Downregulation of MiR-218 can alleviate high-glucose-induced renal proximal tubule injury by targeting GPRC5A

ABSTRACT

The purpose of this study was to explore the functional implication of microRNA-218 (miR-218) in diabetic nephropathy (DN) through high-glucose-stimulated renal proximal tubule impairment. Biological function experiments showed that miR-218 and inflammatory factors TNF-α and IL-1β were highly expressed in renal proximal tubule under high-glucose conditions. Inhibiting miR-218 alleviated renal tubular cell injury, which was represented by miR-218 inhibitor facilitating renal tubular cell vitality whilst reducing its apoptosis and levels of inflammation factors. In addition, we confirmed that miR-218 directly targeted GPRC5A and negatively regulated its expression. Co-transfection assay showed that overexpression of GPRC5A accentuated the mitigated action of miR-218 inhibitor on renal proximal tubule cell injury induced by high-glucose. Accordingly, these data indicated that downregulation of miR-218 can assuage high-glucose-resulted renal tubular cell damage, and its ameliorative effect was achieved by negative regulation of GPRC5A, which provides a novel direction for unearthing the pathogenesis and even further biological treatment of DN.     

TLR4 signaling is involved in the protective effect of propofol in BV2 microglia against OGD/reoxygenation

Propofol exhibits neuroprotective effects against hypoxic–ischemic brain injury, but the underlying mechanisms are still not clear. Toll-like receptor 4 (TLR4) plays a considerable role in the induction of innate immune and inflammatory responses. The purposes of this study are to investigate the effect of propofol on the oxygen and glucose deprivation (OGD)/reoxygenation (OGD/R) BV2 microglia and to explore the role of TLR4/myeloid differentiation protein 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway in the neuroprotective effects of propofol. BV2 microglia were placed into an airtight chamber and in glucose-free medium for OGD/reoxygenation. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay. TLR4 and its downstream signaling molecules, MyD88 and NF-κB expressions were detected by Western blotting. Level of tumor necrosis factor alpha (TNF-α) in culture medium was determined with enzyme-linked immunosorbent assay. BV2 microglia apoptosis was determined by flow cytometry. We found that pretreatment with propofol significantly alleviated the hypoxic injury in BV2 microglia. Propofol inhibited upregulation of TLR4, MyD88, and NF-κB expressions in BV2 microglia exposed to OGD/reoxygenation. Propofol pretreatment also significantly reduced the production of TNF-α and apoptosis in OGD/reoxygenation BV2 microglia. The results indicated that TLR4 and its downstream MyD88-dependent signaling pathway contributed to neuroprotection of propofol to microglia exposed to OGD/reoxygenation.     

Improved inhibitory activities against tumor-cell migration and invasion by 15-benzylidene substitution derivatives of andrographolide

In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure–activity relationships were studied. Compared to 1, compounds 8a–8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.     

阿维菌素对半闭弯尾姬蜂保护酶系和解毒酶系的影响

为明确阿维菌素对半闭弯尾姬蜂保护酶系和解毒酶系的影响,采用试管药膜法以阿维菌素亚致死浓度(LC10和LC25)处理半闭弯尾姬蜂成虫,分别于处理后1、12、24和48 h测定其体内保护酶和解毒酶活性变化。结果表明,阿维菌素亚致死浓度处理后,随着时间的延长,对寄生蜂体内超氧化物歧化酶(SOD)和过氧化物酶(POD)活性总体表现为诱导作用;对过氧化氢酶(CAT)活性表现为先抑制后诱导作用;对酯酶(EST)、谷胱甘肽S-转移酶(GST)和多功能氧化酶(MFO)具有显著的抑制作用。研究结果为深入了解半闭弯尾姬蜂对阿维菌素的防御机理提供了一定的理论基础。     

内质网压力响应相关的蛋白质降解

内质网相关蛋白质降解途径(ERAD),即蛋白质分泌过程中错误折叠或未折叠的蛋白质在内质网中被识别并逆向运输到细胞质经聚泛素化后由蛋白酶体降解的过程.自从发现该途径后对其机制的阐明一直处于不断探索的阶段.近年来,对ERAD底物识别、逆向运输和泛素化新组分的发现以及新技术的应用,使得该途径的具体分子机制更加清晰.本文全面梳理并综述了内质网应激响应、ERAD降解过程与机理的最新进展,并对模式蛋白底物和最新研究方法进行了总结,以期展示该领域的研究概况.     

