Xueyan Chen

Fasudil Hydrochloride Hydrate, a Rho-Kinase Inhibitor, Suppresses 5-Hydroxytryptamine-Induced Pulmonary Artery Smooth Muscle Cell Proliferation via JNK and ERK1/2 Pathway

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary artery hypertension, and inhibition of PASMC proliferation has been shown to be beneficial to patients with this disease. Recent studies indicate that Rho/ROCK is critically involved in the proliferation of smooth muscle cells. However, the signal transduction of Rho/ROCK and its downstream signaling are not fully understood. In the present study, we investigated the antiproliferation effect of fasudil hydrochloride hydrate, a Rho-kinase inhibitor, on rat PASMC proliferation, and the possible relation of Rho/ROCK to ERK, JNK pathways. The results indicate that fasudil effectively inhibited 5-HT-induced PASMC proliferation, as evaluated by MTT assay and protein expression of proliferating cell nuclear antigen. Flow cytometry analysis showed that fasudil markedly blocked 5-HT-induced cell-cycle progression by arresting the cells in the G₀/G1 phase. Consistently, 5-HT-induced ROCK-1 mRNA expression and MYPT-1 phosphorylation were markedly suppressed by fasudil. In addition, fasudil significantly decreased 5-HT-induced JNK activation, ERK translocation to the nucleus and subsequent c-fos and c-jun expression. Taken together, these results indicate that Rho/ROCK is essential for PASMC proliferation produced by 5-HT. Fasudil effectively suppressed 5-HT-induced PASMC proliferation and cell-cycle progression, which was associated with inhibition of JNK activation, ERK translocation to nucleus and subsequent c-fos and c-jun expression.

Exogenous melatonin for sleep disorders in neurodegenerative diseases: a meta-analysis of randomized clinical trials

The purpose of this work is to investigate the efficacy of exogenous melatonin in the treatment of sleep disorders in patients with neurodegenerative disease. We searched Pubmed, the Cochrane Library, and ClinicalTrials.gov, from inception to July 2015. We included randomized clinical trials (RCTs) that compared melatonin with placebo and that had the primary aim of improving sleep in people with neurodegenerative diseases, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). We pooled data with the weighted mean difference in sleep outcomes. To assess heterogeneity in results of individual studies, we used Cochran’s Q statistic and the I2 statistic. 9 RCTs were included in this research. We found that the treatment with exogenous melatonin has positive effects on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in PD patients (MD: 4.20, 95xa0% CI: 0.92–7.48; Pxa0=xa00.01), and by changes in PSQI component 4 in AD patients (MD: 0.67, 95xa0% CI: 0.04–1.30; Pxa0=xa00.04), but not on objective sleep outcomes in both AD and PD patients. Treatment with melatonin effectively improved the clinical and neurophysiological aspects of rapid eye movement (REM) sleep behavior disorder (RBD), especially elderly individuals with underlying neurodegenerative disorders. This meta-analysis provided some evidence that melatonin improves sleep quality in patients with AD and PD, and melatonin can be considered as a possible sole or add-on therapy in neurodegenerative disorders patients with RBD.

Protective effect of berberine on doxorubicin‑induced acute hepatorenal toxicity in rats

Doxorubicin (DOX), a potent broad‑spectrum chemotherapeutic agent used for the treatment of several types of cancer, is largely limited due to its serious side effects on non‑target organs. Thus, the present study aimed to investigate whether berberine (Ber), an isoquinoline alkaloid, could reduce DOX‑induced acute hepatorenal toxicity in rats. Fifty rats were randomly divided into five groups: i)xa0Control group, ii)xa0DOX group, iii)xa0DOX+Ber (5xa0mg kg) group; iv)xa0DOX+Ber (10xa0mg kg), and v)xa0DOX+Ber (20xa0mg kg) group. In the tests, body weight, organ index, general condition and mortality were observed. In addition, the serum levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total cholesterol (TCHO) and blood urea nitrogen (BUN) were determined to evaluate hepatorenal function. Hepatorenal toxicity was further assessed using hematoxylin and eosin stained sections. Furthermore, the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and malondialdehyde (MDA) in rat serum or tissue homogenate were also assessed to determine the mechanisms of action. Results suggested that pretreatment with Ber ameliorated the DOX‑induced liver and kidney injury by lowering the serum ALT, AST, TCHO and BUN levels, and the damage observed histologically, such as hemorrhage and focal necrosis of liver and kidney tissues induced by DOX were also attenuated by Ber. Furthermore, Ber also exerted certain antioxidative properties through reversing the changes in the levels of MDA, SOD, GSH and MDA induced by DOX. These findings indicate that Ber has protective effects against DOX‑induced acute hepatorenal toxicity in rats. Combination of Ber with DOX is a novel strategy that has the potential for protecting against DOX‑induced hepatorenal toxicity in clinical practice.

Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials

BACKGROUNDnPrevious meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings.nnnMETHODSnPubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95%xa0CIs for dichotomous data and standardized mean differences for continuous data.nnnRESULTSnIn total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vsxa0placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95%xa0CI, 0.33 to 0.76]; Pxa0= .001), 6-min walk test (mean difference, 31.10xa0m [95%xa0CI, 25.40 to 36.80]; Pxa0< .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95%xa0CI, 1.51 to 4.07]; Pxa0= .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vsxa0monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96xa0m [95%xa0CI, 15.35 to 24.57]; Pxa0< .00001), functional class (OR, 1.65 [95%xa0CI, 1.20 to 2.28]; Pxa0= .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95%xa0CI, 1.54 to 2.61]; Pxa0<xa0.00001) but not for mortality reduction (OR, 0.98 [95%xa0CI, 0.57 to 1.68]; Pxa0= .94).nnnCONCLUSIONSnOur meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it hadxa0no proven effect on mortality. Combination therapy had a much higher incidence of withdrawalxa0due to adverse effects than monotherapy.

Original Research: Pulmonary Vascular DiseaseEfficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials

BACKGROUNDnPrevious meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings.nnnMETHODSnPubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95%xa0CIs for dichotomous data and standardized mean differences for continuous data.nnnRESULTSnIn total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vsxa0placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95%xa0CI, 0.33 to 0.76]; Pxa0= .001), 6-min walk test (mean difference, 31.10xa0m [95%xa0CI, 25.40 to 36.80]; Pxa0< .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95%xa0CI, 1.51 to 4.07]; Pxa0= .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vsxa0monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96xa0m [95%xa0CI, 15.35 to 24.57]; Pxa0< .00001), functional class (OR, 1.65 [95%xa0CI, 1.20 to 2.28]; Pxa0= .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95%xa0CI, 1.54 to 2.61]; Pxa0<xa0.00001) but not for mortality reduction (OR, 0.98 [95%xa0CI, 0.57 to 1.68]; Pxa0= .94).nnnCONCLUSIONSnOur meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it hadxa0no proven effect on mortality. Combination therapy had a much higher incidence of withdrawalxa0due to adverse effects than monotherapy.

Resveratrol synergistically augments anti-tumor effect of 5-FU in vitro and in vivo by increasing S-phase arrest and tumor apoptosis:

Many studies have shown that natural dietary agents, in combination with chemical agents, can improve the therapeutic response of cancers to chemotherapy and reduce the associated side-effects. In the present study, we investigated the therapeutic potential and mechanisms of anticancer effects for the combination of 5-fluorouracil (5-FU) and resveratrol (Res). In these studies, we employed the cancer cell lines TE-1 and A431 and an animal model of skin cancer. The presented results provide the first evidence that Res can enhance the anti-tumor potency of 5-FU by inducing S-phase arrest. The combination of Res and 5-FU demonstrates synergistic efficacy, causing tumor regression in a two-stage model of mouse skin carcinogenesis induced by DMBA and TPA. There was clear evidence of Res augmenting the growth inhibitory effect of 5-FU on the TE-1 and A431 cancer cells in vitro. In the in vivo studies, the tumor regression rate in the combination group increased significantly after four weeks of treatment (Pu2009<u20090.01). The combination of 5-FU and Res significantly increased the percentage of apoptotic cells and the level of activated caspase-3, cleaved PARP and p53 proteins as well as increased the Bax/Bcl-2 ratio. In conclusion, the 5-FU/Res combination enabled a more effective inhibition of cell growth and the induction of apoptosis in cancer cells than 5-FU alone. The results of this study suggest that chemotherapy using natural dietary agents with chemical agents represents a superior cancer treatment option.

