Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

A review of the impact of school based interventions on cardiovascular metabolic risk in children / 中国学校卫生

Abstract@#School based lifestyle interventions have many advantages, which can effectively reduce the prevalence of overweight and obesity, improve children and their families knowledge of overweight and obesity, and enhance their cognition of behaviors related to energy balance. Moreover, it can improve the level of cardiometabolic risk (CMR). By searching PubMed, CNKI and Wanfang databases, the article review the effects of school based physical activity and dietary interventions on children s blood pressure, blood lipids, blood glucose, and other CMR indicators, and analyze the differences among different groups of people, such as gender, age, and race, in order to provide the evidence for future school based intervention studies on overweight and obesity in children.

Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.

Heat shock protein 90 (HSP90) has been recognized as a crucial target in cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 µM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

Role of eNOS/PKG-1 pathway in L-Arginine against right ventricular remodeling induced by monocrotaline in rats / 中国药理学通报

Aim To investigate the role of eNOS/PKG- 1 pathway in L-arginine (L-arg) intervention in right ventricular remodeling induced by monocrotaline (MCT) in Sprague Dawley (SD) rats with the aid of the tool medicine L-NAME. Methods Twenty SD rats were randomly divided into control group, MCT group, L-Arg group and L-Arg + L-NAME group. The general condition of rats was observed; the right ventricular pressure of rats was measured by right heart catheterization; the rats and the right ventricle were weighed and the right ventricular mass index was calculated; the morphological changes of the right ventricular were observed by H&E staining; the protein expressions of cTnl, eNOS and PKG-1 were detected by Western blot in the right ventricular. Results Compared with control group, right ventricular max pressure and right ventricular mass index significantly increased ( P < 05) ; the weight of rats in MCT group was significantly reduced ( P < 0. 05); the right ventricular myocytes were hypertrophic, disordered and infiltrated with inflammatory cells; the protein expression of cTnl was obviously up-regulated ( P < 0. 05 ) ; the protein expressions of eNOS and PKG-1 were significantly down- regulated ( P < 0. 05 ) . L-arg could significantly improve the above changes ( P < 0. 05 ). However, the effects of L-arg were inhibited by eNOS inhibitor L- NAME. Conclusions L-arg can improve the right ventricular remodeling in rats induced by MCT, and the mechanism may be related to the up-regulation of the protein levels of eNOS and PKG-1.

Icariin improves myocardial fibrosis induced by isoproterenol via regulating expression of a-SMA and MMPs/TIMP / 中国药理学通报

Abstract; Aim To explore the effect of icariin (ISO) in mice. Methods C57BL/6 mice were ran- (ICA) on myocardial fibrosis induced by isoproterenol domly divided into control group, ISO group, low-dose (15 mg • kg"1), middle-dose (30 mg • kg"1) and high-dose (60 mg • kg"1) of ICA-treated group and Losartan-treated group ( 9 mg • kg"1 ). The control group was subcutaneously injected with normal saline, and the other groups were subcutaneously injected with ISO (5 mg • kg"1, qd) continuously 14 days to established the myocardial fibrosis model. The ICA-treated groups and Losartan-treated group were simultaneously intragastrically administered of ICA or Losartan, respectively. And the other groups received the same a- mount of double distilled water. The left ventricular e- jection fraction (LVEF) and the left ventricular fraction shortening rate ( LVFS) were evaluated by the small animal ultrasound. The heart mass index (HMI) was calculated. The left ventricular collagen deposition was detected by Masson staining. The protein expressions of a-SMA, MMP-2, MMP-9 and TIMP-1 in the left ventricular tissue were detected by Western blot. Results ICA (30, 60 mg • kg"1) and Losartan could inhibit the decreased LVEF and LVFS, the increased HMI and left ventricular collagen deposition, the up- regulated a-SMA and MMP-9 protein expression, the down-regulated MMP-2 and TIMP-1 protein expression in the left ventricular tissues induced by ISO. Conclusions ICA can improve myocardial fibrosis induced by ISO in mice, and the underlying mechanism may be related to the regulation of the protein expression of a- SMA and MMPs/TIMP-1.

