Chuanzhitongluo Inhibits Neuronal Apoptosis in Mice with Acute Ischemic Stroke by Regulating the PI3K/AKT Signaling Pathway.

BACKGROUND AND PURPOSE: Apoptosis is involved in the occurrence and development of acute ischemic stroke (AIS). This study aimed to assess whether Chuanzhitongluo (CZTL), a multi-target and multi-pathway compound preparation, plays a neuroprotective role in AIS by modulating neuronal apoptosis via the PI3K/AKT signaling pathway. METHODS: A mouse model of AIS was established by photochemical processes. Cerebral infarction volume was measured by 2% staining with 2, 3, and 5-triphenyl tetrazole chloride (TTC). Neuron apoptosis was assessed by TUNEL staining. Apoptosis RNA arrays were used to detect changes in apoptosis-related gene expression profiles. Western blotting was used to detect proteins involved in the PI3K/AKT signaling pathway. RESULTS: The study demonstrated that CZTL could potentially mitigate neuronal apoptosis in AIS mice. This appears to be achieved via the up-regulation of certain genes such as BCL-2, Birc6, and others, coupled with the down-regulation of genes like BAX, Bid, and Casp3. Further validation revealed that CZTL could enhance the expression of BCL-2 and reduce the expression of Cleaved Caspase-3 and BAX at both the gene and protein levels. The study also found that CZTL can enhance the phosphorylation level of the PI3K/AKT signaling pathway. In contrast to these findings, the PI3K inhibitor LY294002 notably amplified neuronal apoptosis in AIS mice. CONCLUSIONS: These findings imply that CZTL's ability to inhibit neuronal apoptosis may be linked to the activation of AIS's PI3K/AKT signaling pathway.

Subtyping treatment response of tirofiban in acute ischemic stroke based on neuroimaging features.

In a previously published clinical trial, we demonstrated that tirofiban was effective and safe in acute ischemic stroke (AIS) patients who did not undergo early recanalization treatments. We aimed to evaluate neuroimaging characteristics and their clinical significance to guide tirofiban treatment. In this post hoc analysis, location of infarcts (anterior circulation stroke [ACS] vs. posterior circulation stroke [PCS]), degree of cerebral artery stenosis (≤69% vs. ≥70% or occlusion), total infarct volume, and ASPECTS were used to predict the treatment effects of tirofiban, defined as the proportions of excellent and favorable functional outcome (modified Rankin Scale [mRS] score of 0-1, 0-2) at 90 days. ACS patients were more likely to achieve excellent (OR 2.08; 95% CI 1.25-3.45; p = 0.004) and favorable functional outcome (OR 2.28; 95% CI 1.24-4.22; p = 0.008) when treated with tirofiban. However, there was no significant difference in PCS patients between tirofiban and the control group. For patients with severe stenosis (≥70% or occlusion), tirofiban treatment improved the proportion of good outcomes (OR 2.84; 95% CI 1.44-5.60; p = 0.002 for mRS 0-1; OR 2.42; 95% CI 1.22-4.77; p = 0.011 for mRS 0-2). Meanwhile, we found that tirofiban improved outcome in patients with ASPECTS 8-10 and was independent of total infarct volume. These findings support the hypothesis that patients with ACS and severe stenosis may be recommended for tirofiban treatment, which can be predicted independent of total infarct volume.

ABHD5 protects cardiac function in alcoholic cardiomyopathy via HDAC4-NT to inhibit CAMKII/MEF2 axis.

Excessive intake of Alcohol is associated with a high incidence of alcoholic cardiomyopathy (ACM), which may impair cardiac function. In our study, we explored the Abhydrolase Domain Containing 5 (ABHD5) mechanism in ACM about histone deacetylase 4 (HDAC4) and CaM-CaMKII/MEF2 signaling pathway. Rat models of ACM were established in Wistar rats, and in vitro cell models were constructed in rat cardiomyocytes H9C2 utilizing 12-h of treatment of Alcohol (200 mM) to study the regulatory role of ABHD5 in ACM with the involvement of HDAC4 and CaM-CaMKII/MEF2 signaling pathway, as evidenced by determination of cardiac function, myocardial fibrosis, apoptosis of cardiomyocytes and oxidative stress condition. We found that both ABHD5 mRNA and protein expression was significantly lower in the ACM rats and rat cardiomyocytes H9C2. ACM rats with oe-ABHD5 injection showed repressed myocardial hypertrophy and myocardial fibrosis. Also, overexpression of ABHD5 reduced apoptosis and oxidative stress in H9C2 cells. Mechanistic studies demonstrated that ABHD5 via HDAC4-NT inhibits CAMKII/MEF2 axis. This study highlighted that ABHD5 decreased cardiac hypertrophy and myocardial fibrosis and limited cardiomyocyte apoptosis and oxidative stress injury in ACM.

Hardening Mechanism of Coral Aggregates in Cement-Based Systems.