Protective effect of berberine on aconite‑induced myocardial injury and the associated mechanisms

Aconitum plants, which have analgesic, diuretic and anti-inflammatory effects, have been widely used to treat various types of disease. However, the apparent toxicity of Aconitum-derived agents, particularly in the cardiovascular system, has largely limited their clinical use. Thus, the present study investigated whether berberine (Ber), an isoquinoline alkaloid, may reduce myocardial injury induced by aconitine (AC) in rats and the underlying mechanisms. Rats (n=40) were randomly divided into four groups: Control, Chuan-wu and Chuan-wu + Ber (8 and 16 mg/kg doses). Electrocardiograms (ECG) of the rats were recorded and serum biomarkers of cardiac function [lactate dehydrogenase (LDH), creatine kinase (CK) and CK-MB] were assayed. Histopathological changes were assessed using myocardial tissue sectioning and hematoxylin and eosin staining. Additionally, the effects of Ber on AC-induced arrhythmias in rats were observed. The changes in ECG following AC perfusion were observed, and the types and onset time of arrhythmias were analyzed. Furthermore, the effects of Ber and AC on papillary muscle action potentials were observed. The results suggested that Ber ameliorated myocardial injury induced by Chuan-wu, which was indicated by reduced arrhythmias and decreased LDH, CK and CK-MB levels in serum. Furthermore, histological damage, including dilation of small veins and congestion, was also markedly attenuated by Ber. In addition, the occurrence of arrhythmias was significantly delayed, and the dosage of AC required to induce arrhythmias was also increased by Ber pretreatment. Additionally, AC-induced changes in action potential amplitude, duration of 30% repolarization and duration of 90% repolarization in the papillary muscle were attenuated by Ber. All of these results indicate that Ber had a preventive effect on acute myocardial injury induced by Chuan-wu and arrhythmias caused by AC, which may be associated with the inhibition of delayed depolarization and triggered activity caused by AC. Thus, combination treatment of Ber with Aconitum plants may be a novel strategy to prevent AC-induced myocardial injury in clinical practice.

N-[4-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methylphenyl]-N'-[2-(dimethylamino)] benzoylurea induces cell-cycle arrest and apoptosis in human cancer cells.

N-[4-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methylphenyl]-N′-[2-(dimethylamino)]benzoylurea (SUD) is a novel synthesized benzoylurea derivative. We selected several human cancer cell lines to investigate whether SUD can inhibit the growth of cancer cells. We selected the liver cell line L-02 to investigate the effect of SUD on the normal cells. Flow cytometric analysis was used to detect the effect of SUD on cell cycle, Hoechstu200933258 staining was used to evaluate the apoptosis induced by SUD, real-time fluorescence quantitative PCR was used to investigate the expression of the cell cycle-relevant and apoptosis-relevant genes, a reactive oxygen species (ROS) assay was used to observe the production of ROS, and western blotting was used to determine the level of cell cycle-relevant and apoptosis-relevant proteins. According to the results of the MTT assay, the growth of human cancer cell lines was significantly inhibited by SUD treatment in a time-dependent and concentration-dependent manner; however, the growth of human normal cells was not significantly inhibited by SUD treatment. The results of flow cytometric analyses showed that SUD induced cell-cycle arrest at the G2-phase in MCF-7 cells and at the G1-phase in BGC-823 cells. The results of Hoechstu200933258 staining showed that SUD induced apoptosis in MCF-7 and BGC-823 cells. The results of the ROS assay showed that the production of ROS was increased by SUD in MCF-7 and BGC-823 cells. Our research suggests that the growth-inhibitory effect of SUD on MCF-7 cells was related to G2-phase arrest, which was associated with the upregulated expression of p53 and Chk1 proteins, and downregulation of the cyclin B1 gene, cdc25a, and cyclin-dependent kinase 1 (CDK1) proteins; the growth-inhibitory effect of SUD on BGC-823 cells was related to G1-phase arrest, which was associated with upregulation of the p53 gene and Chk1 protein and downregulation of cdc25a protein and the CDK4 gene. SUD also induced apoptosis in MCF-7 and BGC-823 cell lines through the mitochondrial pathway in a p53-dependent manner.