MicroRNA-29b-3p promotes intestinal permeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

Irritable bowel syndrome with predominant diarrhea (IBS-D) is characterized by increased intestinal permeability. Previous studies have shown that the microRNA-29 gene is involved in the regulation of intestinal permeability in patients with IBS-D. NF-κB was proved to play a key role in inflammatory response of intestine and resultant disruption of tight junction integrity, whose activity could be inhibited by TNF Receptor-Associated Factor 3 (TRAF3). However, the exact mechanism that induces increased intestinal permeability in IBS-D patients has not been clarified. In this study, we found that microRNA-29b­3p (miR-29b-3p) was significantly upregulated, while TRAF3 was decreased and the NF-κB-MLCK pathway was activated within the colonic tissue of IBS-D patients. Subsequently, we confirmed the targeting relationship between miR-29b-3p and TRAF3 through a double-luciferase reporter assay. Lentivirus transfection of NCM460 cells with miR-29b-3p-overexpressing and -silencing vectors demonstrated that the expression of TRAF3 was negatively correlated with the level of miR-29b-3p. The NF-κB/MLCK pathway was activated in the miR-29b-3p-overexpressing group and inhibited to some extent in the miR-29b-3p-silencing group. Results in WT and miR-29 knockout mice showed that miR-29b-3p levels were increased, TRAF3 levels were decreased, and the NF-κB/MLCK signaling was activated in the WT IBS-D group as compared with the WT control group. The protein levels of TRAF3 and TJs in the miR-29b-/- IBS-D group were partially recovered and NF-κB/MLCK pathway indicators were, to a certain extent, decreased as compared with the WT IBS-D group. These results suggested that miR-29b-3p deletion enhances the TRAF3 level in IBS-D mice and alleviates the high intestinal permeability. In brief, through the analysis of intestinal tissue samples from IBS-D patients and miR-29b-/- IBS-D mice, we showed that miR-29b-3p is involved in the pathogenesis of intestinal hyperpermeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

APOBEC3B is overexpressed in cervical cancer and promotes the proliferation of cervical cancer cells through apoptosis, cell cycle, and p53 pathway.

Objective: APOBEC3B (A3B), a member of the APOBEC family of cytidine deaminases, has been gradually regarded as a key cancerous regulator. However, its expression and mechanism in cervical cancer (CC) have not been fully elucidated. This study was to investigate its expression pattern and potential mechanism on the cell cycle, as well as HPV oncogenes in CC. Methods: Data from The Cancer Genome Atlas (TCGA) and Gene Expression (GEO) were used to indicate the mRNA expression pattern of A3B in cervical cancer. Western blot assay was used to detect A3B levels in SiHa and Hela cell lines. Immunohistochemistry (IHC) was used to explore A3B protein abundance and sublocation in cervical cancer as well as normal cervical tissues. Based on the Protein atlas (www.proteinatlas.org), A3B expression in the SiHa cell line is lower than in the HeLa cell line. Therefore, the SiHa cell line was used for A3B gene overexpression experiments while the HeLa cell line was used for knockdown experiments. Flow cytometry analysis was used to detect cell apoptosis. Biological function and cancer-related pathways of A3B were conducted using bioinformatics analysis. Results: A3B mRNA was significantly overexpressed in cervical cancer in TCGA-cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), GSE67522, and GSE7803. A3B was more highly expressed in cervical cancers than in high-grade squamous intraepithelial lesions and normal controls. A3B expression was found to be progressively activated during cervical cancer development. IHC results showed that A3B was significantly higher in cervical cancer tissues than in normal cervical tissues. A3B plasmid-mediated overexpression experiments and A3B siRNA-mediated knockdown experiments showed that A3B significantly promotes cell proliferation, migration, cell cycle, and chemoresistance in cervical cancer cells by the p53 pathway. GO and KEGG analyses showed that A3B expression was strikingly associated with cell proliferation, apoptosis, and immune-associated pathways. Conclusions: Taken together, our study implies that A3B promotes cell proliferation, migration, and cell cycle and inhibits cancer cell apoptosis through the p53-mediated signaling pathway. Moreover, A3B could also contribute to chemoresistance in cervical cancer cells. It may be a potential diagnostic biomarker and therapeutic target for chemoresistant cervical cancers.

Ferroptosis and Its Emerging Role in Pre-Eclampsia.

