Arsenic activated GLUT1-mTORC1/HIF-1α-PKM2 positive feedback networks promote proliferation and migration of bladder epithelial cells.

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

The hippo-YAP1/HIF-1α pathway mediates arsenic-induced renal fibrosis.

Epidemiological evidence reveals that arsenic increases the risk of chronic kidney disease (CKD) in humans, but its mechanism of action has so far been unclear. Fibrosis is the manifestation of end-stage renal disease. Hypoxia is recognized as a vital event accompanying the progression of renal fibrosis. KM mice were exposed to 0, 20, 40, and 80 mg/L NaAsO2 for 12 weeks. HK-2 cells were treated with 1 µM NaAsO2 for 4 weeks. The results showed that arsenic increased the expression of hypoxia-inducible factor 1α (HIF-1α) (P < 0.05), which is involved in inorganic arsenic-induced renal fibrosis. The Hippo signaling pathway is the upstream signal of HIF-1α and the kinase cascade of Large tumor suppressor kinase 1 (LATS1) and Yes-associated protein 1 (YAP1) is the heart of the Hippo pathway. Our results showed that protein expressions of LATS1 and phosphorylated YAP1 were decreased, and dephosphorylated YAP1 expression increased in arsenic-treated mouse kidneys and human HK-2 cells (P < 0.05). Our research manifested that arsenic treatment suppressed the Hippo signaling and induced high expression of YAP1 into the nucleus. We also found that YAP1 was involved in arsenic-induced renal fibrosis by forming a complex with HIF-1α and maintaining HIF-1α stability. Our findings indicate that YAP1 is a potential target for molecular-based therapy for arsenic-mediated renal fibrosis.

Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian randomization and colocalization analyses.

To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [ß] = -0.288, 95% confidence interval [CI]: -0.534 - -0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW ß = 1.564, 95% CI: 0.155 - 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW ß = -1.654, 95% CI: -3.063 - -0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio ß = -0.082, 95% CI: -0.165 - 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW ß = 0.042, 95% CI: 0.007 - 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW ß = -0.200, 95% CI: -0.579 - 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW ß = -0.089, 95% CI: -0.166 - -0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, ß was 0.540 (95% CI: 0.040-1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.

Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.

Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (ß = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (ß = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (ß = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (ß = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (ß = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (ß = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (ß = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (ß = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (ß = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (PH4 = 0.836) and E. hallii (PH4 = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.

SLC1A5 regulates cell proliferation and self-renewal through ß-catenin pathway mediated by redox signaling in arsenic-treated uroepithelial cells.

Arsenic exposure increases the risk of bladder cancer in humans, but its underlying mechanisms remain elusive. The alanine, serine, cysteine-preferring transporter 2 (ASCT2, SLC1A5) is frequently overexpressed in cancer cells. The aim of this study was to evaluate the effects of arsenic on SLC1A5, and to determine the role of SLC1A5 in the proliferation and self-renewal of uroepithelial cells. F344 rats were exposed to 87 mg/L NaAsO2 or 200 mg/L DMAV for 12 weeks. The SV-40 immortalized human uroepithelial (SV-HUC-1) cells were cultured in medium containing 0.5 µM NaAsO2 for 40 weeks. Arsenic increased the expression levels of SLC1A5 and ß-catenin both in vivo and in vitro. SLC1A5 promoted cell proliferation and self-renewal by activating ß-catenin, which in turn was dependent on maintaining GSH/ROS homeostasis. Our results suggest that SLC1A5 is a potential therapeutic target for arsenic-induced proliferation and self-renewal of uroepithelial cells.

Fluoride regulates the differentiation and atrophy through FGF21/ERK signaling pathway in C2C12 cells.

Excess intake of fluoride leads to a serious health issue called fluorosis. Fluorosis patients exhibit the symptom of muscle damage, but the specific mechanism remains unclear. Fibroblast growth factor 21 (FGF21) is a novel myokine that is involved in the regulation of myogenic differentiation, but whether fluoride induces skeletal muscle damage via FGF21 signaling has not been reported yet. In the current study, C2C12 cells were used to investigate the impact of fluoride on myogenic development and the involved regulatory role of FGF21/ERK signaling pathway. The expressions of the markers of myoblasts development and FGF21/ERK signaling pathway-related molecules were detected after fluoride treatment. The results indicated that fluoride notably inhibited the expressions of myogenic regulatory genes MyoD, MyoG and MyHC in C2C12 cells. In addition, fluoride increased the expressions of muscle atrophy-related markers MuRF1 and MAFbx. We proved that fluoride significantly inhibited the expression of FGF21 based on the RNA-seq results, and detected the expressions of downstream molecules FGFR1, KLB, Raf, MEK and ERK. Moreover, FGF21 pretreatment reversed the adverse effect of fluoride on the C2C12 cells and alleviated the atrophy of myotubes. Taken together, these findings indicated that fluoride suppressed differentiation and aggravated atrophy via FGF21/ERK signaling pathway in C2C12 cells. Our study has provided new evidence for the role of FGF21/ERK in fluoride-induced skeletal muscle damage and FGF21 may be one of the potential targets for prevention and treatment of fluorosis.

