Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome.

Reciprocal interactions between the metabolic system and immune cells play pivotal roles in diverse inflammatory diseases, but the underlying mechanisms remain elusive. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Here, we demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis. TGR5 bile acid receptor-induced PKA kinase activation led to the ubiquitination of NLRP3, which was associated with the PKA-induced phosphorylation of NLRP3 on a single residue, Ser 291. Furthermore, this PKA-induced phosphorylation of NLRP3 served as a critical brake on NLRP3 inflammasome activation. In addition, in vivo results indicated that bile acids and TGR5 activation blocked NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation, alum-induced peritoneal inflammation, and type-2 diabetes-related inflammation. Altogether, our study unveils the PKA-induced phosphorylation and ubiquitination of NLRP3 and suggests TGR5 as a potential target for the treatment of NLRP3 inflammasome-related diseases.

Novel scoring system incorporating lipoproteins to predict outcomes of epithelial ovarian cancer patients.

OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecological malignancy worldwide. While common prognostic factors are identified, the impact of serum lipoproteins remains controversial. This retrospective cohort study aims to investigate the association between specific lipoprotein levels and prognosis. METHODS: Clinical data of 420 participants with epithelial ovarian cancer registered at Women's Hospital, School of Medicine, Zhejiang University, between January 2014 and April 2021 were included. Cox regression analyses and Kaplan-Meier methods were used to assess prognosis, estimated by hazard ratio (HR) with 95% confidence interval (CI). A novel prognostic model incorporating lipoproteins was developed for evaluating the prognosis. Meta-analysis was applied to assess the impact of low density lipoprotein cholesterol (LDL-C) on prognosis. RESULTS: Among 420 patients, those in advanced stages exhibited higher low density lipoprotein cholesterol (LDL-C) (p=0.008) and lower high density lipoprotein cholesterol (HDL-C) levels (p<0.001), with no significant differences in total cholesterol or triglyceride levels. Elevated LDL-C level was significantly associated with worse overall survival (HR 1.72; 95% CI 1.15 to 2.58; p=0.010) and progression free survival (HR 1.94; 95% CI 1.46 to 2.58; p<0.001), whereas higher HDL-C level was linked to better overall survival (HR 0.56; 95% CI 0.37 to 0.85; p=0.004) and progression free survival (HR 0.61; 95% CI 0.46 to 0.81; p<0.001). A novel prognostic model, low density lipoprotein cholesterol-high density lipoprotein cholesterol-fibrinogen-lactate dehydrogenase-prealbumin-Fe-stage (LH-FLPFS), was established to enhance prognostic predictive efficacy. The meta-analysis further suggested that higher LDL-C level was associated with worse overall survival (HR 1.82; 95% CI 1.39 to 2.38; p<0.001). CONCLUSIONS: In this study, preoperative LDL-C and HDL-C levels emerged as potential prognostic factors for ovarian cancer. Establishment of a novel prognostic model, LH-FLPFS, holds promise for significantly improving prognostic predictive efficacy.

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-ß/SMADs signaling pathway.

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25-2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-ß/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-ß/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

Low dose PFDA induces DNA damage and DNA repair inhibition by promoting nuclear cGAS accumulation in ovarian epithelial cells.

Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.

Toxicogenomics scoring system: TGSS, a novel integrated risk assessment model for chemical carcinogenicity prediction.

