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Abstract: Objective: Chronic ischemia is associated with alterations in genes that result in myocardial remodeling. An important biochemical basis of cardiac remodeling is generation of reactive oxygen species (ROS). A few studies have suggested that acute ischemia triggers signals for remodeling. We examined the hypothesis that targeted deletion of lectin-like oxidized-LDL receptor (LOX-1) may inhibit signals related to cardiac remodeling. Methods and results: We generated LOX-1 knockout (KO) mice on C57BL/6 (wild-type mice) background, and subjected wild-type and KO mice to ischemia–reperfusion (I–R). The wild-type mice developed a marked reduction in left ventricular systolic pressure and ±dp/dtmax and an increase in left ventricular end-diastolic pressure following I–R, and this change was much less in the LOX-1 KO mice, indicating preservation of left ventricular function with LOX-1 deletion. There was evidence for marked oxidative stress (NADPH oxidase expression, malondialdehyde and 8-isoprostane) following I–R in the wild-type mice, much less so in the LOX-1 KO mice (P <0.01). In concert, collagen deposition (Masson''s trichrome and Picro-sirius red staining) increased dramatically in the wild-type mice, but only half as much in the LOX-1 KO mice (P <0.01). Collagen staining data was corroborated with procollagen-I expression. Further, fibronectin and osteopontin expression increased in the wild-type mice, but to a much smaller extent in the LOX-1 KO mice (P <0.01). Conclusions: These findings provide compelling evidence that LOX-1 is a key modulator of cardiac remodeling which starts immediately following I–R. [Copyright &y& Elsevier]

Abstract: Previous studies have indicated that GABAergic disinhibition contributes to cognitive deficits mediated by NMDA receptor hypofunction in schizophrenia model of rats. However, the underlying mechanism of GABAergic disinhibition in schizophrenia remains elusive. In this study, we found that the maintenance of long term potentiation (LTP) was impaired in the hippocampus of rats with MK-801-induced cognitive impairments. The impairment of LTP maintenance was significantly reversed by picrotoxinin, a specific GABAA receptor-chloride channel blocker and furosemide, a K+–Cl− cotransporter 2 (KCC2) blocker, respectively. Furthermore, immunoblotting results indicated KCC2 expression in hippocampal CA1 of MK-801-treated rats was lower than that of normal rats before LTP induction. Additionally, LTP-accompanied downregulation of KCC2 was prevented in MK-801-treated rats during LTP induction. Our results suggested that KCC2 expression in hippocampal CA1 of MK-801-treated rats was not further decreased by LTP induction because of its low expression caused by MK-801 treatment. Accordingly, GABAergic inhibition was not further decreased during LTP induction due to the depressed basal GABAergic tone in MK-801-treated rats, Therefore, GABAergic disinhibition in MK-801-treated rats restricts the further downregulation of KCC2 during LTP induction and contributes to the stable GABAergic inhibition and the impaired LTP expression. Our results thus reveal the mechanism that GABAergic disinhibition contributes to cognitive deficits. [Copyright &y& Elsevier]

Background: Coronavirus disease 2019 (COVID-19) is highly contagious and deadly and is associated with coagulopathy. Pentraxin-3(PTX3) participates in innate resistance to infections and plays a role in thrombogenesis., Purpose: The present study aimed to investigate the role of PTX3 in coagulopathy in patients with COVID-19., Methods: A retrospective study, including thirty-nine COVID-19 patients, enrolled in Hunan, China, were performed. The patients were classified into the D-dimer&#95;L (D-dimer <1mg/L) and D-dimer&#95;H (D-dimer≥1mg/L) groups basing on the plasma D-dimer levels on admission. Serum PTX3 levels were detected by enzyme-linked immunosorbent assays and compared between those two groups, then receiver operating characteristic (ROC) curve analysis, correlation analysis, and linear regression models were performed to analyze the association between PTX3 and D-dimer., Results: Our results showed that serum PTX3 levels (median values, 10.21 vs. 3.36, P <0.001), computerized chest tomography (C.T.) scores (median values, 10.0 vs. 9.0, P <0.05), and length of stay (LOS) (mean values, 16.0 vs. 10.7, P =0.001) in the D-dimer&#95;H group were significantly higher than that in D-dimer&#95;L group. ROC curve analysis revealed that the AUC of white blood corpuscle counts, C-reaction protein, erythrocyte sedimentation rate, and PTX3 for COVID-19 were 0.685, 0.863, 0.846, and 0.985, respectively. Correlation analysis showed that there was a positive relationship between PTX3 and D-dimer (r=0.721, P <0.001), chest CT imaging score (r=0.418, P =0.008), and LOS (r=0.486, P =0.002). Multiple linear regression analysis showed that the coefficient of determination was 0.657 ( P < 0.001)., Conclusion: Serum level of PTX3 was positively correlated with disease severity and coagulopathy. Detection of serum PTX3 level could help identify severer patients on admission and may be a potential therapeutic target for coagulopathy in patients with COVID-19., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Objective: To explore the role of calpain in pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension and the underlying mechanisms.
, Methods: Sprague-Dawley rats were randomly divided into the hypoxia group and the normoxia control group. Right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored by a method with right external jugular vein cannula. Right ventricular hypertrophy index was presented as the ratio of right ventricular weight to left ventricular weight (left ventricle plus septum weight). Levels of calpain-1, -2 and -4 mRNA in pulmonary artery were determined by real-time PCR. Levels of calpain-1, -2 and -4 protein were determined by Western blot. Primary rat pulmonary arterial smooth muscle cells (PASMCs) were divided into 4 groups: a normoxia control group, a normoxia+MDL28170 group, a hypoxia group and a hypoxia+MDL28170 group. Cell proliferation was detected by MTS and flow cytometry. Levels of Ki-67 and proliferating cell nuclear antigen (PCNA) mRNA were determined by real-time PCR.
, Results: RVSP, mPAP and right ventricular remodeling index were significantly elevated in the hypoxia group compared to those in the normoxia group. In the hypoxia group, pulmonary vascular remodeling was significantly developed, accompanied by up-regulation of calpain-1, -2 and -4. MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs concomitant with the suppression of Ki-67 and PCNA mRNA expression.
, Conclusion: Calpain mediates vascular remodeling via promoting proliferation of PASMCs in hypoxia-induced pulmonary hypertension.

