazine may inhibit the proliferation and inflammation of PASMCs by regulating the activation of the PI3K/AKT signaling pathway, thereby attenuating MCT-induced PAH in rats. Collectively, these findings suggest that ligustrazine may be a promising therapeutic for PAH.

ASIC1a inhibits cell pyroptosis induced by acid-induced activation of rat hepatic stellate cells.

The activation of hepatic stellate cells (HSCs) is associated with liver fibrosis, the pathological feature of most forms of chronic hepatic damage, and is accompanied by abnormal deposition of the extracellular matrix (ECM). During the pathological process, acid-sensing ion channel 1a (ASIC1a), which is responsible for Ca2+ transportation, is involved in the activation of HSCs. It has previously been identified that ASIC1a is related to pyroptosis in articular chondrocytes. However, it remains unclear whether ASIC1a restrains pyroptosis during liver fibrosis. Here, we determined that the levels of pyroptosis-associated speck-like protein, gasdermin D, caspase-1, nucleotide-binding oligomerization domain (NOD)-like receptor 3, and apoptosis-associated speck-like protein (ASC) decreased, while the level of α-smooth muscle actin and collagen-I increased upon introduction of ASIC1a into an acid-induced model. Inhibition or silencing of ASIC1a and the use of Ca2+ -free medium were able to promote the pyroptosis of activated HSCs, which reduced their deposition. In summary, our study indicates that ASIC1a inhibits pyroptosis of HSCs and that inhibition of ASIC1a may be able to promote pyroptosis to relieve liver fibrosis.