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Long noncoding RNAs (lncRNAs) have a profound effect on biological processes in various malignancies. However, few studies have investigated their functions and specific mechanisms in endometrial cancer. In this study, we focused on the role and mechanism of lncRNA‐ZXF1 in endometrial cancer. Bioinformatics and in vitro and in vivo experiments were used to explore the expression and function of lncRNA‐ZXF1. We found that lncRNA‐ZXF1 altered the migration and invasion of endometrioid endometrial cancer (EEC) cells. Furthermore, our results suggest that lncRNA‐ZXF1 regulates EEC cell proliferation. This regulation may be achieved by the lncRNA‐ZXF1‐mediated alteration in the expression of P21 through two mechanisms. One is that lncRNA‐ZXF1 functions as a molecular sponge of miR‐378a‐3p to regulate PCDHA3 expression and then modulate the expression of P21. The other is that lncRNA‐ZXF1 inhibits CDC20‐mediated degradation of ubiquitination by directly binding to P21. To the best of our knowledge, this study is the first to explore lncRNA‐ZXF1 functioning as a tumor‐suppressing lncRNA in EEC. LncRNA‐ZXF1 may become therapeutic, diagnostic, and prognostic indicator in the future., In this study, we found that lncRNA‐ZXF1 may act as a tumor suppressor gene to regulate the proliferation and invasion of endometrioid endometrial cancer (EEC). LncRNA‐ZXF1 potentially alters P21 expression in EEC through two mechanisms: by regulating P21 protein expression through the miR‐378a‐3p/PCDHA3 axis and by directly binding to P21 to prevent its CDC20‐mediated ubiquitin degradation.

Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo. The above datas suggest that targeting CNR1 may reverse the progesterone resistance in endometrial cancer and may coordinate the role of ERK pathway activation.

Studies have shown that hyperglycemia aggravates brain damage by affecting vascular endothelial function. However, the precise mechanism remains unclear. Male Sprague-Dawley rat models of diabetes were established by a high-fat diet combined with an intraperitoneal injection of streptozotocin. Rat models of traumatic brain injury were established using the fluid percussion method. Compared with traumatic brain injury rats without diabetic, diabetic rats with traumatic brain injury exhibited more severe brain injury, manifested as increased brain water content and blood-brain barrier permeability, the upregulation of heme oxygenase-1, myeloperoxidase, and Bax, the downregulation of occludin, zona-occludens 1, and Bcl-2 in the penumbra, and reduced modified neurological severity scores. The intraperitoneal injection of a nitric oxide synthase inhibitor N(5)-(1-iminoethyl)-L-ornithine (10 mg/kg) 15 minutes before brain injury aggravated the injury. These findings suggested that nitric oxide synthase plays an important role in the maintenance of cerebral microcirculation, including anti-inflammatory, anti-oxidative stress, and anti-apoptotic activities in diabetic rats with traumatic brain injury. The experimental protocols were approved by the Institutional Animal Care Committee of Harbin Medical University, China (approval No. ky2017-126) on March 6, 2017.

Non-alcoholic fatty liver disease is associated with gut microbiota, oxidative stress, and inflammation. We aimed to investigate the possible mechanism by which noni fruit polysaccharide (NFP) improved hepatic oxidative stress and inflammation in rats under a high-fat diet (HFD) by modulating short-chain fatty acids (SCFAs), the intestinal barrier, and gut microbiota. Hepatic oxidative stress, inflammation, and gut dysbiosis in rats were induced through HFD feeding for 4 weeks, followed by intervention with NFP treatment (100 mg per kg bw) for 5 weeks. The results showed that NFP reduced body weight gain and improved lipid metabolism, hepatic oxidative stress, and inflammation in rats under a HFD. Aside from these beneficial effects, NFP positively affected the SCFA production and reversed the HFD-induced gut dysbiosis as indicated by improved microbiota diversity and composition. The levels of Lactobacillus, Ruminococcaceae_UCG_014, Parasutterella, [Eubacterium]_coprostanoligenes_group, and Ruminococcus_1 improved, whereas the levels of Prevotella_9, Collinsella, Bacteroides, and Turicibacter decreased. Furthermore, NFP maintained the colonic barrier integrity (increased the mRNA relative expression of CCL5, ZO-1, and occludin in the colon, and decreased the serum CCL5 level), and decreased the serum lipopolysaccharide level. Thus, NFP may modulate the gut microflora and SCFA production and reduce the permeability of the colonic barrier and metabolic endotoxemia, thereby alleviating hepatic oxidative stress and inflammation in rats under a HFD.

Objectives: Most patients with gallbladder cancer (GBC) present with advanced-stage disease and have a poor prognosis. Radical resection remains the only therapeutic option to improve survival in patients with GBC. This study aimed to analyze the prognostic factors in patients with stage ⅣGBC and to identify a subgroup of patients who might benefit from R0 resection. Methods: A total of 285 patients with stage ⅣGBC were retrospectively analyzed at our institution from January 2008 to December 2012. Factors potentially influencing the prognosis of GBC after surgery were analyzed by univariate and multivariate analyses. Results: The 1-, 3-, and 5-year overall survival rates were 6.6% (15/229), 0.9% (2/229), and 0 (0/229), respectively. Ascites (relative risk [RR] ＝ 1.631, 95% confidence interval [CI]: 1.221-2.180, P ＝ 0.001), pathological grade (RR ＝ 1.337, 95% CI: 1.050-1.702, P ＝0.018), T stage (RR ＝1.421, 95% CI: 1.099-1.837, P ＝0.000), M stage (RR ＝1.896, 95% CI: 1.409-2.552, P ＝ 0.000), and surgery (RR ＝ 1.542, 95% CI: 1.022-2.327, P ＝ 0.039) were identified as independent risk factors influencing prognosis. The median survival time (MST) was significantly higher in patients undergoing R0 resection than in those undergoing R1/R2 resection (6.0 vs. 2.7 months; P < 0.001). In subgroup analyses, stage IVA patients benefited from R0 resection (MST for R0 vs. R1/R2, 11.0 vs. 4.0 months; P ＝ 0.003), while R0 resection had a significant survival benefit than R1/R2 resection in patient with stage IVB GBC without distant metastasis (MST for R0 vs. R1/R2, 6.0 vs. 3.0 months; P ＝ 0.007). Conclusion: Ascites, pathological grade, T stage, M stage, and surgery were independent risk factors influencing prognosis in patients with stage ⅣGBC. N2 lymph node metastasis did not preclude curative resection, and radical resection should be considered in patients with stage ⅣGBC without distant metastasis once R0 margin was achieved. Key words: Gallbladder cancer; Surgery; Prognosis; Tumor-node-metastasis (TNM) stage

Aim Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth. Methods Immunohistochemistry and quantitative real‐time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real‐time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro. Results We found that MAGL was overexpressed in EC and was significantly correlated with surgical‐pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA‐mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl‐2. Conclusion In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.

MicroRNAs (miRNAs) are powerful regulators in the tumorigenesis of cholangiocarcinoma (CCA). Previous studies report that miR‐551b‐3p acts as an oncogenic factor in ovarian cancer, but plays a tumour suppressive role in gastric cancer. However, the expression pattern and potential function of miR‐551b‐3p were still unclear in CCA. Therefore, this study aimed to explore the expression of miR‐551b‐3p and its role as well as molecular mechanism in CCA. Analysis of TCGA dataset suggested that miR‐551b‐3p was under‐expressed in CCA tissues compared to normal bile duct tissues. Furthermore, our data confirmed the decreased levels of miR‐551b‐3p in CCA samples and cell lines. Interestingly, TCGA data suggested that low miR‐551b‐3p level indicated reduced overall survival of CCA patients. Gain‐ and loss‐of‐function experiments found that miR‐551b‐3p inhibited the proliferation, G1‐S phase transition and induced apoptosis of CCA cells. In vivo experiments revealed that ectopic expression of miR‐551b‐3p inhibited tumour growth of CCA in mice. Further investigation demonstrated that miR‐551b‐3p directly bond to the 3′‐UTR of Cyclin D1 (CCND1) mRNA and negatively regulated the abundance of CCND1 in CCA cells. An inverse correlation between miR‐551b‐3p expression and the level of CCND1 mRNA was detected in CCA tissues from TCGA dataset. Notably, CCND1 knockdown showed similar effects to miR‐551b‐3p overexpression in HuCCT‐1 cells. CCND1 restoration rescued miR‐551b‐3p‐induced inhibition of proliferation, G1 phase arrest and apoptosis in HuCCT‐1 cells. In summary, miR‐551b‐3p inhibits the expression of CCND1 to suppress CCA cell proliferation and induce apoptosis, which may provide a theoretical basis for improving CCA treatment.

