circ-PTTG1IP/miR-671-5p/TLR4 axis regulates proliferation, migration, invasion and inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis.

Circular RNAs (circRNAs) are related to rheumatoid arthritis (RA) development. However, the function and mechanism of circRNA pituitary tumor-transforming 1 interacting protein (circ- PTTG1IP) in RA are unknown. The expression of circ-PTTG1IP in synovial tissues of RA patients and fibroblast-like synoviocytes from RA patients (RA-FLSs) were detected by RT-qPCR. The results uncovered that circ-PTTG1IP was overexpressed in RA patients and RA-FLSs, and circ-PTTG1IP knockdown suppressed cell proliferation, migration, invasion and inflammatory response in RA-FLSs. Besides, we found that circ-PTTG1IP could directly bind to miR-671-5p, and toll-like receptor 4 (TLR4) was a target of miR-671-5p, which was confirmed by dual-luciferase reporter assay. miR-671-5p inhibitor attenuated the effects of circ-PTTG1IP knockdown on RA-FLSs, while the effects of miR-671-5p mimic on RA-FLSs were partly reversed by TLR4 overexpression. Furthermore, circ-PTTG1IP could upregulate TLR4 expression by miR-671-5p. Thus, circ-PTTG1IP knockdown repressed cell proliferation, migration, invasion and inflammatory response in RA-FLSs by regulating the miR-671-5p/TLR4 axis.

Cross talk between increased intracellular zinc (Zn2+) and accumulation of reactive oxygen species in chemical ischemia.

Both zinc (Zn2+) and reactive oxygen species (ROS) have been shown to accumulate during hypoxic-ischemic stress and play important roles in pathological processes. To understand the cross talk between the two of them, here we studied Zn2+ and ROS accumulation by employing fluorescent probes in HeLa cells to further the understanding of the cause and effect relationship of these two important cellular signaling systems during chemical-ischemia, stimulated by oxygen and glucose deprivation (OGD). We observed two Zn2+ rises that were divided into four phases in the course of 30 min of OGD. The first Zn2+ rise was a transient, which was followed by a latent phase during which Zn2+ levels recovered; however, levels remained above a basal level in most cells. The final phase was the second Zn2+ rise, which reached a sustained plateau called Zn2+ overload. Zn2+ rises were not observed when Zn2+ was removed by TPEN (a Zn2+ chelator) or thapsigargin (depleting Zn2+ from intracellular stores) treatment, indicating that Zn2+ was from intracellular storage. Damaging mitochondria with FCCP significantly reduced the second Zn2+ rise, indicating that the mitochondrial Zn2+ accumulation contributes to Zn2+ overload. We also detected two OGD-induced ROS rises. Two Zn2+ rises preceded two ROS rises. Removal of Zn2+ reduced or delayed OGD- and FCCP-induced ROS generation, indicating that Zn2+ contributes to mitochondrial ROS generation. There was a Zn2+-induced increase in the functional component of NADPH oxidase, p47phox, thus suggesting that NADPH oxidase may mediate Zn2+-induced ROS accumulation. We suggest a new mechanism of cross talk between Zn2+ and mitochondrial ROS through positive feedback processes that eventually causes excessive free Zn2+ and ROS accumulations during the course of ischemic stress.

Comparison of multi-modal early oral nutrition for the tolerance of oral nutrition with conventional care after major abdominal surgery: a prospective, randomized, single-blind trial.

