High temperature and humidity in the environment disrupt bile acid metabolism, the gut microbiome, and GLP-1 secretion in mice.

High temperature and humidity in the environment are known to be associated with discomfort and disease, yet the underlying mechanisms remain unclear. We observed a decrease in plasma glucagon-like peptide-1 levels in response to high-temperature and humidity conditions. Through 16S rRNA gene sequencing, alterations in the gut microbiota composition were identified following exposure to high temperature and humidity conditions. Notably, changes in the gut microbiota have been implicated in bile acid synthesis. Further analysis revealed a decrease in lithocholic acid levels in high-temperature and humidity conditions. Subsequent in vitro experiments demonstrated that lithocholic acid increases glucagon-like peptide-1 secretion in NCI-H716 cells. Proteomic analysis indicated upregulation of farnesoid X receptor expression in the ileum. In vitro experiments revealed that the combination of lithocholic acid with farnesoid X receptor inhibitors resulted in a significant increase in GLP-1 levels compared to lithocholic acid alone. In this study, we elucidate the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature and humidity condition.

Nutrition in children with exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI) is a condition defined as pancreatic loss of exocrine function, including decreased digestive enzymes and bicarbonate secretion, which leads to maldigestion and malabsorption of nutrients. It is a common complication in many pancreatic disorders. If left undiagnosed, EPI can cause poor digestion of food, chronic diarrhea, severe malnutrition and related complications. Nutritional status and fat-soluble vitamins should be carefully assessed and monitored in patients with EPI. Early diagnosis of EPI is clinically important for appropriate nutritional support and initiating pancreatic enzyme replacement therapy (PERT) which could significantly improve patient outcomes. The evaluation of nutritional status and related unique management in children with EPI will be discussed in this review.

Gene expression analysis in endometriosis: Immunopathology insights, transcription factors and therapeutic targets.

Background: Endometriosis is recognized as an estrogen-dependent inflammation disorder, estimated to affect 8%-15% of women of childbearing age. Currently, the etiology and pathogenesis of endometriosis are not completely clear. Underlying mechanism for endometriosis is still under debate and needs further exploration. The involvement of transcription factors and immune mediations may be involved in the pathophysiological process of endometriosis, but the specific mechanism remains to be explored. This study aims to investigate the underlying molecular mechanisms in endometriosis. Methods: The gene expression profile of endometriosis was obtained from the gene expression omnibus (GEO) database. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were applied to the endometriosis GSE7305 datasets. Cibersort and MCP-counter were used to explore the immune response gene sets, immune response pathway, and immune environment. Differentially expressed genes (DEGs) were identified and screened. Common biological pathways were being investigated using the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Transcription factors were from The Human Transcription Factors. The least absolute shrinkage and selection operator (Lasso) model identified four differential expressions of transcription factors (AEBP1, HOXB6, KLF2, and RORB). Their diagnostic value was calculated by receiver operating characteristic (ROC) curve analysis and validated in the validation cohort (GSE11691, GSE23339). By constructing the interaction network of crucial transcription factors, weighted gene coexpression network analysis (WGCNA) was used to search for key module genes. Metascape was used for enrichment analysis of essential module genes and obtained HOXB6, KLF2. The HOXB6 and KLF2 were further verified as the only two intersection genes according to Support Vector Machine Recursive Feature Elimination (SVM-RFE) and random forest models. We constructed ceRNA (lncRNA-miRNA-mRNA) networks with four potential transcription factors. Finally, we performed molecular docking for goserelin and dienogest with four transcription factors (AEBP1, HOXB6, KLF2, and RORB) to screen potential drug targets. Results: Immune and metabolic pathways were enriched in GSVA and GSEA. In single sample gene set enrichment analysis (ssGSEA), most immune infiltrating cells, immune response gene sets, and immune response pathways are differentially expressed between endometriosis and non-endometriosis. Twenty-seven transcription factors were screened from differentially expressed genes. Most of the twenty-seven transcription factors were correlated with immune infiltrating cells, immune response gene sets and immune response pathways. Furthermore, Adipocyte enhancer binding protein 1 (AEBP1), Homeobox B6 (HOXB6), Kruppel Like Factor 2 (KLF2) and RAR Related Orphan Receptor B (RORB) were selected out from twenty-seven transcription factors. ROC analysis showed that the four genes had a high diagnostic value for endometriosis. In addition, KLF2 and HOXB6 were found to play particularly important roles in multiple modules (String, WGCNA, SVM-RFE, random forest) on the gene interaction network. Using the ceRNA network, we found that NEAT1 may regulate the expressions of AEBP1, HOXB6 and RORB, while X Inactive Specific Transcript (XIST) may control the expressions of HOXB6, RORB and KLF2. Finally, we found that goserelin and dienogest may be potential drugs to regulate AEBP1, HOXB6, KLF2 and RORB through molecular docking. Conclusions: AEBP1, HOXB6, KLF2, and RORB may be potential biomarkers for endometriosis. Two of them, KLF2 and HOXB6, are critical molecules in the gene interaction network of endometriosis. Discovered by molecular docking, AEBP1, HOXB6, KLF2, and RORB are targets for goserelin and dienogest.