BACKGROUND: Given the increasing exposure of humans to environmental chemicals and the limitations of conventional toxicity test, there is an urgent need to develop next-generation risk assessment methods. OBJECTIVES: This study aims to establish a novel computational system named Toxicogenomics Scoring System (TGSS) to predict the carcinogenicity of chemicals coupling chemical-gene interactions with multiple cancer transcriptomic datasets. METHODS: Chemical-related gene signatures were derived from chemical-gene interaction data from the Comparative Toxicogenomics Database (CTD). For each cancer type in TCGA, genes were ranked by their effects on tumorigenesis, which is based on the differential expression between tumor and normal samples. Next, we developed carcinogenicity scores (C-scores) using pre-ranked GSEA to quantify the correlation between chemical-related gene signatures and ranked gene lists. Then we established TGSS by systematically evaluating the C-scores in multiple chemical-tumor pairs. Furthermore, we examined the performance of our approach by ROC curves or prognostic analyses in TCGA and multiple independent cancer cohorts. RESULTS: Forty-six environmental chemicals were finally included in the study. C-score was calculated for each chemical-tumor pair. The C-scores of IARC Group 3 chemicals were significantly lower than those of chemicals in Group 1 (P-value = 0.02) and Group 2 (P-values = 7.49 ×10-5). ROC curves analysis indicated that C-score could distinguish "high-risk chemicals" from the other compounds (AUC = 0.67) with a specificity and sensitivity of 0.86 and 0.57. The results of survival analysis were also in line with the assessed carcinogenicity in TGSS for the chemicals in Group 1. Finally, consistent results were further validated in independent cancer cohorts. CONCLUSION: TGSS highlighted the great potential of integrating chemical-gene interactions with gene-cancer relationships to predict the carcinogenic risk of chemicals, which would be valuable for systems toxicology.

A novel lncRNA lnc-PPRL promotes pterygium development by activating PI3K/PDK1 signaling pathway.

A sight threatening, pterygium is a common proliferative and degenerative disease of the ocular surface. LncRNAs have been widely studied in the occurrence and development of various diseases, however, the study of lncRNAs in pterygium has just relatively lacking. In the present study, we performed the high-throughput RNA sequencing (HTS) technology to identify differentially expressed lncRNAs in pterygium. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to forecast the regulatory and functional role of lncRNAs in pterygium. Notably, we identified a novel lncRNA, LOC102724238, which we named pterygium positively-related lncRNA (lnc-PPRL), was up-regulated in pterygium. Lnc-PPRL showed to be preferentially accumulated in cytoplasm, and it can promote cell proliferation, migration and invasion of human pterygium epithelium cells (hPECs). Further study of underlying mechanisms demonstrated that lnc-PPRL may exert its biological effect by activating canonical PI3K/PDK1 pathway, and subsequently promoting the activation of Akt/mTOR signaling pathway and its downstream effectors. Interestingly, lnc-PPRL was also proved to influence YAP nuclear localization. Taken together, our study firstly suggested that the "big molecule" lnc-PPRL have potential as a novel therapeutic target for the prevention and treatment of pterygium.

Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq.

Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon compound, is a carcinogen that causes head and neck cancers. Despite intensive research, the molecular mechanism of BaP in the development of oral squamous cell carcinoma (OSCC) remains largely unknown. In the present study, the SCC-9 human OSCC cell line was cultured in vitro, separated into treatment groups, and treated with dimethyl sulfoxide or BaP at various concentrations. The malignant behavior ascribed to the BaP treatment was investigated by cell proliferation, clony formation assay, and Transwell assays. Furthermore, transcriptome sequencing was performed to detect the differentially expressed genes, followed by quantitative real-time PCR to measure the expression levels of nine of these genes. Moreover, the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the biological processes and signaling pathways in which the target genes were involved. Significant effects on SCC-9 cell proliferation, tumorigenicity, cell migration, and invasion were observed after exposure to 8 µM BaP. Additional results revealed that BaP inhibited apoptosis in a dose-dependent manner. The transcriptome sequencing results showed 137 upregulated genes and 135 downregulated genes induced by BaP, associated with tumor-related biological processes and signaling pathways, mainly including transcriptional dysregulation in cancer, the tumor necrosis factor signaling pathway, metabolism of xenobiotics by cytochrome P450, mitogen-activated protein kinase signaling pathway, and so forth. Our study demonstrates that BaP may regulate the expression of certain genes involved in tumor-associated signaling pathways, thereby promoting the proliferative, tumorigenic, and metastatic behaviors of OSCC cells while suppressing their apoptosis.

mTOR regulates GPVI-mediated platelet activation.