Iron is essential for cell survival, and iron deficiency is a known risk factor for many reproductive diseases. Paradoxically, such disorders are also more common in cases of iron overload. Here, we evaluated the role of ferroptosis in women's health, particularly focusing on pre-eclampsia (PE). PE is a multisystem disorder and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Nevertheless, the exact etiological mechanism of PE remains unclear. Interestingly, ferroptosis, as a regulated iron-dependent cell death pathway, involves a lethal accumulation of lipid peroxides and shares some characteristics with PE pathophysiology. In this review, we comprehensively reviewed and summarized recent studies investigating the molecular mechanisms involved in the regulation and execution of ferroptosis, as well as ferroptosis mechanisms in the pathology of PE. We propose that ferroptosis not only plays an important role in PE, but may also become a novel therapeutic target for PE.

Light availability regulated by particulate organic matter affects coral assemblages on a turbid fringing reef.

Recently, increasing evidence suggests that reef-building corals exposed to elevated suspended solids (SS) are largely structured by changes in underwater light availability (ULA). However, there are few direct and quantitative observations in situ support for this hypothesis; in particular, the contribution of SS to the diffuse attenuation coefficient of the photosynthetically active radiation (Kd-PAR) variations is not yet fully understood. Here, we investigated the variations in ULA, the structure of coral assemblages, and the concentration and composition of SS on the Luhuitou fringing reef, Sanya, China. Light attenuation was rapid (Kd-PAR: 0.60 ± 0.39 m-1) resulting in a shallow euphotic depth (Zeu-PAR) (<11 m). Benthic PAR showed significant positive correlations with branching and corymbose corals (e.g. Acropora spp.), while massive and encrusting species (e.g. Porites spp.) dominated the coral communities and showed no significant correlations with PAR. These results indicate that the depth range available for coral growth is shallow and the tolerance to low-light stress differs among coral species. Notably, Kd-PAR showed no significant correlations with the grain size fractions of SS, whereas significant positive correlations were found with its organic fraction content, demonstrating that the light attenuation of SS is mainly regulated by particulate organic matter (POM). Intriguingly, our isotopic evidence revealed that POM concentration contributed the most to changes in Kd-PAR, with its source being slightly less important. Combined, our results highlight ULA regulated by POM is an important factor in contributing to changes in coral assemblages on inshore turbid reefs, and reducing the input of terrestrial materials, especially POM, is an effective measure to alleviate the low-light stress on sensitive coral species.

The Emerging Role of PRMT6 in Cancer.

Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that is involved in epigenetic regulation of gene expression through methylating histone or non-histone proteins, and other processes such as alternative splicing, DNA repair, cell proliferation and senescence, and cell signaling. In addition, PRMT6 also plays different roles in various cancers via influencing cell growth, migration, invasion, apoptosis, and drug resistant, which make PRMT6 an anti-tumor therapeutic target for a variety of cancers. As a result, many PRMT6 inhibitors are being utilized to explore their efficacy as potential drugs for various cancers. In this review, we summarize the current knowledge on the function and structure of PRMT6. At the same time, we highlight the role of PRMT6 in different cancers, including the differentiation of its promotive or inhibitory effects and the underlying mechanisms. Apart from the above, current research progress and the potential mechanisms of PRMT6 behind them were also summarized.

Expression profiling of lncRNAs and mRNAs in placental site trophoblastic tumor (PSTT) by microarray.

As a rare type of gestational trophoblastic disease, placental site trophoblastic tumor (PSTT) is originated from intermediate trophoblast cells. Long noncoding RNAs (lncRNAs) regulate numerous biological process. However, the role of lncRNAs in PSTT remains poorly understood. In the present study, expression levels of lncRNAs and mRNAs in four human PSTT tissues and four normal placental villi were investigated. The results of microarray were validated by the reverse transcription and quantitative real-time polymerase reaction (RT-qPCR) and immunohistochemistry analyses. Furthermore, GO and KEGG pathway analyses were performed to identify the underlying biological processes and signaling pathways of aberrantly expressed lncRNAs and mRNAs. We also conducted the coding-non-coding gene co-expression (CNC) network to explore the interaction of altered lncRNAs and mRNAs. In total, we identified 1247 up-regulated lncRNAs and 1013 down-regulated lncRNAs as well as 828 up-regulated mRNAs and 1393 down-regulated mRNAs in PSTT tissues compared to normal villi (fold change ≥ 2.0, p < 0.05). GO analysis showed that mitochondrion was the most significantly down-regulated GO term, and immune response was the most significantly up-regulated term. A CNC network profile based on six confirmed lncRNAs (NONHSAT114519, NR_103711, NONHSAT003875, NONHSAT136587, NONHSAT134431, NONHSAT102500) as well as 354 mRNAs was composed of 497 edges. GO and KEGG analyses indicated that interacted mRNAs were enriched in the signal-recognition particle (SRP)-dependent cotranslational protein targeting to membrane and Ribosome pathway. It contributes to expand the understanding of the aberrant lncRNAs and mRNAs profiles of PSTT, which may be helpful for the exploration of new diagnosis and treatment of PSTT.

