MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3.

The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted attention and concern for a long time, but the molecular mechanism of action for cisplatin is not clear. MicroRNA-483 is involved in several diseases, such as tumorigenesis and osteoarthritis, but its renal target and potential role in AKI are unknown. In this study, we explored the pathogenic role and underlying mechanism of miR-483-5p in cisplatin-induced AKI, using transgenic mice, clinical specimen, and in vitro cell line. We found that miR-483-5p was significantly upregulated by cisplatin in a cisplatin-induced mouse model, in serum samples of patients who received cisplatin therapy, and in NRK-52E cells. Overexpression of miR-483-5p in mouse kidneys by stereotactic renal injection of lentiviruses mediated miR-483-5p or generation of conditional miR-483-overexpressing transgenic mice accentuated cisplatin-induced AKI by increasing oxidative stress, promoting apoptosis, and inhibiting autophagy of tubular cells. Furthermore, our results revealed miR-483-5p directly targeted to GPX3, overexpression of which rescued cisplatin-induced AKI by inhibiting oxidative stress and apoptosis of tubular cells, but not by regulating autophagy. Collectively, miR-483-5p is upregulated by cisplatin and exacerbates cisplatin-induced AKI via negative regulation of GPX3 and contributing oxidative stress and tubular cell apoptosis. These findings reveal a pathogenic role for miR-483-5p in cisplatin-induced AKI and suggest a novel target for the diagnosis and treatment of AKI.

Micheliolide ameliorates diabetic kidney disease by inhibiting Mtdh-mediated renal inflammation in type 2 diabetic db/db mice.

Diabetic kidney disease (DKD) is the principal cause of end-stage renal disease worldwide and few treatments are available. Because immunomodulators are pivotal to DKD pathophysiology, anti-inflammatory agents may be useful for treating DKD. This study was conducted to investigate the effect of micheliolide (MCL), a novel guaianolide sesquiterpene lactone with well-known anti-inflammatory effects, on DKD. Treatment with dimethylaminomicheliolide (DMAMCL), the pro-drug of MCL currently under clinical trial in oncology, protected the kidneys against proteinuria, renal failure, histopathological injury, and inflammation in db/db mice. This effect was associated with metadherin (Mtdh) downregulation. We observed aberrant upregulation of Mtdh in the kidneys of db/db mice and high-glucose (HG)-induced mouse tubular epithelial cells (mTECs). Downregulation of Mtdh obviously inhibited nuclear factor-κB signaling activation and suppressed its downstream inflammatory cytokines, such as monocyte chemotactic peptide-1, interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in HG-induced mTECs, which was similar to the effect of MCL. Mtdh overexpression largely reversed the anti-inflammatory role of MCL. Moreover, MCL downregulated Mtdh by both inhibiting the transcription level and promoting ubiquitin-mediated degradation. These findings suggest that DMAMCL is a promising anti-inflammatory agent useful for preventing renal injury in DKD by inhibiting Mtdh-mediated renal inflammation.

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10.

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-ß1 (TGF-ß1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

miR-214-5p inhibits human prostate cancer proliferation and migration through regulating CRMP5.

OBJECTIVES: In men, human prostate cancer (PCa) has become the second most common cancer. miRNAs are short non-coding RNAs that can inhibit target gene mRNAs. Studies have showed that the alternation of miRNAs expression in cancer is relevant to pathogenesis of tumor. In present study, we aimed to investigate functions of miR-214-5p in PCa. MATERIALS AND METHODS: 10 paired human prostate tumor tissues and homologous para-tumor tissues were recruited, and the levels of miR-214-5p and CRMP5 were respectively determined by qRT-PCR assay. Luciferase activity analysis was performed to explore the regulation of CRMP5 mRNA 3'UTR by miR-214-5p. Then, cell experiments, including cell proliferation, apoptosis, cell cycle, migration and colony formation ability, were performed after proper plasmids or RNAs transfection. RESULTS: In PCa tissues and cell lines, expression of miR-214-5p was decreased compared with para-tumor tissues or normal prostate epithelial cell lines. Luciferase activity assay showed a direct combination of miR-214-5p and CRMP5 mRNA 3'UTR, and indicated that the absence of miR-214-5p in PCa cells may contributes to a high level of CRMP5. Cell experiments showed that miR-214-5p can induce inhibition of tumor cell growth, migration and colony forming efficiency, promotion of apoptosis and G1-phase arrest, on the other hand, co-expression of CRMP5 somewhat counteracted these phenotype induced by miR-214-5p. CONCLUSION: Taken together, miR-214-5p shows tumor suppression effects in PCa cells. Loss expression of miR-214-5p in PCa increase levels of CRMP5 through regulating CRMP5 3'UTR, which could be a potential therapy target for PCa.