BACKGROUND: Due to mTOR (mammalian/mechanistic target of rapamycin) gene-loss mice die during embryonic development, the role of mTOR in platelets has not been evaluated using gene knockout technology. METHODS: A mouse model with megakaryocyte/platelet-specific deletion of mTOR was established, and be used to evaluate the role of mTOR in platelet activation and thrombus formation. RESULTS: mTOR-/- platelets were deficient in thrombus formation when grown on low-concentration collagen-coated surfaces; however, no deficiency in thrombus formation was observed when mTOR-/- platelets were perfused on higher concentration collagen-coated surfaces. In FeCl3-induced mouse mesenteric arteriole thrombosis models, wild-type (WT) and mTOR-/- mice displayed significantly different responses to low-extent injury with respect to the ratio of occluded mice, especially within the first 40 min. Additionally, mTOR-/- platelets displayed reduced aggregation and dense granule secretion (ATP release) in response to low doses of the glycoprotein VI (GPVI) agonist collagen related peptide (CRP) and the protease-activated receptor-4 (PAR4) agonist GYPGKF-NH2; these deficiencies were overcame by stimulation with higher concentration agonists, suggesting dose dependence of the response. At low doses of GPVI or PAR agonist, the activation of αIIbß3 in mTOR-/- platelets was reduced. Moreover, stimulation of mTOR-/- platelets with low-dose CRP attenuated the phosphorylation of S6K1, S6 and Akt Ser473, and increased the phosphorylation of PKCδ Thr505 and PKCε Ser729. Using isoform-specific inhibitors of PKCs (δ, ɛ, and α/ß), we established that PKCδ/ɛ, and especially PKCδ but not PKCα/ß or PKCθ, may be involved in low-dose GPVI-mediated/mTOR-dependent signaling. CONCLUSION: These observations indicate that mTOR plays an important role in GPVI-dependent platelet activation and thrombus formation.

Mutations of key driver genes in colorectal cancer progression and metastasis.

The association between mutations of key driver genes and colorectal cancer (CRC) metastasis has been investigated by many studies. However, the results of these studies have been contradictory. Here, we perform a comprehensive analysis to screen key driver genes from the TCGA database and validate the roles of these mutations in CRC metastasis. Using bioinformatics analysis, we identified six key driver genes, namely APC, KRAS, BRAF, PIK3CA, SMAD4 and p53. Through a systematic search, 120 articles published by November 30, 2017, were included, which all showed roles for these gene mutations in CRC metastasis. A meta-analysis showed that KRAS mutations (combined OR 1.18, 95% CI 1.05-1.33) and p53 mutations (combined OR 1.49, 95% CI 1.23-1.80) were associated with CRC metastasis, including lymphatic and distant metastases. Moreover, CRC patients with a KRAS mutation (combined OR 1.29, 95% CI 1.13-1.47), p53 mutation (combined OR 1.35, 95% CI 1.06-1.72) or SMAD4 mutation (combined OR 2.04, 95% CI 1.41-2.95) were at a higher risk of distant metastasis. Subgroup analysis stratified by ethnic populations indicated that the BRAF mutation was related to CRC metastasis (combined OR 1.42, 95% CI 1.18-1.71) and distant metastasis (combined OR 1.51, 95% CI 1.20-1.91) in an Asian population. No significant association was found between mutations of APC or PIK3CA and CRC metastasis. In conclusion, mutations of KRAS, p53, SMAD4 and BRAF play significant roles in CRC metastasis and may be both potential biomarkers of CRC metastasis as well as therapeutic targets.

Myricetin inhibits NLRP3 inflammasome activation via reduction of ROS-dependent ubiquitination of ASC and promotion of ROS-independent NLRP3 ubiquitination.