The role of Mitochondrial Fission Proteins in Mitochondrial Dynamics in Kidney Disease.

Mitochondria have many forms and can change their shape through fusion and fission of the outer and inner membranes, called "mitochondrial dynamics". Mitochondrial outer membrane proteins, such as mitochondrial fission protein 1 (FIS1), mitochondrial fission factor (MFF), mitochondrial 98 dynamics proteins of 49 kDa (MiD49), and mitochondrial dynamics proteins of 51 kDa (MiD51), can aggregate at the outer mitochondrial membrane and thus attract Dynamin-related protein 1 (DRP1) from the cytoplasm to the outer mitochondrial membrane, where DRP1 can perform a scissor-like function to cut a complete mitochondrion into two separate mitochondria. Other organelles can promote mitochondrial fission alongside mitochondria. FIS1 plays an important role in mitochondrial-lysosomal contacts, differentiating itself from other mitochondrial-fission-associated proteins. The contact between the two can also induce asymmetric mitochondrial fission. The kidney is a mitochondria-rich organ, requiring large amounts of mitochondria to produce energy for blood circulation and waste elimination. Pathological increases in mitochondrial fission can lead to kidney damage that can be ameliorated by suppressing their excessive fission. This article reviews the current knowledge on the key role of mitochondrial-fission-associated proteins in the pathogenesis of kidney injury and the role of their various post-translational modifications in activation or degradation of fission-associated proteins and targeted drug therapy.

Low-dose arsenite causes overexpression of EGF, TGFα, and HSP90 through Trx1-TXNIP-NLRP3 axis mediated signaling pathways in the human bladder epithelial cells.

Epidemiological studies have demonstrated an increased incidence of bladder cancer in arseniasis- endemic areas; however, the precise molecular mechanisms remain unknown. Our previous results have shown that the protein levels of EGF, TGFα, and HSP90 in arsenite-treated bladder uroepithelial cells increased markedly and contributed to hyperactivation of EGF receptors. The aim of this study was to further explore the regulatory ways underlying overexpression of EGF, TGFα, and HSP90 in these cells. The present results showed that both Trx and GSH systems were stimulated in arsenite-treated cells, and ROS levels in 2 µM arsenite-treated cells did not changed obviously; however, ROS levels in 4 µM arsenite-treated cells increased significantly. By using the antioxidant and specific inhibitors, we found that in 2 µM arsenite-treated cells, JNK/NF-κB signaling pathway was involved in overexpression of EGF and TGFα, and ERK/NF-κB signaling pathway contributed to HSP90 overexpression, however in 4 µM arsenite-treated cells, both ERK/ and JNK/NF-κB signaling pathways were involved in overexpression of EGF, TGFα, and HSP90, and PI3K/AKT/NF-κB signaling pathway contributed to overexpression of EGF and TGFα. Furthermore, our results also showed that the Trx1-TXNIP-NLRP3 axis was activated in arsenite-treated cells, and played a pivotal role in activation of the signaling pathways involved in overexpression of EGF, TGFα, and HSP90. In conclusion, the Trx1-TXNIP-NLRP3 axis might be activated by arsenite-induced redox imbalance in bladder uroepithelial cells, and mediate the activation of signaling pathways involved in overexpression of EGF, TGFα, and HSP90.

Loss of Pleckstrin homology like domain, family A, member 1 promotes type â ¡ alveolar epithelial cell apoptosis in chronic obstructive pulmonary disease emphysematous phenotype via interaction with tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon.

