Association Between Nitrite and Nitrate Intake and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND Studies have shown inconsistent associations of nitrite and nitrate intake with the risk of gastric cancer or its associated mortality. We performed a meta-analysis of observational studies to evaluate the correlation of nitrite and nitrate intake with the risk of gastric cancer. MATERIAL AND METHODS We searched for studies reporting effect estimates and 95% confidence intervals (CIs) of gastric cancer in PubMed, EMBASE, and the Cochrane Library through November 2018. The summary results of the included studies were pooled using a random-effects model. RESULTS Eighteen case-control and 6 prospective cohort studies recruiting 800 321 participants were included in this study. The summary results indicated that the highest (odds ratio [OR], 1.27; 95%CI, 1.03-1.55; P=0.022) or moderate (OR: 1.12; 95%CI, 1.01-1.26; P=0.037) nitrite intake were associated with a higher risk of gastric cancer. However, we noted that high (OR, 0.81; 95%CI, 0.68-0.97; P=0.021) or moderate (OR, 0.86; 95%CI, 0.75-0.99; P=0.036) nitrate intakes were associated with a reduced risk of gastric cancer. These associations differed when stratified by publication year, study design, country, the percentage of male participants, assessment of exposure, adjusted model, and study quality. CONCLUSIONS High or moderate nitrite intake was associated with higher risk of gastric cancer, whereas high or moderate nitrate intake was correlated with lower risk of gastric cancer.

miR-27b-3p is Involved in Doxorubicin Resistance of Human Anaplastic Thyroid Cancer Cells via Targeting Peroxisome Proliferator-Activated Receptor Gamma.

Chemotherapy is one of the most effective forms of cancer treatment. It has been widely used in the treatment of various malignant tumours. To investigate molecular mechanisms responsible for the chemoresistance of anaplastic thyroid cancer (ATC), we established the doxorubicin (Dox) resistance of human ATC SW1736 and 8305C cells and named them SW1736/Dox and 8305C/Dox, respectively. We evaluated the expression of various micro-RNAs (miRNAs) between control and Dox-resistant ATC cells and found that the expression of miR-27b-3p was significantly increased in Dox-resistant ATC cells. Targeted inhibition of miR-27b can increase the sensitivity of SW1736/Dox and 8305C/Dox cells. Bioinformatics analysis revealed that miR-27b can directly target peroxisome proliferator-activated receptor gamma (PPARγ) within the 3' untranslated region (UTR). This was proved by the results that miR-27b-3p down-regulated the protein and mRNA levels of PPARγ. While the mutant in the core binding sites of PPARγ abolished miR-27b-3p-induced down-regulation of luciferase activity. Over-expression of PPARγ can increase the Dox sensitivity of SW1736/Dox and 8305C/Dox cells. Basic fibroblast growth factor (bFGF) might be involved in miR-27b-3p/PPARγ-regulated Dox resistance of ATC cells. The activation of p65 nuclear factor-κB (NF-κB) regulated the up-regulation of miR-27b-3p in Dox-resistant ATC cells. Collectively, our data revealed that miR-27b-3p/PPARγ is involved in the Dox resistance of human ATC cells. It suggested that targeted inhibition of miR-27b-3p might be helpful to overcome the drug resistance of ATC cells.

miRNA­148a inhibits cell growth of papillary thyroid cancer through STAT3 and PI3K/AKT signaling pathways.

The function of miRNA­148a in lymphatic metastases of papillary thyroid cancer and its mechanism were tested. In this investigation, miRNA­148a expression of lymphatic metastases of papillary thyroid cancer patients was inhibited, compared with normal group. We found that miRNA­148a overexpression was effectively reduced cell cell proliferation and metastases, and induced apoptosis of papillary thyroid cancer in vitro. Overexpression of miRNA­148a significantly induced Bax protein expression and caspase­3/9 levels, and suppressed phosphorylation STAT3 (p­STAT3), PI3K and p­Akt protein expression of papillary thyroid cancer in vitro. Next, si­STAT3, could inhibit p­STAT3 protein expression, reducing cell-cell proliferation and metastases, and inducing apoptosis of papillary thyroid cancer following miRNA­148a overexpression. Then, the PI3K inhibitor was able to inhibit PI3K and p­Akt protein expression, reduced cell cell proliferation and metastases, and induced apoptosis of papillary thyroid cancer following miRNA­148a overexpression. Taken together, our results suggest that miRNA­148a inhibits lymphatic metastases of papillary thyroid cancer through STAT3 and PI3K/AKT signaling pathways.

Defective CFTR leads to aberrant ß-catenin activation and kidney fibrosis.

