Search Results (13)

Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM. Full article

Cadmium (Cd) is a toxic metal which is harmful to humans and the environment. Cd levels and adverse effects may be associated with genetic polymorphisms in genes involved in its toxicokinetics. This study investigated Cd levels in 198 residents of a condominium in Rio de Janeiro, Brazil, built on industrial steel slag waste and the influence of glutathione S-transferase pi isoform 1 (GSTP1) rs1695 A>G polymorphism. Polymorphism was genotyped using a validated TaqMan assay; Cd levels were measured in blood (BCd) and urine (UCd) by graphite furnace atomic absorption spectrometry. Associations were evaluated by multiple logistic regression, odds ratios (ORs), and 95% confidence intervals (CIs). The mean Cd levels were 0.70 ± 0.20 µg L⁻¹ (BCd), 0.58 ± 0.57 µg L⁻¹ (UCd), and 0.61 ± 0.65 µg g⁻¹ in urine corrected by creatinine (UcCd), and the Cd results were above tolerable levels (BCd > 0.5 µg L⁻¹) in 87.4% of subjects. Higher blood Cd levels (>0.69 µg L⁻¹) were associated with respiratory disease (OR = 2.4; 95%CI = 1.2–5.0), as almost 30% of people with respiratory diseases had higher Cd levels. The GSTP1 rs1695AA genotype frequency was 38.1%, and there were no significant differences between the SNP and Cd levels. High Cd levels and a high prevalence of diseases highlight the importance of implementing public policies and the continuous monitoring of this at-risk population. Full article

Prostate cancer remains a significant public health concern in sub-Saharan Africa, particularly impacting South Africa with high mortality rates. Despite many years of extensive research and significant financial expenditure, there has yet to be a definitive solution to prostate cancer. It is not just individuals who vary in their response to treatment, but even different nodules within the same tumor exhibit unique transcriptome patterns. These distinctions extend beyond mere differences in gene expression levels to encompass the control and networking of individual genes. Escalating chemotherapy resistance in prostate cancer patients has prompted increased research into its underlying mechanisms. The heterogeneous nature of transcriptomic organization among men makes the pursuit of universal biomarkers and one-size-fits-all treatments impractical. This study delves into the expression of drug resistance-associated genes, ABCB1 and CYP1B1, in cancer cells. Employing bioinformatics, we explored the molecular pathways and cascades linked to drug resistance following upregulation of these genes. Samples were obtained from archived prostate cancer patient specimens through pre-treatment biopsies of two categories: good vs. poor responders, with cDNAs synthesized from isolated RNAs subjected to qPCR analysis. The results revealed increased ABCB1 and CYP1B1 expression in tumor samples of the poor responders. Gene enrichment and network analysis associated ABCB1 with ABC transporters and LncRNA-mediated therapeutic resistance (WP3672), while CYP1B1 was linked to ovarian steroidogenesis, tryptophan metabolism, steroid hormone biosynthesis, benzo(a)pyrene metabolism, the sulindac metabolic pathway, and the estrogen receptor pathway, which are associated with drug resistance. Both ABCB1 and CYP1B1 correlated with microRNAs in cancer and the Nuclear Receptors Meta-Pathway. STRING analysis predicted protein–protein interactions of ABCB1 and CYP1B1 with Glutathione S-transferase Pi, Catechol O-methyltransferase, UDP-glucuronosyltransferase 1-6, Leucine-rich Transmembrane and O-methyltransferase (LRTOMT), and Epoxide hydrolase 1, with scores of 0.973, 0.971, 0.966, 0.966, and 0.966, respectively. Furthermore, molecular docking analysis of the chemotherapy drug, docetaxel, with CYP1B1 and ABCB1 revealed robust molecular interactions, with binding energies of −20.37 and −15.25 Kcal/mol, respectively. These findings underscore the susceptibility of cancer patients to drug resistance due to increased ABCB1 and CYP1B1 expression in tumor samples from patients in the poor-responders category that affects associated molecular pathways. The potent molecular interactions of ABCB1 and CYP1B1 with docetaxel further emphasize the potential basis for chemotherapy resistance. Full article