Emphysematous phenotype is the most important phenotypic component of chronic obstructive pulmonary disease and is associated with substantial morbidity and mortality. The current pharmaceutical treatments and therapeutic procedures do not reduce pulmonary damage in patients with emphysematous phenotype. Therefore, it is important to identify effector molecules that can be used as interfering targets in such patients. Apoptosis of type II alveolar epithelial cells plays a key role in the phenotypic formation. This study aimed to further explore the molecular mechanisms involved in this process. The number of type II alveolar epithelial cells was significantly reduced due to increased apoptosis in patients with emphysematous phenotype compared to those with non-emphysematous phenotype. Pleckstrin homology like domain, family A, member 1 (PHLDA1) was mainly distributed in type II alveolar epithelial cells in both groups but was markedly reduced in patients with emphysematous phenotype. Overexpression of PHLDA1 prevented cigarette smoke extract-stimulated apoptosis of type II alveolar epithelial cells, whereas its knockdown worsened the apoptosis. PHLDA1 binding ability to tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE) was weakened after exposure to cigarette smoke extract, with decreased PHLDA1 level lowering the abundance of YWHAE and attenuating the binding ability of YWHAE to p-Bad. These results demonstrate that considerable apoptosis of type II alveolar epithelial cells occurs in patients with emphysematous phenotype, and PHLDA1 may act as an effective antiapoptotic factor via YWHAE. Moreover, PHLDA1 may serve as a potential interfering target, providing insights into therapeutic strategies for emphysematous phenotype.

2, 2', 4, 4'-tetrabromodiphenyl ether induces placental toxicity via activation of p38 MAPK signaling pathway in vivo and in vitro.

2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) is one of the most important polybrominated diphenyl ethers (PBDEs) congeners, and epidemiological studies have shown that it can cause adverse pregnancy outcomes. The aim of our study was to investigate the role of placental injury in BDE-47-induced adverse pregnancy outcomes through in vivo and in vitro models. From day 0.5 to day 16.5 of pregnancy of ICR mice, BDE-47 oral doses of 0, 25, 50 and 100 mg/kg/day were administered. Immunohistochemical staining found that BDE-47 inhibited the expression of CD34 in mouse placenta, and ELISA results showed that BDE-47 reduced the levels of VEGF and PlGF in the serum of pregnant mice. Western blot assays found that the expression levels of VEGF-A and invasion-related factors were decreased in the placentas of BDE-47-treated group, which indicated that BDE-47 could impair placental angiogenesis. Furthermore, BDE-47 inhibited proliferation, increased apoptosis and autophagy, and activated p38 MAPK signaling pathway in mouse placental tissue. In vitro, HTR-8/SVneo cells were treated with 0, 5, 10, 20 µM BDE-47 for 24 h. Wound healing assays and Transwell assays showed that BDE-47 inhibited the migration and invasion ability of HTR-8/SVneo cells. We also found that BDE-47 inhibited the proliferation of HTR-8/SVneo cells and increased apoptosis and autophagy. BDE-47 activated p38 MAPK signaling pathway in HTR-8/SVneo cells, and inhibition of p38 MAPK signaling pathway in HTR-8/SVneo cells restored the effects caused by BDE-47. In conclusion, BDE-47 impairs placental angiogenesis by inhibiting cell migration and invasion, and induces placental toxicity by inhibiting proliferation, increasing apoptosis and autophagy. In vitro, activation of p38 MAPK signaling pathway is involved in the processes of placental injury by BDE-47.

Role of Wnt/ß-catenin signaling pathway in ameloblast differentiation in relevance to dental fluorosis.

Excess consumption of fluoride during the development of tooth enamel will cause dental fluorosis, but the exact molecular mechanisms remain to be elucidated. Circadian rhythm is implicated in many physiological processes and various diseases. There is increasing evidence indicates that ameloblast differentiation is under the control of clock genes. However, it has not been reported whether fluoride regulates ameloblast differentiation through clock genes and the downstream PPARγ. To explore the effect of fluoride on ameloblast differentiation and the underlying regulatory mechanism, we used both rat dental fluorosis model and an ameloblast cell line LS8 to conduct a series of experiments. Our results showed that fluoride significantly reduced the expression of PCNA, RUNX2 and MMP9 in rat ameloblasts and LS8 cells (P < 0.05). Fluoride increased nuclear translocation of ß-catenin in vivo and in vitro, and 0.1 µg/ml Dkk1 pretreatment ameliorated the decreased expression of CXXC5, RUNX2 and MMP9 induced by fluoride. Furthermore, we found fluoride significantly inhibited the expression of Clock, Bmal1, Per2 and PPARγ in rat mandibular ameloblasts and LS8 cells by immunostaining, qPCR and Western blot (P < 0.05). Flow cytometry analysis showed that fluoride promoted ROS generation. Remarkably, 50 µM resveratrol significantly ameliorated the inhibitory effect of fluoride on ameloblast differentiation markers, clock genes and PPARγ, and inhibited the Wnt/ß-catenin signaling (P < 0.05). Taken together, these findings suggested that excessive fluoride promoted ROS generation, leading to the inhibition of clock genes, which resulted in reduced PPARγ and activated Wnt/ß-catenin signaling pathway, thus inhibiting ameloblast differentiation and matrix degradation. This study provides a better understanding of the molecular mechanism of enamel defects in dental fluorosis.