Previous studies proposed that acidic reperfusion may be a protective strategy for myocardial ischemia–reperfusion therapy with potential of clinical transformation. In this study, we investigated whether therapeutic hypercapnia could mimic acidosis postconditioning in isolated hearts with a 30-min left coronary artery ligation–reperfusion model in rats. Therapeutic hypercapnia (inhalation 20% CO2 for 10 min) is cardioprotective with a strict therapeutic time window and acidity: it reduced the infarct ratio and serum myocardial enzyme and increased the myocardial ATP content. Furthermore, mitochondrial morphology damage, the loss of mitochondrial membrane potential, and the formation of mitochondrial permeability transition pore were effectively inhibited, indicating the improvements in mitochondrial function. The expression of the mitochondrial biogenesis regulators was upregulated simultaneously. These findings indicated therapeutic hypercapnia in animals can mimic ex vivo acidosis postconditioning to alleviate myocardial ischemia–reperfusion injury. The effect is related to improvement in mitochondrial function and regulation of the mitochondrial biogenesis pathway.

Background: Sufficient supply of deoxyribonucleoside triphosphates (dNTPs) is required for the uncontrolled replication of cancers. The current study aimed to investigate the biological and clinical role of ribonucleotide reductase subunit M2 (RRM2), a key enzyme regulating the dNTP pool, in clear-cell renal cell carcinoma (ccRCC). Methods: The expression of RRM2 on disease progression and patient outcome was assessed in ccRCC. Then, the effect of RRM2 inhibition on renal cell carcinoma (RCC) growth using siRNA or Triapine, an RRM2-specific inhibitor, was characterized in RCC cell lines. Results: The expression of RRM2 was up-regulated in ccRCC tissues as compared to the normal tissues. Patients with high RRM2 expression tend to have advanced pT stages, high Fuhrman grades, and shortened overall survival (OS). RRM2-siRNAs or Triapine significantly inhibited the cell growth by inducing G0/G1 cell cycle arrest in RCC cells through the attenuation of dNTP pool. Conclusions: The current results provided evidence that RRM2 might act as a novel target for ccRCC, and exploration of nonnucleoside, reversible, small-molecule inhibitors against RRM2 could be promising.

The clinical efficiency of everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is palliative as sequential or second-line therapy for renal cell carcinoma (RCC). However, the limited response of everolimus in RCC remains uncertain. In the present study, everolimus-resistant RCC models were established to understand the mechanisms and to seek combination approaches. Consequently, the activation of ERK was found to contribute toward everolimus-acquired resistance and poor prognosis in patients with RCC. In addition, the efficacy and mechanism of combination treatment underlying RCC using everolimus and ERK inhibitors was investigated. The ERK inhibitor in combination with everolimus synergistically inhibited the proliferation of RCC cells by arresting the cell cycle in the G1 phase. The combination treatment markedly attenuated the deoxyribonucleoside triphosphate (dNTP) pools by downregulating the mRNA expression of RRM1 and RRM2 through E2F1. The overexpression of E2F1 or supplementation of dNTP rescued the anti-proliferation activity of the everolimus-SCH772984 combination. The antitumor efficacy of combination therapy was reiterated in RCC xenograft models. Thus, the current findings provided evidence that the everolimus-ERK inhibitor combination is a preclinical therapeutic strategy for RCC. Keywords: renal cell carcinoma, ERK inhibitor, everolimus, dNTP, ribonucleotide reductase

Background Progesterone resistance is a problem in endometrial carcinoma, and its underlying molecular mechanisms remain poorly understood. The aim of this study was to elucidate the molecular mechanisms of progesterone resistance and to identify the key genes and pathways mediating progesterone resistance in endometrial cancer using bioinformatics analysis. Methods We developed a stable MPA (medroxyprogesterone acetate)-resistant endometrial cancer cell subline named IshikawaPR. Microarray analysis was used to identify differentially expressed genes (DEGs) from triplicate samples of Ishikawa and IshikawaPR cells. PANTHER, DAVID and Metascape were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and cBioPortal for progesterone receptor (PGR) coexpression analysis. GEO microarray (GSE17025) was utilized for validation. The protein–protein interaction network (PPI) and modular analyses were performed using Metascape and Cytoscape. Further validation were performed by real-time polymerase chain reaction (RT-PCR). Results In total, 821 DEGs were found and further analyzed by GO, KEGG pathway enrichment and PPI analyses. We found that lipid metabolism, immune system and inflammation, extracellular environment-related processes and pathways accounted for a significant portion of the enriched terms. PGR coexpression analysis revealed 7 PGR coexpressed genes (ANO1, SOX17, CGNL1, DACH1, RUNDC3B, SH3YL1 and CRISPLD1) that were also dramatically changed in IshikawaPR cells. Kaplan–Meier survival statistics revealed clinical significance for 4 out of 7 target genes. Furthermore, 8 hub genes and 4 molecular complex detections (MCODEs) were identified. Conclusions Using microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of progesterone resistance. We offered several possible mechanisms of progesterone resistance and identified therapeutic and prognostic targets of progesterone resistance in endometrial cancer. Electronic supplementary material The online version of this article (10.1186/s12967-019-1814-6) contains supplementary material, which is available to authorized users.

It has been shown that endogenous adenosine-induced by ischemia postconditioning attenuates apoptosis in recent studies; however, they focus only on parenchymal cells. The detailed mechanism has not been clearly clarified in any research and the subtype of adenosine receptors involved remains unknown. In our study, dermal microvascular endothelial cells (DMECs) are used to explore the role of adenosine AThe epigastric skin flaps of rabbits were elevated. After 4 h of ischemia, the flaps were either abruptly reperfused or postconditioned by six cycles of brief reperfusion (15s) and re-ischemia (15s). Adenosine A2a receptor agonist (CGS-21680) and antagonist (ZM-241385) were used separately in other groups. The apoptosis-related proteins and adenosine A2a receptors were determined by immunohistochemical staining. Then apoptosis index was calculated by TUNEL.Ischemia/reperfusion caused severe damages in DMECs of flaps as demonstrated by an increase in apoptosis index and an increase in expressions of apoptosis-related proteins, which can be significantly attenuated by IPC treatment or exposure to a selective adenosine AIschemia postconditioning protects DMECs of rabbit skin flap against apoptosis via activation of adenosine A

This study compared the abilities of γ-[Glu]n-Trp (EW) and whey protein hydrolysate (WPH) with a high ratio of Trp : 5 large neutral amino acids (5LNAAs) to reverse chronic restraint stress-corticosterone injection induced anxiety/depression-like behaviors in C57BL/6 male mice. EW was synthesized using L-glutaminase from Bacillus amyloliquefaciens. Acid protease, trypsin, pancreatin or flavorzyme was used to produce WPHs. The WPH with the highest Trp/5LNAAs ratio (17.38%; by trypsin) was selected for animal trials. EW (dose 2.0, 5.0 or 10.0 mg kg−1 d−1) and WPH (dose 0.5, 1.0 or 2.0 mg g−1 d−1) reversed behavioral dysfunctions, suppressed serum inflammatory cytokines (TNF-α, IL-6, IL-1β and IFN-γ), and reduced the activity of indoleamine 2,3-dioxygenase (key rate-limiting enzyme of the kynurenine pathway) while increasing the activity of tryptophan hydroxylase (key rate-limiting enzyme of the serotonin pathway) in the hypothalamus, hippocampus and prefrontal cortex, with EW acting more effectively. EW could also increase body weight gain and might act more effectively via the kynurenine pathway. These findings are of significance to promote the future practical application of kokumi γ-[Glu]n-Trp peptides.

