Long intergenic noncoding RNAs (lincRNAs) have been gradually identified to be functional in a variety of different mechanisms associating with development and epigenetic regulation of cellular homeostasis. However, the study of lincRNAs in diabetic nephropathy (DN) is still in its infancy. Here, we have found dysexpressed long noncoding RNAs (lncRNAs) in renal tissues of db/db DN mice compared with db/m mice by RNA sequencing. In this study, 5 lincRNAs were confirmed to express in a consistent trend among these DN-related lncRNAs both in vivo and in vitro. Particularly, 1700020I14Rik was the downregulated one. Moreover, our data showed overexpression or knockdown of 1700020I14Rik could regulate cell proliferation and fibrosis in mouse mesangial cells (MCs). Furthermore, 1700020I14Rik was found to interact with miR-34a-5p via both the directly targeting way by bioinformatic investigation and luciferase assay and the Ago2-dependent manner by RIP assay. Results also displayed that overexpression of 1700020I14Rik inhibited cell proliferation and expressions of renal fibrosis markers through miR-34a-5p/Sirt1/HIF-1α pathway in MCs under high glucose condition, while knockdown of 1700020I14Rik could increase cell proliferation and expressions of renal fibrosis markers. In conclusion, these results provide new insights into the regulation between 1700020I14Rik and miR-34a-5p/Sirt1/HIF-1α signaling pathway during the progression of DN.

BackgroundMicrosporidian Nosema bombycis has received much attention because the pébrine disease of domesticated silkworms results in great economic losses in the silkworm industry. So far, no effective treatment could be found for pébrine. Compared to other known Nosema parasites, N. bombycis can unusually parasitize a broad range of hosts. To gain some insights into the underlying genetic mechanism of pathological ability and host range expansion in this parasite, a comparative genomic approach is conducted. The genome of two Nosema parasites, N. bombycis and N. antheraeae (an obligatory parasite to undomesticated silkworms Antheraea pernyi), were sequenced and compared with their distantly related species, N. ceranae (an obligatory parasite to honey bees).ResultsOur comparative genomics analysis show that the N. bombycis genome has greatly expanded due to the following three molecular mechanisms: 1) the proliferation of host-derived transposable elements, 2) the acquisition of many horizontally transferred genes from bacteria, and 3) the production of abundnant gene duplications. To our knowledge, duplicated genes derived not only from small-scale events (e.g., tandem duplications) but also from large-scale events (e.g., segmental duplications) have never been seen so abundant in any reported microsporidia genomes. Our relative dating analysis further indicated that these duplication events have arisen recently over very short evolutionary time. Furthermore, several duplicated genes involving in the cytotoxic metabolic pathway were found to undergo positive selection, suggestive of the role of duplicated genes on the adaptive evolution of pathogenic ability.ConclusionsGenome expansion is rarely considered as the evolutionary outcome acting on those highly reduced and compact parasitic microsporidian genomes. This study, for the first time, demonstrates that the parasitic genomes can expand, instead of shrink, through several common molecular mechanisms such as gene duplication, horizontal gene transfer, and transposable element expansion. We also showed that the duplicated genes can serve as raw materials for evolutionary innovations possibly contributing to the increase of pathologenic ability. Based on our research, we propose that duplicated genes of N. bombycis should be treated as primary targets for treatment designs against pébrine.

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Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). However, the exact mechanism is not clearly understood. In this study, our results showed that 24 h urinary protein, kidney index, and glomerular area were decreased, while creatinine clearance ratio was increased in DN rats when the rats were treated with NAR 50 mg/d for 6 weeks. Mesangial cell (MMCs) proliferation was inhibited in the NAR group by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and the cell cycle analysis showed that cells stayed in G2 phase in NAR group. And NAR treatment attenuated the deposition of ECM in DN rats and MMCs. Moreover, our data showed that let-7a was downexpressed in both DN rats and MMCs under high glucose condition. Surprisingly, NAR affected the expressions of Col4 and FN through upregulating let-7a in MMCs. In addition, we found that let-7a negatively regulated the expression of transforming growth factor-β1 receptor 1 (TGFBR1), and TGFBR1 was required for the let-7a-mediated downregulation of TGF-β1/smad signaling. Interestingly, NAR inhibited TGF-β1/smads signaling activation by upregulating let-7a. Therefore, our findings indicated that NAR ameliorated kidney injury by regulating let-7a/TGFBR1 signaling.