Identification of the hormetic dose-response and regulatory network of multiple metals co-exposure-related hypertension via integration of metallomics and adverse outcome pathways.

Environmental stressors, including heavy metals, can be associated with hypertension development. However, little information regarding the dose-response relationship and toxicity mechanisms of metal mixtures with hypertension development is currently available. Therefore, we recruited 940 participants from six factories in northeastern China and measured the urinary concentrations of 19 metals. Then, we used Bayesian kernel machine regression (BKMR) to explore associations between metals co-exposure and hypertension. The BKMR model indicated a hermetic dose-response relationship between eight urinary metals (Co, Cr, Ni, Cd, As, Fe, Zn, and Pb) and hypertension risk. Moreover, heterogeneous and non-linear association patterns were detected across different metals/metalloids concentrations. Next, for the first time, we analyzed data of chemicals containing specific metal elements in the Comparative Toxicogenomics Database (CTD) from a disease perspective and provided insights from various biological levels to explain heavy metal co-exposure-related hypertension. On the molecular scale, 43 chemical components and 112 potential target genes were detected for metal exposure-related hypertension. Further, the network topology analysis indicated that target genes such as insulin (INS, degree = 78), albumin (ALB, degree = 74), renin (REN, degree = 71), interleukin-6 (IL6, degree = 70), endothelin 1 (EDN1, degree = 70), and endothelial nitric oxide synthase (NOS3, degree = 69) have a strong correlation with heavy metals co-exposure. Finally, we used integrative analyses in the adverse outcome pathway (AOP) wiki to analyze the co-exposure of heavy metals and hypertension and support an integrated metallomics approach. We selected the AOP 149 as the framework and found that the molecular initiating events (MIEs) of hypertension stems from the oxidation of AA residues on critical peptides of the NO pathway. The NOS3 was particularly promising since its subunit has three metal ion cross-linking domains with Zn2+, Fe2+, and Ga3+, which might serve as a binding site for heavy metal ions.

Identification of Proteomic Signatures in Chronic Obstructive Pulmonary Disease Emphysematous Phenotype.

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease. Emphysematous phenotype is the most common and critical phenotype, which is characterized by progressive lung destruction and poor prognosis. However, the underlying mechanism of this structural damage has not been completely elucidated. A total of 12 patients with COPD emphysematous phenotype (COPD-E) and nine patients with COPD non-emphysematous phenotype (COPD-NE) were enrolled to determine differences in differential abundant protein (DAP) expression between both groups. Quantitative tandem mass tag-based proteomics was performed on lung tissue samples of all patients. A total of 29 and 15 lung tissue samples from patients in COPD-E and COPD-NE groups, respectively, were used as the validation cohort to verify the proteomic analysis results using western blotting. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted for DAPs. A total of 4,343 proteins were identified, of which 25 were upregulated and 11 were downregulated in the COPD-E group. GO and KEGG analyses showed that wound repair and retinol metabolism-related pathways play an essential role in the molecular mechanism of COPD emphysematous phenotype. Three proteins, namely, KRT17, DHRS9, and FMO3, were selected for validation. While KRT17 and DHRS9 were highly expressed in the lung tissue samples of the COPD-E group, FMO3 expression was not significantly different between both groups. In conclusion, KRT17 and DHRS9 are highly expressed in the lung tissue of patients with COPD emphysematous phenotype. Therefore, these proteins might involve in wound healing and retinol metabolism in patients with emphysematous phenotype and can be used as phenotype-specific markers.

Targeting SLC1A5 blocks cell proliferation through inhibition of mTORC1 in arsenite-treated human uroepithelial cells.