Aims To seek new conservative treatments for young women with early-stage endometrial carcinoma (EC) who desire to retain fertility, we investigated the effects and the underlying mechanism of silibinin in EC, which exhibits promising anti-cancer and tumour-suppressing properties in many malignant tumours. Main methods Through relevant experiments such as MTT assay, cell colony formation assay and subcutaneous xenograft experiment, we showed that silibinin inhibited the proliferation of EC cells and tumours. Silibinin significantly induced cell cycle arrest and promoted apoptosis in vitro. In vivo TUNEL assay confirmed the apoptotic effect caused by silibinin. STAT3 is activated in the development of tumours. Silibinin notably inhibited the expression of STAT3 phosphorylation and regulated the expression of downstream genes involved in cell cycle and apoptosis at protein and mRNA levels in EC cells. Furthermore, silibinin decreased the expression of intranuclear SREBP1, which is a key regulator of lipid metabolism in the nucleus, and reduced the lipid accumulation in EC cells. Downregulation of the expression levels of SREBP1 and its downstream genes associated with lipid metabolism was also observed in silibinin-treated EC cells. Key findings The results revealed that a novel anticancer drug, silibinin, markedly suppressed cell proliferation, cell cycle progression, apoptosis inhibition and lipid accumulation by blocking STAT3 and SERBP1 signalling pathways in EC cells. Significance Silibinin has anti-tumour characteristics and inhibits abnormal lipid metabolism in EC. This compound is expected to contribute to the conservative and adjuvant treatment of EC and should therefore be investigated further.

Over the last decade, more than 10 independent SNPs have been discovered to be associated with the risk of renal cell carcinoma among different populations. However, the biological functions of them remain poorly understood. In this study, we performed eQTL analysis, ChIP-PCR, luciferase reporter assay, and Cox regression analysis to identify the functional role and underlying mechanism of rs67311347 in RCC. The ENCORI database, which contains the lncRNA–miRNA–mRNA interactions, was used to explore the possible target miRNA of ENTPD3-AS1. The results showed that the G > A mutation of rs67311347 created a binding motif of ZNF8 and subsequently upregulated ENTPD3-AS1 expression by acting as an enhancer. The TCGA-KIRC and our cohorts both confirmed the downregulation of ENTPD3-AS1 in RCC tissues and demonstrated that increased ENTPD3-AS1 expression was associated with good OS and PFS. Furthermore, ENTPD3-AS1 interacted with miR-155-5p and activated the expression of HIF-1α, which was an important tumor suppressor gene in the development of RCC. The functional experiments revealed that overexpression of ENTPD3-AS1 inhibited cell proliferation in RCC cell lines and the effect could be rescued by knocking down HIF-1α. Our findings reveal that SNP-mediated lncRNA-ENTPD3-AS1 upregulation suppresses renal cell carcinoma via miR-155/HIF-1α signaling.

Ethno pharmacological relevance Curcuma longa L is traditionally used as an anti-inflammatory remedy in Chinese traditional medicine. Curcuma oil (CO), a lipophilic fraction from Curcuma longa L. has been reported to have anti-proliferative, anti-inflammatory and anti-oxidant activities. However, CO has never been investigated for its possible therapeutic effects on benign prostatic hyperplasia (BPH). Aims of the study The study is thus to determine the therapeutic effects of curcuma oil on BPH and also the possible mechanism (s) of action. Materials &methods A BPH-1 cell line and Sprague Dawley (SD) rats were used to establish BPH models in vitro and in vivo, respectively. Rats were treated by CO (2.4, 7.2 mg/kg/i.g.) and finasteride (5 mg/kg/i.g.), respectively. Histological changes were examined by hematoxylin and eosin (H&E) staining. Protein expression was analyzed for 5α-reductase (5AR), dihydrotestosterone (DHT), interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α by ELISA. Ki-67, Caspase-8,-9 and -3 expressions were evaluated via immunohistochemistry (IHC). Results CO effectively induced apoptosis in BPH-1 cells. BPH was successfully established by administration of testosterone propionate (TP) in rats, which upregulated both 5α-reductase expression and DHT production. Importantly, TP establishment significantly stimulated the phosphorylation of p65, one subunit of NF-κB, thus led to activation of the NF-κB signaling pathway in prostatic tissues of rats. In turn, the activation of NF-κB pathway induced concomitant upregulation of proinflammatory factors IL-1β, IL-6, TNF-α, and COX-2 and significant increase of the Bcl2/Bax expression ratio for enhanced cell survival, contributing to the initiation and progression of BPH in rats. Notably, CO therapy significantly decreased prostate weight and hyperplasia in BPH-induced animals. Also CO was found to suppress the expression of 5α-reductase and thus the production of DHT, which is essential for the amelioration of BPH. More importantly, CO was shown to suppress the activation of NF-κB pathway through decreasing the expression of phosphorylated p65 and consequently reduced the inflammatory responses and cell survival in prostatic tissues, leading to the inhibition of BPH development in rats. Conclusion Curcuma oil is very effective for ameliorating BPH in rats. The underlying mechanisms involve in reduced inflammatory responses and cell survival through suppression of the NF-κB signaling pathway by CO in prostatic tissues.

Objective: A large number of studies had found that small nucleolar RNA host gene 20 (SNHG20) was a long noncoding RNA (lncRNA) that played important regulatory functions in numerous tumors. Nevertheless, the expression and pathophysiological role of SNHG20 in cholangiocarcinoma (CCA) are currently unclear. The objective of this study is to reveal the clinical significance and pathophysiological function of SNHG20 in CCA. Methods: The tumor tissues and adjacent normal tissues of CCA were obtained to determine the expression and clinical significance of SNHG20, and the targets of related genes were predicted through bioinformatics analysis. The function and regulatory mechanism of SNHG20 in CCA were evaluated by transfection, CCK-8 experiment, and luciferase reporter assay. Result: In CCA, SNHG20 was highly expressed. Overexpressed SNHG20 was markedly interrelated with the lymph node invasion and TNM stage. In addition, it could be used as indicator to evaluate the prognosis of patients. SNHG20 sponging miR-520f-3p could accelerate the proliferation of CCA tumor cells. MiR-520f-3p acted as a tumor suppressor in CCA and could also serve as a prognostic indicator. Abolition of miR-520f-3p caused an antagonistic effect and diminished the impacts of SNHG20 knockdown. SNHG20 combined with miR-520f-3p could better predict the prognosis of CCA patients. Conclusion: These data confirmed the knockdown SNHG20 expression in CCA could inhibit the proliferation by means of sponging miR-520f-3p.

Objective Periostin (POSTN) overexpression observed in various cancer types is correlated with metastasis and tumor progression. However, its effect on the crosstalk between ovarian cancer cells and cancer-associated fibroblasts (CAFs) remains elusive. This study aims to ascertain the role of CAF-derived POSTN in the ovarian cancer microenvironment. Methods POSTN expression in high-grade serous ovarian cancer (HGSC) was detected through immunochemistry. Transwell assay was conducted to determine cell migration and invasion. POSTN was knocked down or overexpressed using lentiviral vectors. The potential downstream effects of POSTN were explored and verified by RNA sequencing and western blotting, respectively. In vitro metastatic capability of ovarian cancer cells regulated by POSTN was determined by indirect co-culture. Results POSTN was highly enriched in HGSC stromal components, particularly in fibroblasts, while its overexpression was correlated with reduced overall survival (OS). CAF-derived POSTN functioned as a ligand for integrin αvβ3, fueling the migration and invasion of ovarian cancer cells by activating the PI3K/Akt pathway and inducing the epithelial-mesenchymal transition (EMT). Additionally, the pro-metastatic properties and the activation of fibroblasts induced by TGF-β1 partly relied on POSTN. Conclusions Stromal-derived POSTN drives the remodeling of the pro-metastatic microenvironment, which might be as a potential therapeutic target in patients with ovarian cancer.

Long noncoding RNAs (lncRNAs) are a group of RNAs over 200 nucleotides in length involved in diverse processes in tumor cells including proliferation, invasion and apoptosis. Given these facts, it is hardly accidental that variations in the expression of some lncRNAs have been found to be closely related to carcinogenesis and tumor growth and metastasis. HOTAIRM1, first discovered as an important factor for granulocytic differentiation in NB4 promyelocytic leukemia, has been shown to be a salient cancer-related lncRNA abnormally expressed in a variety of tumors. In this review, we summarize current evidence on the critical role of HOTAIRM1 in human malignancy, its potential mechanism of action and future use in the development of effective therapeutics.