Regulation, genomics, and clinical characteristics of cuproptosis regulators in pan-cancer.

Background: Cuproptosis, a copper-dependent controlled cell death, is a novel form of cell death that differs from known cell death mechanisms; however, its overall regulation in cancer remains elusive. Methods: Multiple open-source bioinformatic platforms were used to comprehensively elucidate the expression levels, prognostic efficiency, potential biological functions, genomic and epigenetic characteristics, immune microenvironment, and drug sensitivity of cuproptosis regulators (ATP7A, ATP7B, DLAT, DLD, FDX1, GLS, LIAS, LIPT1, MTF1, NLRP3, PDHA1, PDHB, and SLC31A1) in pan-cancer. Results: Cuproptosis-related genes (CRGs) were upregulated in most cancers tested. In KIRC, KIRP, LGG, MESO, and PCPG, most highly expressed CRGs predicted a better prognosis but poorer prognosis in patients with ACC, LIHC, and UCEC. Pathway analysis confirmed that cuproptosis regulators were associated with the metabolism-related pathways. The expression of MTF1, NLRP3, and SLC31A1 was positively related with ImmuneScore, StromalScore, and ESTIMATEScore in almost all types of tumor, whereas ATP7B, DLAT, DLD, LIAS, PDHA1, and PDHB were significantly negatively correlated with the scores. In addition, CRGs were significantly correlated with RNA stemness score, DNA stemness score, microsatellite instability, and tumor mutational burden. The expression of ATP7A, ATP7B, LIAS, and DLAT was significantly positively correlated with the drug sensitivity of Docetaxel. ATP7A, LIAS, and FDX1 were significantly negatively correlated with the drug sensitivity of UNC0638, XMD13-2, YM201636, and KIN001-260. Conclusions: The altered genomic and clinical characteristics of cuproptosis regulators were comprehensively elucidated, providing a preliminary basis for understanding the functions of cuproptosis in pan-cancer.

Identification of pyroptosis-related signature for cervical cancer predicting prognosis.

Cervical cancer (CC) is one of the most common malignancies encountered in gynecology practice. However, there is a paucity of information about specific biomarkers that assist in the diagnosis and prognosis of CC. Pyroptosis is a form of programmed cell death whose different elements are related to the occurrence, invasion, and metastasis of tumors. However, the role of pyroptosis phenomena in the progression of CC has not yet been elucidated. This study focuses on the development of a pyroptosis-associated prognostic signature for CC using integrated bioinformatics to delineate the relationships among the signature, tumor microenvironment, and immune response of the patients. In this respect, we identified a prognostic signature that depends on eight pyroptosis-related genes (PRGs) that designate with better prognostic survival in the low-risk group (P<0.05) and where AUC values were greater than 0.7. A multi-factor Cox regression analysis indicated that such a signature could be used as an independent prognostic factor, and both the DCA and the Nomogram suggested that the proposed prognostic signature had good predictive capabilities. Interestingly, this prognostic signature can be applied to multiple tumors and thus, is versatile from a clinical point of view. In addition, there were significant differences in the tumor microenvironment and immune infiltration status between the high- and low-risk groups (P<0. 05). The core gene granzyme B (GZMB) was screened and the CC-associated regulatory axis, GZMB/ miR-378a/TRIM52-AS1, was constructed, which may promote CC progression, and further experimentation is needed to validate these results.