In terms of the infrastructure construction near coral reefs, native coral aggregates have been widely implemented as alternative efficient building materials to prepare the "coral concrete". This study focused on the mechanical properties and hardening mechanism of coral particles under cement-based systems. Firstly, coral particles were divided into two categories: coral biological debris particles (calcium sand) and coral parent rock particles (limestone). Subsequently, several elementary laboratory tests were conducted to compare the physical and chemical properties of the samples. The results demonstrate that the specific surface area and open pores of coral particles are bigger than those of quartz sand. Moreover, the water absorption rate of debris and parent rock particles reach 9.9% and 22%, respectively. To further examine the hardening mechanism of coral particles, we carried out particle crushing strength tests, compressive strength tests and nanoindentation tests. Regardless of the tested groups and particle categories, the results show that the wrapped cement slurry universally demonstrated the successful enhancement of crushing strength σ0,d. Particularly, in the size range from 1.18-2.36 mm, wrapped particles of debris and parent rock both reached unusually high σ0,d values: 10.14 MPa and 8.74 MPa, respectively. However, in the size range from 9.5 mm to 16 mm, the σ0,d values of wrapped debris and parent rock reached 4.75 MPa and 3.18 MPa, respectively. According to the nanoindentation tests, the sub-microscopic strength of ITZs was enhanced to more than 1 GPa, which is higher than that of conventional concrete, in terms of the sample with 28-day maintenance. In conclusion, this study has provided a further basis for studying coral concrete material and its hardening mechanism.

Association of TLR3 (rs3775291) and IL-10 (rs1800871) gene polymorphisms with susceptibility to Hepatitis B infection: A meta-analysis.

TLR3 and IL-10 play a crucial role in antiviral defence. However, there is a controversy between TLR3 rs3775291 and IL-10 rs1800871 polymorphisms and the risk of hepatitis B virus (HBV) infection. The purpose of this study is to explore the relationship between the two single nucleotide mutations and the risk of HBV infection by meta-analysis. Medline, EMBASE, Web of Science, CNKI, China Wanfang database were searched for the case-control studies on the relationship between TLR3 rs3775291 and IL-10 rs1800871 polymorphism and susceptibility to HBV, updated to June 2020. The data were analysed by Stata 15.0 software. A total of 22 articles were included. The results showed that in the analysis of IL10 rs1800871 polymorphism and the risk of HBV infection, the pooled OR was 1.21 (95% CI 1.06-1.37), 1.28 (95% CI 1.04-1.56) and 1.20 (95% CI 1.06-1.37) and 1.40 (95% CI 1.07-1.83) in the allele model (C vs. T), dominant model (CC+CT vs. TT), recessive model (CC vs. CT+TT) and homozygous model (CC vs. TT), respectively. There was no statistical significance in the heterozygote model. A subgroup analysis of the Asian population showed similar results. The analysis of TLR3 rs3775291 polymorphism and the risk of HBV showed that in the allele model (T vs. C), the pooled OR was 1.30 (95% CI 1.05-1.61). Except for the recessive model, no significances were found in other genetic models. In conclusion, TLR3 rs3775291 and IL-10 rs1800871 polymorphisms are associated with the risk of HBV. Allele C and genotype CC at IL10 rs1800871 loci, as well as allele T and genotype TT at TLR rs3775291 loci, may increase susceptibility to Hepatitis B infection.

Effect of microRNA-133a-3p/matrix metalloproteinase-9 axis on the growth of atherosclerotic vascular smooth muscle cells.

Atherosclerosis (AS) is the leading cause of cardiovascular disease and poses a threat to human health. MicroRNAs (miRNAs/miRs) are a group of endogenous small non-coding RNAs that have been identified to serve important roles in AS. However, the expression and role of miR-133a-3p in AS remains unclear. The aim of the present study was to investigate miR-133a-3p in AS and to determine its underlying mechanism. The level of miR-133a-3p expression in the blood and vascular plaque tissue of patients with AS was detected via reverse transcription-quantitative PCR (RT-qPCR). The role of miR-133a-3p in human vascular smooth muscle cells (hVSMCs) was investigated, following upregulation and downregulation of this miR in hVSMCs. Cell proliferation and apoptosis were determined using a Cell Counting kit-8 assay and flow cytometry, respectively. The results demonstrated the downregulation of miR-133a-3p in the blood and vascular plaque tissue of patients with AS. Matrix metallopeptidase-9 (MMP-9) was revealed to be a direct target gene of miR-133a-3p, which was upregulated in the blood and vascular plaque tissue of patients with AS. Furthermore, MMP-9 was determined to be negatively regulated by miR-133a-3p in hVSMCs. In addition, significant inhibition of hVSMC proliferation and induction of cell apoptosis were observed following MMP-9 downregulation and following transfection with the miR-133a-3p mimic. The effects of the miR-133a-3p mimic on hVSMC proliferation and apoptosis were reversed by MMP-9 over-expression. Overall, the results indicated that miR-133a-3p was downregulated in AS, which results in the inhibition of hVSMC proliferation and the induction of cell apoptosis via MMP-9. miR-133a-3p may therefore be a promising therapeutic target for the treatment of AS.