Myricetin is a plant-derived flavonoid that exhibits diverse pharmacological properties. The NLRP3 (NLR family, pyrin domain-containing 3 protein) inflammasome is a cytosolic multiprotein complex that plays a critical role in the innate immune response and pathogenesis of multiple inflammatory disorders. The present study found that myricetin inhibited NLRP3 inflammasome assembly via promotion of reactive oxygen species (ROS)-independent ubiquitination of NLRP3 and reduction of ROS-dependent ubiquitination of ASC (apoptosis-associated speck-like protein containing a CARD), which disrupted the interaction between ASC and NLRP3 and inhibited ASC oligomerization. This effect was further confirmed in vivo using mouse models of lipopolysaccharide (LPS)-induced sepsis and alum-induced peritonitis. These results suggest the therapeutic value of myricetin by targeting NLRP3-driven inflammatory diseases.

HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.

The airway smooth muscle (ASM) cells' proliferation, migration, and their progenitor's migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling.

Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p.

BACKGROUND: The function of a new long non-coding RNA linc00673 remains unclear. While identified as an oncogenic player in non-small cell lung cancer (NSCLC), linc00673 was found to be anti-oncogenic in pancreatic ductal adenocarcinoma (PDAC). However whether linc00673 regulated malignancy and epithelial mesenchymal transition (EMT) has not been characterized. METHODS: Cell proliferation was assessed using CCK-8 and EdU assays, and cell migration and invasion were assessed using scratch assays and transwell invasion assays. Epithelial mesenchymal transition was examined using western blot, qRT-PCR and immunofluorescence staining. Interaction between miRNA and linc00673 was determined using luciferase reporter assays. In vivo experiments were performed to assess tumor formation. In addition, the expression data of NSCLC specimens of TCGA and patient survival data were utilized to explore the prognostic significance of linc00673. RESULTS: In the present study, we found high linc00673 expression was associated with poor prognosis of NSCLC patients. In vitro experiments showed linc00673 knockdown reversed TGF-ß induced EMT, and miR-150-5p was predicted to target linc00673 through bioinformatics tools. Overexpression of miR-150-5p suppressed lin00673's expression while inhibition of miR-150-5p led to significant upregulation of lin00673, suggesting that linc00673 could be negatively regulated by miR-150-5p, which was further confirmed by the inverse correlation between linc00673 and miR-150-5p in NSCLC patients' specimen. Furthermore, we proved that miR-150-5p could directly target linc00673 through luciferase assay, so linc00673 could sponge miR-150-5p and modulate the expression of a key EMT regulator ZEB1 indirectly. In addition, miR-150-5p inhibition abrogated linc00673 silence mediated proliferation, migration, invasion and EMT suppressing effect. Moreover, the inhibition of linc00673 significantly attenuated the tumorigenesis ability of A549 cells in vivo. CONCLUSIONS: We validated linc00673 as a novel oncogenic lncRNA and demonstrated the molecular mechanism by which it promotes NSCLC, which will advance our understanding of its clinical significance.

IL-17A, but not IL-17F, is indispensable for airway vascular remodeling induced by exaggerated Th17 cell responses in prolonged ovalbumin-challenged mice.

We previously demonstrated an essential role of Th17 cells in excessive mucous secretion and airway smooth muscle proliferation in a prolonged OVA-challenged C57BL/6 mouse model. However, the impact of Th17 cells in vascular remodeling, another characteristic feature of airway remodeling in asthma, remains elusive. This issue was further investigated in this study. The time-course experiments showed that progressively increasing levels of Th17 cells and IL-17A (not IL-17F) in the lungs of prolonged allergen-challenged mice were positively correlated with microvessel density in peribronchial tissues. In addition, exaggerated airway vascular remodeling in this mouse model was exacerbated by airway administration of IL-17A or adoptive transfer of Th17 cells. This effect was dramatically alleviated by the administration of anti-IL-17A Ab, but not anti-IL-17F Ab. Boyden chamber assays indicated that IL-17A accelerates endothelial progenitor cell (EPC) migration. Furthermore, EPC accumulation in the airways of allergen-exposed mice after adoptive transfer of Th17 cells was eliminated by blockade of IL-17A. We found that IL-17A promoted tubule-like formation rather than proliferation of pulmonary microvascular endothelia cells (PMVECs) in vitro. In addition, IL-17A induced PMVEC tube formation via the PI3K/AKT1 pathway, and suppression of the PI3K pathway markedly reduced the formation of tubule-like structures. Collectively, our results indicate that Th17 cells contribute to the airway vascular remodeling in asthma by mediating EPC chemotaxis, as well as PMVEC tube formation, via IL-17A rather than IL-17F.