Obstetric and Gynecologic Outcomes after the Transvaginal Repair of Cesarean Scar Defect in a Series of 183 Women.

STUDY OBJECTIVE: To analyze retrospectively the effect of hysteroscopy combined with transvaginal repair on the cesarean section diverticulum (CSD) and explore the clinical significance of this procedure. DESIGN: Retrospective study. SETTING: University-affiliated hospital and a gynecology hospital. PATIENTS: A total of 183 patients with scar diverticulum after cesarean section were recruited from the Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan and Shenzhen In Vitro Fertilization Gynecological Hospital. INTERVENTIONS: In this study, we reported a surgical method for repairing uterine scar through uterine therapy and explored its clinical efficacy and pregnancy outcome. MEASUREMENTS AND MAIN RESULTS: The time of operation, volume of bleeding, and duration of hospitalization were recorded. The size of the scar diverticulum and the remaining myometrium were examined by B-mode ultrasonography before and after the operation. The length of the menstrual cycle and pelvic pain were recorded during follow-up to check the recovery of patients after surgery. The pregnancy of patients with pregnancy needs was recorded to check the pregnancy outcome. All 183 patients successfully completed the repair of the transvaginal uterus scar diverticulum with the help of a hysteroscopy examination. The mean (± standard deviation) operation time was 58.61 ± 18.56 minutes. The mean blood loss was 36.97 ± 22.32 mL. The mean hospital stay was 6.08 ± 1.89 days. In 57.14% of patients, the CSD completely disappeared, whereas the volume of CSD shrank by at least 50% in 88.95% of patients. The mean menstrual period of patients after surgery was 7.72 ± 2.68 days, which was significantly shorter than that recorded preoperatively (13.45 ± 3.69 days) (t = 19.62, p = .00). The pelvic pain disappeared in 81.08% of the patients. The mean postoperative thickness of the remaining muscular layer was 5.30 ± 1.27-mm, which was significantly higher than the preoperative value of 2.25 ± 0.92-mm (t = 28.21, p = .00). The mean postoperative thickness of the remaining muscular layer of patients with improved menstrual cycle was 5.40 ± 1.27-mm, which was significantly higher than the thickness of 4.88 ± 1.11-mm in patients without improved menstrual cycle (t = 2.31, p = .025). A total of 124 patients attempted to become pregnant, 83 of whom were successful. The pregnancy rate was as high as 66.95%, which included 2 scar pregnancies, 4 ectopic pregnancies, and 87 intrauterine pregnancies. No uterine rupture occurred. CONCLUSION: The transvaginal repair of the uterine diverticulum improved the symptoms and probability of a successful pregnancy effectively. This process is a surgical procedure to increase the thickness of the residual uterine muscle wall effectively.

Identification of an immune gene signature for predicting the prognosis of patients with uterine corpus endometrial carcinoma.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is a frequent gynecological malignancy with a poor prognosis particularly at an advanced stage. Herein, this study aims to construct prognostic markers of UCEC based on immune-related genes to predict the prognosis of UCEC. METHODS: We analyzed expression data of 575 UCEC patients from The Cancer Genome Atlas database and immune genes from the ImmPort database, which were used for generation and validation of the signature. We constructed a transcription factor regulatory network based on Cistrome databases, and also performed functional enrichment and pathway analyses for the differentially expressed immune genes. Moreover, the prognostic value of 410 immune genes was determined using the Cox regression analysis. We then constructed and verified a prognostic signature. Finally, we performed immune infiltration analysis using TIMER-generating immune cell content. RESULTS: The immune cell microenvironment as well as the PI3K-Akt, and MARK signaling pathways were involved in UCEC development. The established prognostic signature revealed a ten-gene prognostic signature, comprising of PDIA3, LTA, PSMC4, TNF, SBDS, HDGF, HTR3E, NR3C1, PGR, and CBLC. This signature showed a strong prognostic ability in both the training and testing sets and thus can be used as an independent tool to predict the prognosis of UCEC. In addition, levels of B cells and neutrophils were significantly correlated with the patient's risk score, while the expression of ten genes was associated with immune cell infiltrates. CONCLUSIONS: In summary, the ten-gene prognostic signature may guide the selection of the immunotherapy for UCEC.

