Huanlong Liu

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.

The inhibitory effects of m-nisoldipine on the 5-hydroxytryptamine-induced proliferation of pulmonary artery smooth muscle cells via Ca2+ antagonism and antioxidant mechanisms.

The excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) plays a critical role in the development of pulmonary arterial hypertension. Recent studies indicate that Ca(2+) and reactive oxygen species are critically involved in the process of smooth muscle cell proliferation stimulated by mitogens, such as 5-hydroxytryptamine (5-HT). Because m-nisoldipine, a Ca(2+) channel blocker of the dihydropyridine class, possesses some calcium antagonistic and antioxidant properties, we investigated the effect of m-nisoldipine on PASMC proliferation. The results indicated that m-nisoldipine inhibited 5-HT-induced PASMC proliferation, evaluated by BrdU incorporation and the MTT assay, and this effect was associated with a decreased expression of proliferating cell nuclear antigen (PCNA). Flow cytometry analysis showed that m-nisoldipine blocked 5-HT-induced cell-cycle progression by arresting the cells in the G(0)/G(1) phase. Next, the production of reactive oxygen species and the levels of [Ca(2+)](i) in PASMCs were measured by laser scanning confocal microscopy; m-nisoldipine pretreatment attenuated the [Ca(2+)](i) elevation and the production of reactive oxygen species induced by 5-HT. In addition, m-nisoldipine significantly decreased the 5-HT-induced activation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) and the subsequent c-fos and c-jun mRNA expression. Meanwhile, results also showed that N-acetylcysteine (a reactive oxygen species scavenger) suppressed the proliferation and the ERK1/2 and JNK activation induced by 5-HT. In summary, this study demonstrated that m-nisoldipine effectively suppressed the 5-HT-induced PASMC proliferation, ERK1/2 and JNK activation and subsequent c-fos and c-jun mRNA expression, all of which might be associated with the Ca(2+) antagonistic and antioxidant properties of m-nisoldipine.

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.