Urolithin A ameliorates obesity-induced metabolic cardiomyopathy in mice via mitophagy activation.

Metabolic cardiomyopathy (MC) is characterized by intracellular lipid accumulation and utilizing fatty acids as a foremost energy source, thereby leading to excess oxidative stress and mitochondrial dysfunction. There is no effective therapy available yet. In this study we investigated whether defective mitophagy contributed to MC and whether urolithin A (UA), a naturally occurring microflora-derived metabolite, could protect against MC in experimental obese mice. Mice were fed high fat diet for 20 weeks to establish a diet-induced obese model. We showed that mitochondrial autophagy or mitophagy was significantly downregulated in the heart of experimental obese mice. UA (50 mg·kg-1·d-1, for 4 weeks) markedly activated mitophagy and ameliorated MC in obese mice by gavage. In PA-challenged H9C2 cardiomyocytes, UA (5 µM) significantly increased autophagosomes and decreased autolysosomes. Furthermore, UA administration rescued PINK1/Parkin-dependent mitophagy and relieved mitochondrial defects in the heart of obese mice, which led to improving cardiac diastolic function and ameliorating cardiac remodelling. In PA-challenged primarily isolated cardiomyocytes, both application of mitophagy inhibitor Mdivi-1 (15 µM) and silencing of mitophagy gene Parkin blunted the myocardial protective effect of UA. In summary, our data suggest that restoration of mitophagy with UA ameliorates symptoms of MC, which highlights a therapeutic potential of UA in the treatment of MC.

Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. AIM OF THE STUDY: Here, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. MATERIALS AND METHODS: A total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000m), TXL group (rats living in environment equal to that at altitude of 5000m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2gkg-1d-1) for 28 days, and the VDNF group was given VDNF (0.1gkg-1d-1) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. RESULTS: After 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5mmHg versus 18mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. CONCLUSIONS: The automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension.

[Expression of occludin and zona occluden-1 and their morphologic changes in vagina mucosal cells in patients undergoing vaginal construction by using sigmoid colon].

OBJECTIVE: In order to evaluate the changes of neovaginal defense function in the sight of physical barrier by investigating the changes in the histological morphology and expression of occludin, zona occluden-1 (ZO-1) in mucosal cells of the neovagina in patients undergoing vaginal construction by sigmoid colon. METHODS: Fifteen cases with neovagina constructed by sigmoid colon matched with 15 cases' vaginal mocusa as control specimens were observed with light microscopic and electron microscopic methods. At the same time, the expression of occludin and ZO-1 were semiquantitatively measured by streptavidin-perosidase (SP) immunohistochemical method. RESULTS: (1) Squamous metaplasia was observed in colonic mucosa from lower one-third of the artificial vagina in 10 cases (67%, 10/15). (2) The intercellular tight junctions of neovaginal mucosa became shorter and wider, the number of them were decreased or disappeared by electron microscopic study. (3) In upper neovagina, the positive rates of occludin and ZO-1 expression in mucosal cells were 80% (12/15) and 73% (11/15), respectively. In lower neovaginal mucosa where squamous metaplasia occurred, the positive rates of two protein expression in cells were both 100% (10/10) and also was 100% (15/15) in control group, which showed significant difference (P < 0.05, P < 0.01). In lower neovaginal mucosa where squamous metaplasia hadn't occurred, the positive expression of two protein in cells (4/5, 2/5) were significantly lower than those in lower neovaginal mucosa where squamous metaplasia had happened 100% (10/10), 100% (10/10) and in control group [100% (15/15), 100% (15/15)] (P < 0.05), while there were no significantly difference in positive expression of two protein in cells between this group and upper neovagina (P > 0.05). CONCLUSIONS: The squamous metaplasia had occurred in lower neovaginal mucosa. The decreased expression of occludin and ZO-1 in upper and lower neovaginal mucosa where squamous metaplasia didn't occurred. However, In lower neovaginal mucosa where squamous metaplasia occurred, the expression of occludin and ZO-1 in cells were similar to those in control group, which might play a role in the defense function of neovaginal mucosa.

[Morphologic change and expression of neuronal nitric oxide synthase in neovaginal mucosa of patients undergoing vaginal construction with sigmoid colon].

OBJECTIVE: To study the changes of the histology and expression of neuronal nitric oxide synthase (nNOS) in the neovaginal mucosa of the patients undergoing vaginal construction with sigmoid colon. METHODS: Biopsy samples of upper one-third and lower one-third of the artificial vagina were obtained from 14 patients who underwent vaginal construction with sigmoid colon 9 - 48 months before and samples of normal sigmoid colon were collected from another 14 patients during vaginal construction with sigmoid colon as control group. The pathological and ultrastructural changes were comparatively observed by light microscopy and electron microscopy. At the same time, the expression of nNOS was semiquantitatively evaluated with immunohistochemical method. RESULTS: The upper one-third of the artificial vagina muscular layer of mucosa was hyperplastic and hypertrophic and the density of the submucosal nerve plexus was 3.6 +/- 1.5, significantly higher than that of the control group (1.7 +/- 0.8, P < 0.05). Squamous metaplasia was seen in the colonic mucosa from some 3 samples of lower one-third of the artificial vagina. Partial fusion of the intercellular tight junction, disappearance and fusion of mitochondrial cristae, and degranulation of rough endoplasmic reticulum could be seen in the vaginal colonic mucosa. Compared with the normal control, the expression of nNOS in the vaginal colonic mucosa was significantly decreased. CONCLUSION: Morphologic changes occur nNOS expression decreases in the colonic mucosa of the artificial vagina.

[Analysis on the relative factors of trichomonal vaginitis in married childbearing age women in rural impoverished area].

OBJECTIVE: To investigate the status and relative factors of trichomonal vaginitis among married childbearing age women in rural impoverished area of the northwestern part of China and hence identify the risk factors and provide a basis for the prevention and treatment of trichomonal vaginitis. METHODS: Questionnaire investigation, gynecological and laboratory examination were carried out in 480 women who had been selected by multi-stage cluster sampling in rural impoverished area of Bao Ji in ShannXi province. A case-control study was conducted to analyze the relative factors of trichomonal vaginitis and other reproductive tract infection (RTI) complications. RESULTS: The prevalence rate of trichomonal vaginitis was 12.9%, and 64.5% of the cases were complicated with chronic cervicitis, 17.7% were complicated with adnexitis. Uni-variated and multi-variated logistic regression analyses revealed that lack of reproductive health knowledge, bath with polluted water, washing vulva or penis with polluted water before sexual intercourse, having intercourse during menstrual period, having past history of trichomonal vaginitis, as well as no-income woman's and husband's negative attitude towards wife's RTIs were risk factors of trichomonal vaginitis and complicating chronic cervicitis or adnexitis. And lack of reproductive health knowledge, bath with polluted water, washing penis with polluted water before sexual intercourse, past history of trichomonal vaginitis, husband's negative attitude to wife's RTIs were relative factors of trichomonal vaginitis and complicating chronic cervicitis or adnexitis revealed by the binary logistic regression analysis. The less score of reproductive health knowledge, the more risk of suffering from trichomonal vaginitis complicating chronic cervicitis. CONCLUSION: Compositive and successive prevention and treatment scheme should be used to control trichomonal vaginitis and other RTI complications in rural impoverished area of northwestern China. The scheme should be focused on four ways, including improving sanitation behaviors in couples, insisting on normative treatment, generalizing reproductive health knowledge and mobilizing husbands to pay attention.