Port Wine Birthmarks (PWBs) are a congenital vascular malformation on the skin, occurring in 1–3 per 1000 live births. We have recently generated PWB-derived induced pluripotent stem cells (iPSCs) as clinically relevant disease models. The metabolites associated with the pathological phenotypes of PWB-derived iPSCs are unknown, and so we aim to explore them in this study. Metabolites were separated by ultra-performance liquid chromatography and screened with electrospray ionization mass spectrometry. Orthogonal partial least-squares discriminant, multivariate, and univariate analyses were used to identify differential metabolites (DMs). KEGG analysis was used to determine the enrichment of metabolic pathways. A total of 339 metabolites was identified. There were 22 DMs, among which nine were downregulated—including sphingosine—and 13 were upregulated, including glutathione in PWB iPSCs, as compared to controls. Pathway enrichment analysis confirmed the upregulation of glutathione and the downregulation of sphingolipid metabolism in PWB-derived iPSCs as compared to normal ones. We next examined the expression patterns of the key molecules associated with glutathione metabolism in PWB lesions. We found that hypoxia-inducible factor 1α (HIF1α), glutathione S-transferase Pi 1 (GSTP1), γ-glutamyl transferase 7 (GGT7), and glutamate cysteine ligase modulatory subunit (GCLM) were upregulated in PWB vasculatures as compared to blood vessels in normal skin. Other significantly affected metabolic pathways in PWB iPSCs included pentose and glucuronate interconversions; amino sugar and nucleotide sugars; alanine, aspartate, and glutamate; arginine, purine, D-glutamine, and D-glutamate; arachidonic acid, glyoxylate, and dicarboxylate; nitrogen, aminoacyl-tRNA biosynthesis, pyrimidine, galactose, ascorbate, and aldarate; and starch and sucrose. Our data demonstrated that there were perturbations in sphingolipid and cellular redox homeostasis in PWB vasculatures, which could facilitate cell survival and pathological progression. Our data implied that the upregulation of glutathione could contribute to laser-resistant phenotypes in some PWB vasculatures. Full article

Platinum-based chemotherapy regimens have been proven to be effective in various cancers; however, considerable toxicities may develop and can even lead to treatment discontinuation. Diverse factors may influence adverse treatment events, with pharmacogenetic variations being one prime example. Polymorphisms within the glutathione S-transferase pi 1 (GSTP1) gene may especially alter enzyme activity and, consequently, various toxicities in patients receiving platinum-based chemotherapy. Due to a lack of consistency in the degree of elevated complication risk, we performed a systematic literature review and meta-analysis to determine the level of platinum-associated toxicity in patients with the GSTP1 rs1695 polymorphism. We conducted a systematic search for eligible studies published before January 2022 from PubMed, Web of Science, and EMBASE based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between the rs1695 polymorphism and various toxicities. Ten eligible studies met the inclusion criteria. The pooled ORs for hematological toxicity and neutropenia in the patients with the variant (G) allele were 1.7- and 2.6-times higher than those with the AA genotype (95% CI 1.06–2.73 and 1.07–6.35), respectively. In contrast, the rs1695 polymorphism resulted in a 44% reduced gastrointestinal toxicity compared to wild-type homozygotes. Our study found that the GSTP1 rs1695 polymorphism was significantly correlated with platinum-induced toxicities. The study also revealed that rs1695 expression exhibited tissue-specific patterns and thus yielded opposite effects in different tissues. A personalized chemotherapy treatment based on these polymorphisms may be considered for cancer patients in the future. Full article