Association between dietary carbohydrate intake, glycemic index and glycemic load, and risk of gastric cancer.

PURPOSE: The association between dietary carbohydrate intake, glycemic index (GI) and glycemic load (GL), and risk of gastric cancer (GC) has been investigated by many studies. However, the results of these studies were controversial. The aim of our study was to systematically assess this issue. METHODS: PUBMED and EMBASE were searched up to March 2015, and either a fixed- or a random-effects model was adopted to estimate overall relative risks (RRs). Dose-response, meta-regression, subgroup, and publication bias analyses were applied. RESULTS: Twenty-six studies with approximately 540,000 participants were finally included in this meta-analysis. High level of dietary carbohydrate intake (pooled RR 1.17, 95 % CI 0.91-1.50), GI (pooled RR 1.17, 95 % CI 0.80-1.69), and GL (pooled RR 1.06, 95 % CI 0.90-1.26) were all nonsignificantly associated with incidence of GC. In addition, no significant dose-response relationship was observed between carbohydrate intake, GI and GL, and the risk of GC. However, further subgroup analyses based on gender and geographic region suggested a significant association between higher carbohydrate intake (pooled RR 1.52, 95 % CI 1.10-2.08), GL (pooled RR 1.41, 95 % CI 1.04-1.92), and GC risk in males subgroup, and between higher carbohydrate intake (pooled RR 1.69, 95 % CI 1.36-2.09) and GC risk in Asian studies. CONCLUSIONS: No significant association was found between dietary carbohydrate intake, GI and GL, and risk of GC. However, significantly positive association was observed in the males subgroup and Asian studies.

Sec22 regulates endoplasmic reticulum morphology but not autophagy and is required for eye development in Drosophila.

The endoplasmic reticulum (ER) is a highly dynamic organelle that plays a critical role in many cellular processes. Abnormal ER morphology is associated with some human diseases, although little is known regarding how ER morphology is regulated. Using a forward genetic screen to identify genes that regulated ER morphology in Drosophila, we identified a mutant of Sec22, the orthologs of which in yeast, plants, and humans are required for ER to Golgi trafficking. However, the physiological function of Sec22 has not been previously investigated in animal development. A loss of Sec22 resulted in ER proliferation and expansion, enlargement of late endosomes, and abnormal Golgi morphology in mutant larvae fat body cells. However, starvation-induced autophagy was not affected by a loss of Sec22. Mosaic analysis of the eye revealed that Sec22 was required for photoreceptor morphogenesis. In Sec22 mutant photoreceptor cells, the ER was highly expanded and gradually lost normal morphology with aging. The rhabdomeres in mutants were small and sometimes fused with each other. The morphology of Sec22 mutant eyes resembled the eye morphology of flies with overexpressed eyc (eyes closed). eyc encodes for a Drosophila p47 protein that is required for membrane fusion. A loss of Syntaxin5 (Syx5), encoding for a t-SNARE on Golgi, also phenocopied the Sec22 mutant. Sec22 formed complexes with Syx5 and Eyc. Thus, we propose that appropriate trafficking between the ER and Golgi is required for maintaining ER morphology and for Drosophila eye morphogenesis.

Prognostic value of long non-coding RNA MALAT1 in cancer patients.

Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) was identified to be the first long non-coding RNA as a biomarker of independent prognostic value for early stage non-small cell lung cancer patient survival. In recent years, the association between upregulated tissue MALAT1 level and incidence of various cancers including bladder cancer, colorectal cancer, and renal cancer has been widely discussed. The aim of our present study was to assess the potential prognostic value of MALAT1 in various human cancers. PubMed, Embase, Ovid, and Cochrane Library databases were systematically searched, and eligible studies evaluating the prognostic value of MALAT1 in various cancers were included. Finally, 11 studies encompassing 1216 participants reporting with sufficient data were enrolled in the current meta-analysis. The pooled hazard ratio (HR) was 2.05 (95 % confidence interval (CI) 1.64-2.55, p < 0.01) for overall survival (OS) and 2.66 (95 % CI 1.86-3.80, p < 0.01) for disease-free survival (DFS). In conclusion, high tissue MALAT1 level was associated with an inferior clinical outcome in various cancers, suggesting that MALAT1 might serve as a potential prognostic biomarker for various cancers.