BACKGROUND & AIMS: Early oral nutrition (EON) has been shown to improve recovery of gastrointestinal function, length of stay and mortality after abdominal surgery; however, early oral nutrition often fails during the first week after surgery. Here, a multi-modal early oral nutrition program is introduced to promote recovery of gastrointestinal function and tolerance of oral nutrition. METHODS: Consecutive patients scheduled for abdominal surgery were randomized to the multimodal EON group or a group receiving conventional care. The primary endpoint was the time of first defecation. The secondary endpoints were outcomes and the cost-effectiveness ratio in treating infectious complications. The rate of infectious-free patients was regarded as the index of effectiveness. RESULTS: One hundred seven patients were randomly assigned to groups. Baseline characteristics were similar for both groups. In intention-to-treat analysis, the success rate of oral nutrition during the first week after surgery in the multimodal EON group was 44 (83.0%) versus 31 (57.4%) in the conventional care group (P = 0.004). Time to first defecation, time to flatus, recovery time of bowel sounds, and prolonged postoperative ileus were all less in the multimodal EON group (P < 0.05). The median postoperative length of stay in the multimodal EON group was 8 days (6, 12) versus 10 days (7, 18) in the conventional care group (P < 0.001). The total cost of treatment and nutritional support were also less in the multi-modal early oral nutrition group (P < 0.001). The effectiveness was 84.9 and 79.9% in the multimodal EON and conventional care group, respectively (P = 0.475). However, the cost-effectiveness ratio was USD 537.6 (506.1, 589.3) and USD 637.8 (593.9, 710.3), respectively (P < 0.001). CONCLUSION: The multi-modal early oral nutrition program was an effective way to improve tolerance of oral nutrition during the first week after surgery, decrease the length of stay and improve cost-effectiveness after abdominal surgery. TRIAL REGISTRATION: Registration number: ChiCTR-TRC-14004395 . Registered 15 March 2014.

Impact of nutritional support that does and does not meet guideline standards on clinical outcome in surgical patients at nutritional risk: a prospective cohort study.

OBJECTIVE: To investigate the impact of nutritional support on clinical outcomes in patients at nutritional risk who receive nutritional support that meets guideline standards and those who do not. METHODS: This prospective cohort study enrolled hospitalized patients from the Second Affiliated Hospital of Kunming Medical University from February 2010 to June 2012. The research protocols were approved by the university's ethics committee, and the patients signed informed consent forms. The clinical data were collected based on nutritional risk screening, administration of enteral and parenteral nutrition, surgical information, complications, and length of hospital stay. RESULTS: During the study period, 525 patients at nutritional risk were enrolled in the cohorts. Among patients who received nutritional support that met the guideline standards (Cohort 1), the incidence of infectious complications was lower than that in patients who did not meet guideline standards (Cohort 2) (17.1 % vs. 26.9 %, P = 0.01). Subgroup analysis showed that individuals who received a combination of parenteral nutrition (PN) and enteral nutrition (EN) for 7 or more days had a significantly lower incidence of infectious complications (P = 0.001) than those who received only PN for 7 or more days or those who received nutritional support for less than 7 days or at less than 10 kcal/kg/d. Binary logistic regression analysis showed that, after adjusting for confounding factors, nutritional support that met guideline standards for patients with nutritional risk was a protective factor for complications (OR: 0.870, P < 0.002). CONCLUSIONS: In patients at nutritional risk after abdominal surgery, nutritional support that meets recommended nutrient guidelines (especially regimens involving PN + EN ≥ 7 days) might decrease the incidence of infectious complications and is worth recommending; however, well-designed trials are needed to confirm our findings. Nutritional support that does not meet the guideline standards is considered clinically undesirable.

Causal associations between gut microbiota and synovitis-tenosynovitis: a two-sample Mendelian randomization study.

Background: Increasing evidence indicates that gut microbiota dysbiosis is related to synovitis and tenosynovitis. Nonetheless, whether these associations are causal is currently unknown. Objectives: A two-sample Mendelian randomization (MR) study was performed to reveal the causality of gut microbiota with synovitis and tenosynovitis. Methods: The summary statistical data from a large-scale genome-wide association study (GWAS) were applied as the basis for a two-sample MR analysis. The causal effect was estimated using inverse variance weighted (IVW), weighted median, simple mode, MR-Egger, and weighted mode methods, of which IVW was the important method. Meanwhile, the pleiotropy and heterogeneity were detected and measured using MR-Egger regression, Cochran's Q statistics, funnel plots, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Results: The IVW technique demonstrated that genetically predicted five genera, namely Gordonibacter [odds ratio (OR) = 0.999, 95% confidence interval (CI): (0.9977, 0.9998), p = 0.019], Paraprevotella [OR = 0.999, 95% CI: (0.9971, 0.9999), p = 0.036], Lachnoclostridium [OR = 0.998, 95% CI: (0.9954, 0.9999), p = 0.041], RuminococcaceaeUCG003 [OR = 0.997, 95% CI: (0.9955, 0.9994), p = 0.011], and FamilyXIIIAD3011group [OR = 0.997, 95% CI: (0.9954, 0.9992), p = 0.006] were negatively correlated with the risk of synovitis and tenosynovitis, while two other genera, namely Ruminococcustorquesgroup [OR = 1.003, 95% CI: (1.0004, 1.0049), p = 0.019] and Parabacteroides [OR = 1.003, 95% CI: (1.0002, 1.0052), p = 0.035] were positively associated with synovitis and tenosynovitis risk. In addition, the data of sensitivity analyses demonstrated that there were no outliers, horizontal pleiotropy, or heterogeneity in the causal relationship of the above-mentioned gut microbiota on synovitis and tenosynovitis (p > 0.05). Conclusion: The results of the study suggested that the gut microbiota was causally involved in synovitis and tenosynovitis and identified specific bacterial taxa that affect synovitis and tenosynovitis, which provide new insights into the pathogenesis underlying the development of synovitis and tenosynovitis mediated by gut microbiota.