ZBTB7A, a potential biomarker for prognosis and immune infiltrates, inhibits progression of endometrial cancer based on bioinformatics analysis and experiments.

BACKGROUD: ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. METHODS: In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. RESULTS: We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. CONCLUSIONS: In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro.

RNF183 Is a Prognostic Biomarker and Correlates With Tumor Purity, Immune Infiltrates in Uterine Corpus Endometrial Carcinoma.

RNF183, a member of the E3 ubiquitin ligase, has been shown to involve in carcinogenesis and proposed as one of the biomarkers in Uterine Corpus Endometrial Carcinoma (UCEC). However, no research focused on the role of RNF183 in UCEC. We analyzed the expression and immune infiltration of RNF183 in UCEC. TIMER, UALCAN, and GEPIA were used to analyze the gene expression of RNF183. We emplored Kaplan-Meier Plotter to examine the overall survival and progression-free survival of RNF183, and applied GeneMANIA to identify RNF183-related functional networks. LinkedOmics was helpful to identify the differential gene expression of RNF183, and to further analyze gene ontology and the genome pathways in the Kyoto Protocol. Finally, we used TIMER to investigate the immune infiltration of RNF183 in UCEC. Otherwise, we partly verified the results of bioinformatics analysis that RNF183 controlled ERα expression in ERα-positive Ishikawa cells dependent on its RING finger domain. We also found that ERα increased the stability of RNF183 through the post-translational mechanism. Together, patients with a high level of RNF183 harbor favorable overall and progression-free survival. High expression of RNF183 was associated with a low stage, endometrioid, and TP53 Non-Mutant status in endometrial cancer. The RNF183 expression was greater at higher expression and the tumor stage was greater at the lower level. On the side of immunization, high level of RNF183 in UCEC is negatively related to tumor purity, infiltrating levels of CD4 + T cells, neutrophils, and dendritic cells. Besides, the expression of RNF183 in UCEC is significantly correlated with the expression of several immune cell markers, including B cell, M1 macrophage marker, M2 Macrophage, Dendritic cell, Th1 markers, Th2 markers, Treg markers, and T cell exhaustion markers, indicating its role in regulating tumor immunity. These results suggested that RNF183 may be considered as a novel prognostic factor in endometrial cancer and an early diagnostic indicator for patients with UCEC.

Web-based cognitive-behavioral intervention for pain in pediatric acute recurrent and chronic pancreatitis: Protocol of a multicenter randomized controlled trial from the study of chronic pancreatitis, diabetes and pancreatic cancer (CPDPC).

INTRODUCTION: Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response. METHODS: This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10-18) with ARP/CP and their parents from twenty-one INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization. CONCLUSIONS: This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.

Analysis of medication data of women with uterine fibroids based on data mining technology.

The purpose of this study was to analyze the characteristics of the diagnosis and treatment of female uterine fibroids based on data mining technology and the medication rule. Clinical literature related to the treatment of uterine fibroids by Chinese National Knowledge Infrastructure (CNKI) from 2004 to 2018 were searched, and the literature meeting the requirements were selected according to the inclusion criteria and exclusion criteria. The contents of the prescription were recorded into the database, and the results of drug frequency, common drugs and core rules, etc. were obtained by the rule analysis of the software, so as to analyze the medication rules of modern doctors in treating uterine fibroids. Through research and analysis, it showed that common clinical drugs include leuprorelin (GnRH-a), danazol (androgen), gestrinone (progestin), mifepristone (progesterone receptor antagonist), and some cases of combination therapy. Based on the analysis of the frequency of drug, treatment effect and adverse drug reactions, it was found that the clinical application of mifepristone in the treatment of uterine fibroids was relatively common, with significant drug effect and mild adverse reactions, which was worthy of clinical promotion and application. Therefore, the results of this study provide a new basis for the clinical and basic research of traditional Chinese medicine in the treatment of uterine fibroids, but it still needs the verification of expert interpretation, experimental research and other methods.

