16α-OHE1, a novel oestrogen metabolite, attenuates dysfunction of left ventricle contractility via regulation of autophagy after myocardial ischemia and reperfusion.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) can exacerbate the initial cardiac damage in the myocardial functional changes, including dysfunction of left ventricular contractility. Oestrogen has been proven to protect the cardiovascular system. However, whether the oestrogen or its metabolites play the main role in attenuating dysfunction of left ventricular contractility is unknown. METHODS AND RESULTS: This study used the LC-MS/MS to detect oestrogen and its metabolites in clinical serum samples (n = 62) with heart diseases. After correlation analysis with markers of myocardial injury including cTnI (P < 0.01), CK-MB (P < 0.05), and D-Dimer (P < 0.001), 16α-OHE1 was identified. The result from LC-MS/MS in female and ovariectomised (OVX) rat serum samples (n = 5) matched the findings in patients. In MI/R model of animal, the recovery of left ventricular developed pressure (LVDP), rate pressure product (RPP), dp/dtmax and dp/dtmin after MI/R in OVX or male group were worsened than those in female group. Also, the infarction area of OVX or male group was larger than that in females (n = 5, p < 0.01). Furthermore, LC3 II in the left ventricle of OVX and male group was lower than that in females (n = 5, p < 0.01) by immunofluorescence. In H9C2 cells, after the application of 16α-OHE1, the number of autophagosomes was further increased and other organelles improved in MI/R. Simultaneously, LC3 II, Beclin1, ATG5, and p-AMPK/AMPK were increased, and p-mTOR/mTOR was decreased (n = 3, p < 0.01) by Simple Western. CONCLUSION: 16α-OHE1 could attenuate left ventricle contractility dysfunction via autophagy regulation after MI/R, which also offered fresh perspectives on therapeutical treatment for attenuating MI/R injury.

Sarsasapogenin restores podocyte autophagy in diabetic nephropathy by targeting GSK3ß signaling pathway.

Podocyte injury following abnormal podocyte autophagy plays an indispensable role in diabetic nephropathy (DN), therefore, restoration of podocyte autophagy is considered as a feasible strategy for the treatment of DN. Here, we investigated the preventive effects of sarsasapogenin (Sar), the main active ingredient in Anemarrhena asphodeloides Bunge, on the podocyte injury in diabetic rats, and tried to illustrate the mechanisms underlying the effects in high glucose (HG, 40 mM)-treated podocytes (MPs). Diabetes model was established in rats with single streptozocin (60 mg· kg-1) intraperitoneal administration. The rats were then treated with Sar (20, 60 mg· kg-1· d-1, i.g.) or a positive control drug insulin (INS) (40 U· kg-1· d-1, i.h.) for 10 weeks. Our results showed that both Sar and insulin precluded the decreases of autophagy-related proteins (ATG5, Beclin1 and LC3B) and podocyte marker proteins (podocin, nephrin and synaptopodin) in the diabetic kidney. Furthermore, network pharmacology was utilized to assess GSK3ß as the potential target involved in the action of Sar on DN and were substantiated by significant changes of GSK3ß signaling in the diabetic kidney. The underlying protection mechanisms of Sar were explored in HG-treated MPs. Sar (20, 40 µM) or insulin (50 mU/L) significantly increased the expression of autophagy- related proteins and podocyte marker proteins in HG-treated MPs. Furthermore, Sar or insulin treatment efficiently regulatedphosphorylation at activation and inhibition sites of GSK3ß. To sum up, this study certifies that Sar meliorates experimental DN through targeting GSK3ß signaling pathway and restoring podocyte autophagy.

Sirt1 inhibits renal tubular cell epithelial-mesenchymal transition through YY1 deacetylation in diabetic nephropathy.

Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial-mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg-1·d-1. ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 µM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 µM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.

A novel compound AB38b attenuates oxidative stress and ECM protein accumulation in kidneys of diabetic mice through modulation of Keap1/Nrf2 signaling.

