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We demonstrated that the gene of glutathione peroxidase-1 (GPx-1), a major antioxidant enzyme, is a potential protectant against the neurotoxicity and conditioned place preference induced by cocaine. Because the sigma (σ)-1 receptor is implicated in cocaine-induced drug dependence, we investigated whether the GPx-1 gene modulates the σ-1 receptor in the behavioral sensitization induced by cocaine. Cocaine-induced behavioral sensitization was more pronounced in GPx-1 knockout (KO) than wild-type (WT) mice and was less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than non-TG mice. Cocaine treatment significantly enhanced the oxidative burden and reduced the GSH levels in the striatum of WT, GPx-1 KO, and non-TG mice but not in that of GPx-1 TG mice. In addition, cocaine significantly increased the nuclear translocation, its DNA binding activity of nuclear factor erythroid-2-related factor 2 (Nrf2) as well as the mRNA expression of γ-glutamylcysteine (GCL). The genetic depletion of GPx-1 inhibited the Nrf2-related glutathione system, whereas the genetic overexpression of GPx-1 activated this system against behavioral sensitization. BD1047, a σ-1 receptor antagonist, and U0126, an ERK inhibitor significantly induced the Nrf2-related antioxidant potential against behavioral sensitization. Unlike BD1047, U0126 did not affect the cocaine-induced σ-1 receptor immunoreactivity, suggesting that the σ-1 receptor is an upstream molecule for ERK signaling. Importantly, BD1047 and U0126 failed to affect the σ-1 receptor immunoreactivity and ERK phosphorylation induced by cocaine in GPx-1 TG mice. Our results suggest that GPx-1 is a critical mediator for the attenuation of cocaine-induced behavioral sensitization via modulating σ-1 receptor-mediated ERK activation by the induction of the Nrf2-related system.

Background Nonalcoholic steatohepatitis (NASH) is closely related to reactive oxygen species (ROS). Superoxide anion radicals, the main product of ROS, can be reduced by manganese superoxide dismutase (SOD2) to hydrogen peroxide, which is further reduced by catalase (CAT) and glutathione peroxidase (GPX) to water. We aimed to investigate the association between the most important genetic variants of SOD2, CAT, and GPX1 and susceptibility to NASH. Methods A total of 126 adults with liver tissue-verified NASH, 56 patients with liver tissue-verified nonalcoholic fatty liver (NAFL), and 153 healthy controls were enrolled. Their DNA profiles were retrieved for genotype assessment of SOD2 47T>C (rs4880), CAT -262C>T (rs1001179), and GPX1 593C>T (rs1050450) variation. Results There were statistical differences between the SOD2 and CAT genotypes across the NASH, NAFL, and control groups, but not GPX1. The NASH group had a significantly higher frequency of subjects with SOD2 C allele (38.8%) compared with the NASL group (25.0%) and the controls (22.9%, p = 0.010). Similarly, the NASH group had a significantly higher percentage of subjects with CAT T allele (23.0%) compared with the NAFL group (10.7%) and the controls (7.2%, p = 0.001). For subjects with both the SOD2 C allele and CAT T allele, 88.2% were in the NASH group. After adjusting for confounders, the CAT mutant T allele and SOD2 mutant C allele were still the highest independent risk factors for NASH (odds ratio [OR] 3.10 and 2.36, respectively). In addition, there was a synergistic effect for those two alleles and the occurrence of NASH with an adjusted OR of 8.57 (p = 0.030). Conclusion The genetic variations of CAT and SOD2 may increase the risk of NASH, which may aid in the screening of patients who are at high risk of NASH, and offer a potential anti-oxidant targeting route for the treatment of NASH.

Oxidative stress is one of the earliest defects involved in the development of diabetes-induced cognitive impairment. Nrf2 is the master regulator of the cellular antioxidant system can be regulated by some microRNAs. The study aimed to evaluate the effects of quercetin (QC) and quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) on Nrf2-controlled antioxidant genes through the redox-sensitive miR-27a. Expression levels of miR-27a, Nrf2, SOD1, GPX1, and CAT were measured by quantitative real-time PCR. Moreover, the oxidative stress parameters including total antioxidant capacity (TAC) and histological alterations were investigated. The expression level of miR-27a was significantly up-regulated in diabetic rats. While expression levels of Nrf2, SOD1, GPX1, and CAT were significantly down-regulated under diabetic condition. Interestingly, QCSPIONs decreased expression level of miR-27a and subsequently enhanced the expression levels of Nrf2, SOD1, and CAT to the control level. No significant difference was observed in the expression level of GPX1. Besides, QC in pure and especially conjugated form was able to normalize TAC and regenerate pathological lesions in STZ-diabetic rats. Our result demonstrates that QCSPIONs as an effective combined therapy can decrease miR-27a expression, which in turn increases the Nrf2 expression and responsive antioxidant genes, resulting in improvement of memory dysfunction in diabetic rats.