Genetic polymorphism and population structure of Torghut Mongols and comparison with a Mongolian population 3000 kilometers away.

Mongolians played a pivotal role in shaping the culture and genetic architecture of modern Eurasia through the rapid expansion of the Mongol Empire in the 13th century. While the historical aspects of the Mongolian Empire are well documented, research on the genetic variations among Mongolian populations is still insufficient. In this study, we examined the genetic diversity of 70 Torghut Mongols residing in the Ili region of China compared with 88 Jalaid Mongols residing 3000 km away. Over 200 forensically relevant genetic markers, including autosomal short tandem repeats (A-STRs), X chromosomal STRs (X-STRs), Y chromosomal STRs (Y-STRs), identity-informative single nucleotide polymorphisms (iiSNPs), ancestry-informative SNPs (aiSNPs), and phenotype-informative SNPs (piSNPs), were genotyped to uncover the genetic polymorphism of the Torghut Mongols. The STR genotyping results showed that 80 alleles (39 A-STRs, 25 Y-STRs, and 16 X-STRs; 14.4% of 554 alleles) identified in Torghut Mongols were not identified in Jalaid Mongols, while 155 alleles (84 A-STRs, 59 Y-STRs and 12 X-STRs; 24.6% of 630 alleles) identified in Jalaid Mongols were not observed in Torghut Mongols. Calculation of the forensic parameters demonstrated that the STRs and SNPs analyzed here could be employed in forensic applications. Interpopulation comparisons via principal component analysis (PCA), phylogenetic tree, and STRUCTURE analysis showed that the two Mongolian populations were closely related by their genetic background, although genetic differences were also discovered. When both the sequence-based A-STRs and iiSNPs were included in the STRUCTURE analysis, the Torghut population was more similar to the Uyghur population than to Jalaid Mongols, indicating certain population structure differences between the two Mongolian populations. The Y-DNA haplogroup prediction showed that although haplogroup C (C2-M217) was dominant in both Mongolian populations, haplogroup O2-M122 was rarely presented in Torghut Mongols, which differentiated the Torghut Mongols from the other Mongolian populations. This study not only uncovered the genetic features of the two Mongolian tribes, providing valuable frequency data for forensic applications, but the genetic patterns of the two Mongolian populations also provide a genetic evidence that the Torghut Mongols may have developed via the gradual intermixing of nomadic groups of Mongol and Turkic origin, as recorded in historical records. This study also highlighted the importance of building regional reference databases that consider both ethnic and geographic location information, instead of a more universal reference database, for forensic applications.

Revisiting the potential power of human leukocyte antigen (HLA) genes on relationship testing by massively parallel sequencing-based HLA typing in an extended family.

The human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome and have great power in forensic applications, especially in relationship testing and personal identification. However, the extreme polymorphism of HLA has made unambiguous genotyping of these genes very challenging and resulted in the limited application in relationship testing. Fortunately, massively parallel sequencing (MPS) technology offers the promise of unambiguous and high-throughput HLA typing. In this study, 11 HLA genes were typed in one extended family residing in North China and encompassing six generations. Phase-resolved genotypes for HLA genes were generated and HLA haplotype structure was defined. The paternity/kinship index, or in other words, likelihood ratio (LR) was calculated. A total of 88 alleles were identified, of which eight alleles were newly discovered. The inheritance of HLA alleles followed Mendelian law. With the discovery of new HLA alleles and three recombination events, a total of eleven new HLA haplotypes were identified in this population. LR distribution showed that, when HLA alleles were applied, the Log10LR for a single locus could reach very high and the median average Log10LRs of HLA genes were much higher than that of short tandem repeat loci. The result showed that high-throughput HLA genotyping could be achieved rapidly by MPS, and the contribution of HLA genes on system performance could be high, which may be applied as a supplement in forensic genetics studies. This study was also valuable in demonstrating the genetic mechanisms governing the generation of polymorphisms of the HLA genes.