Dairy products intake and cancer mortality risk: a meta-analysis of 11 population-based cohort studies.

BACKGROUND: Dairy products are major components of daily diet and the association between consumption of dairy products and public health issues has captured great attention. In this study, we conducted a meta-analysis to investigate the association between dairy products intake and cancer mortality risk. METHODS: After a literature search in PubMed and EMBASE, 11 population-based cohort studies involving 778,929 individuals were considered eligible and included in the analyses. Data were extracted and the association between dairy products intake and cancer mortality risk was estimated by calculating pooled relative risks (RRs) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses and subgroup analyses based on regions, genders and dairy types were performed as well. Potential dose-response relationship was further explored by adopting the generalized least squares (GLST) method. RESULTS: Total dairy products intake was not associated with all cancer mortality risk, with the pooled RR of 0.99 (95 % CI 0.92-1.07, p = 0.893). Subgroup analyses showed that the pooled RRs were 0.97 (95 % CI 0.92-1.03, p = 0.314) for milk, 0.88 (95 % CI 0.71-1.10, p = 0.271) for yogurt, 1.23 (95 % CI 0.94-1.61, p = 0.127) for cheese and 1.13 (95 % CI 0.89-1.44, p = 0.317) for butter in male and female, however the pooled RR was 1.50 (95 % CI 1.03-2.17, p = 0.032) for whole milk in male, which was limited to prostate cancer. Further dose-response analyses were performed and we found that increase of whole milk (serving/day) induced elevated prostate cancer mortality risk significantly, with the RR of 1.43 (95 % CI 1.13-1.81, p = 0.003). CONCLUSIONS: Total dairy products intake have no significant impact on increased all cancer mortality risk, while low total dairy intake even reduced relative risk based on the non-linear model. However, whole milk intake in men contributed to elevated prostate cancer mortality risk significantly. Furthermore, a linear dose-response relationship existed between increase of whole milk intake and increase of prostate cancer mortality risk.

Cypermethrin Induces Macrophages Death through Cell Cycle Arrest and Oxidative Stress-Mediated JNK/ERK Signaling Regulated Apoptosis.

Cypermethrin is one of the most highly effective synthetic pyrethroid insecticides. The toxicity of cypermethrin to the reproductive and nervous systems has been well studied. However, little is known about the toxic effect of cypermethrin on immune cells such as macrophages. Here, we investigated the cytotoxicity of cypermethrin on macrophages and the underlying molecular mechanisms. We found that cypermethrin reduced cell viability and induced apoptosis in RAW 264.7 cells. Cypermethrin also increased reactive oxygen species (ROS) production and DNA damage in a dose-dependent manner. Moreover, cypermethrin-induced G1 cell cycle arrest was associated with an enhanced expression of p21, wild-type p53, and down-regulation of cyclin D1, cyclin E and CDK4. In addition, cypermethrin treatment activated MAPK signal pathways by inducing c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 ERK1/2 phosphorylation, and increased the cleaved poly ADP-ribose polymerase (PARP). Further, pretreatment with antioxidant N-acetylcysteine (NAC) effectively abrogated cypermethrin-induced cell cytotoxicity, G1 cell cycle arrest, DNA damage, PARP activity, and JNK and ERK1/2 activation. The specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) effectively reversed the phosphorylation level of JNK and ERK1/2, and attenuated the apoptosis. Taken together, these data suggested that cypermethrin caused immune cell death via inducing cell cycle arrest and apoptosis regulated by ROS-mediated JNK/ERK pathway.