Network Pharmacology and Bioinformatics Methods Reveal the Mechanism of Berberine in the Treatment of Ischaemic Stroke.

Aim: To elucidate the mechanism of action of berberine on ischaemic stroke based on network pharmacology, bioinformatics, and experimental verification. Methods: Berberine-related long noncoding RNAs (lncRNAs) were screened from public databases. Differentially expressed lncRNAs in ischaemic stroke were retrieved from the Gene Expression Omnibus (GEO) database. GSE102541 was comprehensively analysed using GEO2R. The correlation between lncRNAs and ischaemic stroke was evaluated by the mammalian noncoding RNA-disease repository (MNDR) database. The component-target-disease network and protein-protein interaction (PPI) network of berberine in the treatment of ischaemic stroke were constructed by using network pharmacology. We then performed gene ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses. Finally, according to the molecular docking analysis and the binding probability between the lncRNA and key proteins, the effectiveness of the results was further verified by in vitro experiments. Results: After matching stroke-related lncRNAs with berberine-related lncRNAs, four genes were selected as potential targets of berberine in the treatment of ischaemic stroke. Subsequently, lncRNA H19 was identified as the potential crucial regulatory lncRNA of berberine. Here, 52 target proteins of berberine in the treatment of ischaemic stroke were identified through database mining. Through topological analysis, 20 key targets were identified which were enriched in inflammation, apoptosis, and immunity. Molecular docking results showed that MAPK8, JUN, and EGFR were central genes. Finally, in vitro experiments demonstrated that lncRNA H19, p-JNK1/JNK1, p-c-Jun/c-Jun, and EGFR expressions were significantly increased in hypoxia-treated SH-SY5Y cells and were restored by berberine treatment. Conclusion: The potential targets and biological effects of berberine in the treatment of ischaemic stroke were predicted in this study. The lncRNA H19/EGFR/JNK1/c-Jun signalling pathway may be a key mechanism of berberine-induced neuroprotection in ischaemic stroke.

Anti-inflammatory and immunomodulatory effects of baicalin in cerebrovascular and neurological disorders.

Inflammatory responses play an extraordinary role in the pathogenesis of cerebrovascular and neurological disorders. Baicalin is one of the important flavonoids, which is extracted from Scutellaria baicalensis Georgi. Recently, numerous in vivo and in vitro studies have shown that baicalin has salutary effects for anti-inflammatory and immunomodulatory and has been demonstrated to exert beneficial therapeutic properties in cerebrovascular and neurological diseases. In this review, we aim to discuss that baicalin exerts anti-inflammatory effects through multiple pathways and targets, thus affecting the production of a variety of inflammatory cytokines and neuroprotective process of neurological diseases; furthermore, the related targets of the anti-inflammatory effects of baicalin were analyzed via using the tools of network pharmacology, to provide theoretical basis and innovative ideas for the future clinical application of baicalin.

Enhanced cardiomyocyte reactive oxygen species signaling promotes ibrutinib-induced atrial fibrillation.

Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-ß protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca2+ release and mitochondrial structures, as well as atrial fibrosis and atrial hypertrophy in ibrutinib-treated mice, and apocynin reduced the expression of these proteins. Ibrutinib-treated mice were also more likely to develop AF, and AF occurred over longer periods. In conclusion, our study has established a pathophysiological role for ROS signaling in atrial cardiomyocytes, and it may be that ox-CaMKII and p-CaMKII (Thr-286) are activated by ROS to increase AF susceptibility following ibrutinib treatment. We have also identified the inhibition of NOX as a potential novel AF therapy approach.

A Pooled Analysis of the Prognostic Significance of Brugada Syndrome with Atrial Fibrillation.