Cystic fibrosis transmembrane conductance regulator (CFTR), known as a cAMP-activated Cl- channel, is widely expressed at the apical membrane of epithelial cells in a wide variety of tissues. Of note, despite the abundant expression of CFTR in mammalian kidney, the role of CFTR in kidney disease development is unclear. Here, we report that CFTR expression is downregulated in the UUO (unilateral ureteral obstruction)-induced kidney fibrosis mouse model and human fibrotic kidneys. Dysfunction or downregulation of CFTR in renal epithelial cells leads to alteration of genes involved in Epithelial-Mesenchymal Transition (EMT) and kidney fibrosis. In addition, dysregulation of CFTR activates canonical Wnt/ß-catenin signaling pathways, whereas the ß-catenin inhibitor reverses the effects of CFTR downregulation on EMT marker. More interestingly, CFTR interacts with Dishevelled 2 (Dvl2), a key component of Wnt signaling, thereby suppressing the activation of ß-catenin. Compared to wild type, deltaF508 mice with UUO treatment exhibit significantly higher ß-catenin activity with aggregated kidney fibrogenesis, which is reduced by forced overexpression of CFTR. Taken together, our study reveals a novel mechanism by which CFTR regulates Wnt/ß-catenin signaling pertinent to progression of kidney fibrosis and indicates a potential treatment target.

Selenium suppresses glutamate-induced cell death and prevents mitochondrial morphological dynamic alterations in hippocampal HT22 neuronal cells.

BACKGROUND: Previous studies have indicated that selenium supplementation may be beneficial in neuroprotection against glutamate-induced cell damage, in which mitochondrial dysfunction is considered a major pathogenic feature. However, the exact mechanisms by which selenium protects against glutamate-provoked mitochondrial perturbation remain ambiguous. In this study glutamate exposed murine hippocampal neuronal HT22 cell was used as a model to investigate the underlying mechanisms of selenium-dependent protection against mitochondria damage. RESULTS: We find that glutamate-induced cytotoxicity was associated with enhancement of superoxide production, activation of caspase-9 and -3, increases of mitochondrial fission marker and mitochondrial morphological changes. Selenium significantly resolved the glutamate-induced mitochondria structural damage, alleviated oxidative stress, decreased Apaf-1, caspases-9 and -3 contents, and altered the autophagy process as observed by a decline in the ratio of the autophagy markers LC3-I and LC3-II. CONCLUSION: These findings suggest that the protection of selenium against glutamate stimulated cell damage of HT22 cells is associated with amelioration of mitochondrial dynamic imbalance.

Overexpression of selenoprotein H prevents mitochondrial dynamic imbalance induced by glutamate exposure.

Selenium and selenoproteins play important roles in neuroprotection against glutamate­induced cell damage, in which mitochondrial dysfunction is considered a major pathogenic feature. Recent studies have revealed that mitochondrial fission could activates mitochondrial initiated cell death pathway. The objectives of the study are to determine whether glutamate induced cell death is mediated through mitochondrial initiated cell death pathway and activation of autophagy, and whether overexpression of selenoprotein H can protect cells from glutamate toxicity by preserving mitochondrial morphology and suppressing autophagy. Vector- or human selenoprotein H (SelH)-transfected HT22 cells (V-HT22 and SelH-HT22, respectively) were exposed to glutamate. The results showed that glutamate-induced cytotoxicity was associated with increased ROS production and imbalance in mitochondrial dynamics and autophagy. These alterations were reversed and cellular integrity restored by overexpression of SelH in HT22 cells.

Induction of apoptosis and autophagy in metastatic thyroid cancer cells by valproic acid (VPA).

The present study investigated the effect of valproic acid (VPA) on the inhibition of RET signaling and induction of apoptosis in human thyroid carcinoma cells. VPA inhibited the viability of ARO and WRO cells and also inhibited cyclin D1 and caused caspase-3 cleavage. VPA decreased the level of RET protein and blocked the activation of RET downstream targets including phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6. VPA induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented VPA-inducible cytotoxicity, suggesting that autophagy was protective in VPA-treated cells. VPA has a wide spectrum of activity against human thyroid carcinoma cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of VPA molecular targets in metastatic human thyroid carcinoma cells suggests that VPA has a potential to become a thyroid cancer therapeutic agent.

Upregulation of ICAM-1 in diabetic rats after transient forebrain ischemia and reperfusion injury.

BACKGROUND: Hyperglycemia exacerbates brain damage caused by cerebral ischemia. Neuroinflammation may play a role in mediating such enhanced damage. The objectives of this study were to examine the mRNA and protein levels and cell type distribution of ICAM-1 after cerebral ischemia in normo-and diabetic hyperglycemic rats. RESULTS: Compared to normoglycemic ischemia animals, diabetes aggravated neuronal death, decreased Nissl body staining, and increased ICAM-1 mRNA and protein levels in the frontal cortex. The increased ICAM-1 was located not only in vascular endothelial cells but also in cortical neurons. CONCLUSIONS: Our results suggest that exacerbated neuro-inflammation in the brain may mediate the detrimental effects of diabetes on the ischemic brain.