Paeoniflorin alleviates inflammatory response in IBS-D mouse model via downregulation of the NLRP3 inflammasome pathway with involvement of miR-29a.

Paeoniflorin has been traditionally used to treat pain and immunologic derangement in China. However, its detailed mechanism remains to be illuminated. We investigated the mechanism by which paeoniflorin alleviates the inflammatory response in a mouse model of irritable bowel syndrome with predominant diarrhea (IBS-D). C57BL/6 wild type (WT) and miR-29a knockout (KO) mice were randomly divided into control, model, rifaximin, and paeoniflorin groups (n = 7). IBS-D model was induced by single intracolonic instillation of 0.1 mL trinitro-benzene-sulfonic acid (TNBS, 50 mg/mL) combined with restraint stress for seven consecutive days. The treatment groups received rifaximin (100 mg/kg) and paeoniflorin (50 mg/kg) via intragastric administration for seven days, respectively. The results showed that the fecal water content, fecal pellet output, visceral sensitivity, and histopathological score after paeoniflorin treatment were lower than those of the model group in both WT and miR-29a KO mice (P < 0.05). In both lineage mice, damage was observed in the colon tissues of model group, while paeoniflorin treatment partially ameliorated the tissue damage. Serum levels of DAO, DLA, IL-1ß, IL-18, TNF-α, and MPO were decreased after paeoniflorin treatment (P < 0.05), with miR-29a KO mice in a lower level compared with that of WT mice. RT-PCR showed that the relative expression of miR-29a, NF-κB (p65), NLRP3, ASC, caspase-1, IL-1ß, and TNF-α was downregulated while NKRF was upregulated after paeoniflorin treatment (P < 0.05). Immunohistochemistry showed that intestinal epithelial protein levels of NLRP3, ASC, and caspase-1 decreased while those of Claudin-1 and ZO-1 increased in the paeoniflorin treatment group (P < 0.05). In general, compared with WT mice, NLRP3 inflammasome pathway targets was in much lower expression level than miR-29a KO mice. In conclusion, paeoniflorin could inhibit abnormal activation of the NLRP3 inflammasome pathway by inhibiting miR-29a in IBS-D, thereby relieving the inflammatory response of the intestinal mucosa and reconstructing the intestinal epithelial barrier.

Efficacy of apatinib on multiple advanced-stage nongastric cancers.

BACKGROUND: Apatinib has been approved for the treatment of advanced gastric adenocarcinoma and gastric-esophageal junctional adenocarcinoma, but its efficacy is unknown for other advanced solid tumors. AIMS AND OBJECTIVES: We retrospectively reviewed the use of apatinib for multiple advanced-stage non-gastric cancers. Ninety-two patients from 7 hospitals who received additional treatment except apatinib more than once were enrolled. MATERIALS AND METHODS: The primary end-point was the overall response rate (ORR), and the secondary end-points included progression-free survival (PFS), disease control rate (DCR), overall survival, and adverse reactions. We categorized all the patients into six groups according to their cancer type. RESULTS: In the lung cancer group, the ORR was 9% (95% confidence interval [CI], 3%-23%), DCR was 88% (95% CI, 74%-96%), and median PFS was 3 months (95% CI, 1.9-5.4 months). In the cervical cancer group, the ORR was 25% (95% CI, 3%-65%), DCR reached 100%, and median PFS was 3.5 months (95% CI, 0.6-9.0 months). There were different ORRs between the other cancer groups. In addition, the most common adverse effect of apatinib was palmar-plantar erythrodysesthesia syndrome (37%), followed by proteinuria (14%) and hypertension (13%). CONCLUSION: These results suggest that apatinib might be effective for not only gastric cancer but also other carcinomas including lung cancer, colorectal cancer, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Thus, apatinib is a promising targeted drug for multiple types of cancer.