Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation.

Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-ß1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-ß1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.

Anti-neuroinflammatory sesquiterpenoids from Chloranthus henryi.

Hupelactones A (1) and B (2), two new eudesmanolide-type enantiomers of the corresponding compounds, along with four mono- (3-6) and nine dimeric- (7-15) known sesquiterpenoids were isolated from the whole plant of Chloranthus henryi var. hupehensis (syn. C. henryi). The new structures including the absolute configurations were determined by comparison with previously reported enantiomers, extensive spectroscopic methods in combination with electronic circular dichroism (ECD) calculations. All the isolates were evaluated for their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine BV-2 microglial cells. Among them, the dimeric lindenane sesquiterpenoids shizukaols F (8) and G (11) exhibited the most potent activities, with IC50 values of 2.65 and 4.60 µM, respectively.

Further terpenoids from the Chloranthaceae plant Chloranthus multistachys and their anti-neuroinflammatory activities.

Three labdane-type [multisins A-C (1-3)], two guaiane-type [multisins D (4) and E (5)], and one eudesmane-type [multisin F (6)] previously undescribed terpenoids, together with 14 mono- (7-20) and seven dimeric- (21-27) known terpenoids, were isolated from the 90% MeOH extract of the whole plant of Chloranthus multistachys. Their structures and absolute configurations were determined by extensive spectroscopic methods and electronic circular dichroism (ECD) calculations. Compounds 4 and 5 are rare trinor-sesquiterpenes with a de-isopropyl guaiane skeleton, whereas compound 6 is a rearranged dinor-eudesmene featuring an uncommon octahydro-1H-indene ring system. Among the isolates, the dimeric lindenane sesquiterpenoid shizukaol C (25) exhibited the most potent (IC50 = 8.04 µM) anti-neuroinflammatory activity by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells.

Correlation between psychopathological symptoms, coping style in adolescent and childhood repeated physical, emotional maltreatment / 中华儿科杂志

<p><b>OBJECTIVE</b>To study possible relationship between psychopathological symptoms, positive and negative coping styles in adolescents who experienced repeated serious childhood physical abuse (CPA), moderate CPA, and childhood emotional abuse (CEA).</p><p><b>METHODS</b>A total of 5453 students were recruited as subjects from 9 middle schools at grades 7, 8, 10, and 11. They provided informed consent and participated in the self-administered anonymous survey on their frequencies of serious or moderate physical abuse and emotional abuse by his/her parents or other caregivers about average times of experiencing maltreatment every year during primary school. The Symptoms Checklist 90 (SCL-90) was used to rate general mental problem and 9 special psychopathological symptoms. The trait positive and negative coping styles were assessed with the Trait Coping Style Questionnaire (TCSQ). Totally 5141 respondents substantially completed surveys. It was defined as repeating childhood maltreatment that the adolescent reported he/she had suffered 3 or more episodes of one or more forms of serious CPA, moderate CPA, and CEA. Multinomial logistic regression model was used to analyze the effect of the types and quantities of repeating childhood experiences on mental health when the positive, negative coping styles, and both of them entered the statistics model, taking the demographic variables as covariates.</p><p><b>RESULTS</b>Of respondents, 9.1 percent were rated as having general mental health problem. The rates of somatization, obsession, interpersonal susceptivity, depression, anxiety, phobia, paranoia, and psychotic symptoms were 1.3%, 3.6%, 3.6%, 2.8%, 2.2%, 4.0%, 2.1%, 2.8% and 1.6%, respectively. Dose-response trend existed between the number of items of repeating serious CPA, moderate CPA, CEA, and rates of general mental problems, 9 kinds of psychopathological symptoms, number of positive items of psychopathological symptoms. Compared with the respondents without serious CPA, moderate CPA or CEA, those with repeating childhood maltreatment had higher scores of negative coping styles. In the respondents with repeating childhood maltreatments, the prevalence of general mental problems and number of positive psychopathological symptoms increased with the rising of scores of negative coping styles. The results from multinomial logistic regression analysis showed that negative coping style decreased the odds ratio (OR) of repeating serious CPA, moderate CPA, and CEA with general mental health problems, but positive coping style did not.</p><p><b>CONCLUSIONS</b>The experiences of repeating childhood physical or emotional maltreatment are associated with a wide variety of psychopathological symptoms and general mental health problems. Negative coping strategies may moderate the links of childhood abusive experiences and mental problems.</p>