Manganese overexposure results in ferroptosis through the HIF-1α/p53/SLC7A11 pathway in ICR mouse brain and PC12 cells.

Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.

Urogenital schistosomiasis transmission, malaria and anemia among school-age children in Northern Ghana.

Background: In sub-Saharan Africa, co-morbidity with malaria, schistosomiasis, and soil transmitted helminths (STH) is common among young children. The current study investigated malaria, urinary schistosomiasis and their co-infection and anemia among school-age children in an endemic community, Nakolo in the Kassena-Nankana East District of northern Ghana. Methods: A cross-sectional survey of 336 school-age children, 5-16 years was undertaken. Urine samples were examined for Schistosoma haematobium ova using microscopy. Finger prick blood samples were examined for Plasmodium parasites using microscopy and haemoglobin concentration measured with HemoCue Hb301 photometer. Results: The mean age was 10.52 (Standard deviation: ±2.27; range: 5-16 years), of which 50.6% (170/336) were males. The overall prevalence of urinary schistosomiasis and Plasmodium (P.) falciparum was 12.8% (43/336) and 37.8% (127/336), respectively with 6.0% (20/336) coinfection. Participants with only P. falciparum infection had 17.8% (19/107) of moderate anemia whilst 21.7% (5/23) of children infected with only S. haematobium had moderate anemia and 4.3% (1/23) had severe anemia. 5.0 % (1/20) of moderate anemia was observed in concurrent infections of P. falciparum and S. haematobium. Use of open water bodies was associated with increased risk of S. haematobium infection (OR = 1.21; 95% CI = [1.06-1.39]; p = 0.001), with females being at reduced risk (OR = 0.93; 95%CI = [0.87-0.99]; p = 0.005). Absence of self-reported haematuria had 0.81 times reduced odds of S. haematobium infection (OR = 0.81; 95%CI = [0.74-0.87]; p < 0.001). Conclusion: This study has revealed that urinary schistosomiasis remains prevalent in Kassena-Nankana East district and suggests that urinary schistosomiasis may contribute to moderate anemia among school-age children as compared to asymptomatic malaria infection. These findings call for an evaluation of the annual mass drug administration of Praziquantel among in-school children to ascertain its impact on urinary schistosomiasis prevalence across the district.

Ferroptosis contributes to methylmercury-induced cytotoxicity in rat primary astrocytes and Buffalo rat liver cells.

OBJECTIVE: Ferroptosis is an iron-dependent nonapoptotic form of cell death, characterized by iron accumulation and lipid peroxidation. However, the role of ferroptosis in methylmercury (MeHg)-induced cytotoxicity has yet to be fully characterized. The purpose of this study was to investigate the role of ferroptosis in MeHg-induced cytotoxicity in both brain and liver cells. METHODS: The effects of MeHg on cell viability, cytotoxicity, intracellular iron content, reduced glutathione (GSH) content, ferroptosis-related proteins, cytosolic and lipid reactive oxygen species (ROS) generation were determined in rat primary astrocytes (AST) and Buffalo Rat Liver (BRL) cells in the absence or presence of the ferroptosis inhibitors deferoxamine (DFO) or ferrostatin-1 (Fer-1). RESULTS: MeHg treatment decreased cell viability and increased cytotoxicity in AST and BRL cells. MeHg induced ferroptosis in AST and BRL cells was reflected by increased cytosolic ROS, lipid ROS and intracellular iron content, all of which were inhibited by the ferroptosis inhibitors DFO and/or Fer-1. MeHg inhibited the expression of ferritin heavy chain 1 (FTH1). Furthermore, MeHg treatment decreased the expression of glutathione peroxidase 4 (GPx4) without altering solute carrier family 7 member 11 (SLC7A11). DFO and Fer-1 significantly increased the expression of GPx4, yet had no effect on SLC7A11 upon MeHg treatment. CONCLUSIONS: Our novel results are consistent with ferroptosis as a key event mediating MeHg-induced toxicity, inhibiting GPx4 in AST and BRL cells. Ferroptosis may offer a new target for attenuating MeHg-induced toxic injury.

Differential susceptibility of PC12 and BRL cells and the regulatory role of HIF-1α signaling pathway in response to acute methylmercury exposure under normoxia.