Efficacy and Safety of Botulinum Toxin Type A Injection in Patients with Bilateral Trapezius Hypertrophy.

OBJECTIVE: To evaluate aesthetic outcomes in patients with bilateral trapezius hypertrophy treated by botulinum toxin type A (BTxA) injection for aesthetic reconstruction of the upper trapezius. METHODS: From May 2015 to May 2016, 30 women with a short neck shape resulting from bilateral trapezius hypertrophy were treated with botulinum toxin type A (BTxA) injection at the most affected area of the upper trapezius. Pre- and postoperative values of SACDF (irregularly shaped area of the four points A, C, D, and F) and SACDE (irregularly shaped area of the four points A, C, D, and E), responses to patients' and doctors' Global Aesthetic Improvement Scale (GAIS) questionnaires for neck aesthetic assessment, as well as reported adverse events, were recorded and analyzed. RESULTS: Duration of follow-up ranged from 4 to 12 months. Subjects experienced non-severe adverse events and complete recovery after a single BTxA injection. In patients' GAIS questionnaires, "very much improved" accounted for 53%, "much improved" accounted for 13%, and "improved" accounted for 27%. In doctors' GAIS questionnaires, "very much improved" accounted for 27%, "much improved" accounted for 33%, "improved" accounted for 33%, and "no change" accounted for 7%. The overall degree of improvement was high. Statistically significant differences were observed with respect to the "very much improved" response to GAIS questionnaires between patients and doctors (P = 0.035). CONCLUSION: A single injection of BTxA for aesthetic reconstruction of the upper trapezius is safe and effective in patients with bilateral trapezius hypertrophy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Percentages of peripheral blood γδ T cells and regulatory T cells and expression of associated cytokines in infants with human cytomegalovirus infection].

OBJECTIVE: To investigate the percentages of peripheral blood γδ T cells and regulatory T cells (Treg) and the expression of associated cytokines, interleukin 17 (IL-17) and transforming growth factor-ß1 (TGF-ß1), in infants with human cytomegalovirus (HCMV) infection. METHODS: Twenty-two infants with HCMV infection (HCMV group) and 22 healthy infants who underwent physical examination (control group) were enrolled in this study. The percentages of peripheral blood γδ T cells and Treg cells were determined by flow cytometry. The levels of IL-17 and TGF-ß1 in plasma were measured using ELISA. RESULTS: Compared with the control group, the HCMV group had significantly higher percentage of γδ T cells and IL-17 level (P<0.01) and significantly lower percentage of Treg cells and TGF-ß1 level (P<0.01). In the HCMV group, the percentage of γδ T cells was negatively correlated with the percentage of Treg cells and TGF-ß1 level (P<0.05), but positively correlated with IL-17 level (P<0.05); the percentage of Treg cells was positively correlated with TGF-ß1 level (P<0.05), but negatively correlated with IL-17 level (P<0.05); there was no correlation between IL-17 level and TGF-ß1 level (P>0.05). CONCLUSIONS: There is an imbalance between γδ T cells and Treg cells in the peripheral blood of infants with HCMV infection, and γδ T cells may be involved in the secretion of IL-17.