Transport oil product consumption and GHG emission reduction potential in China: An electric vehicle-based scenario analysis.

China's transport sector is facing enormous challenges from soaring energy consumption and greenhouse gas (GHG) emissions. Transport electrification has been viewed as a major solution to transportation decarbonization, and electric vehicles (EVs) have attracted considerable attention from policymakers. This paper analyzes the effects of the introduction of EVs in China. A system dynamics model is developed and applied to assess the energy-saving and emission-reducing impacts of the projected penetration of EVs until the year 2030. Five types of scenarios of various EV penetration rates, electricity generation mixes, and the speed of technological improvement are discussed. Results confirm that reductions in transport GHG emissions and gasoline and diesel consumption by 3.0%-16.2%, 4.4%-16.1%, and 15.8%-34.3%, respectively, will be achieved by 2030 under China's projected EV penetration scenarios. Results also confirm that if EV penetration is accompanied by decarbonized electricity generation, that is, the use of 55% coal by 2030, then total transport GHG emissions will be further reduced by 0.8%-4.4%. Moreover, further reductions of GHG emissions of up to 5.6% could be achieved through technological improvement. The promotion of EVs could substantially affect the reduction of transport GHG emissions in China, despite the uncertainty of the influence intensity, which is dependent on the penetration rate of EVs, the decarbonization of the power sector, and the technological improvement efficiency of EVs and internal combustion engine vehicles.

The expression of special AT-rich binding protein 1 in cervical cancer and its clinical significance.

BACKGROUND: The oncogenic potential of special AT-rich binding protein 1 (SATB1) has been reported in various types of cancer, but its function in cervical cancer remains not fully investigated. This study aimed to investigate the effect of SATB1 mRNA expression on tumor progression and outcomes in the cervical cancer patients. METHODS: A total of 33 cervical cancer patients treated in our hospital from September 2012 to December 2015 were included. The mRNA expression level of STAB1 in cervical cancer tissue was determined by real-time PCR, and the patients were divided into dichotomous groups based on their SATB1 expression level. Clinical characteristics, recurrence, and survival outcomes were compared between groups. RESULTS: Compared with the SATB1-low group, the SATB1-high group had significantly advanced International Federation of Gynecology and Obstetrics (FIGO) stages (P=0.037) and histologic grade (P=0.036). Kaplan-Meier analysis showed that SATB1-high group had a worse overall survival (P=0.078, marginal significant). In the subgroup analysis of pathological types, adenocarcinomas group (n=8) had a significantly higher SATB1 expression level as compared with the squamous cell carcinomas (n=18) and adenosquamous carcinomas (n=7) groups (both P<0.05). Cervical squamous cell carcinomas patients with a high-expression SATB1 (n=8) had more advanced FIGO stages (P=0.015) and histologic grades (P=0.060, marginal significant) as well as a higher (P=0.069, marginal significant) incidence of lymphatic metastasis than those with a low expression of SATB1 (n=10). CONCLUSION: These results showed that expression of SATB1 may have an effect on the disease progression and survival outcome of cervical cancer.

INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study: Design and Rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

S-Adenosylmethionine and methylthioadenosine inhibit ß-catenin signaling by multiple mechanisms in liver and colon cancer.