This study compared enhanced serotonin (5-HT) synthesis roles of γ-[Glu]n-Trp (EW) and whey protein hydrolysate (WPH, Val-Ala-Gly-Thr-Trp-Tyr, Val-Ala-Gly-Thr-Trp, Ser-Ala-Trp-Tyr, Trp-Tyr-Ser, Gly-Thr-Trp) using anxious depression C57BL/6 mice. As an index of serotonergic activity, we assessed 5-HT levels in response to Trp oligopeptide ingestion. The neuroprotective and hypothalamic-pituitaryadrenal (HPA) axis hormones were examined in order to characterize the suggested improvements of anxious depression observed in mice after ingestion Trp oligopeptide. The 5-HT levels were increasingly enhanced by the EW and WPH diet, with the EW being more effective. But WPH had higher capacity on anti-oxidative than EW. EW and WPH could normalize the levels of HPA axis hormones, and promote brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling. In conclusion, Trp oligopeptide ingestion neuroprotective and HPA regulation effects possibly related to serotonergic activation and anti-oxidation. Consumed Trp oligopeptide diets may induce beneficial effects on anxious depression.

Sequence type 59 (ST59) is a predominant clonal lineage of community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA) in Asia. Despite its increasing clinical relevance in China, the evolution and geographic expansion of ST59 has been relatively uncared for. Previous study has shown that ST59 was the predominant clone in food-related MRSA in China. This study compared the genomes of 87 clonal complex (CC) 59 S. aureus isolates sourced from food chain and infection cases to reconstruct the molecular evolution and geographical spread of ST59. Accordingly, three major sub-clades of ST59 were identified and these did not correlate with isolation source or location. Phylogenetic analysis estimated that ST59 in mainland China diverged from a most common recent ancestor around 1974, and most of the cases of cross-country transmission occurred between 1987 and 2000. Notably, two recent events of cross-country transmission through the food chain were observed, the isolates from these events diverged within relatively short time intervals. These isolates also showed high similarity in terms of their core genome, accessory genes, and antibiotic resistance patterns. These findings provide a valuable insight into the potential route of ST59 expansion in China and indicate a need for robust food chain surveillance to prevent the spread of this pathogen.

A novel sulfonated chitosan-derived carbon-based catalyst was successfully prepared via isoamyl nitrite-assisted sulfanilic acid sulfonation, and its catalytic activity was examined using dehydration of fructose. The structural and chemical properties of sulfonated chitosan-derived carbon were characterized by SEM, FTIR, XRD, XPS, element analysis, N2 adsorption-desorption experiment, and acid-base titration experiment. KOH was used as activating agent in the synthesizing of carbon supports, and it was found that properly increasing the dose of KOH during activation stage had a positive effect on the subsequent sulfonation of prepared activated carbon. 4KSCC, with the highest sulfonation degree (2.04 mmol/g), exhibited high performance for the conversion of fructose to HMF in various solvent, and an optimal HMF yield of 80.9% was obtained at 140 °C in 40 min. In addition, the reusability of 4KSCC for fructose dehydration was fairly good.

Emerging evidence has revealed markedly roles for long noncoding RNAs (lncRNAs) in various cancer processes. Prostate cancer associated transcript 6 (PCAT6) is a novel lncRNA which displays vital regulatory functions in multiple cancers. However, the functions of PCAT6 in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Our study confirmed that PCAT6 expression was upregulated in PDAC and the expression of PCAT6 was related to TNM stage, lymph node invasion and overall survival of PDAC patients. PCAT6 might act as an effective tumor biomarker for PDAC patients. Moreover, knockdown of PCAT6 inhibited cell proliferation, migration and invasion of PDAC in vitro. For the mechanism, miR-185-5p expression was decreased and chromobox 2 (CBX2) expression was increased in PDAC, and further PCAT6 could upregulated the expression of oncogene CBX2 by sponging miR-185-5p. The results above suggested that PCAT6/miR-185-5p/CBX2 exerted crucial functions in tumorigenesis and progression of PDAC.

Obesity is characterized by low-grade chronic inflammation. As an acute-phase reactant to inflammation and infection, C-reactive protein (CRP) has been found to be the strongest factor associated with obesity. Here we show that chronic elevation of human CRP at baseline level causes the obesity. The obesity phenotype is confirmed by whole-body magnetic resonance imaging (MRI), in which the total fat mass is 6- to 9- fold higher in the CRP rats than the control rats. Univariate linear regression analysis showed different growth rates between the CRP rats and the control rats, and that the difference appears around 11 weeks old, indicating that they developed adult-onset obesity. We also found that chronic elevation of CRP can prime molecular changes broadly in the innate immune system, energy expenditure systems, thyroid hormones, apolipoproteins, and gut flora. Our data established a causal role of CRP elevation in the development of adult-onset obesity.

Inflammatory bowel disease (IBD) is a chronic relapsing inflammation involving the gut system, and disequilibrium of T helper (Th) cell paradigm has been recognized as critical pathogenesis. Pycnoporus sanguineus (L.) Murrill is a species of the white-rot basidiomycetes listed as food- and cosmetic-grade microorganisms. In this study, anti-inflammatory activity of the ethanol extract from P. sanguineus (PSE) was investigated in dextran sulfate sodium (DSS)-induced experimental colitis model. PSE recovered the DSS-caused weight loss, reversed the colon shortening, and ameliorated the histopathological lesion in colon, resulting in lower disease activity index (DAI). Levels of serumal lipopolysaccharide (LPS), colonic myeloperoxidase (MPO) in the colitis-suffering mice were declined by PSE treatment. PSE also improved the mucosal integrity by enhancing the expression of tight junction and adherens junction proteins in the colon, including ZO-1, occludin, claudin-1, and E-cadherin. Besides, PSE reduced helper T cells (Th) in the colon, together with an evident decrease of several Th cell-related cytokines. Moreover, it was found that in vitro, PSE suppressed T cells and the Th subset upon Concanavalin A (ConA)-stimulation by inducing apoptosis. In summary, PSE displayed a remission on the colitis-related inflammation, which would possibly rely on the epithelial barrier restoration by suppressing Th cells via apoptosis induction, highlighting a promising potential in the treatment for IBD.

Due to the lack of effective strategies on the treatment of castration resistant prostate cancer (CRPC), we established a multifunctional nanoplatform (GNS@IR820/DTX-CD133) for the synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy (CT) under the monitoring of multimodal near-infrared (NIR) fluorescence/photoacoustic (PA) imaging. Benefiting from the guided effect of CD133 antibody, GNS@IR820/DTX-CD133 can targetedly deliver the loaded drug to the tumor tissues, which can further contribute to the combined therapeutic effect. Our experimental results prove that the bio-distribution of GNS@IR820/DTX-CD133 can be monitored with NIR fluorescence and PA imaging. In addition, the application of GNS@IR820/DTX-CD133 for in vitro and in vivo therapy achieves the excellent antitumor effects of the synergistic PTT/PDT/CT strategies under the NIR-light irradiation. Therefore, as a multifunctional nanoplatform integrating the PTT/PDT/CT strategies with tumor multimodal imaging or drug tracing, GNS@IR820/DTX-CD133 has the great potential for clinical applications in the antitumor therapy of CRPC.

The prevalence of endometrial cancer (EC) is increasing worldwide. Progestin therapy is effective for both early stage EC patients who require preserving fertility and advanced or recurrent patients. Progestin resistance resulting from downregulation of progesterone receptor (PR) remains a major problem, and its mechanism is currently unclear. It was demonstrated that Sirtuin 1 (SIRT1), forkhead transcription factor 1 (FoxO1) and sterol regulatory element binding protein-1 (SREBP-1) may act as a pathway and play crucial roles in the development of EC in our previous studies. In the present study, we investigated the effect on the development of progestin resistance and the relationship with PR of SIRT1/FoxO1/SREBP-1. A progestin-resistant Ishikawa cell line was established in the stimulation and selection of medroxyprogesterone acetate (MPA), and the resistance was analyzed by MTT assay, flow cytometry, and Transwell invasion assay. qRT-PCR and western blotting were conducted to detect the expression of SIRT1, FoxO1, SREBP-1 and PR. SIRT1 knockdown progestin-resistant cells were established by lentiviral transduction. The new progestin-resistant cell line presented sufficient resistance to MPA in aspects of proliferation, distribution of cell cycle and apoptosis compared with original Ishikawa cells. Besides, the invasion capability of progestin-resistant cells was observably increased. In both protein and mRNA levels, SIRT1 and SREBP-1 were upregulated in progestin-resistant cells, while PR and FoxO1 were downregulated. SIRT1 was knocked down by lentivirus transfection in progestin-resistant cells, resulting in upregulation of PR, FoxO1 and downregulation of SREBP-1, thereby SIRT1 knockdown cells were more sensitive to MPA compared with progestin-resistant cells. SIRT1/FoxO1/SREBP-1 act as a pathway targeting PR and involve in the development of progestin resistance in Ishikawa cells.