Effect of stability of PTEN on hepatocellular carcinoma.

BACKGROUND: As an antioncogene gene, phosphataseandtensinhomolog (PTEN) is closely related to tumorigenesis. However, after mutation, PTEN will lose its function and no longer exert a tumor suppression effect. Through this research, we explored the impact of PTEN mutation on hepatic carcinoma (HCC) and the mechanism of PTEN for regulating HCC. METHODS: First, bioinformatics was used to analyze the prognosis of PTEN in HCC. PTEN-related genes were then further analyzed by the LinkedOmics database, and GO and KEGG functional enrichment analysis were performed. Next, databases were utilized to predict the mutation and mutation frequency of PTEN. Eventually, CRISPR-Cas12a was applied to detect the R130Q mutation on PTEN in clinical samples of HCC. Finally, the fact that miR-92a-3p targets PTEN was identified by dual luciferase reporter gene assays, RT-qPCR, western blot, and rescue experiments. RESULTS: Bioinformatics analysis indicated the high mutation frequency of R130Q/G/L* site on the PTEN gene. Through CRISPR-Cas12a, R130Q mutation was detected on PTEN in 26 out of 40 clinical samples of HCC. CONCLUSIONS: On the one hand, our study revealed that CRISPR-Cas12a might play an important role in the screening and prognosis of HCC as a new clinical method to detect PTEN mutation.

Six undescribed 23-norursane triterpenoids from the biotransformation of ilexgenin a by endophytic fungi and their vascular protective activity.

Biotransformation of ursane-type triterpenoid ilexgenin A by endophytic fungi Lasiodiplodia sp. MQD-4 and Pestalotiopsis sp. ZZ-1, isolated from Ilex pubescences and Callicarpa kwangtungensis respectively, was investigated for the first time. Six previously undescribed metabolites (1-6) with 23-norursane triterpenoids skeleton were isolated and their structures were unambiguously established by the analysis of spectroscopic data and single-crystal X-ray crystallographic experiments. Decarboxylation, oxidation, and hydroxylation reactions were observed on the triterpenoid skeleton. Especially, the decarboxylation of C-23 provided definite evidence to understand the biogenetic process of 23-norursane triterpenoids. Moreover, the qualitative analysis of the extract of I. pubescences showed metabolites 1, 3, 4, and 6 could be detected in the originated plant, indicating biotransformation by endophytic fungi is a practical strategy for the isolation of novel natural products. Finally, all isolates were evaluated for the protective activities against H2O2-induced HUVECs dysfunction in vitro. Compound 5 could improve the viability of endothelial cells and decrease the level of intracellular ROS.

Protective effect of autophagy inhibition on ischemia-reperfusion-induced injury of N2a cells.