S-Adenosylmethionine (SAMe), the principal methyl donor that is available as a nutritional supplement, and its metabolite methylthioadenosine (MTA) exert chemopreventive properties against liver and colon cancer in experimental models. Both agents reduced ß-catenin expression on immunohistochemistry in a murine colitis-associated colon cancer model. In this study, we examined the molecular mechanisms involved. SAMe or MTA treatment in the colitis-associated cancer model lowered total ß-catenin protein levels by 47 and 78%, respectively. In an orthotopic liver cancer model, increasing SAMe levels by overexpressing methionine adenosyltransferase 1A also reduced total ß-catenin levels by 68%. In both cases, lower cyclin D1 and c-Myc expression correlated with lower ß-catenin levels. In liver (HepG2) and colon (SW480, HCT116) cancer cells with constitutively active ß-catenin signaling, SAMe and MTA treatment inhibited ß-catenin activity by excluding it from the nuclear compartment. However, in liver (Huh-7) and colon (RKO) cancer cells expressing wild-type Wnt/ß-catenin, SAMe and MTA accelerated ß-catenin degradation by a glycogen synthase kinase 3-ß-dependent mechanism. Both agents lowered protein kinase B activity, but this was not mediated by inhibiting phosphoinositide 3-kinase. Instead, both agents increased the activity of protein phosphatase 2A, which inactivates protein kinase B. The effect of MTA on lowering ß-catenin is direct and not mediated by its conversion to SAMe, as blocking this conversion had no influence. In conclusion, SAMe and MTA inhibit Wnt/ß-catenin signaling in colon and liver cancer cells regardless of whether this pathway is aberrantly induced, making them ideal candidates for chemoprevention and/or chemotherapy in these cancers.

Remifentanil preconditioning alleviating brain damage of cerebral ischemia reperfusion rats by regulating the JNK signal pathway and TNF-α/TNFR1 signal pathway.

Tumor necrosis factor (TNF) and the TNF receptor (TNFR) superfamily play very important roles for cell death as well as normal immune regulation. Previous studies have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. The purpose of this investigation was to examine the protective effect of remifentanil preconditioning in cerebral ischemia/reperfusion injury (CIR) and its possible molecular mechanism. Results showed that Remifentanil pretreatment significantly decreased the CD4(+) and increased the CD8(+) in cerebral tissues. Additionally, CD4(+)/CD8(+) in CIR + Remifentanil group was markedly lower than that in CIR group. TNF-α and TNFR1 in CIR + Remifentanil group rats was found to be significant lower than that in CIR group rats. The expression levels of Cyt-c, caspase-3, caspase-9 and pJNK proteins in brain of CIR + Remifentanil group rats were found to significantly decreased compared to CIR group rats. In addition, decreased ROS level indirectly inhibit JNK activation and cell death in CIR rat receiving Remifentanil preconditioning. From current experiment results, at least two signal pathways involve into the process of Remifentanil preconditioning inhibiting cerebral damage induced by ischemia reperfusion. The inhibitory effects of Remifentanil preconditioning on the brain damage are achieved probably through blocking the activation of TNF-α/TNFR1, JNK signal transduction pathways, which implies that Remifentanil preconditioning may be a potential and effective way for prevention of the ischemic/reperfusion injury through the suppression extrinsic apoptotic signal pathway induced by TNF-α/TNFR1, JNK signal pathways. Taken together, this study indicated that regulation of the TNF-α/TNFR1 and JNK signal pathways may provide a new therapy for cerebral damage induced by ischemia and reperfusion.

Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells.

Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATß) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose-dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATß interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATß and MATα2. Because MATß lowers the Ki of MATα2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATß, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth-suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATß induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATß, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling.

Fibrin scaffolds containing ectomesenchymal stem cells enhance behavioral and histological improvement in a rat model of spinal cord injury.

