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.

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.

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.

Trends in global, regional and national incidence of pneumoconiosis caused by different aetiologies: an analysis from the Global Burden of Disease Study 2017.

OBJECTIVES: Pneumoconiosis remains a major global occupational health hazard and illness. Accurate data on the incidence of pneumoconiosis are critical for health resource planning and development of health policy. METHODS: We collected data for the period between 1990 and 2017 on the annual incident cases and the age-standardised incidence rates (ASIR) of pneumoconiosis aetiology from the Global Burden of Disease Study 2017. We calculated the average annual percentage changes of ASIR by sex, region and aetiology in order to determine the trends of pneumoconiosis. RESULTS: Globally, the number of pneumoconiosis cases increased by a measure of 66.0%, from 36 186 in 1990 to 60 055 in 2017. The overall ASIR decreased by an average of 0.6% per year in the same period. The number of pneumoconiosis cases increased across the five sociodemographic index regions, and there was a decrease in the ASIR from 1990 to 2017. The ASIR of silicosis, coal workers' pneumoconiosis and other pneumoconiosis decreased. In contrast, measures of the ASIR of asbestosis displayed an increasing trend. Patterns of the incidence of pneumoconiosis caused by different aetiologies were found to have been heterogeneous for analyses across regions and among countries. CONCLUSION: Incidence patterns of pneumoconiosis which were caused by different aetiologies varied considerably across regions and countries of the world. The patterns of incidence and temporal trends should facilitate the establishment of more effective and increasingly targeted methods for prevention of pneumoconiosis and reduce associated disease burden.

The effects of heavy metals on human metabolism.

As technology continues to advance, heavy metals in drinking water have exceeded recommended limits from regulators around the world. The main source of human exposure to heavy metals is from contaminated drinking water. The effects of drinking water contaminated with heavy metals, such as arsenic, lead, nickel, cadmium and mercury, have gradually caught the attention of the relevant departments and personnel. It is well known that occupational exposure to heavy metals occurs as a result of using these metals in a variety of industrial processes in and/or a variety of materials, including color pigments and alloys. A series of adverse effects on human metabolism has resulted from exposure to heavy metal-contaminated drinking water, which has been recorded from around the world. The general mechanism of heavy metal toxicity is through the production of reactive oxygen species, the appearance of oxidative damage, and subsequent adverse effects on health. Therefore, water contaminated with heavy metals causes high morbidity and mortality worldwide. In order to address concern regarding the health effects of different heavy metals, this paper reviews its sources, distribution and effects of heavy metal on human metabolism.HIGHLIGHTSThe accumulation of heavy metals such as lead, arsenic, mercury, cadmium and nickel will destroy the main metabolic process of human body.Redox reactions in biological systems are caused by carcinogenic metal ions such as nickel and arsenic. The free radicals produced by these reactions cause oxidative damage to proteins and DNA.The accumulation of heavy metals eventually produces reactive oxygen species that can cause oxidative stress, which may lead to the production of various diseases.

Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice.

Manganese (Mn) induced learning and memory deficits through mechanisms that are not fully understood. In this study, we discovered that the demethylase FTO was significantly downregulated in hippocampal neurons in an experimental a mouse model of Mn exposure. This decreased expression of FTO was associated with Mn-induced learning and memory impairments, as well as the dysfunction in synaptic plasticity and damage to regional neurons. The overexpression of FTO, or its positive modulation with agonists, provides protection against neurological damage and cognitive impairments. Mechanistically, FTO interacts synergistically with the reader YTHDF3 to facilitate the degradation of GRIN1 and GRIN3B through the m6A modification pathway. Additionally, Mn decreases the phosphorylation of SOX2, which specifically impairs the transcriptional regulation of FTO activity. Additionally, we found that the natural compounds artemisinin and apigenin that can bind molecularly with SOX2 and reduce Mn-induced cognitive dysfunction in mice. Our findings suggest that the SOX2-FTO-Grins axis represents a viable target for addressing Mn-induced neurotoxicity and cognitive impairments.

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.

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.