Autophagy is a conserved and programmed catabolic process that degrades damaged proteins and organelles. But the underlying mechanism and functions of autophagy in the ischemia-reperfusion (IR)-induced injury are unknown. In this study, we employed simulated IR of N2a cells as an in vitro model of IR injury to the neurons and monitored autophagic processes. It was found that the levels of Beclin-1 (a key molecule of autophay complex, Beclin-1/class III PI3K) and LC-3II (an autophagy marker) were remarkably increased with time during the process of ischemia and the process of reperfusion after 90 min of ischemia, while the protein kinases p70S6K and mTOR which are involved in autophagy regulation showed delayed inactivation after reperfusion. Administration of 3-methyladenine (3MA), an inhibitor of class III PI3K, abolished autophagy during reperfusion, while employment of rapamycin, an inhibitor of mTORC1 (normally inducing autophagy), surprisingly weakened the induction of autophagy during reperfusion. Analyses of mitochondria function by relative cell viability demonstrated that autophagy inhibition by 3-MA attenuated the decline of mitochondria function during reperfusion. Our data demonstrated that there were two distinct dynamic patterns of autophagy during IR-induced N2a injury, Beclin-1/class III PI3K complex-dependent and mTORC1-dependent. Inhibition of over-autophagy improved cell survival. These suggest that targeting autophagy therapy will be a novel strategy to control IR-induced neuronal damage.

Unveiling the ecological significance of phosphorus fractions in shaping bacterial and archaeal beta diversity in mesotrophic lakes.

Both community variation and phosphorus (P) fractions have been extensively studied in aquatic ecosystems, but how P fractions affect the mechanism underlying microbial beta diversity remains elusive, especially in sediment cores. Here, we obtained two sediment cores to examine bacterial and archaeal beta diversity from mesotrophic lakes Hongfeng Lake and Aha Lake, having historically experienced severe eutrophication. Utilizing the Baselga's framework, we partitioned bacterial and archaeal total beta diversity into two components: species turnover and nestedness, and then examined their sediment-depth patterns and the effects of P fractions on them. We found that total beta diversity, species turnover or nestedness consistently increased with deeper sediment layers regarding bacteria and archaea. Notably, there were parallel patterns between bacteria and archaea for total beta diversity and species turnover, which is largely underlain by equivalent processes such as environmental selection. For both microbial taxa, total beta diversity and species turnover were primarily constrained by metal oxide-bound inorganic P (NaOH-Pi) and sediment total phosphorus (STP) in Hongfeng Lake, while largely affected by reductant-soluble total P or calcium-bound inorganic P in Aha Lake. Moreover, NaOH-Pi and STP could influence bacterial total beta diversity by driving species nestedness in Hongfeng Lake. The joint effects of organic P (Po), inorganic P (Pi) and total P fractions indicated that P fractions are important to bacterial and archaeal beta diversity. Compared to Po fractions, Pi fractions had greater pure effects on bacterial beta diversity. Intriguingly, for total beta diversity and species turnover, archaea rather than bacteria are well-explained by Po fractions in both lakes, implying that the archaeal community may be involved in Po mineralization. Overall, our study reveals the importance of P fractions to the mechanism underlying bacterial and archaeal beta diversity in sediments, and provides theoretical underpinnings for controlling P sources in biodiversity conservation.

The effect and mechanism of Huangqin-Baishao herb pair in the treatment of dextran sulfate sodium-induced ulcerative colitis.

Background: The haungqing (Scutellariae Radix) and baishao (Paeoniae Radix Alba) herb pair (HBHP) is a common prescribed herbal formula or is added to other traditional Chinese medicine (TCM) prescriptions to treat ulcerative colitis (UC). However, the underlying mechanism is unclear. Purpose: Elucidate the efficacy and potential mechanism of HBHP against UC. Methods: First, The UC model of mice induced by dextran sulfate sodium (DSS) was established. The mice were randomly divided into Control group, DSS group, SASP group (390 mg/kg), and HPHP group (1.95 g/kg), with 8 mice per group. Drugs were administrated via oral gavage for 7 days. Then, Disease activity index (DAI), length of the colon, histopathology, and changes in inflammatory cytokines in colonic tissues were analyzed to assess the effect of HBHP on UC. Besides, Network pharmacology was applied to identify the active compounds, core targets of HBHP in the treatment of UC, and the corresponding signaling pathways to explore the underlying mechanisms. Finally, Western blot (WB), immunohistochemistry (IHC) and molecular docking were performed to validate the results. Results: HBHP significantly reduced DAI score and decreased colon length shortening in DSS-induced UC mice. The administration of HBHP was able to effectively alleviated mucosal ulceration and epithelial destruction. In addition, HBHP treatment obviously - reduced the expressions of TNF-α, IL-6, and IL-1ß in colon tissues (p < 0.05 or p < 0.01). 35 bioactive compounds and 290 HBHP targets related to UC were obtained. Among them 3 key active compounds (baicalein, panicolin, and norwogonin) with higher degree values in the drug-compound-target network and 21 hub genes (STAT3, JAK2, SRC, AKT1, PIK3CA, and VEGFA, etc.) were identified. KEGG enrichment analysis suggested that HBHP's mechanisms mainly involve the JAK-STAT pathway. Abnormal activation of JAK/STAT signaling is believed to be involved in the pathogeneses of UC. Notably, WB and IHC showed that HBHP significantly down-regulated the protein expression levels of p-JAK2 (p < 0.05) and p-STAT3 (p < 0.05 or p < 0.01). JAK2 and STAT3 might be core targets for the action of HBHP; this possibility was also supported by molecular docking. Conclusions: HBHP could alleviate DSS-induced UC, reduce tissue inflammation, and its mechanism might primarily be achieved by inhibiting JAK2/STAT3 signaling pathway. Meanwhile, our work revealed that network pharmacology combined with experimental verification is a cogent means of studying the mechanism of TCM.