BACKGROUND: Guidelines have previously suggested that atrial fibrillation (AF) is associated with an increased risk of arrhythmic death in Brugada syndrome (BrS) patients. However, only two articles consisting of 17 AF patients with BrS supported these views. The risk stratification of BrS patients with AF remains controversial. Thus, a meta-analysis is used to estimate the risk stratification of BrS patients with AF. METHODS: We searched for relevant studies published from 2000 to December 30, 2018. A total of 1712 patients with BrS from five studies were included: 200 patients (12%) were reported with AF, among whom 37 patients (19%) had arrhythmic events. RESULTS: BrS patients with AF in all studies (OR 1.92, 95% CI:0.91to 4.04, P =0.09; Heterogeneity: P = 0.03, I2=61%) and some European studies (OR 1.12, 95% CI: 0.18 to 6.94, P=0.91; Heterogeneity: P = 0.006, I2=80%) did not display a higher risk of arrhythmic events than those without AF, but BrS patients with AF in Japanese studies (OR 2.32, 95% CI: 1.37 to 3.93, P=0.002; Heterogeneity: P = 0.40, I2=0%) had a higher risk of arrhythmic events than those without AF. The proportion of BrS patients with AF was greater in Japanese studies than in some European studies (16% vs. 9%, P<0.001). CONCLUSION: On the whole, BrS patients with AF showed no higher risk of arrhythmic events than those without AF, but BrS patients with AF in Japan had a higher risk of arrhythmic events than those without AF.

Does heart failure increase the risk of incident cancer? A meta-analysis and systematic review.

Recently, several studies have demonstrated that heart failure (HF) may increase the risk of incident cancer. However, this association has not been statistically and systematically verified by any comprehensive pooled analyses. We performed a meta-analysis on cancer morbidity and co-mortality of adults with HF in a large sample size to explore the relationship between HF and the risk of developing cancer. From inception to April 2019, we searched PubMed and EMBASE for published relevant articles on patients with HF diagnosed with cancer afterwards, with reported outcomes of morbidity and mortality. Two investigators independently reviewed these included studies. Study data were independently extracted using predefined data extraction forms. Random and fixed-effects models were fit for the study duration. This analysis consisted of 4 cohort studies comprising 5,004,251 participants. The relative risk (RR) for incident cancer was 1.22 (95% confidence interval (CI), 1.13-1.33) indicating that patients with HF may have a higher risk of developing cancer. The pooled RR of co-mortality was 2.03 (95% CI, 1.13-3.65), indicating that HF associated with cancer increases the risk of mortality. In this meta-analysis and systematic review, our results demonstrated that heart failure may increase the risk of incident cancer and that HF associated with cancer increases the risk of mortality.

Efficacy and Safety of NaoShuanTong Capsule in the Treatment of Ischemic Stroke: A Meta-Analysis.

Background: Ischemic stroke (IS) is a leading cause of death and long-term disability worldwide. The NaoShuanTong capsule (NSTC), a traditional Chinese patent medicine, has been extensively used in the treatment of stroke in China. However, the clinical efficacy and safety of this treatment has not been statistically and systematically verified by any comprehensive pooled analysis. We therefore performed a meta-analysis to evaluate the efficacy and safety of NSTC in the treatment of IS. Methods: Randomized controlled trials (RCTs) of NSTC in the treatment of IS conducted before September 2018 were retrieved from five databases, according to specific inclusion and exclusion criteria. Two investigators independently reviewed the included studies and extracted relevant data. The methodological quality of the included studies was assessed using criteria from the Cochrane Handbook, and analyzed using Review Manager 5.3 software. Results: Thirteen RCTs comprising a total of 1,360 participants were included in this study. NSTC was shown to significantly improve the overall response rate (OR = 3.04, 95% CI [1.76, 5.26], P < 0.00001), and neurological function (NSTC increased Modified Barthel Index (MD = 8.15, 95% CI [3.79, 12.52], P = 0.0005), Functional Independence Measure (MD = 29.61, 95% CI [10.11, 49.10], P = 0.003) and European Stroke Scale scores (MD = 8.51, 95% CI [7.00, 10.01], P = 0.03). In addition, NSTC significantly increased serum adiponectin level (MD = 0.66, 95% CI [0.23, 1.08], P = 0.002). Moreover, NSTC reduced atherosclerotic plaque area (MD = -2.24, 95% CI [-4.02, -0.46], P = 0.01) and intima-media thickness (MD = -0.09, 95% CI [-0.13, -0.05], P < 0.0001). However, there was no significant difference between NSTC treatment and conventional therapy with respect to Fugl-Meyer Assessment score (MD = 10.59, 95% CI [-1.78, 22.96], P = 0.09) or Crouse score (MD = -0.78, 95% CI [-1.79, -0.22], P = 0.13). Conclusions: The results of this meta-analysis showed that NSTC exhibits efficacy in the treatment of cerebral infarction. NSTC can improve the overall response rate and neurological function, increase blood adiponectin, reduce neurological deficits, and decrease atherosclerotic plaque area.