Accurate data imputation requires ethnicity-matched reference panels. However, recent admixtures have created mosaic human genomes, different chromosomal segments have different ethnic backgrounds, so it is impossible for a single-ethnicity reference panel to be the matched for data imputation. In this study, we explored a novel strategy for imputation. We created individualized mosaic reference panel for each person according to his/her ethnic backgrounds at each genomic locus. We examined on datasets with 70% missing values on haplotypes and 50% missing values on genotypes. Results showed that the imputation with mosaic references steadily yielded high imputation accuracy and outperforms the other strategies. With the mosaic reference panels, the imputation accuracy was 98.8 ± 0.1% (CEU), 98.7 ± 0.1% (YRI), 98.5 ± 0.1% (CHB), 98.6 ± 0.1% (ASW), 97.3 ± 0.1% (MKK) and 98.2 ± 0.1% (MXL). Mosaic reference panel will be one option for future missing value imputation in big data era.

Background From adolescence to menopause, hormone levels during the menstrual cycle affect various body systems, from the cardiovascular system to the water and electrolyte balance. This study investigated the effect of different phases of the menstrual cycle on circulatory function relative to changes in body position and combined spinal-epidural anaesthesia (CSEA). Methods Forty-six women were selected who underwent scheduled gynaecological surgery, were classified as American Society of Anesthesiology (ASA) I-II, and met the test criteria. The sample was divided into the follicular and corpus luteal groups. Preoperative heart rate and blood pressure measurements were taken from the supine and standing positions. Heart rate measurements as well as systolic, diastolic, and mean blood pressure measurements were taken upon entering the operating room, at the beginning of the spinal-epidural anaesthesia, and 10, 20, and 30 min after anaesthesia was administered. Results The heart rates of patients in the corpus luteal group were higher than those of patients in the follicular group both before and after anaesthesia (P

Accumulating reports have demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the occurrence and metastasis of cholangiocarcinoma (CCA). LncRNA myocardial infarction associated transcript (MIAT) has been widely reported in hepatocellular carcinoma, pancreatic cancer and colorectal cancer, but the relationship between MIAT and CCA progression has not yet been investigated. In the present study, we found that the expression of MIAT in CCA tissues was prominently higher than that in normal bile duct tissues. Moreover, TCGA-CHOL data in the GEPIA platform further revealed the upregulated expression of MIAT in CCA tissues. Additionally, quantitative real-time PCR results showed that MIAT expression was increased in CCA cell lines compared to the human intrahepatic biliary epithelial cell line. Functionally, MIAT knockdown significantly inhibited cell proliferation and induced G0/G1 phase arrest as well as apoptosis in HuCCT-1 and QBC939 cells. Conversely, ectopic expression of MIAT obviously facilitated the proliferation, cell cycle progression and apoptosis resistance of RBE cells. Mechanistically, MIAT directly interacted with miR-551b-3p and inversely modulated miR-551-3p level in CCA cells. Furthermore, MIAT knockdown reduced the expression of cyclin D1 (CCND1), which was rescued by miR-551b-3p silencing in HuCCT-1 cells. Importantly, CCND1 restoration partially reversed MIAT knockdown-induced proliferation inhibition, G0/G1 phase arrest and apoptosis in HuCCT-1 cells. In conclusion, MIAT was frequently overexpressed in CCA. MIAT contributed to the growth of CCA cells by targeting miR-551b-3p/CCND1 axis.

Inflammatory bowel disease (IBD) is a chronic autoimmune disease associated with various risk factors. Pycnoporus sanguineus (L.) Murrill is a saprotrophic fungus used worldwide for its industrial and medical purposes. Here, polysaccharide from P. sanguineus (PPS) was explored for its antiinflammatory potential in a murine colitis model of IBD induced by dextran sulfate sodium (DSS). PPS ameliorated the colitis as manifested by the lowered disease activity index (DAI), prolonged colon, and reduced serum lipopolysaccharide (LPS). PPS recovered the histological lesion by upregulating the expressions of Zonula occludens-1 (ZO-1), E-cadherin, and proliferating cell nuclear antigen (PCNA). PPS inhibited the helper T cells (Th)-mediated immune response by decreasing the proportions of Th cells (including Th2 cells, Th17 cells, and regulatory T cells), which was accompanied with reductions on myeloperoxidase (MPO) activity and releases of several interleukins and chemokines within the colon. Moreover, PPS exhibited an evident inhibition on autophagy, in which the ratio of light chain 3 (LC3) II/I was declined, while the expression of p62 and Beclin-1 was increased. The present study highlighted important clinical implications for the treatment application of PPS against IBD, which relies on the regulation of Th cells repertoire and autophagy suppression to restore epithelium barrier.

Accumulating evidence indicates that sirtuin7 (SIRT7) plays an oncogenic role in the main types of liver cancer, hepatocellular carcinoma (HCC). Nevertheless, the clinical significance of SIRT7 and its role in cholangiocarcinoma (CCA) is largely undiscovered. Here, we found that SIRT7 displayed higher expression in CCA tissues compared to intrahepatic normal bile duct and surrounding liver tissues based on The Cancer Genome Atlas (TCGA) data. Our data further confirmed that SIRT7 was overexpressed in CCA patient tissues and cell lines. Clinical analysis revealed that high SIRT7 expression was correlated with large tumor size and advanced tumor-node-metastasis (TNM) stage. Furthermore, SIRT7 overexpression independently predicted poor prognosis of CCA patients. Functionally, we demonstrated that SIRT7 knockdown suppressed proliferation and cell cycle progression of HUCCT1 cells in vitro and in vivo. SIRT7 restoration promoted the growth of QBC-939 cells. Mechanistically, SIRT7 reduced p21 expression and increased the levels of Cyclin D1 and cyclin dependent kinase 2 (CDK2) in CCA cells. Furthermore, microRNA-125b-5p (miR-125b-5p) was recognized as a direct negative regulator of SIRT7 and reduced SIRT7 abundance in CCA cells. Notably, miR-125b-5p restoration showed similar effects to SIRT7 knockdown on the growth of CCA cells. Taken together, we demonstrate for the first time that miR-125b-5p regulation of SIRT7 functions as an oncogene and a potential prognostic biomarker in CCA.

Background: Unilateral renal tumor cryoablation and contralateral radical nephrectomy of bilateral renal tumors were performed by transumbilical three-dimensional (3D) multichannel laparoendoscopic single-site (LESS) surgery, in an attempt to verify the feasibility and safety of the procedure, sum up the operational experience, and evaluate the surgical outcome. Case Presentation: This was a 47-year-old female patient with a body mass index of 27.34 kg/m2 without backache, low back pain, hematuria, urinary urgency, frequent urination, dysuria, and other symptoms. Contrast-enhanced CT scan of the kidney on admission showed four masses in the left kidney and two masses in the right kidney. Preoperative serum creatinine (SCr) was 87 μmol/L. Operation was performed under general anesthesia by first laying the patient in a left lateral position. A 2-cm longitudinal transumbilical skin incision was made to expose the right kidney for complete dissection of the two tumors. First, puncture biopsy was performed, and then two freeze–thaw cryoablation cycles for the two tumors were performed. At last, the patient was laid in a right lateral position for radical nephrectomy of the left kidney. The operative duration, cryoablation time, and estimated blood loss were 200 minutes, 40 minutes, and 100 mL, respectively. Postoperative pathological examination revealed clear-cell renal cell carcinoma. The right glomerular filtration rate tested was 42.36 mL/minute and SCr was 131 μmol/L at day 5 after surgery. There was no evidence of contrast enhancement at the cryoablative region as shown by renal contrasted CT scan performed 4 days after surgery and renal contrasted MRI scan performed 6 weeks after surgery, indicating that there was no tumor remnant or recurrence. Conclusion: Our preliminary experience shows that the treatment of bilateral renal tumors with unilateral renal tumor cryoablation and contralateral radical nephrectomy by transumbilical 3D LESS is safe, feasible, and effective. It may prove to be a viable option for patients with significant comorbidities and an insensitive treatment intention.