Plastid and nuclear phylogenomic incongruences and biogeographic implications of Magnolia s.l. (Magnoliaceae)

Magnoliaceae, an assemblage of early diverged angiosperms, comprises two subfamilies, speciose Magnolioideae with approximately 300 species in varying numbers of genera and monogeneric Liriodendroideae with two species in Liriodendron L. This family occupies a pivotal phylogenetic position with important insights into the diversification of early angiosperms, and shows intercontinentally disjunct distribution patterns between eastern Asia and the Americas. Widespread morphological homogeneity and slow substitution rates in Magnolia L. s.l. resulted in poorly supported phylogenetic relationships based on morphology or molecular evidence, which hampers our understanding of the genus’ temporal and spacial evolution. Here, based on the newly generated genome skimming data for 48 Magnolia s.l. species, we produced robust Magnolia phylogenies using genome-wide markers from both plastid genomes and single nucleotide polymorphism data. Contrasting the plastid and nuclear phylogenies revealed extensive cytonuclear conflicts in both shallow and deep relationships. ABBA-BABA and PhyloNet analyses suggested hybridization occurred within sect. Yulania, and sect. Magnolia, which is in concordance with the ploidy level of the species in these two sections. Divergence time estimates and biogeographic reconstruction indicated that the timing of the three tropical Magnolia disjunctions coincided with the mid-Eocene cooling climate and/or late Eocene climate deterioration, and two temperate disjunctions occurred much later, possibly during the warm periods of the Miocene, hence supporting the boreotropical flora concept of Magnolia s.l.     

Hypoxic conditioned medium derived from bone marrow mesenchymal stromal cells protects against ischemic stroke in rats

In recent years, studies have shown that the secretome of bone marrow mesenchymal stromal cells (BMSCs) contains many growth factors, cytokines, and antioxidants, which may provide novel approaches to treat ischemic diseases. Furthermore, the secretome may be modulated by hypoxic preconditioning. We hypothesized that conditioned medium (CM) derived from BMSCs plays a crucial role in reducing tissue damage and improving neurological recovery after ischemic stroke and that hypoxic preconditioning of BMSCs robustly improves these activities. Rats were subjected to ischemic stroke by middle cerebral artery occlusion and then intravenously administered hypoxic CM, normoxic CM, or Dulbecco modified Eagle medium (DMEM, control). Cytokine antibody arrays and label-free quantitative proteomics analysis were used to compare the differences between hypoxic CM and normoxic CM. Injection of normoxic CM significantly reduced the infarct area and improved neurological recovery after stroke compared with administering DMEM. These outcomes may be associated with the attenuation of apoptosis and promotion of angiogenesis. Hypoxic preconditioning significantly enhanced these therapeutic effects. Fourteen proteins were significantly increased in hypoxic CM compared with normoxic CM as measured by cytokine arrays. The label-free quantitative proteomics analysis revealed 163 proteins that were differentially expressed between the two groups, including 107 upregulated proteins and 56 downregulated proteins. Collectively, our results demonstrate that hypoxic CM protected brain tissue from ischemic injury and promoted functional recovery after stroke in rats and that hypoxic CM may be the basis of a potential therapy for stroke patients.     

Retracted: Impaired Th17 cell proliferation and decreased pro-inflammatory cytokine production in CXCR3/CXCR4 double-deficient mice of vulvovaginal candidiasis

Vulvovaginal candidiasis (VVC) is a common observed infection, affecting approximately 75% of women of reproductive age. Drug resistance represents a troublesome stumbling block associated with VVC therapy. Thus the aim of the present study was to provide information regarding the selection of potential drug targets for VVC. CXCR3-, CXCR4-, or CXCR/CXCR4 double-deficient mouse models of VVC were subsequently established, with changes to the load of Candida Albicans evaluated accordingly. The biological behaviors of the vaginal epithelial cells were characterized in response to the CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout in vivo. Our initial observations revealed that in mice with VVC, CXCR3-, CXCR4-, or CXCR3 - CXCR4 double-knockout resulted in a decreased load of C. Albicans as well as reduced levels and proportion of Th17 cells. Proinflammatory cytokine production was found to be inhibited by CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout whereby the mRNA and protein expressions CXCR3, CXCR4, IL-17, IL-6, and TNF-α exhibited decreased levels. CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout appeared to function as positive proliferation factors, while playing a negative role in the processes of apoptosis and the cell cycle of vaginal epithelial cells. Taken together, the key findings of the study suggested that CXCR3/CXCR4 double-knockout could act to hinder the progression of VVC, highlighting its promise as a novel therapeutic target in the treatment of VVC. CXCR3 and CXCR4 genes may regulate Th17/IL-17 immune inflammatory pathways to participate in antifungal immunity.