Regulatory Mechanisms of the NLRP3 Inflammasome, a Novel Immune-Inflammatory Marker in Cardiovascular Diseases.

The nod-like receptor family pyrin domain containing 3 (NLRP3) is currently the most widely studied inflammasome and has become a hot topic of recent research. As a macromolecular complex, the NLRP3 inflammasome is activated to produce downstream factors, including caspase-1, IL-1ß, and IL-18, which then promote local inflammatory responses and induce pyroptosis, leading to unfavorable effects. A growing number of studies have examined the relationship between the NLRP3 inflammasome and cardiovascular diseases (CVDs). However, some studies have shown that the NLRP3 inflammasome is not involved in the occurrence of certain diseases. Therefore, identifying the mechanism of action of the NLRP3 inflammasome and its potential involvement in the pathological process of disease progression is of utmost importance. This review discusses the mechanisms of NLRP3 inflammasome activation and the relationship between the inflammasome and CVDs, including coronary atherosclerosis, myocardial ischemia/reperfusion, cardiomyopathies, and arrhythmia, as well as CVD-related treatments.

The Mechanism of Exosomes Function in Neurological Diseases: A Progressive Review.

Exosomes are extracellular microparticles (≈30-100 nm in diameter) secreted from nearly all types of cells, containing a whole set of biological information including proteins, ribonucleic acid (RNA) and lipids. Latest studies show that exosomes contribute to cell-cell communication and are considered closely related with the modulation of angiogenesis and neurogenesis in many neurological diseases. In the past decade, numerous researchers were devoted to exosomes study, but the mechanism of exosomes function and delivery is uncertain. In this review, we summarized several potential mechanisms of exosomes function in angiogenesis, neurogenesis and Blood Brain Barrier (BBB) delivery, and differentiate various sources of exosomes in stroke, tumor, Traumatic Brain Injury (TBI) and Alzheimer's Disease (AD) aimed to report the most advanced mechanical theories in related past three years to provide a new sight for this research area.

Effects of Xuebijing Injection for Patients With Sepsis-induced Acute Kidney Injury After Wenchuan Earthquake.

Context • Earthquakes are devastating disasters that have claimed countless lives in the past, partially owing to the danger of direct and indirect injuries to vital organs. In the deadly earthquake that occurred in Sichuan Province of China on May 12, 2008, some victims suffered from severe damage to multiple organs and tissue and developed sepsis, a systematic inflammatory reaction resulting from infection and trauma. Xuebijing injection (CCXG) could beneficial for improvement of clinical symptoms in those patients, but no research has yet examined its potential. Objective • The study intended to investigate whether a combination of conventional treatment and CCXG was superior to conventional treatment alone, or the control group (CG), in the treatment of clinical symptoms in patients with sepsis-induced acute kidney injury (AKI). Design • The study retrospectively analyzed the medical records of individuals who were injured in an earthquake that occurred in the Sichuan Province of China on May 12, 2008, and who developed AKI. Setting • The study took place in the hospital associated with Chengdu University of Traditional Chinese Medicine (Chengdu, Sichuan, China). Participants • Participants were 55 injured individuals who were treated at the hospital. The CG included 27 patients and the CCXG group included 28 patients. Intervention • Both the intervention group (CCXG group) and the CG received the conventional treatment. The CCXG group was also given intravenous drips containing 100 mL of CCXG. The CG was given 100 mL of a 10% normal saline injection in addition to conventional treatment. Both received the treatments within 30 to 40 min, 3 ×/d. Outcome Measures • Blood urea nitrogen (BUN), creatine phosphate kinase (CPK), serum creatinine (Cr), interleukin 1 (IL-1), and interleukin 6 (IL-6) were measured before treatment and on days 5, 7, and 10 after treatment. Results • The levels of CPK, BUN, Cr, and IL-6 for both groups were significantly lower than at baseline on day 5, 7, and 10 after treatment (P < .05). The levels of the CCXG group were significantly lower than those of the CG group on days 5, 7, and 10 (P < .05). Conclusions • As a supplement, CCXG is an effective method of improving the clinical symptoms of sepsis-induced AKI.