Mesenchymal stem cells (MSCs) are a prospective cell source for tissue regeneration due to their self-renewal abilities and potential to differentiate into different cell lineages, but the molecular mechanisms of the directed differentiation and proliferation are still unknown. Recently, multiple studies have indicated the crucial role of HOX genes in MSC differentiation and proliferation. However, the role of HOXA5 in MSCs remains unknown. Here, we investigated HOXA5 function in stem cells from the apical papilla (SCAPs). After HOXA5 depletion, the results showed a significant decrease in ALP activity and a weakened mineralization ability of SCAPs. The real-time RT-PCR results showed prominently lessened expression of OPN and BSP. The CCK8 and CFSE results displayed inhibited proliferation of SCAPs, and flow cytometry assays revealed arrested cell cycle progression at the S phase. Furthermore, we found that depletion of HOXA5 upregulated p16INK4A and p18INK4C and downregulated the Cyclin A. Our research demonstrated that depletion of HOXA5 inhibited osteogenic differentiation and repressed cell proliferation by arresting cell cycle progression at the S phase via p16INK4A , p18INK4C , and Cyclin A in SCAPs, indicating that HOXA5 has a significant role in maintaining the proliferation and differentiation potential of dental-tissue-derived MSCs.

Background and Objectives To determine whether radical resection can benefit patients with advanced gallbladder adenocarcinoma using a Bayesian network (BN) with clinical data. Methods In total, 362 patients who had undergone surgical treatment of gallbladder adenocarcinoma at a tertiary institute were evaluated to establish two BN models using a tree-augmented naive Bayes algorithm. We then chose 250 patients with T3-4N0-2M0 stage gallbladder adenocarcinoma to test the posterior probability after the surgical type was taken into account. Results In total, 170 patients (≤7 months) and 137 patients (>7 months) were correctly classified in the median survival time model (accuracy, 84.81%), and 204 patients (≤12 months), 15 patients (12-36 months), 17 patients (36-60 months), and 34 patients (>60 months) were correctly classified in the 1-, 3-, and 5-year survival model (accuracy, 74.59%), respectively. Every posterior probability in the two models upregulated the ratio of the longer survival time and suggested a better prognosis for gallbladder adenocarcinoma that can be improved by R0 resection. Conclusions These BN models indicate that stages T4 and N2 gallbladder adenocarcinoma are not contraindications for surgery and that R0 resection can improve survival in patients with advanced gallbladder adenocarcinoma.

Background In recent years, many studies have demonstrated that endogenous adenosine induced by ischemia postconditioning reduces apoptosis in various models, but no study has clearly elucidated the effects of hypoxic postconditioning (HPC) in human dermal microvascular endothelial cells (HDMECs) of flaps, and the subtype of adenosine receptors involved remains unknown. In our study, we sought to identify the role of adenosine A 2a receptor in the antiapoptotic effects of HPC. Materials and methods The HDMECs were isolated from human upper eyelid tissue. After hypoxia for 6 h, the HDMECs were either abruptly reperfused with medium for 12 h (reoxygenation) or postconditioned by three cycles of 5 min of transitory reoxygenation and 5 min of rehypoxia followed by 11.5 h of reoxygenation. CGS-21680 was used as an adenosine A 2a agonist. Results Adenosine A 2a receptors were found in the cytoplasm of HDMECs. Hypoxia/reoxygenation (H/R) resulted in severe injury in HDMECs as evidenced by an increase in apoptosis percentage and an increase in expressions of apoptosis-related proteins (the ratio of Bax/Bcl-2 and caspase-3), which can be significantly attenuated by HPC treatment or exposure to CGS-21680, a selective adenosine A 2a receptor agonist (all P values 2a receptors compared with the hypoxia/reoxygenation group ( P versus P 2a receptors ( r 2 = 0.8177, P Conclusions HPC protects against apoptosis induced by reoxygenation via activation of adenosine A 2a receptors on HDMECs.

Background The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia. Methods Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral "Kunlun" (BL60), "Zusanli" (ST36), and "Sanyinjiao" (SP6) acupoints in the rat model of inflammatory pain (complete Freund's adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection. Results ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression. Conclusions The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.

Coordination of cell division and cell fate is crucial for the successful development of mammalian early embryos. Aurora kinases are evolutionarily conserved serine/threonine kinases and key regulators of mitosis. Aurora kinase B (AurkB) is ubiquitously expressed while Aurora kinase C (AurkC) is specifically expressed in gametes and preimplantation embryos. We found that increasing AurkC level in one blastomere of the 2-cell embryo accelerated cell division and decreasing AurkC level slowed down mitosis. Changing AurkB level had the opposite effect. The kinase domains of AurkB and AurkC were responsible for their different ability to phosphorylate Histone H3 Serine 10 (H3S10P) and regulate metaphase timing. Using an Oct4-photoactivatable GFP fusion protein (Oct4-paGFP) and fluorescence decay after photoactivation assay, we found that AurkB overexpression reduced Oct4 retention in the nucleus. Finally, we show that blastomeres with higher AurkC level elevated pluripotency gene expression, which were inclined to enter the inner cell mass lineage and subsequently contributed to the embryo proper. Collectively, our results are the first demonstration that the activity of mitotic kinases can influence cell fate decisions in mammalian preimplantation embryos and have important implications to assisted reproduction. Electronic supplementary material The online version of this article (doi:10.1007/s13238-017-0407-5) contains supplementary material, which is available to authorized users.

The demand for using parasympathetic activation for stroke therapy is unmet. In the current study, we investigated whether the neuroprotection provided by electroacupuncture (EA) in an experimental stroke model was associated with activation of the parasympathetic nervous system (PNS). The results showed that parasympathetic dysfunction (PD), performed as unilateral vagotomy combined with peripheral atropine, attenuated both the functional benefits of EA and its effects in improving cerebral perfusion, reducing infarct volume, and hindering apoptosis, neuronal and peripheral inflammation, and oxidative stress. Most importantly, EA rats showed a dramatically less reduction in the mRNA level of choline acetyltransferase, five subtypes of muscarinic receptors and α7nAChR, suggesting the inhibition of the impairment of the central cholinergic system; EA also activated dorsal motor nucleus of the vagus, the largest source of parasympathetic pre-ganglionic neurons in the lower brainstem (detected by c-fos immunohistochemistry), and PD suppressed these changes. These findings indicated EA may serve as an alternative modality of PNS activation for stroke therapy.

Renal cell carcinoma (RCC) is one of the most common kidney cancers worldwide. Although great progressions have been made in the past decades, its morbidity and lethality remain increasing. Long noncoding RNAs (lncRNAs) are demonstrated to play significant roles in the tumorigenesis. This study aimed to investigate the detailed roles of lncRNA FTX in RCC cell proliferation and metastasis. Our results showed that the transcript levels of FTX in both clinical RCC tissues and the cultured RCC cells were significantly upregulated and associated with multiple clinical parameters of RCC patients, including familial status, tumor sizes, lymphatic metastasis, and TNM stages. With cell proliferation assays, colony formation assays, and cell cycle assays, we testified that knockdown of FTX in A498 and ACHIN cells with specific shRNAs inhibited cell proliferation rate, colony formation ability, and arrested cell cycle in the G0/G1 phase. FTX depletion also suppressed cell migration and invasion with Transwell assays and wound-healing assays. These data indicated the pro-oncogenic potential of FTX in RCC, which makes it a latent therapeutic target of RCC diagnosis and treatment in the clinic.

