Cilostazol alleviate nicotine induced cardiomyocytes hypertrophy through modulation of autophagy by CTSB/ROS/p38MAPK/JNK feedback loop.

Nicotine is proved to be an important factor for cardiac hypertrophy. Autophagy is important cell recycling system involved in the regulation of cardiac hypertrophy. Cilostazol, which is often used in the management of peripheral vascular disease. However, the effects of cilostazol on nicotine induced autophagy and cardiac hypertrophy are unclear. Here, we aim to determine the role and molecular mechanism of cilostazol in alleviating nicotine-induced cardiomyocytes hypertrophy through modulating autophagy and the underlying mechanisms. Our results clarified that nicotine stimulation caused cardiomyocytes hypertrophy and autophagy flux impairment significantly in neonatal rat ventricular myocytes (NRVMs), which were evidenced by augments of LC3-II and p62 levels, and impaired autophagosomes clearance. Interestingly, cathepsin B (CTSB) activity decreased dramatically after stimulation with nicotine in NRVMs, which was crucial for substrate degradation in the late stage of autophagy process, and cilostazol could reverse this effect dramatically. Intracellular ROS levels were increased significantly after nicotine exposure. Meanwhile, p38MAPK and JNK were activated after nicotine treatment. By using ROS scavenger N-acetyl-cysteine (NAC) could reverse the effects of nicotine by down-regulation the phosphorylation of p38MAPK and JNK pathways, and pretreatment of specific inhibitors of p38MAPK and JNK could restore the autophagy impairment and cardiomyocytes hypertrophy induced by nicotine. Moreover, CTSB activity of lysosome regained after the treatment with cilostazol. Cilostazol also inhibited the ROS accumulation and the activation of p38MAPK and JNK, which providing novel connection between lysosome CTSB and ROS/p38MAPK/JNK related oxidative stress pathway. This is the first demonstration that cilostazol could alleviate nicotine induced cardiomyocytes hypertrophy through restoration of autophagy flux by activation of CTSB and inhibiting ROS/p38/JNK pathway, exhibiting a feedback loop on regulation of autophagy and cardiomyocytes hypertrophy.

[Therapeutic efficacy of compound Xuanju capsule on type III prostatitis].

OBJECTIVE: To evaluate the therapeutic effect of Compound Xuanju Capsule on type III prostatitis. METHODS: A total of 242 patients with type III prostatitis diagnosed by the NIH criteria were randomly divided into an experimental and a control group of equal number, the former treated with Compound Xuanju Capsule + Tamsulosin Hydrochloride, and the latter with Quinolinone antibiotics + Tamsulosin and Hydrochloride, both for 6 months. After treatment, we assessed the therapeutic effects based on the NIH-CPSI scores and the improvement of relevant complications. RESULTS: All the 242 patients completed the treatment. The total effectiveness rate was 77.69% (94/121) in the experimental group, 71.56% (78/109) in those with complications. In comparison, it was only 47.10% (57/121) in the control group, 31.78% (34/107) in those with complications. Both the NIH-CPSI scores and the improvement of complications were significantly higher in the experimental than in the control group (P < 0.05). CONCLUSION: Compound Xuanju Capsule has a good therapeutic effect on type III prostatitis.

Combination of raloxifene, aspirin and estrogen as novel paradigm of hormone replacement therapy in rabbit model of menopause.

AIM: To assess a novel hormone replacement therapy (HRT) paradigm using raloxifene, aspirin combined with estrogen in rabbit model of menopause. METHODS: Female New Zealand white rabbits were ovariectomized or sham-operated. The ovariectomized rabbits were divided into 7 groups: estradiol valerate (E(2)), raloxifene, aspirin, E(2) /raloxifene, E(2)/aspirin, E(2) /raloxifene/aspirin and vehicle. Two weeks after the operation, the rabbits were administered the above drugs for 12 weeks. Then, the mammary glands were examined histologically, uterus was weighted, and blood sample was collected for analyzing the levels of estrogen, serum lipids and monocyte chemoattractant protein (MCP)-1, and platelet aggregation. The aortic tissue was examined morphometrically. RESULTS: Compared with E(2) 0.1 mg·kg(-1)·d(-1) treatment alone, the pairing of raloxifene 10 mg·kg(-1)·d(-1) with E(2) significantly decreased the extent of mammary gland branches and ducts (5.53%±1.23% vs 15.4%±2.17%, P<0.01), as well as the uterine weight (2.16±0.35 g vs 4.91±0.75 g, P<0.01). However, E(2)/raloxifene or E(2) alone treatment significantly stimulated platelet aggregation relative to vehicle group. Addition of aspirin 5 mg·kg(-1)·d(-1) reduced platelet aggregation to almost the same level as the vehicle group. E(2) treatment exerted a positive effect on serum lipids and MCP-1, and a regression in aortic intimal plaque size compared to the vehicle. Raloxifene reinforced the positive effects of E(2). CONCLUSION: The combination of raloxifene, aspirin and E(2) exhibits positive lipid, MCP-1 and atherosclerotic responses with minimal stimulation of breast and uterine tissues as well as platelet aggregation in a rabbit model of the menopause.