Arsenic is an environmental contaminant, which is widely distributed in soil, air, and water. There is sufficient evidence to indicate that arsenic increases the risk of bladder cancer in humans. However, its underlying mechanisms remain elusive. Glutamine (Gln) has multiple functions that promote carcinogenesis. Indeed, Gln transporters on cancer cells surface are often upregulated. Elevated expression levels of Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) have been reported in many types of human tumors. This study characterized the role of SLC1A5 in cell proliferation in arsenite-treated cells. In short-term experiments, SV-40 immortalized human uroepithelial (SV-HUC-1) cells were treated with Sodium arsenite (NaAsO2) (0, 0.5, 1, 2, 4, 8 µM) for 24 h. In long-term experiments, SV-HUC-1 cells were exposed to 0.5 µM NaAsO2 for 40 weeks. In both short-term and long-term experiments, arsenite increased expression of SLC1A5 by 1.89-fold and 2.25-fold, respectively. Arsenite increased Gln consumption of SV-HUC-1 cells, and Gln starvation inhibited cell proliferation in long-term arsenite-treated cells. Importantly, inhibiting SLC1A5 blocked cell proliferation by downregulating mTORC1 in long-term arsenite-treated cells. Moreover, SLC1A5 regulated mTORC1 in an αKG-dependent manner. Our results suggest that SLC1A5 plays an important role in cell proliferation of arsenite-treated SV-HUC-1 cells.

Roles and Mechanisms of Axon-Guidance Molecules in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive memory decline and cognitive dysfunctions. Although the causes of AD have not yet been established, many mechanisms have been proposed. Axon-guidance molecules play the roles in the occurrence and development of AD by participating in different mechanisms. Therefore, what roles do axon-guidance molecules play in AD? This study aimed at elucidating how axon-guidance molecules Netrins, Slits, Semaphorins, and Ephrins regulate the levels of Aß, hyperphosphorylation of tau protein, Reelin, and other ways through different signaling pathways, in order to show the roles of axon-guidance molecules in the occurrence and development of AD. And it is hoped that this study can provide a theoretical basis and new perspectives in the search for new therapeutic targets for AD.

A benchmark dose analysis for urinary cadmium and type 2 diabetes mellitus.

Cadmium (Cd) is a heavy metal referred to as one of the environmental endocrine disruptors. The dose-dependent association between Cd and type 2 diabetes mellitus (T2DM) has been elucidated, but the corresponding threshold has not been established. To evaluate the urinary Cd levels associated with T2DM, we perform a benchmark dose (BMD) analysis based on data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES). Weighted datasets were generated by the inverse probability of treatment weighting analysis to develop the robustness of our analysis. We inferred a strong positive association between urinary Cd and T2DM in unweighted and weighted populations. BMD and its low limit (BMDL) estimates for 5% benchmark responses (BMR) was 0.297 (0.198) and 0.190 (0.178) µg/g creatinine for each population, respectively. The sensitivity analysis by race, followed by weight of sum method showed similar estimates of urinary Cd level for the risk of developing T2DM, which are rather low and far less than those for the renal or bone disease development risk. This indicates that T2DM can be a sensitive outcome of Cd exposure and therefore should be taken into account in the development of standard regulatory limits for safe exposure to Cd.

HER2 overexpression triggers the IL-8 to promote arsenic-induced EMT and stem cell-like phenotypes in human bladder epithelial cells.

Arsenic is a natural chemical element that is strongly associated with bladder cancer. Understanding the underlying mechanisms behind the association between arsenic and bladder cancer as well as identifying effective preventive interventions will help reduce the incidence and mortality of this disease. The epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties play key roles in cancer development and progression. Here, we reported that chronic exposure to arsenic resulted in EMT and increased levels of the CSC marker CD44 in human uroepithelial cells. Furthermore, IL-8 promoted a mesenchymal phenotype and upregulated CD44 by activating the ERK, AKT and STAT3 signaling. Phosphorylation of the human epidermal growth factor receptor 2 (HER2) was key for arsenic-induced IL-8 overexpression and depended on the simultaneous activation of the MAPK, JNK, PI3K/AKT and GSK3ß signaling pathways. We also found that genistein inhibited arsenic-induced HER2 phosphorylation and downregulated its downstream signaling pathways, thereby inhibiting progression of EMT, and reducing CD44 expression levels. These results demonstrate that the HER2/IL-8 axis is related to the acquisition of an EMT phenotype and CSCs in arsenic-treated cells. The inhibitory effects of genistein on EMT and CSCs provide a new perspective for the intervention and potential chemotherapy against arsenic-induced bladder cancer.

Arsenic-induced HER2 promotes proliferation, migration and angiogenesis of bladder epithelial cells via activation of multiple signaling pathways in vitro and in vivo.