Dental pulp stem cells (DPSCs) are considered a remarkable source for the regeneration of dental pulp tissues, but their therapeutic effectiveness remains limited, especially in elderly people. Previous studies found that senescence has a negative effect on the proliferation and differentiation potential of DPSCs. Moreover, numerous long non-coding RNA (lncRNA) and messenger RNA were significantly differentially regulated in DPSCs from young and elderly donors. However, the changes in DPSCs protein during senescence have not been addressed. In this study, differences in DPSC protein expression profiles and coexpression of protein and lncRNA were analyzed using proteomics and bioinformatics. The results showed 75 upregulated proteins and 69 downregulated proteins in DPSCs from elderly donors. Vasopressin-regulated water reabsorption, Parkinson's disease, Alzheimer's disease, and protein export were the top four functional pathways associated with DPSCs. High mobility group N1 (HMGN1), HMGN2, UCHL1, and the family with sequence similarity 96 member B homeobox gene (FAM96B) were associated with DPSCs senescence. Then, we investigated FAM96B function in DPSCs. After FAM96B depletion, telomerase reverse transcriptase (TERT) activity decreased, but the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and the protein levels of p16, p53 were significantly increased. Gain-of-function assays suggested that FAM96B overexpression was positively correlated with TERT activity, but negatively correlated with the number of SA-β-gal positive cells and the protein levels of P16 and P53. Moreover, after FAM96B overexpression, the results showed a significant increase in alkaline phosphatase activity and an enhanced mineralization ability of DPSCs. The reverse-transcription polymerase chain reaction results also showed that dentin sialophosphoprotein and osteocalcin were expressed at greater levels. The carboxyfluorescein succinimidyl ester (CFSE) results displayed that FAM96B increased the proliferation potential of DPSCs. Our study revealed candidate proteins that might be related to DPSCs senescence and provided information to elucidate the mechanism of the biological changes in DPSCs' aging. Moreover, FAM96B was demonstrated to play an important role in suppressing DPSCs senescence and promoting osteogenic differentiation and proliferation.

Objectives Hypoxia is a hallmark of the tumor microenvironment, and hypoxia regions are frequently found in gastrointestinal cancers, which are associated with worse patients’ survival and therapy resistance. However, the potential mechanisms of hypoxic tumor microenvironment still need to be further elucidated, especially about the roles of long non-coding RNAs (lncRNAs) in hypoxic tumor regions. In recent years, a great mount of independent research showed that many lncRNAs were modulated by hypoxia, and these lncRNAs were named as “hypoxia-regulated lncRNAs”. In this review, the recent developments in the expression, regulation and functions of hypoxia-regulated lncRNAs in gastrointestinal cancers were summarized. Materials and methods In this review, we summarized and figured out recent studies concerning the expression and biological mechanisms of hypoxia-regulated lncRNAs in gastrointestinal cancers. The related studies were obtained through a systematic search of PubMed, Embase and Cochrane Library. Results Hypoxia-regulated lncRNAs have various roles in the regulation of metabolism, autophagy, invasion and metastasis in the hypoxic microenvironment. More importantly, hypoxic-regulated lncRNAs have a variety of potential mechanisms in gastrointestinal tumors, including epigenetic, lncRNA-miRNA interaction, lncRNA-protein interactions. Conclusions Hypoxia-regulated lncRNAs will undoubtedly be developed as targets and promote the progress in ideal therapies for gastrointestinal cancer patients.

Listeria monocytogenes is a foodborne pathogen with a high mortality rate in humans. This study aimed to identify the pathogenic potential of L. monocytogenes isolated from ready-to-eat (RTE) foods and pasteurized milk in China on the basis of its phenotypic and genotypic characteristics. Approximately 7.7% (44/570) samples tested positive for L. monocytogenes among 10.8% (39/360) RTE and 2.4% (5/210) pasteurized milk samples, of which 77.3% (34/44) had < 10 MPN/g, 18.2% (8/44) had 10–110 MPN/g, and 4.5% (2/44) had > 110 MPN/g. A total of 48 strains (43 from RTE foods and five from milk samples) of L. monocytogenes were isolated from 44 positive samples. PCR-serogroup analysis revealed that the most prevalent serogroup was II.2 (1/2b-3b-7), accounting for 52.1% (25/48) of the total, followed by serogroup I.1 (1/2a-3a) accounting for 33.3% (16/48), serogroup I.2 (1/2c-3c) accounting for 12.5% (6/48), and serogroup II.1 (4b-4d-4e) accounting for 2.1%. All isolates were grouped into 11 sequence types (STs) belonging to 10 clonal complexes (CCs) and one singleton (ST619) via multi-locus sequence typing. The most prevalent ST was ST87 (29.2%), followed by ST8 (22.9%), and ST9 (12.5%). Virulence genes determination showed that all isolates harbored eight virulence genes belonging to Listeria pathogenicity islands 1 (LIPI-1) (prfA, actA, hly, mpl, plcA, plcB, and iap) and inlB. Approximately 85.4% isolates carried full-length inlA, whereas seven isolates had premature stop codons in inlA, six of which belonged to ST9 and one to ST5. Furthermore, LLS (encoded by llsX gene, representing LIPI-3) displays bactericidal activity and modifies the host microbiota during infection. LIPI-4 enhances neural and placental tropisms of L. monocytogenes. Results showed that six (12.5%) isolates harbored the llsX gene, and they belonged to ST1/CC1, ST3/CC3, and ST619. Approximately 31.3% (15/48) isolates (belonging to ST87/CC87 and ST619) harbored ptsA (representing LIPI-4), indicating the potential risk of this pathogen. Antimicrobial susceptibility tests revealed that > 95% isolates were susceptible to 16 antimicrobials; however, 60.4 and 22.9% isolates were intermediately resistant to streptomycin and ciprofloxacin, respectively. The results show that several isolates harbor LIPI-3 and LIPI-4 genes, which may be a possible transmission route for Listeria infections in consumers.

BACKGROUND The factors affecting the prognosis and role of adjuvant therapy in advanced gallbladder carcinoma (GBC) after curative resection remain unclear. AIM To provide a survival prediction model to patients with GBC as well as to identify the role of adjuvant therapy. METHODS Patients with curatively resected advanced gallbladder adenocarcinoma (T3 and T4) were selected from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. A survival prediction model based on Bayesian network (BN) was constructed using the tree-augmented naive Bayes algorithm, and composite importance measures were applied to rank the influence of factors on survival. The dataset was divided into a training dataset to establish the BN model and a testing dataset to test the model randomly at a ratio of 7:3. The confusion matrix and receiver operating characteristic curve were used to evaluate the model accuracy. RESULTS A total of 818 patients met the inclusion criteria. The median survival time was 9.0 mo. The accuracy of BN model was 69.67%, and the area under the curve value for the testing dataset was 77.72%. Adjuvant radiation, adjuvant chemotherapy (CTx), T stage, scope of regional lymph node surgery, and radiation sequence were ranked as the top five prognostic factors. A survival prediction table was established based on T stage, N stage, adjuvant radiotherapy (XRT), and CTx. The distribution of the survival time (>9.0 mo) was affected by different treatments with the order of adjuvant chemoradiotherapy (cXRT) > adjuvant radiation > adjuvant chemotherapy > surgery alone. For patients with node-positive disease, the larger benefit predicted by the model is adjuvant chemoradiotherapy. The survival analysis showed that there was a significant difference among the different adjuvant therapy groups (log rank, surgery alone vs CTx, P < 0.001; surgery alone vs XRT, P = 0.014; surgery alone vs cXRT, P < 0.001). CONCLUSION The BN-based survival prediction model can be used as a decision-making support tool for advanced GBC patients. Adjuvant chemoradiotherapy is expected to improve the survival significantly for patients with node-positive disease.