Upregulating miR-27a-3p inhibits cell proliferation and inflammation of rheumatoid arthritis synovial fibroblasts through targeting toll-like receptor 5.

Rheumatoid arthritis (RA) is a serious chronic inflammatory disease and synovial fibroblasts (SFs) serve a vital role in the pathogenesis and progression of RA. Current studies have demonstrated that dysregulation of microRNAs is involved in RA etiopathogenesis. The present study aimed to investigate the role of microRNA (miR)-27a-3p in RASFs, as well as its molecular mechanism. RASFs were isolated from synovial tissues from patients with RA. Expression of miR-27a-3p and toll-like receptor 5 (TLR5) was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation, apoptosis and inflammatory response were measured with MTT assay, flow cytometry and ELISA kits, respectively. The target binding between miR-27a-3p and TLR5 was predicted on DIANA TOOLS software, and confirmed by dual-luciferase reporter assay and Biotin-coupled miRNA pull-down assay. Expression of miR-27a-3p was downregulated and TLR5 was upregulated in synovial tissues and RASFs isolated from patients with RA. Functionally, upregulating miR-27a-3p may promote the apoptosis rate of RASFs and suppress cell proliferation and secretions of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α. TLR5 was validated as a downstream target for miR-27a-3p in RASFs, and its expression was negatively regulated by miR-27a-3p. Silencing TLR5 in RASFs may exert similar effects to miR-27a-3p-overexpression; whereas, restoring TLR5 counteracted the suppression of miR-27a-3p-overexpression on RASF proliferation and inflammation, as well as the promotion on apoptosis. miR-27a-3p upregulation may suppress RA progression by inhibiting RASFs proliferation and inflammation through targeting TLR5.

Long non-coding RNA ADAMTS9-AS2 inhibits liver cancer cell proliferation, migration and invasion.

Long non-coding RNA (lncRNA) ADAM metallopeptidase with thrombospondin type 1 motif 9 antisense RNA 2 (ADAMTS9-AS2) is involved in various types of cancer, such as ovarian cancer, lung cancer and clear cell renal cell carcinoma. However, the roles of ADAMTS9-AS2 in liver cancer are not completely understood. The present study aimed to determine the functional role of ADAMTS9-AS2 in human liver cancer and investigate the potential underlying molecular mechanisms. The expression levels of ADAMTS9-AS2 and ADAMTS9 were determined following ADAMTS9-AS2 overexpression and knockdown. The results indicated that ADAMTS9-AS2 overexpression and knockdown increased and decreased ADAMTS9 mRNA and protein expression levels, respectively, indicating that alterations in ADAMTS9 expression corresponded with ADAMTS9-AS2 expression. Subsequently, the effects of ADAMTS9-AS2 on liver cancer cell proliferation, migration and invasion were analyzed by performing Cell Counting Kit-8, wound healing and Transwell assays, respectively. The results demonstrated that ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion. Finally, the effect of ADAMTS9 on PI3K/AKT/mTOR signaling pathway-associated proteins [AKT, phosphorylated-AKT, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit ß (PIK3CB), mTOR and phosphorylated-mTOR], several key autophagy-related proteins [light chain 3-I/II (LC3-I/II), beclin 1 (BECN1) and sequestosome 1 (SQSTM1)] and apoptosis-related proteins (Bax and Bcl-2) was detected via western blotting. The results suggested that ADAMTS9-AS2 downregulated the phosphorylation of AKT and mTOR, the protein expression level of PIK3CB, as well as the expression levels of autophagy protein SQSTM1 and antiapoptotic protein Bcl-2. By contrast, ADAMTS9-AS2 upregulated the expression levels of autophagy proteins LC3-II and BECN1, and the proapoptotic protein Bax. Collectively, ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion via inhibiting the PI3K/AKT/mTOR signaling pathway. The present study provided a novel insight into the role of ADAMTS9-AS2 in liver cancer.