MicroRNA-199a-5p aggravates primary hypertension by damaging vascular endothelial cells through inhibition of autophagy and promotion of apoptosis.

The present study investigated the expression of microRNA (miRNA or miR)-199a-5p in the peripheral blood of patients with primary hypertension, and examined its mechanism of action in vascular endothelial cell injury induced by hypertension. A total of 57 patients with primary hypertension, who were treated at the Affiliated Hospital of Qingdao University (Qingdao, China) between December 2014 and November 2015 were included in the present study. Peripheral blood was collected from all patients. The expression of miR-199a-5p was measured using reverse-transcription quantitative polymerase chain reaction analysis. Human umbilical vein endothelial cells (HUVECs) were divided into negative control, miR-199a-5p mimics and rescue (co-transfected with miR-199a-5p mimics and inhibitor) groups. After transfection, the proliferation and apoptosis of HUVECs were evaluated by a Cell Counting Kit-8 assay, a bromodeoxyuridine incorporation assay and flow cytometry. Western blot analysis was used to determine the expression of proteins involved in autophagy-associated and adenosine monophosphate kinase (AMPK)/unc-51 like autophagy activating kinase 1 (ULK1) signaling pathways. Laser scanning confocal microscopy and electron microscopy were used to observe the autophagy of HUVECs. The expression of miR-199a-5p was elevated in peripheral blood of patients with hypertension, and was correlated with the progression of hypertension. Overexpression of miR-199a-5p inhibited the proliferation and promoted the apoptosis of HUVECs. Upon expression of miR-199a-5p, the transition between microtubule-associated proteins 1A/1B light chain 3B (LC3B)I and LC3BII proteins was inhibited, the expression of p62 protein was upregulated. In addition, miR-199a-5p decreased the numbers of autophagosomes and autolysosomes in HUVECs. The present study demonstrated that expression of miR-199a-5p is positively correlated with the severity of hypertension. Expression of miR-199a-5p aggravated vascular endothelial injury by inhibiting autophagy and promoting the apoptosis of HUVECs via downregulation of the AMPK/ULK1 signaling pathway.

Isoquercetin ameliorates myocardial infarction through anti-inflammation and anti-apoptosis factor and regulating TLR4-NF-κB signal pathway.

The aim of the present study was to investigate the protective mechanisms and identify the effects of isoquercetin on myocardial infarction in a rat model of acute myocardial infarction (AMI). Isoquercetin ameliorated myocardial infarct size, creatine kinase (CK), CK­MB and lactic dehydrogenase activity and inhibited inflammation, oxidative stress and heart cell apoptosis in a rat with AMI. Isoquercetin increased endothelial nitric oxide synthase, reduced inducible nitric oxide synthase levels and suppressed the Toll-like receptor 4­nuclear factor (TLR4­NF)­κB signaling pathway in a rat with AMI. Overall, isoquercetin ameliorated AMI through anti­inflammatory and anti­apoptotic factors, and regulation of the TLR4­NF­κB signaling pathway. Isoquercetin may therefore potentially exert a protective effect against AMI or other heart diseases.

MicroRNA-185 suppresses pancreatic cell proliferation by targeting transcriptional coactivator with PDZ-binding motif in pancreatic cancer.

The aim of the present study was to compare the expression of transcriptional coactivator with the PDZ-binding motif (TAZ) in pancreatic cancer (PC) patients, and to investigate the regulation mechanisms of TAZ in the proliferation of PC. PC tissues and matched peritumoral tissues, pancreatic juice and serum were collected from PC patients who underwent pancreatectomy between June 2012 and December 2015 at the Affiliated Hospital of Qingdao University (Qingdao, China). Pancreatic juice and serum were collected from patients with chronic pancreatitis as a control. The levels of taz mRNA expression in the samples were examined by reverse-transcription quantitative polymerase chain reaction, and the protein expression of TAZ was assessed by western blot analysis and ELISA. MicroRNAs (miRNAs) that regulate TAZ expression were also predicted by bioinformatics analysis and validated by dual luciferase reporter and rescue assays. In addition, the proliferation of PC cells was evaluated after transfection with TAZ small interfering RNA (siRNA) or its upstream miRNA agomir. Expression of TAZ was significantly increased in the PC tissues, pancreatic juice and serum of PC patients at the mRNA and protein levels compared with controls (P<0.05). Furthermore, TAZ was predicted and verified to be a target of miRNA (miR)-185, and miR-185 and TAZ were inversely expressed in samples from PC patients (P<0.05). In addition, TAZ siRNA or agomiR-185 transfection significantly inhibited human pancreatic adenocarcinoma cell proliferation (P<0.05). However, overexpression of TAZ in the agomiR-185 group rescued the inhibition (P<0.05). Finally, the expression of TAZ effector proteins, namely ankyrin repeat domain-containing protein and cysteine-rich 61, were upregulated in PC tissues (P<0.05), but repressed following transfection of PC cells with agomiR-185 (P<0.05). Thus, miR-185 may regulate the proliferation of PC by targeting TAZ, making it a promising diagnostic marker for PC.