Tumor necrosis factor-alpha (TNF-α) signaling regulates phosphorylation of L-plastin, which is involved in forming the nascent sealing zone, a precursor zone for the matured sealing ring. This study aimed to illustrate the molecular mechanisms of L-plastin phosphorylation and the subsequent formation of the nascent sealing zone in osteoclasts treated with TNF-α. Here, we report that anti-TNF-receptor 1, inhibitors of signaling proteins (Src, PI3-K, Rho, and Rho-kinase), and siRNA of TRAF-6 attenuated the phosphorylation of LPL and filamentous actin content significantly in the presence of TNF-α. An inhibitor of integrin αvβ3, PKC, or PKA did not inhibit TNF-α-induced L-plastin phosphorylation. Inhibitors of Src and PI3-K and not Rho or Rho-kinase reduced tyrosine phosphorylation of TRAF-6, suggesting that Src and PI3-K regulate TRAF-6 phosphorylation, and Rho and Rho-kinase are downstream of TRAF-6 regulation. Osteoclasts expressing constitutively active or kinase-defective Src proteins were used to determine the role of Src on L-plastin phosphorylation; similarly, the effect of Rho was confirmed by transducing TAT-fused constitutively active (V14) or dominant-negative (N19) Rho proteins into osteoclasts. Pull-down analysis with glutathione S-transferase-fused SH2 and SH3 domains of Src and PI3-K demonstrated coprecipitation of L-plastin and TRAF-6 with the SH3 and SH2 domains of the PI3-K and Src proteins. However, the actual order of the interaction of proteins requires further elucidation; a comprehensive screening should corroborate the initial findings of protein interactions via the SH2/SH3 domains. Ultimately, inhibition of the interaction of proteins with SH2/SH3 could reduce L-plastin phosphorylation and affect NSZ formation and bone resorption in conditions that display osteoclast activation and bone loss. Full article

Environmental di(2-Ethylhexyl) phthalate (DEHP) is widely used in various industries as a plasticizer, and has been reported to induce reproductive and developmental toxicities in organisms. The purpose of this study was to evaluate the detoxification capacity of Lycium barbarum polysaccharides (LBP) and wolfberry juice (WJ) against DEHP-induced hepatotoxicity. Two groups of rats were purchased to study two different intervention method experiments: LBP (50, 100, 200 mg/kg·bw) intervention before DEHP (2000 mg/kg·bw) exposure, and LBP (200 mg/kg·bw) or WJ (8 mL/kg·bw) intervention after DEHP (3000 mg/kg·bw) exposure. The rats were exposed to DEHP once, while the intervention lasted for seven days. At the end of the intervention, enzyme-linked immunosorbent assay (ELISA) was used to measure the related index. The LBP intervention before DEHP exposure experiment (the first experimental method) found that LBP group rats showed a strong capacity toward DEHP detoxification, evidenced by the significant upregulation of activities and concentrations of the partner retinoid, X receptor alpha (RXRα), and downstream regulators Cytochrome P4502E1 (CYP2E1), Cytochrome P4503A1 (CYP3A1), Glutathione S-Transferase Pi (GSTpi), and UDP-glucuronosyltransferase 1 (UGT1) in a dose-dependent manner. The LBP and WJ intervention after DEHP exposure experiment (the second intervention experiment) found that WJ could downregulate pregnane X receptor (PXR), and upregulate downstream regulators, CYP2E1, CYP3A1, and Glutathione S-Transferase (GST) with the extension of intervention time, to alleviate the toxicity of DEHP. However, the intervention effect of WJ was more obvious than that of LBP. These results suggested that LBP and WJ might be effective detoxification agents against DEHP-induced toxic effects, by activating PXR and PXR-related detoxifying enzymes. Full article

Background: Myocardial infarction (MI) is still a major contributor to mortality worldwide, and therefore, searching for new drugs is an urgent priority. Natural products are a renewable source for medicinally and pharmacologically active molecules. The objective of this study was to explore the potential of geraniol, a monoterpene alcohol, to protect against MI. Methods: Five groups of Wister rats were used: a control group; a group treated only with geraniol; a group treated only with isoproterenol, to induce MI; and two groups pretreated with geraniol (100 or 200 mg/kg, respectively) for 14 days and challenged with isoproterenol on the 13th and 14th days. Several parameters were measured including electrocardiogram (ECG), cardiac markers, the expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and other downstream antioxidant enzymes, as well as the expression of phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and other downstream apoptotic and inflammatory mediators. Results: Geraniol treatment reduced the size of the infarct region, attenuated the levels of cardiac indicators, and diminished myocardial necrosis and immune cell infiltration. Geraniol treatment also activated the Keap1/Nrf2/heme oxygenase-1 (HO-1) pathway, increased antioxidant enzyme activities, modulated the PI3K/Akt/mTOR pathway, and ameliorated myocardial autophagy, inflammation, and apoptosis. Conclusion: Geraniol may possess a protective effect against MI through moderating MI-induced myocardial oxidative stress (glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and Keap1/Nrf2 pathway), inflammation (IL-1β, IL-6, TNF-α, and Nuclear factor-κB (NF-κB)), apoptosis (caspase-3, caspase-9, Bcl2, and Bax), and autophagy (PI3K/Akt/mTOR pathway). Full article