Consensus recommendations of three-dimensional visualization for diagnosis and management of liver diseases.

Three-dimensional (3D) visualization involves feature extraction and 3D reconstruction of CT images using a computer processing technology. It is a tool for displaying, describing, and interpreting 3D anatomy and morphological features of organs, thus providing intuitive, stereoscopic, and accurate methods for clinical decision-making. It has played an increasingly significant role in the diagnosis and management of liver diseases. Over the last decade, it has been proven safe and effective to use 3D simulation software for pre-hepatectomy assessment, virtual hepatectomy, and measurement of liver volumes in blood flow areas of the portal vein; meanwhile, the use of 3D models in combination with hydrodynamic analysis has become a novel non-invasive method for diagnosis and detection of portal hypertension. We herein describe the progress of research on 3D visualization, its workflow, current situation, challenges, opportunities, and its capacity to improve clinical decision-making, emphasizing its utility for patients with liver diseases. Current advances in modern imaging technologies have promised a further increase in diagnostic efficacy of liver diseases. For example, complex internal anatomy of the liver and detailed morphological features of liver lesions can be reflected from CT-based 3D models. A meta-analysis reported that the application of 3D visualization technology in the diagnosis and management of primary hepatocellular carcinoma has significant or extremely significant differences over the control group in terms of intraoperative blood loss, postoperative complications, recovery of postoperative liver function, operation time, hospitalization time, and tumor recurrence on short-term follow-up. However, the acquisition of high-quality CT images and the use of these images for 3D visualization processing lack a unified standard, quality control system, and homogeneity, which might hinder the evaluation of application efficacy in different clinical centers, causing enormous inconvenience to clinical practice and scientific research. Therefore, rigorous operating guidelines and quality control systems need to be established for 3D visualization of liver to develop it to become a mature technology. Herein, we provide recommendations for the research on diagnosis and management of 3D visualization in liver diseases to meet this urgent need in this research field.

Analysis of potential functional significance of microRNA­3613­3p in human umbilical vein endothelial cells affected by heat stress.

Dysregulation of microRNA­3613­3p (miR­3613­3p) was previously reported in endothelial cells (ECs) during heat stress. The aim of the present study was to investigate the precise role of miR­3613­3p in heat stress. In the present study, potential gene targets of miR­3613­3p in heat­treated ECs were assessed, and the potential effects of miR­3613­3p were determined using Gene Ontology enrichment analysis. Kyoto Encyclopedia of Genes and Genomes pathway analysis was used to identify signaling pathways that may be affected by miR­3613­3p in heat­treated cells. Reverse transcription­quantitative PCR, western blotting and annexin V­FITC/propidium iodide staining were performed to detect miRNA expression, protein expression and apoptosis, respectively. Luciferase gene reporter assay was performed to evaluate the association between miR­3613­3p and mitogen­activated protein kinase kinase kinase 2 (MAP3K2). Bioinformatics analysis revealed 865 potential gene targets for miR­3613­3p and a series of functions and pathways in heat­treated ECs. 'Negative regulation of apoptotic process' was identified as a potential function of miR­3613­3p. In addition, functional analysis confirmed the downregulated expression levels of miR­3613­3p in ECs during heat stress, which was accompanied by an increase in apoptosis; restoration of miR­3613­3p expression inhibited apoptosis. MAP3K2 protein was demonstrated to be upregulated in heat­treated ECs, and overexpression of miR­3613­3p reduced MAP3K2 expression levels. Additionally, MAP3K2 was targeted by miR­3613­3p. These results indicated that miR­3613­3p may have complicated roles in ECs under heat stress. miR­3613­3p may serve an important role in the apoptosis of heat­treated ECs, and this effect may be partly achieved by targeting MAP3K2.