Extracellular matrix (ECM) deposition following reactive oxygen species (ROS) overproduction has a key role in diabetic nephropathy (DN), thus, antioxidant therapy is considered as a promising strategy for treating DN. Here, we investigated the therapeutic effects of AB38b, a novel synthetic α, ß-unsaturated ketone compound, on the oxidative stress (OS) and ECM accumulation in type 2 diabetes mice, and tried to clarify the mechanisms underlying the effects in high glucose (HG, 30 mM)-treated mouse glomerular mesangial cells (GMCs). Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration. The diabetic mice were then treated with AB38b (10, 20, 40 mg· kg-1· d-1, ig) or a positive control drug resveratrol (40 mg· kg-1· d-1, ig) for 8 weeks. We showed that administration of AB38b or resveratrol prevented the increases in malondialdehyde level, lactate dehydrogenase release, and laminin and type IV collagen deposition in the diabetic kidney. Simultaneously, AB38b or resveratrol markedly lowered the level of Keap1, accompanied by evident activation of Nrf2 signaling in the diabetic kidney. The underlying mechanisms of antioxidant effect of AB38b were explored in HG-treated mouse GMCs. AB38b (2.5-10 µM) or resveratrol (10 µM) significantly alleviated OS and ECM accumulation in HG-treated GMCs. Furthermore, AB38b or resveratrol treatment effectively activated Nrf2 signaling by inhibiting Keap1 expression without affecting the interaction between Keap1 and Nrf2. Besides, AB38b treatment effectively suppressed the ubiquitination of Nrf2. Taken together, this study demonstrates that AB38b ameliorates experimental DN through antioxidation and modulation of Keap1/Nrf2 signaling pathway.

MiR-1-5p is down-regulated in gallbladder carcinoma and suppresses cell proliferation, migration and invasion by targeting Notch2.

BACKGROUND: Numerous studies have demonstrated that aberrant microRNAs (miRNAs) are involved in tumorigenesis and tumor progression. Nevertheless, the precise role of miR-1-5p in gallbladder carcinoma cell growth and metastasis remains not fully revealed. MATERIAL AND METHODS: The levels of miR-1-5p were detected in gallbladder carcinoma tissues and cell lines using qRT-PCR method. A series of functional assays, including cell proliferation, colony formation, wound healing and Transwell invasion were conducted using miR-1-5p or miR-1-5p inhibitor transfected cells. RESULTS: MiR-1-5p was remarkably down-regulated in gallbladder carcinoma tissues and cell lines compared to normal. In addition, over-expression of miR-1-5p markedly suppressed the growth, migration and invasion of gallbladder carcinoma cell. Conversely, down-expression of miR-1-5p facilitated gallbladder carcinoma cell proliferation and aggressiveness. Mechanistic investigations demonstrated that neurogenic locus notch homolog protein 2 (Notch2) was the directly target of miR-1-5p and Notch2 mediated the inhibitory effect of miR-1-5p in gallbladder carcinoma cell growth and aggressiveness. CONCLUSION: Our findings demonstrated that miR-1-5p acted as a suppressive miRNA and played vital roles in the growth, migration and invasion of gallbladder carcinoma cell through targeting Notch2.

Clinical impact of galectin-3 in newly diagnosed t (15;17)(q22;q21)/PML-RARa acute promyelocytic leukemia treated with all-trans retinoic acid and arsenic trioxide-based regimens.

Increased galectin-3 expression has been currently showed to be associated with poor prognosis in some hematological malignancies, such as acute myeloid leukemia, diffuse large B cell lymphoma. However, little is known about the clinical significance of galectin-3 in patients with acute promyelocytic leukemia (APL). We investigated the concentration of serum galectin-3 and characterized the relationship between galectin-3 and outcome in patients with APL. Higher galectin-3 levels were detected in patients with APL compared with the healthy controls (p < 0.001). Higher galectin-3 levels were closely associated with older ages (p < 0.001), the medical history of psoriasis (p = 0.036), coagulopathy (p = 0.042), and CD34 expression (p = 0.004). Compared with patients with lower galectin-3 levels, those with higher galectin-3 levels had significant shorter overall survival (p = 0.028) and relapse-free survival (p = 0.001). Multivariate analysis showed that serum galectin-3 was an independent unfavorable factor for relapse-free survival in patients with APL treated with all-trans retinoic acid and arsenic trioxide-based frontline therapy. Clinical impact of galectin-3 should be further investigated in patients with APL.

[Landscape pattern change of Dongzhai Harbour mangrove, South China analyzed with a patch-based method and its driving forces].

According to the interpreted results of three satellite images of Dongzhai Harbour obtained in 1988, 1998 and 2009, the changes of landscape pattern and the differences of its driving forces of mangrove forest in Dongzhai Harbour were analyzed with a patch-based method on spatial distribution dynamics. The results showed that the areas of mangrove forest in 1988, 1998 and 2009 were 1809.4, 1738.7 and 1608.2 hm2 respectively, which presented a trend of decrease with enhanced degree of landscape fragmentation. The transformations among different landscape types indicated that the mangrove, agricultural land and forest land were mainly changed into built-up land and aquaculture pond. The statistical results obtained from three different methods, i.e., accumulative counting, percentage counting and main transformation route counting, showed that natural factors were the main reason for the changes of patch number, responsible for 58.6%, 72.2% and 72.1% of patch number change, respectively, while the percentages of patch area change induced by human activities were 70.4%, 70.3% and 76.4%, respectively, indicating that human activities were the primary factors of the change of patch areas.