Objective: To investigate whether the protection of ischemic preconditioning (IPC) against myocardial ischemia/reperfusion (I/R) injury is mediated by toll-like receptor 4 (TLR4)/NF-κB pathway, and whether these effects are related to the release of calcitonin gene-related peptide (CGRP)., Methods: Sprague-Dawley rats were subjected to 60 min of ligation of the left anterior descending coronary artery followed by 3 h of reperfusion to induce I/R injury. IPC was performed by 4 cycles of 3-min left coronary artery occlusion followed by 5-min reperfusion before the I/R. The expression of TLR4 mRNA was determined by RT-PCR. TLR4 and NF-κB protein expression were analyzed by immunohistochemistry. Myocardial infarct size, CGRP concentration in plasma and activity of creatine kinase in serum were also measured., Results: IPC significantly reduced the infarct size and creatine kinase activity concomitantly with the increase in plasma CGRP concentration. The expressions of TLR4 protein and mRNA and NF-κB protein were increased by myocardial I/R injury, and dramatically inhibited by IPC., Conclusion: IPC protects against myocardial I/R injury by inhibition of TLR4/NF-κB pathway. These effects are related to the increased the release of CGRP.

Cardiac fibroblasts play a pivotal role in cardiac remodeling. In response to various pro-fibrotic stimuli, such as pro-inflammatory cytokines, anoxia-reoxygenation and pressure overload as well as aging, cardiac fibroblasts undergo proliferation, migration and activation, leading to the accumulation of extracellular matrix components and increased thickness and stiffness of heart. The ligands for peroxisome proliferator-activated receptor γ, especially thiazolidinediones, modulate the function of cardiac fibroblasts and the progression of cardiac remodeling, especially under pathological conditions. Unfortunately these agents have not been found to be consistently beneficial in heart failure. Although the precise intracellular signaling pathways are not fully understood, existing evidence strongly supports the involvement of oxidative stress and related signaling pathways. Further, peroxisome proliferator-activated receptor γ and lectin-like oxidized low-density lipoprotein receptor-1 together play critical roles in thiazolidinediones-modulated cardiac fibroblast dysfunction.

Corosolic acid is clinically proven to activate cell glucose-transporter "shuttles" and thus helps balance blood glucose levels. A method was developed for the determination of corosolic acid in Eriobotrya japonica leaves by reversed-phase high performance liquid chromatography (RP-HPLC). The peak of corosolic acid in Eriobotrya japonica leaves was qualitatively analyzed by comparing the retention times and mass spectra of corosolic acid standard and the extract on HPLC-mass spectrometry (MS). Eriobotrya japonica leaves were extracted thrice for 3.0 h at 90 degrees C with 90% ethanol. The extract was concentrated and deposited by water to remove the impurity which interfered the determination. The deposit was dissolved by methanol and separated on an ODS column (250 mm x 4.6 mm i.d., 5 microm). Methanol-1.0% acetic acid (88:12, v/v) was used as the mobile phase with a flow rate of 0.8 mL/min. The detection wavelength was 215 nm. The linearity was good within the range of 1.0-6.0 microg (r = 0.9999). The corosolic acid content of Eriobotrya japonica leaves from Huangshan was 0.36%. The average recovery of corosolic acid was 99%. The method is simple, rapid, accurate and reliable for the determination of corosolic acid in Eriobotrya japonica leaves.