Fibrin has been widely used in wound healing. However, its benefit for spinal cord injury (SCI) is limited. In this study, we investigated the impact of fibrin scaffolds containing ectomesenchymal stem cells (EMSCs) on histological and behavioral recovery after SCI and compared it with fibrin alone. To achieve this, EMSCs derived from adult rat nasal respiratory mucosa were cultured, characterized and transfected with green fluorescent protein adenovirus before transplantation. Then, Sprague-Dawley host rats were randomly assigned into four groups: the control group (laminectomy); the SCI group (laminectomy and transection of spinal cords); the fibrin group (fibrin was transplanted immediately after SCI), and the fibrin cell (FC) group (fibrin scaffolds containing EMSCs were transplanted after SCI). Three days after the operation, a TUNEL assay indicated less apoptotic cells in the FC group than in the fibrin group. Two weeks after SCI, fluorescence staining demonstrated not only the survival and migration of EMSCs into the lesion sites, but also a higher number of nerve fibers in the FC group than in the fibrin group. Histological examination including immunohistochemistry and transmission electron microscopy 12 weeks after the operation showed more nerve fibers and a thicker myelin sheath in the FC group compared to the fibrin group. Western blotting confirmed these morphological results. Consistent with the histological results, Basso, Beattie and Bresnahan locomotor scores of the FC group were higher than those of the fibrin group. These results suggest that fibrin scaffolds containing EMSCs can improve the behavioral and histological recovery after SCI better than fibrin alone.

MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer.

UNLABELLED: Methionine adenosyltransferase 2B (MAT2B) encodes for two variant proteins (V1 and V2) that promote cell growth. Using in-solution proteomics, GIT1 (G Protein Coupled Receptor Kinase Interacting ArfGAP 1) was identified as a potential interacting partner of MAT2B. Here, we examined the functional significance of this interplay. Coimmunoprecipitation experiments examined protein interactions. Tissue expression levels of proteins were examined using immunohistochemistry and western blotting. Expression levels of proteins were varied using transient knockdown or overexpression to observe the effect of alterations in each protein on the entire complex. Direct interaction among individual proteins was further verified using in vitro translated and recombinant proteins. We found both MAT2B variants interact with GIT1. Overexpression of V1, V2, or GIT1 activated mitogen-activated protein kinase kinase 1 (MEK1) and extracellular signal-regulated kinase (ERK), raised cyclin D1 protein level, and increased growth, whereas the opposite occurred when V1, V2, or GIT1 was knocked down. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. MAT2B directly interacts with MEK1, GIT1, and ERK2. Expression level of V1, V2, or GIT1 directly influenced recruitment of GIT1 or MAT2B and ERK2 to MEK1, respectively. In pull-down assays, MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. Increased expression of V1, V2, or GIT1 promoted growth in an orthotopic liver cancer model, whereas increased expression of either V1 or V2 with GIT1 further enhanced growth and lung metastasis. CONCLUSION: MAT2B and GIT1 form a scaffold, which recruits and activates MEK and ERK to promote growth and tumorigenesis. This novel MAT2B/GIT1 complex may provide a potential therapeutic gateway in human liver and colon cancer. (HEPATOLOGY 2012).

[Expression and significance of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis].

OBJECTIVES: To investigate the expression and clinical significance of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis. Mehtods Between Jan.2009 to Aug.2010, 30 patients with endometriosis undergoing laparoscopic surgery in Maternal and Children's Hospital of Foshan. Eutopic and ectopic endometrium were obtained. In the mean time, 30 patients with benign ovary cyst or tubal infertility undergoing laparoscopic surgery were selected as controls. Their uterine endometrium were obtained real-time fluorescent quantitation, western blot and immunohistochemistry technique were used to detect mRNA and protein expression of HOXA10 gene in the eutopic endometrium group, ectopic endometrium group and control group. RESULTS: The mRNA and protein expression of HOXA10 gene were 0.61 ± 0.07 and 0.47 ± 0.05 in the eutopic endometrium of endometriosis, 0.64 ± 0.06 and 0.50 ± 0.05 in ectopic endometrium of endometriosis, which were significantly lower than 1.22 ± 0.14 and 1.42 ± 0.14 in control group (P < 0.01). However, the mRNA and protein expression of HOXA 10 between eutopic and ectopic endometrium of endometriosis did not reach statistical difference (P > 0.05). The expression of HOXA10 in eutopic and ectopic endometrium of endometriosis were decreased by immunohistochemistry staining. CONCLUSION: The lower expression of HOXA10 gene in the eutopic and ectopic endometrium of endometriosis might be associated with pathogenesis and infertility of endometriosis.