Glutathione S-transferase pi-1 (GSTP1) plays an important role in regulating oxidative stress by conjugating glutathione to electrophiles. GSTP1 is overexpressed in breast, colon, lung, and prostate tumors, where it contributes to tumor progression and drug resistance; however, the role of GSTP1 in pancreatic ductal adenocarcinoma (PDAC) is not well understood. Using shRNA, we knocked down GSTP1 expression in three different PDAC cell lines and determined the effect on cell proliferation, cell cycle progression, and reactive oxygen species (ROS) levels. Our results show GSTP1 knockdown reduces PDAC cell growth, prolongs the G₀/G₁ phase, and elevates ROS in PDAC cells. Furthermore, GSTP1 knockdown results in the increased phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the decreased phosphorylation of extracellular signal-regulated kinase (ERK), p65, the reduced expression of specificity protein 1 (Sp1), and the increased expression of apoptosis-promoting genes. The addition of the antioxidant glutathione restored cell viability and returned protein expression levels to those found in control cells. Collectively, these data support the working hypothesis that the loss of GSTP1 elevates oxidative stress, which alters mitogen-activated protein (MAP) kinases and NF-κB signaling, and induces apoptosis. In support of these in vitro data, nude mice bearing orthotopically implanted GSTP1-knockdown PDAC cells showed an impressive reduction in the size and weight of tumors compared to the controls. Additionally, we observed reduced levels of Ki-67 and increased expression of cleaved caspase-3 in GSTP1-knockdown tumors, suggesting GSTP1 knockdown impedes proliferation and upregulates apoptosis in PDAC cells. Together, these results indicate that GSTP1 plays a significant role in PDAC cell growth and provides support for the pursuit of GSTP1 inhibitors as therapeutic agents for PDAC. Full article

Osteoarthritis and its associated comorbidities are important clinical problems that have a negative impact on the quality of life, and its treatment remains unresolved. We investigated whether the systemic administration of slow-releasing hydrogen sulfide (H₂S) donors, allyl isothiocyanate (A-ITC) and phenyl isothiocyanate (P-ITC), alleviates chronic osteoarthritis pain and the associated emotional disorders. In C57BL/6 female mice with osteoarthritis pain induced by the intra-articular injection of monosodium iodoacetate, we evaluated the effects of repeated administration of A-ITC and P-ITC on the (i) mechanical allodynia and grip strength deficits; (ii) emotional conducts; and (iii) glial activity and expression of inducible nitric oxide synthase (NOS2), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and antioxidant enzymes (heme oxygenase 1, NAD(P)H:quinone oxidoreductase-1, glutathione S-transferase mu 1 and alpha 1) in the hippocampus. The administration of A-ITC and P-ITC inhibited the mechanical allodynia, the grip strength deficits, and the depressive-like behaviors accompanying osteoarthritis. Both treatments inhibited microglial activation, normalized the upregulation of NOS2 and PI3K/p-Akt, and maintained high levels of antioxidant/detoxificant enzymes in the hippocampus. Data suggest that treatment with low doses of slow-releasing H₂S donors might be an interesting strategy for the treatment of nociception, functional disability, and emotional disorders associated with osteoarthritis pain. Full article