Microsporidia are a diverse parasite phylum infecting host from all major taxa in all global biomes. This research was conducted to conclude the prevalence of microsporidia in China. All published articles up to February 16, 2018 were considered, including descriptive, cross-sectional, case-control and epidemiology studies. A total of 1052 articles were separated after literature search. After a strict selection according to our criteria, 82 articles were included in qualitative synthesis and ultimately 52 studies were included in quantitative synthesis. Three species of microsporidia were confirmed to exist in China, including Enterocytozoon bieneusi ( E . bieneusi ), Nosema and Encephalitozoon cuniculi ( E . cuniculi ). The highest overall estimated prevalence of E . bieneusi in humans was 8.1%, which was observed in acquired immunodeficiency syndrome patients (AIDS). Moreover, the prevalence of E . bieneusi in animals including the cattle, dogs, pigs, deer, sheep and goats were analyszed in this study. The overall estimated prevalence of E . bieneusi acquired by using the random effects model in meta-analysis in cattle, dogs, pigs, sheep and goats and deer was 20.0% (95% confidence intervals: 0.133–0.266, I 2 = 98.031%, p < 0.0001), 7.8% (95% CI : 0.050–0.106, I 2 = 60.822%, p = 0.0537), 45.1% (95% CI : 0.227–0.674, I 2 = 98.183%, p < 0.0001), 28.1% (95% CI : 0.146–0.415, I 2 = 98.716%, p < 0.0001) and 19.3% (95% CI : 0.084–0.303, I 2 = 96.995%, p < 0.0001) respectively. The overall detection rate of E . bieneusi in water acquired by using the random effects model in meta-analysis was 64.5% (95% CI: 0.433–0.857, I 2 = 98.486%, p < 0.0001). Currently, 221 genotypes of E . bieneusi , 1 genotype of E . cuniculi and 6 Nosema were detected in China. The most prevalent genotype of E . bieneusi was genotype D, followed by BEB6 and EbpC.

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Evidence has shown that long noncoding RNAs (IncRNAs) in the competing endogenous RNA (ceRNA) network are involved in various diseases. However, there is a lack of studies of the ceRNA network in diabetic nephropathy (DN). In this study, we investigated the effect of IncRNAs on mesangial cell (MC) proliferation in DN‐related ceRNA networks. Differences in IncRNA and mRNA expression between DN and normal mouse kidney tissues were detected with RNA‐seq, and DN‐related IncRNA/mRNA/microRNA (miRNA) ceRNA networks were constructed by R3.4.3. Computational analysis was performed, and expression and interactions between the topological RNAs were detected by bioinformatics methods, real‐time quantitative PCR (qPCR), and luciferase assay. Cell proliferation ability was measured by 5‐ethynyl‐2′‐deoxyuridine (EdU) in MCs cultured under high‐ or low‐glucose conditions. Moreover, the effect of the topological key IncRNA histocompatibility 2 K region locus 2 (H2k2) H2k2 on MC proliferation via the miRNA (miR)‐449a/b/triplet motif 11 (Trim11)/Mek signaling pathway was examined by EdU, flow cytometry analysis, and Western blot. In total, 153 IncRNAs, 428 mRNAs, and 2242 interactions were included in the constructed DN‐related ceRNA network. There were 15 RNAs in the top 5% of degree and betweenness. The expression of IncRNA H2k2 and mRNA Trim11 in MCs was increased in DN, which is consistent with the results of RNA‐seq and real‐time qPCR in vivo and in vitro. miR‐449a and miR‐449b, which were down‐regulated in MCs cultured with high glucose, were selected for further analysis. The results of real‐time qPCR and luciferase assay revealed the IncRNA H2k2‐miR‐449a/b‐Trim11 interaction in MCs. In addition, the data showed that H2k2 regulates MC proliferation via the miR‐449ab/Trim11/Mek signaling pathway. Taken together, these results provide new insight into the association between the topological key IncRNA H2k2 in the DN‐related ceRNA network and the miR‐449a/b/Trim11/Mek signaling pathway during MC proliferation in DN.—Chen, W., Peng, R., Sun, Y., Liu, H., Zhang, L., Peng, H., Zhang, Z. The topological key IncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR‐449a/b/Trim11/Mek signaling pathway. FASEB J. 33, 11492–11506 (2019). http://www.fasebj.org

Cervical cancer is the second most commonly diagnosed type of cancer among women after breast cancer. Recent research has addressed the role of microRNAs in cervical cancer. In the present study, we aimed to determine the effect of let‑7a on the regulation of the cell proliferation of cervical cancer and the related signaling pathway. Real‑time RT‑PCR was used to detect the expression of let‑7a in the blood of cervical cancer patients and normal controls. The expression of let‑7a was also assessed in cervical cancer cell lines: HeLa, SiHa and normal human immortalized keratinocyes HaCaT. Cell proliferation was tested by MTT assay, and cell apoptosis and cell cycle were examined by flow cytometric analysis in HeLa cells. Moreover, bioinformatic analysis, dual‑luciferase reporter assay and western blotting were used to confirm the target gene for let‑7a. In addition, the expression of TGF‑β1, SMAD4 and p53 were assessed by western blotting and real‑time PCR. Our studies showed that the expression of let‑7a in cervical cancer was significantly reduced in cervical cancer patients compared with the expression in the normal control group. Cell proliferation of HeLa cells was inhibited by overexpression of let‑7a. The cell cycle analysis showed that an increased population was arrested in the G2 phase in the let‑7a mimic group when compared with that in the mimic control and untreated groups. In addition, the cell cycle‑related factor p53 was increased in the let‑7a overexpression group compared with that in the control and untreated groups. Furthermore, TGFBR1 was confirmed to be a target of let‑7a. Moreover, the expression of TGF‑β1 and SMAD4 proteins was elevated in cervical squamous carcinoma and cervical adenocarcinoma tissues. However, the expression of TGF‑β1 and SMAD4 was decreased in the let‑7a‑overexpressing cervical cancer cell lines (HeLa, SiHa and CaSki). Our data suggest that let‑7a may play a role in the cell proliferation of cervical cancer by regulating the TGF‑β/SMAD pathway, and may participate in the regulation of the occurrence and development of cervical cancer.