Systematic review and meta-analysis of the prognostic significance of microRNAs in cervical cancer.

In this meta-analysis, we analyzed case-control studies that assessed the prognostic potential of miRNAs in cervical cancer. We comprehensively searched EMBASE and PubMed databases and enrolled seven studies with 445 cervical cancer cases. A fixed effects model was used to calculate pooled hazard ratios (HRs) and associated 95% confidence intervals (95% CIs) from the overall survival (OS) data. Our analysis showed that poor OS in cervical cancer was associated with low miR-125 expression (HR = 1.61, 95% CI: 1.02-2.55, P = 0.042; I2 = 10.1%, P = 0.292; n = 99), low miR-145 expression (HR = 1.70, 95% CI: 1.29-2.24, P < 0.001; I2 = 0%, P = 0.560; n = 193) and high miR-196 expression (HR = 0.28, 95% CI: 0.15-0.52, P < 0.001; I2 = 0%, P = 0.950, n = 197). This makes microRNAs such as miR-125, miR-145 and miR-196 potential prognostic biomarkers in cervical cancer.

[Significances of gene differential expression patterns in hepatocirrhosis and non-hepatocirrhosis tissues within different ischemic time].

OBJECTIVE: To investigate the gene differential expression patterns in hepatocirrhosis and non-hepatocirrhosis tissues within different ischemic time. METHODS: The liver tissues were divided into two groups: Group A (non-hepatocirrhosis), Group B (hepatocirrhosis), each of which consisted of 3 groups with different ischemic time: 15, 30 and 45 minutes. The gene differential expression patterns in the two groups within different ischemic time were detected and compared with those in normal liver tissues by using 4000 points gene microarray. RESULTS: In non-hepatocirrhosis tissues, the homeostatic maintenance genes expressed highly during hepatic ischemia for 15 minutes, and no apoptotic gene was expressed; but in hepatocirrhosis tissues, many apoptotic genes expressed highly. As for 30 minutes, in both two groups liver tissue genes expressed to the peak, and the genes related to cell death, oxidative stress and nuclear factors expressed highly. The difference lies in the facts that in Group B pro-apoptosis genes expressed more than those in Group A, and the Ratio values were higher than those in Group A. Many genes of heat shock protein family and antioxidant proteins expressed highly simultaneously in Group A, but comparatively low in Group B. As for 45 minutes, genes of heat shock proteins and antioxidant proteins expressed lowly in Group B. CONCLUSIONS: It suggests that the safe time limit of hepatic ischemia for cell survive is 30 minutes or so. Non-hepatocirrhosis tissues could endure 30 minutes of ischemia and even longer, but it should be restricted within 30 minutes in hepatocirrhosis tissues.

Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling.

Mucin 1 (MUC1) is aberrantly overexpressed in numerous human cancer types, including hepatocellular carcinoma (HCC) and contributes to chemoresistance of tumor cells. The aim of the present study was to evaluate the possible implication of MUC1 in radioresistance of HCC cells and the underlying mechanisms. It was demonstrated that MUC1 was significantly upregulated in HCC cells following irradiation exposure, which was coupled with increased phosphorylation of signal transducer and activator of transcription 3 (STAT3). Enforced expression of MUC1 significantly (P<0.05) promoted the clonogenic survival of HCC cells following irradiation compared with empty vector-transfected cells. MUC1 overexpression resulted in >60% reduction in apoptosis induced by irradiation, as determined by Annexin-V/propidium iodide double staining and flow cytometry analysis. Furthermore, overexpression of MUC1 significantly (P<0.05) attenuated the activation of caspase-3 and poly (ADP-ribose) polymerase in response to irradiation exposure. Mechanistically, MUC1 inhibited irradiation-induced apoptosis through activation of janus kinase 2 (JAK2) and STAT3, and induction of anti-apoptotic proteins induced myeloid leukemia cell differentiation protein Mcl-1 (Mcl-1) and BCL2 like 1 (Bcl-xL). Small hairpin RNA-mediated knockdown of STAT3 or MUC1 resensitized MUC1-overexpressing cells to irradiation-induced apoptosis, which was accompanied by reduced expression of Bcl-xL and Mcl-1. Collectively, MUC1 contributes to radioresistance of HCC cells likely through activation of the JAK2/STAT3 signaling pathway and thus represents a potential target for improving radiotherapy against HCC.