Hypoxia-inducible factor 1 (HIF-1) is a critical nuclear transcription factor for adaptation to hypoxia; its regulatable subunit, HIF-1α, is a cytoprotective regulatory factor. We examined the effects of methylmercury (MeHg) in rat adrenal pheochromocytoma (PC12) cells and the rat hepatocyte cell line BRL. MeHg treatment led to time- and concentration-dependent toxicity in both lines with statistically significant cytotoxic effects at 5 µM and 10 µM in PC12 and BRL, respectively, at 0.5 h. HIF-1α protein levels were significantly decreased at 2.5 (PC12) and 5 (BRL) µM MeHg. Furthermore, MeHg reduced the protein levels of HIF-1α and its target genes (glucose transporter-1, vascular endothelial growth factor-A and erythropoietin). Overexpression of HIF-1α significantly attenuated MeHg-induced toxicity in both cell types. Notably, cobalt chloride, a pharmacological inducer of HIF-1α, significantly attenuated MeHg-induced toxicity in BRL but not PC12. In both cell lines, an inhibitor of prolyl hydroxylase, 3, 4-dihydroxybenzoic acid, and the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal(MG132), antagonized MeHg toxicity, while 2-methoxyestradiol, a HIF-1α inhibitor, significantly increased it. These data establish that: (a) neuron-like PC12 cells are more sensitive to MeHg than non-neuronal BRL cells; (b) HIF-1α plays a similar role in MeHg-induced toxicity in both cell lines; and (c) upregulation of HIF-1α offers general cytoprotection against MeHg toxicity in PC12 and BRL cell lines.

The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis.

BACKGROUND: The overexpression and mutation of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are widespread in cancers and have been recognized as attractive oncologic targets with diverse therapeutic targets. Reports of the overexpression of genes, proteins and mutations of PDGFs/PDGFRs in gastric cancer and their associations with clinicopathological features, Western and Asian patients, as well as prognostic role have shown variable outcomes. This study sought to employ meta-analysis to evaluate PDGFs/PDGFRs status prognostic significance and their association with clinicopathological features of gastric cancer. METHOD: A comprehensive search of PubMed database for studies that investigated the overexpression of mRNA/Protein and mutation of PDGFs/PDGFRs in gastric cancer of Western and Asian patients, their prognostic significance and association with clinicopathological characteristics in May, 2017 or earlier was carried out by two reviewers independently. Pooled odd ratios and hazard ratios at 95% confidence intervals were estimated and summarized using fixed-effect and random-effect Mantel-Haenszel models and Inverse Variance models in Review Manager software version 5.3. RESULTS: Fourteen studies with 16 datasets of 1178 patients were included in meta-analysis. Fourteen studies of 1178 patients with 1446 cases and 7 studies of 1076 patients with 1280 cases were included in meta-analysis of clinicopathological and prognostic significance of high or positive PDGF/PDGFR status respectively. Odd ratio at 95% confidence intervals for different groups of analysis are as follows: males versus females(OR = 1.38, 95% CI: 1.04-1.83, POR = 0.03); ≥T2 stage versus T1 stage(OR = 2.06, 95% CI: 1.22-3.49, POR = 0.007); nodal metastasis versus no nodal metastasis(OR = 2.78, 95% CI: 1.48-5.22, POR = 0.002); TNM stage ≥II versus TNM stage I(OR = 3.55, 95% CI: 1.89-6.69, POR<0.0001). Subgroup analysis of the association of PDGF/PDGFR among Western patients(OR = 0.24 95% CI: 0.10-0.58, POR = 0.002) and association of PDGFs/PDGFRs gene mutation among gastric cancer patients(OR = 0.15, 95% CI: 0.05-0.45, POR = 0.0008) were significant. The association of PDGFs/PDGFRs in young and middle age versus elderly aged, undifferentiated versus well differentiated tumors, large tumor size group(>6 cm) versus small tumor size group(≤6 cm) were insignificant. Subgroup analysis of the association of PDGFs/PDGFRs among Western Asian patients; PDGF/PDGFR mRNA expression and protein expression among gastric cancer patients were insignificant. In addition, PDGF/PDGFR status among gastric cancer patients was insignificant in overall effect analysis PDGF/PDGFR status has shown to predict reduced overall survival(HR = 1.25, 95% CI: 0.49-3.22, PHR = 0.64) and relapse free survival(HR = 0.93, 95% CI: 0.36-2.41, PHR = 0.88) insignificantly. Also, overall prognostic effect analysis(HR = 1.07, 95% CI: 0.58-1.96, PHR = 0.84) was insignificant. CONCLUSION: PDGFs/PDGFRs status amongst gastric cancer patients plays a key role in clinical variables and nodal metastasis. These insights might be helpful in providing guidelines for diagnosis, molecular target therapy, and prognosis of gastric cancer.

PKG II inhibits PDGF-BB triggered biological activities by phosphorylating PDGFRß in gastric cancer cells.

Previous studies revealed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR) which is a widely investigated RTK. PDGFR belongs to family of receptor tyrosine kinases (RTKs) too. However, the effect of PKG II on PDGFR activation is not clear yet. This study investigated potential regulatory effect of PKG II on activation of PDGFRß and the downstream signaling transductions in gastric cancer. The results from CCK8 assay and Transwell assay indicated that PDGF-BB induced cell proliferation and migration. Activated PKG II reversed the above variations caused by PDGF-BB. Immunoprecipitation and Western blotting results showed that PKG II combined with PDGFRß and phosphorylated this receptor, and thereby inhibited PDGF-BB induced activation of PDGFRß, and MAPK/ERK and PI3K/Akt mediated signal transduction pathways. Based on the prediction by phosphorylation site software, Ser643 and Ser712 were mutated to alanine respectively which prevented phosphorylation at these sites. Mutation at Ser712 abolished the inhibitory function of PKG II on PDGFRß activation but mutation of Ser643 had no such an effect, indicating that Ser712 was PKG II-specific phosphorylating site of PDGFRß. In conclusion, PKG II inhibited PDGFRß activation in gastric cancer via phosphorylating Ser712 of this RTK.