Icariside Ⅱ ameliorates myocardial fibrosis in spontaneously hypertensive rats through regulating expression of MMP-2, MMP-9 and TIMP-1 / 中国药理学通报

Aim To investigate the effects of IcarisideⅡ ( ICS Ⅱ) on myocardial fibrosis in spontaneously hypertensive rat( SHR) . Methods Twenty male SHR rats were randomly divided into the model group (group SHR) , ICS Ⅱ low ( ICS Ⅱ-L) , middle ( ICSⅡ-M) and high ( ICS Ⅱ-H) group, and male WKY rats were set as control group ( group WKY) . ICS Ⅱ-L, ICSⅡ-M and ICSⅡ-H groups were intragastrically administered with ICS Ⅱ for 12 weeks. After that the blood pressure was measured in rats. Then, the rats were sacrificed and the left ventricles were separated in order to calculate the left ventricular mass index. Mas-son staining was used to detect the occurrence of inter-stitial fibrosis in cardiac tissues. Real time PCR was used to observe the gene expression of MMP-2, MMP-9 and TIMP-1 in the left ventricle in SHRs. The protein expression levels of MMP-2, MMP-9, TIMP-1, Colla- gen Ⅰ and Collagen Ⅲ were measured by Western blot. Results Compared with SHR group, the myo-cardial fibrosis was reduced after ICS Ⅱ (8, 16 mg· kg-1) treatment. The blood pressure and left ventricu-lar mass index decreased(P<0.05). The expressions of MMP-2, MMP-9, CollagenⅠand CollagenⅢwere down-regulated in left ventricular tissues( P <0.05 ) , while the expression of TIMP-1 was up-regulated( P<0.05) . Conclusion Icariside Ⅱ ameliorates myocar-dial fibrosis in SHR, and the mechanisms might be re-lated to the decrease of blood pressure and down-regu-lation of MMP-2, MMP-9 expression and up-regulation of TIMP-1 expression.

Identification and characterization of a novel capsid protein encoded by Singapore grouper iridovirus ORF038L.

Singapore grouper iridovirus (SGIV) is an important pathogen isolated from grouper, Epinephelus tauvina, and characterized as a novel ranavirus. To better understand the function of viral structural genes involved in SGIV infection and virus-host interactions, a candidate gene, VP38 (ORF038L), was investigated in this study. SGIV VP38 was found to encode a 170-aa peptide containing an RGD motif, and it showed significant identity only to members of the genus Iridovirus, family Iridoviridae, except megalocytivirus. The VP38 gene was identified by temporal expression pattern analysis and drug inhibition assay as a late (L) gene. Immunofluorescence localization revealed that P38 was distributed predominately in the cytoplasm and that association of VP38 with viral factories increased at the late stage of SGIV infection. Consistent results from immunoelectron microscopy (IEM) and western blot analysis revealed that SGIV VP38 is a viral capsid protein. Furthermore, antibodies specific for SGIV VP38 exhibited substantial SGIV-neutralizing activity in vitro, suggesting that VP38 might play an important role in SGIV infectivity.

The detection of serum anti-p53 antibodies from patients with gastric carcinoma in China.

BACKGROUND: Gastric carcinoma is one of the most frequently occurring cancers. The aim of this research was to increase the detection efficiency of anti-p53 antibodies in the sera of patients with gastric carcinoma and to improve the diagnosis for patients with gastric carcinoma. METHODS: We prepared phage-displayed peptide DO7 and established an enzyme-linked immunosorbent assay method to detect the anti-p53 antibodies. We detected the anti-p53 antibodies of 61 patients with gastric carcinoma using the method and our previous ELISA method assisted by the recombinant wild-type human p53 protein to detect the anti-p53 antibodies. We studied the correlation between the anti-p53 antibodies and the clinicopathological data including sex, age, carcinoembryonic antigen, tumor size, tumor TNM staging, and lymph-node status. RESULTS: The anti-p53 antibodies positive rate for patients with gastric carcinoma was increased (31.1%, 19/61) through the combination of p53-ELISA and phage-ELISA. We found that the positive anti-p53 antibodies correlated significantly with tumor size (P=0.047). The combination of the anti-p53 antibodies and carcinoembryonic antigen could improve the diagnosis for patients with gastric carcinoma. CONCLUSIONS: This approach indicated an increased anti-p53 antibodies positive rate for patients with gastric carcinoma and provided a useful marker for clinical diagnosis for patients with gastric carcinoma.