Meta-analysis showing that early response to neoadjuvant chemotherapy predicts better survival among cervical cancer patients.

This study was designed to identify the prognostic value of early response to neoadjuvant chemotherapy (NACT) for long-term survival of cervical cancer patients. We searched Pubmed and EMBASE for studies published through July 2016 on outcomes of cervical patients that received NACT. Eight studies involving 825 cervical cancer patients were ultimately included in our meta-analysis. We pooled the hazard ratios (HR) according to random-effects models and used funnel plots with Egger's and Begg's tests to explore potential publication bias. The HR between early response and 1-year overall survival (OS) was 3.60 (95% CI 1.93-6.72; I2 = 0). Similar results were found in the analysis of 3-year OS (HR 3.34; 95% CI 2.28-4.90; I2 = 0) and 5-year OS (HR 3.44; 95% CI 2.40-4.94; I2 = 0). Sensitivity analysis showed that all of the pooled results were robust, and all logHRs had confidence limits > 0. Our findings indicate that early response is associated with long-term survival, and responders achieved a higher survival rate than non-responders.

Analysis of miRNA expression profiling in human umbilical vein endothelial cells affected by heat stress.

To investigate the regulation of endothelial cell (EC) microRNAs (miRNAs) altered by heat stress, miRNA microarrays and bioinformatics methods were used to determine changes in miRNA profiles and the pathophysiological characteristics of differentially expressed miRNAs. A total of 31 differentially expressed miRNAs were identified, including 20 downregulated and 11 upregulated miRNAs. Gene Ontology (GO) enrichment analysis revealed that the validated targets of the differentially expressed miRNAs were significantly enriched in gene transcription regulation. The pathways were also significantly enriched in the Kyoto Encyclopedia of Genes and Genomes analysis, and most were cancer-related, including the mitogen-activated protein kinase signaling pathway, pathways involved in cancer, the Wnt signaling pathway, the Hippo signaling pathway, proteoglycans involved in cancer and axon guidance. The miRNA-gene and miRNA­GO network analyses revealed several hub miRNAs, genes and functions. Notably, miR­3613-3p played a dominant role in both networks. MAP3K2, MGAT4A, TGFBR1, UBE2R2 and SMAD4 were most likely to be controlled by the altered miRNAs in the miRNA-gene network. The miRNA­GO network analysis revealed significantly complicated associations between miRNAs and different functions, and that the significantly enriched functions targeted by the differentially expressed miRNAs were mostly involved in regulating gene transcription. The present study demonstrated that miRNAs are involved in the pathophysiology of heat-treated ECs. Understanding the functions of miRNAs may provide novel insights into the molecular mechanisms underlying the heat­induced pathophysiology of ECs.

JNK signaling is required for the MIP­1α­associated regulation of Kupffer cells in the heat stroke response.

Severe heat stroke (HS) consists of extreme hyperthermia with thermoregulatory failure, leading to high morbidity and mortality. Liver injury is a complication of HS that is associated with inflammatory responses and Kupffer cells (KCs), which are resident macrophages in the liver that serve as a major source of inflammatory cytokines; however, the association and the underlying mechanisms of KC functions in HS­induced endotoxemia and inflammation require an improved understanding. The important chemokine macrophage inflammatory protein­1α (MIP­1α) increases inflammatory responses and the secretion of inflammatory molecules from KCs, including tumor necrosis factor­α, interleukin (IL)­1ß and IL­6. In addition, the activation of c­Jun N­terminal kinase (JNK) signaling is responsible for the development of liver inflammation. Therefore, HS animal and cell models were constructed in order to investigate the pathways involved in the HS­induced dysfunction of KCs. The results of the present study suggest that JNK may be involved in the MIP­1α­associated pathogenesis of KCs in HS injury.