Expression of GLP-1R protein and its clinical role in intrahepatic cholangiocarcinoma tissues.

The study investigates the expression and clinical role of GLP-1R in intrahepatic cholangiocarcinoma (ICC) tissues. ICC tissue, tissue around tumour and normal liver tissue samples from 176 ICC patients were investigated for GLP-1R expression by immunohistochemistry and western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. High GLP-1R expression levels were detected in tumor tissue samples. Kaplan-Meier method was used for survival analysis of patients follow-up data. Results showed that median survival time of patients with high GLP-1R positive expression in ICC tissue were 22 months. Median survival time of patients with low GLP-1R positive expression in ICC tissue were 19.8 months. There wasn't statistical difference (p = 0.332) between two groups. Immunohistochemistry semi-quantitative analysis showed that tissue differentiation is not prognostic risk factors. In patients with GLP-1R positive expression in ICC tissue, lymph node metastasis was important prognostic factors (p = 0.001). Although statistical analysis showed that GLP-1R can not be judged as a risk prognostic factors, GLP-1 might become a new target for therapy of ICC.

Diabetes inhibits cerebral ischemia-induced astrocyte activation - an observation in the cingulate cortex.

The objective of this study was to study the effect of diabetic hyperglycemia on astrocytes after forebrain ischemia. Streptozotocin (STZ)-injected hyperglycemic and vehicle-injected normoglycemic rats were subjected to 15 minutes of forebrain ischemia. The brains were harvested in sham-operated controls and in animals with 1 and 6 h of recirculation following ischemia. Brain damage was accessed by haematoxylin and eosin (H&E) staining, cleaved caspase-3 immunohistochemistry and TdT-mediated-dUTP nick end labeling (TUNEL). Anti-GFAP antibody was employed to study astrocytes. The results showed that the 15-minute ischemia caused neuronal death after 1 and 6 h of reperfusion as revealed by increased numbers of karyopyknotic cells, edema, TUNEL-positive and active caspase-3-positive cells. Ischemia also activated astrocytes in the cingulated cortex as reflected by astrocyte stomata hypertrophy, elongated dendrites and increases in the number of dendrites, and immunoreactivity of GFAP. Diabetic hyperglycemia further enhanced neuronal death and suppressed ischemia-induced astrocyte activation. Further, diabetes-damaged astrocytes have increased withdrawal of the astrocyte end-foot from the cerebral blood vessel wall. It is concluded that diabetes-induced suppression and damages to astrocytes may contribute to its detrimental effects on recovery from cerebral ischemia.

Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation.

Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²âº influx that leads to prostaglandin E2 (PGE2) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE2 production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.

Lymphocyte CFTR promotes epithelial bicarbonate secretion for bacterial killing.

The expression of cystic fibrosis transmembrane conductance regulator (CFTR) in lymphocytes has been reported for nearly two decades; however, its physiological role remains elusive. Here, we report that co-culture of lymphocytes with lung epithelial cell line, Calu-3, promotes epithelial HCO(3)- production/secretion with up-regulated expression of carbonic anhydrase 2 and 4 (CA-2, CA-4) and enhanced bacterial killing capability. The lymphocyte-enhanced epithelial HCO(3)- secretion and bacterial killing activity was abolished when Calu3 cells were co-cultured with lymphocytes from CFTR knockout mice, or significantly reduced by interfering with E-cadherin, a putative binding partner of CFTR. Bacterial lipopolysaccharide (LPS)-induced E-cadherin and CA-4 expression in the challenged lung was also found to be impaired in CFTR knockout mice compared to that of the wild-type. These results suggest that the interaction between lymphocytes and epithelial cells may induce a previously unsuspected innate host defense mechanism against bacterial infection by stimulating epithelial HCO(3)- production/secretion, which requires CFTR expression in lymphocytes.

Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia.

Cystic fibrosis (CF) is the most common life-limiting recessive genetic disease among Caucasians caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) with over 95% male patients infertile. However, whether CFTR mutations could affect spermatogenesis and result in azoospermia remains an open question. Here we report compromised spermatogenesis, with significantly reduced testicular weight and sperm count, and decreased cAMP-responsive element binding protein (CREB) expression in the testes of CFTR knockout mice. The involvement of CFTR in HCO(3) (-) transport and the expression of the HCO(3) (-) sensor, soluble adenylyl cyclase (sAC), are demonstrated for the first time in the primary culture of rat Sertoli cells. Inhibition of CFTR or depletion of HCO(3) (-) could reduce FSH-stimulated, sAC-dependent cAMP production and phosphorylation of CREB, the key transcription factor in spermatogenesis. Decreased CFTR and CREB expression are also observed in human testes with azoospermia. The present study reveals a previously undefined role of CFTR and sAC in regulating the cAMP-CREB signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia. Altered CFTR-sAC-cAMP-CREB functional loop may also underline the pathogenesis of various CF-related diseases.