Arsenic (As) is a known human carcinogen with a hitherto unknown mechanism of action. Dimethylarsinic acid (DMAV) is a methylated metabolite of arsenicals found in most mammals, and long-term exposure to DMAV can lead to bladder cancer in rats. Human epidermal growth factor receptor 2 (HER2) is an oncogenic factor that is overexpressed in bladder cancer, but its role in the initiation and progression of As-induced bladder cancer has not been elucidated. We found that HER2 was up-regulated in human uroepithelial cells treated with arsenite as well as in the bladder tissues of DMAV-exposed rats. HER2 overexpression correlated to increased cell proliferation, epithelial-to-mesenchymal transition (EMT), migration and angiogenesis in vitro. The anti-HER2 monoclonal antibody trastuzumab significantly decreased serum vascular endothelial-derived growth factor (VEGF) levels and that of proliferation-related proteins in the bladder tissues of DMAV-exposed rats. Furthermore, inhibition of HER2, as well as that of the MAPK, AKT and STAT3 pathways, attenuated arsenite-induced proliferation, migration and angiogenesis of human uroepithelial cells, and increased apoptosis rates in vitro. These findings indicate that HER2 mediates the oncogenic effects of As on bladder epithelial cells by activating the MAPK, PI3K/AKT and Src/STAT3 signaling pathways, and is therefore a promising biomarker.

lncRNA OTUD6B-AS1 Exacerbates As2O3-Induced Oxidative Damage in Bladder Cancer via miR-6734-5p-Mediated Functional Inhibition of IDH2.

Arsenic trioxide (As2O3) is a promising effective chemotherapeutic agent for cancer treatment; however, how and through what molecular mechanisms the oxidative damage of As2O3 is controlled remains poorly understood. Recently, the involvement of dysregulated long noncoding RNA ovarian tumor domain containing 6B antisense RNA1 (lncRNA OTUD6B-AS1) in tumorigenesis is established. Here, for the first time, we characterize the regulation of As2O3 in the oxidative damage against bladder cancer via lncRNA OTUD6B-AS1. As2O3 could activate lncRNA OTUD6B-AS1 transcription in bladder cancer cells, and these findings were validated in a xenograft tumor model. Functional assays showed that lncRNA OTUD6B-AS1 dramatically exacerbated As2O3-mediated oxidative damage by inducing oxidative stress. Mechanistically, As2O3 increased levels of metal-regulatory transcription factor 1 (MTF1), which regulates lncRNA OTUD6B-AS1, in response to oxidative stress. Further, lncRNA OTUD6B-AS1 inhibited mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) expression by stabilizing miR-6734-5p, which contributed to cytotoxicity by enhancing oxidative stress. Together, our findings offer new insights into the mechanism of As2O3-induced oxidative damage and identify important factors in the pathway, As2O3/lncRNA OTUD6B-AS1/miR-6734-5p/IDH2, expanding the knowledge of activity of As2O3 as cancer treatment.

Impact of temperature on the dynamics of the COVID-19 outbreak in China.

A COVID-19 outbreak emerged in Wuhan, China at the end of 2019 and developed into a global pandemic during March 2020. The effects of temperature on the dynamics of the COVID-19 epidemic in China are unknown. Data on COVID-19 daily confirmed cases and daily mean temperatures were collected from 31 provincial-level regions in mainland China between Jan. 20 and Feb. 29, 2020. Locally weighted regression and smoothing scatterplot (LOESS), distributed lag nonlinear models (DLNMs), and random-effects meta-analysis were used to examine the relationship between daily confirmed cases rate of COVID-19 and temperature conditions. The daily number of new cases peaked on Feb. 12, and then decreased. The daily confirmed cases rate of COVID-19 had a biphasic relationship with temperature (with a peak at 10 °C), and the daily incidence of COVID-19 decreased at values below and above these values. The overall epidemic intensity of COVID-19 reduced slightly following days with higher temperatures with a relative risk (RR) was 0.96 (95% CI: 0.93, 0.99). A random-effect meta-analysis including 28 provinces in mainland China, we confirmed the statistically significant association between temperature and RR during the study period (Coefficient = -0.0100, 95% CI: -0.0125, -0.0074). The DLNMs in Hubei Province (outside of Wuhan) and Wuhan showed similar patterns of temperature. Additionally, a modified susceptible-exposed-infectious-recovered (M-SEIR) model, with adjustment for climatic factors, was used to provide a complete characterization of the impact of climate on the dynamics of the COVID-19 epidemic.