PKG II effectively reversed EGF-induced protein expression alterations in human gastric cancer cell lines.

Epidermal growth factor receptor (EGFR) plays an important role in gastric cancer (GC) progression. Our previous data demonstrated that type II cGMP-dependent protein kinase (PKG II) could block the EGF-EGFR axis as well as down-stream signaling pathways, for example, MAPK, PI3 K, and PLC in GC cells. However, the exact mechanisms of PKG II against cancer remain unclear. Therefore, the present work was to address the above question. Human GC cell line AGS was infected with adenoviral construct encoding cDNA of PKG II (Ad-PKG II) to up-regulate PKG II and then treated with 8-pCPT-cGMP. Two-dimensional electrophoresis (2-DE) was used to analyze the changes of protein expression in the cells. The results showed that 17 proteins had more than twofold changes in EGF-treated group compared with control. However, Ad-PKG II could effectively reversed the changes. Furthermore, far upstream element-binding protein 1 (FUBP1) and MarvelD3 were chosen and PKG II activation reversed EGF/EGFR-induced up-regulation of FUBP1 and downregulation of MarvelD3, respectively. MarvelD3 silence effectively abolished the inhibitory effect of PKG II on EGF-triggered migration. These data indicated that the inhibitory effect of PKG II partially was associated with MarvelD3.

Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies.

PURPOSE: To investigate oncogenic platelet-derived growth factor receptor(PDGFR) fusion genes involvement in hematological malignancies, the advances in the PDGFR fusion genes diagnosis and development of PDGFR fusions inhibitors. METHODS: Literature search was done using terms "PDGFR and Fusion" or "PDGFR and Myeloid neoplasm" or 'PDGFR and Lymphoid neoplasm' or "PDGFR Fusion Diagnosis" or "PDGFR Fusion Targets" in databases including PubMed, ASCO.org, and Medscape. RESULTS: Out of the 36 fusions detected, ETV6(TEL)-PDGFRB and FIP1L1-PDGFRA fusions were frequently detected, 33 are as a result of chromosomal translocation, FIP1L1-PDGFRA and EBF1-PDGFRB are the result of chromosomal deletion and CDK5RAP2- PDGFRΑ is the result of chromosomal insertion. Seven of the 34 rare fusions have detectable reciprocals. CONCLUSION: RNA aptamers are promising therapeutic target of PDGFRs and diagnostic tools of PDGFRs fusion genes. Also, PDGFRs have variable prospective therapeutic strategies including small molecules, RNA aptamers, and interference therapeutics as well as development of adaptor protein Lnk mimetic drugs.

The platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are major players in oncogenesis, drug resistance, and attractive oncologic targets in cancer.

The platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) play a key role in signaling pathways in oncogenesis. The overexpression of PDGFs and PDGFRs and the oncogenic alterations of these receptors have been implicated in human cancers and correlated significantly with poor outcomes. This review discusses the biology of the PDGF isoforms and receptors briefly, and their role in oncogenesis. Also, the attractiveness of targeting PDGFs and PDGFRs, based on a wide display of oncologic alterations in cancers, diverse therapeutic strategies, their roles in resistance to cancer treatments with prospects of overcoming drug resistance, and the extent to which validated biomarkers have been developed for effective PDGFs and PDGFRs-based cancer management are discussed.

Platelet-derived growth factor receptor/platelet-derived growth factor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers.

Progress in cancer biology has led to an increasing discovery of oncogenic alterations of the platelet-derived growth factor receptors (PDGFRs) in cancers. In addition, their overexpression in numerous cancers invariably makes PDGFRs and platelet-derived growth factors (PDGFs) prognostic and treatment markers in some cancers. The oncologic alterations of the PDGFR/PDGF system affect the extracellular, transmembrane and tyrosine kinase domains as well as the juxtamembrane segment of the receptor. The receptor is also involved in fusions with intracellular proteins and receptor tyrosine kinase. These discoveries undoubtedly make the system an attractive oncologic therapeutic target. This review covers elementary biology of PDGFR/PDGF system and its role as a prognostic and treatment marker in cancers. In addition, the multifarious therapeutic targets of PDGFR/PDGF system are discussed. Great potential exists in the role of PDGFR/PDGF system as a prognostic and treatment marker and for further exploration of its multifarious therapeutic targets in safe and efficacious management of cancer treatments.