Leaf extract of Nelumbo nucifera (NLE) has been demonstrated to possess anti-atherosclerosis, improve alcohol-induced steatohepatitis, prevent high-fat diet-induced obesity, and inhibit the proliferation and metastasis of human breast cancer cells. This study determines the chemopreventive role of NLE against 2-acetylaminofluorene (AAF)-induced hepatocellular carcinoma (HCC) in rats. AAF was used to induce hepatocarcinogenesis in rats through genetic and nongenetic effects. After administration for 12 weeks, NLE (0.5–2%) supplementation orally inhibited AAF (0.03%)-induced hepatic fibrosis which appears during the development of premalignant lesions in rats. After the 6-month experiment, NLE supplementation resulted in decreasing AAF-induced serum parameters of hepatic injury, including the level of triglycerides, total cholesterol, alpha-fetoprotein (AFP), and inflammatory mediator interleukin (IL)-6 and tumor necrosis factor (TNF)-α as well as the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (γGT). NLE supplementation also reduced AAF-induced lipid peroxidation and 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation in the rat liver. Hepatic histopathological investigation revealed that NLE supplementation attenuated the AAF-induced HCC and glutathione S-transferase-Pi (GST-Pi) expression. Furthermore, NLE supplementation increased the expression of transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream targets, including catalase, glutathion peroxidase (GPx), and superoxide dismutase 1 (SOD-1) in the rat liver. Our findings indicate that NLE supplementation inhibited AAF-induced hepatocarcinogenesis by enhancing antioxidative potential and alleviating inflammation in rats. Full article

Zearalenone (ZEA) is a prevalent mycotoxin with high toxicity in animals. In order to study its effect on juvenile grass carp (Ctenopharyngodon idella), six diets supplemented with different levels of ZEA (0, 535, 1041, 1548, 2002, and 2507 μg/kg diet) for 10 weeks were studied to assess its toxicity on intestinal structural integrity and potential mechanisms of action. Our report firstly proved that ZEA led to growth retardation and body deformity, and impaired the intestinal structural integrity of juvenile grass carp, as revealed by the following findings: (1) ZEA accumulated in the intestine and caused histopathological lesions; (2) ZEA resulted in oxidative injury, apoptosis, and breached tight junctions in the fish intestine, which were probably associated with Nuclear factor-erythroid 2-related factor 2 (Nrf2), p38 mitogen activated protein kinases (p38MAPK), and myosin light chain kinase (MLCK) signaling pathways, respectively. ZEA had no influence on the antioxidant gene levels of Kelch-like ECH associating protein 1 (Keap1)b (rather than Keap1a), glutathione-S-transferase (GST)P1, GSTP2 (not in the distal intestine (DI)), tight junctions occludin, claudin-c (not in the proximal intestine (PI)), or claudin-3c (not in the mid intestine (MI) or DI). Full article

Background: Phthalate exposure may increase the risk of asthma. Little is known about whether oxidative-stress related genes may alter this association. First, this motivated us to investigate whether genetic polymorphisms of the oxidative-stress related genes glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1), superoxide dismutase 2 (SOD2), catalase (CAT), myeloperoxidase (MPO), and EPHX1 in children are associated with phthalate urine concentrations. Second, we addressed the question whether these genes may affect the influence of phthalates on asthma. Methods: In a case-control study composed of 126 asthmatic children and 327 controls, urine phthalate metabolites (monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP) were measured by UPLC-MS/MS at age 3. Genetic variants were analyzed by TaqMan assay. Information on asthma and environmental exposures was also collected. Analyses of variance and logistic regressions were performed. Results: Urine MEHHP levels were associated with asthma (adjusted OR 1.33, 95% CI (1.11–1.60). Children with the GSTP1 (rs1695) AA and SOD2 (rs5746136) TT genotypes had higher MEHHP levels as compared to GG and CC types, respectively. Since only SOD2 TT genotype was significantly associated with asthma (adjusted OR (95% CI): 2.78 (1.54–5.02)), we estimated whether SOD2 variants modify the association of MEHHP levels and asthma. As MEHHP concentrations were dependent on GSTP1 and SOD2, but the assessment of interaction requires independent variables, we estimated MEHHP residuals and assessed their interaction, showing that the OR for SOD2 TT was further elevated to 3.32 (1.75–6.32) when the residuals of MEHHP were high. Conclusions: Urine phthalate metabolite concentrations are associated with oxidative-stress related genetic variants. Genetic variants of SOD2, considered to be reflect oxidative stress metabolisms, might modify the association of phthalate exposure with asthma. Full article