We previously demonstrated that cancer‐associated fibroblasts (CAFs) promoted the proliferation of gallbladder cancer (GBC) cells, but the mechanism is not clear. Neuropilin‐1 (NRP‐1) plays an important role in various malignancies as transmembrane glycoprotein. Our goal was to reveal the relationship between CAFs and NRP‐1 and their potential functions in GBC. In this study, we found NRP‐1 was overexpressed in GBC tissue, associated with poor survival and was up‐regulated by CAFs. The cytokine array cluster analysis revealed IL‐8 secreted by CAFs facilitated the up‐regulation of NRP‐1 in tumour cells. NRP‐1 knockdown suppressed tumour growth in vivo. Gene expression microarray analysis showed 581 differentially regulated genes under NRP‐1 knockdown conditions. Ingenuity pathway analysis demonstrated that NRP‐1 knockdown may inhibit tumour progression by affecting cell proliferation. We then confirmed that NRP‐1 knockdown in NOZ and GBC‐SD cells significantly inhibited cell proliferation. Additionally, the IL‐8 mediated MDM2 and CCNA2 expression were affected by NRP‐1 knockdown. Our findings suggested that NRP‐1 was up‐regulated by CAF‐secreted IL‐8, which subsequently promoted GBC cell proliferation, and these molecules may serve as useful prognostic biomarkers and therapeutic targets for GBC.

Progestin resistance limits the effectiveness of progestin therapy in endometrial carcinoma for patients who desire to preserve fertility. To investigate the molecular mechanism of progestin resistance in endometrial carcinoma, we performed microarray analysis among Ishikawa and progestin resistant cell IshikawaPR cells. We found that epithelial to mesenchymal transition (EMT) was involved in progestin resistance and dachshund family transcription factor 1 (DACH1) is positively correlated with progesterone receptor (PGR). Knockdown of DACH1 in Ishikawa cell promoted proliferation, metastasis ability, and resistance to progestin. Conversely, overexpression of DACH1 in IshikawaPR cell rendered more sensitive to progestin treatment. Xenograft model assay also had similar results. In addition, our data showed that DACH1 overexpression inhibited EMT and decreased c‐Jun, Notch1 and Hes1expression. Our study demonstrated for the first time that EMT is involved in progestin resistance of EC. The response to progestin could be reserved by DACH1 suppressed EMT through Notch1 pathway via c‐Jun.

Pain is the most severe and common symptom of endometriosis. Its underlying pathogenetic mechanism is poorly understood. Nerve sensitization is a particular research challenge, due to the limitations of general endometriosis models and sampling nerve tissue from patients. The chemokine fractalkine (FKN) has been demonstrated to play a key role in various forms of neuropathic pain, while its role in endometriotic pain is unknown. Our study was designed to explore the function of FKN in the development and maintenance of peripheral hyperalgesia and central sensitization in endometriosis using a novel endometriosis animal model developed in our laboratory. After modeling, behavioral tests were carried out and the optimal time for molecular changes was obtained. We extracted ectopic tissues and L4–6 spinal cords to detect peripheral and central roles for FKN, respectively. To assess morphologic characteristics of endometriosis-like lesions—as well as expression and location of FKN/CX3CR1—we performed H&E staining, immunostaining, and western blotting analyses. Furthermore, inhibition of FKN expression in the spinal cord was achieved by intrathecal administration of an FKN-neutralizing antibody to demonstrate its function. Our results showed that implanted autologous uterine tissue around the sciatic nerve induced endometriosis-like lesions and produced mechanical hyperalgesia and allodynia. FKN was highly expressed on macrophages, whereas its receptor CX3CR1 was overexpressed in the myelin sheath of sciatic nerve fibers. Overexpressed FKN was also observed in neurons. CX3CR1/pp38-MAPK was upregulated in activated microglia in the spinal dorsal horn. Intrathecal administration of FKN-neutralizing antibody not only reversed the established mechanical hyperalgesia and allodynia, but also inhibited the expression of CX3CR1/pp38-MAPK in activated microglia, which was essential for the persistence of central sensitization. We concluded that the FKN/CX3CR1 signaling pathway might be one of the mechanisms of peripheral hyperalgesia in endometriosis, which requires further studies. Spinal FKN is important for the development and maintenance of central sensitization in endometriosis, and it may further serve as a novel therapeutic target to relieve persistent pain associated with endometriosis.

Objectives Bone regeneration by bone tissue engineering is a therapeutic option for bone defects. Improving the osteogenic differentiation of mesenchymal stem cells (MSCs) is essential for successful bone regeneration. We previously showed that AP2a enhances the osteogenic differentiation in MSCs. The present study investigated the mechanism of how AP2a regulates the direct differentiation. Materials and methods Co‐immunoprecipitation and ChIP assays were carried out to investigate the underlying mechanism in MSCs differentiation. The osteogenic differentiation potential was determined by mineralization ability and the expression of osteogenic marker in vitro and the in vivo bone‐like tissue generation in nude mice. Results We show that AP2a can compete with RUNX2, a key transcription factor in osteogenic differentiation, to recruit YAP and release the inhibition of RUNX2 activity from YAP by forming YAP‐AP2a protein complex. YAP‐AP2a protein complex also interacts with the BARX1 promoter through AP2a, inhibit the transcription of BARX1. Moreover, BARX1 inhibits osteogenic differentiation of MSCs. Conclusions Our discoveries revealed that AP2a may regulate the osteogenic differentiation in an indirect way through competing with RUNX2 to relieve the RUNX2 activity which inhibited by YAP, and also in a direct way via targeting the BARX1 and directly repressed its transcription. Thus, our discoveries shed new light on the mechanism of direct differentiation of MSCs and provide candidate targets for improving the osteogenic differentiation and enhancing bone tissue regeneration.

Background Endometrial cancer poses a serious threat to women’s health worldwide, and its pathogenesis, although actively explored, is not fully understood. DLGAP5 is a recently identified cell cycle-regulation gene not reported in endometrial cancer. This study was aiming to analyze the role of DLGAP5 in tumorigenesis and development and to investigate its prognostic significance of patients with endometrial cancer. Methodology Microarray datasets (GSE17025, GSE39099 and GSE63678) from the GEO database were used for comparative analysis, and their intersection was obtained by applying the Venn diagram, and DLGAP5 was selected as the target gene. Next, transcriptome data (n = 578) was downloaded from TCGA-UCEC to analyze the mRNA expression profile of DLGAP5. Then, immunohistochemical data provided by HPA were used to identify the different protein expression levels of DLGAP5 in tumor tissues and normal tissues. Subsequently, the prognostic meaning of DLGAP5 in patients with endometrial cancer was explored based on survival data from TCGA-UCEC (n = 541). Finally, the reliability of DLGAP5 expression was verified by RT-qPCR. Results Transcriptome data from TCGA-UCEC, immunohistochemical data from HPA, and RT-qPCR results from clinical samples were used for triple validation to confirm that the expression of DLGAP5 in endometrial cancer tissues was significantly higher than that in normal endometrial tissues. Kaplan–Meier survival analysis announced that the expression level of DLGAP5 was negatively correlated with the overall survival of patients with endometrial cancer. Conclusions DLGAP5 is a potential oncogene with cell cycle regulation, and its overexpression can predict the poor prognosis of patients with endometrial cancer. As a candidate target for the diagnosis and treatment of endometrial cancer, it is worthwhile to make further study to reveal the carcinogenicity of DLGAP5 and the mechanism of its resistance of organisms.

Histone modifications are fundamental epigenetic regulators that control many crucial cellular processes. However, whether these marks can be passed on from mammalian gametes to the next generation is a long-standing question that remains unanswered. Here, by developing a highly sensitive approach, STAR ChIP-seq, we provide a panoramic view of the landscape of H3K4me3, a histone hallmark for transcription initiation, from developing gametes to post-implantation embryos. We find that upon fertilization, extensive reprogramming occurs on the paternal genome, as H3K4me3 peaks are depleted in zygotes but are readily observed after major zygotic genome activation at the late two-cell stage. On the maternal genome, we unexpectedly find a non-canonical form of H3K4me3 (ncH3K4me3) in full-grown and mature oocytes, which exists as broad peaks at promoters and a large number of distal loci. Such broad H3K4me3 peaks are in contrast to the typical sharp H3K4me3 peaks restricted to CpG-rich regions of promoters. Notably, ncH3K4me3 in oocytes overlaps almost exclusively with partially methylated DNA domains. It is then inherited in pre-implantation embryos, before being erased in the late two-cell embryos, when canonical H3K4me3 starts to be established. The removal of ncH3K4me3 requires zygotic transcription but is independent of DNA replication-mediated passive dilution. Finally, downregulation of H3K4me3 in full-grown oocytes by overexpression of the H3K4me3 demethylase KDM5B is associated with defects in genome silencing. Taken together, these data unveil inheritance and highly dynamic reprogramming of the epigenome in early mammalian development.