The effects of selenium nanoparticles (SeNPs) on the antioxidant capacity in Sprague-Dawley (SD) rats were investigated. The rats were given intragastric administration of an SeNP suspension at doses of 0, 2, 4, and 8 mg Se/kg BW for two weeks. The antioxidant capacity in serum and organic tissues (liver, heart, and kidney) and the gene expression levels of glutathione peroxidase 1 (GPX1) and glutathione peroxidase 4 (GPX4) in the liver were measured. Buffalo rat liver (BRL) cell lines were further constructed to explore the cytotoxicity mechanism induced by SeNPs through the determination of antioxidant capacity; cell activity; apoptosis; and Caspase-3, Caspase-8, and Caspase-9 family activities. The results showed that SeNP administration over 4.0 mg Se/kg BW decreased the antioxidant capacities in the serum, liver, and heart and downregulated mRNA expression of GPX1 and GPX4 in the liver. The BRL cell line experiments showed that treatment with over 24 μM SeNPs decreased the viability of the cells and damaged the antioxidant capacity. Flow cytometry analysis showed that decreased cell viability induced by SeNPs is mainly due to apoptosis, rather than cell necrosis. Caspase-3 and Caspase-8 activities were also increased when BRL cells were treated with 24 μM and 48 μM SeNPs. Taken together, a nonlethal level of SeNPs could impair the antioxidant capacity in serum and organic tissues of rats, and the liver is the most sensitive to the toxicity of SeNPs. A pharmacological dose of SeNPs could lead to cytotoxicity and induce cell death through apoptosis and extrinsic pathways contributing to SeNP-induced apoptosis in BRL cells.

Mounting evidence has illustrated the tumor regulatory roles of microRNAs (miRNAs) in T-cell acute lymphoblastic leukemia (T-ALL), a malignant carcinoma originated from T-cell precursors. However, the possible regulation mechanisms underlying miR-29b/29c-3p in T-ALL have not been interrogated yet. The aim of our study was to probe the association and possible molecular mechanism of miR-29b/29c-3p and Glutathione Peroxidase 1 (GPX1), a predicted highly expressed gene in acute myeloid leukemia (LAML) tissues on the cancer genome atlas (TCGA) website. In our paper, it was observed that GPX1 was relatively overexpressed in T-ALL cells, compared with normal T cells. Loss-of-function assays demonstrated that GPX1 knockdown inhibited the proliferation and activated the apoptosis in T-ALL cells. Then miR-29b/29c-3p was confirmed to regulate GPX1 mRNA and protein expression via decreasing Transcription Factor AP-2 Gamma (TFAP2C) expression. In summary, miR-29b-3p and miR-29c-3p targeted TFAP2C so as to repress GPX1 transcription, thereafter inhibiting GPXA expression. In the end, rescue experiments proved the whole regulation mechanism of miR-29b/29c-3p in T-ALL. Overall, the miR-29b/29c-3p -TFAP2C-GPX1 axis helped us to have a better understanding of T-ALL pathogenesis.

Grape seed, as a main source of polyphenols, has many nutritional and medicinal properties in humans. In the current study, the effects of dietary ethanolic grape seed extract (GSE) on the growth performance, antioxidant activity, and some biochemical parameters in rainbow trout were investigated. Ninety fish (initial weight 78.47 g) were randomly distributed among nine cement tanks (1.8 m × 0.22 m × 0.35 m) with 10 fish per tank. Three experimental diets containing either 0, 10, or 50 g kg−1 GSE were prepared and each diet was randomly assigned to three tanks of fish for 60 days. Results showed that feeding GSE enhanced some growth parameters including the specific growth rate and condition factor in comparison with the control group. Among different serum metabolites, the glucose levels in treatment groups significantly decreased compared to the control group. The total product of lipid peroxidation indicated as malondialdehyde significantly decreased in both the GSE-added treatment groups. The gene expression related to the antioxidant enzymes, catalase, glutathione peroxidase 1, and glutathione S-transferase A, were upregulated in the intestine of fish that received a low dose of GSE. The results of the current study suggest that GSE, especially at 10 g kg−1, diet had the potential to improve (1) specific growth rate and condition factor, (2) biochemical parameters including glucose and lipid peroxidation product, and (3) upregulated the expression of antioxidant genes including catalase, glutathione peroxidase 1, and glutathione S-transferase A in rainbow trout.

Endemic arsenism is widely distributed in the world, which can damage multiple organs, especially in skin and liver. The etiology is clear, but the mechanisms involved remain unknown. Ubiquitin-proteasome pathway (UPP) is the main pathway regulating protein degradation of which proteasome subunit beta type-5(PSMB5) plays a dominant role. This paper aims to study the role and mechanism of PSMB5 in sodium arsenite (NaAsO(2))–induced oxidative stress liver injury in L-02 cells. Firstly, L-02 cells were exposed to different concentrations of NaAsO(2) to establish a liver injury model of oxidative stress, and then mechanisms of oxidative stress were studied with carbobenzoxyl-leucyl-leucl-leucll-line (MG132) and knockdown PSMB5 (PSMB5-siRNA). The oxidative stress indicators, levels of 20S proteasome, the transcription and protein expression levels of PSMB5, Cu-Zn superoxide dismutase (SOD1), and glutathione peroxidase 1 (GPx1) were detected. The results demonstrated that NaAsO(2) could induce oxidative stress–induced liver injury and the activity of 20S proteasome and the protein expression of PSMB5, SOD1, and GPx1 decreased. After MG132 or PSMB5-siRNA pretreatment, the gene expression of PSMB decreased. After MG132 or PSMB5-siRNA pretreatment, and then L-02 cells were treated with NaAsO(2), the gene expression of PSMB remarkably decreased; however, the protein expression of SOD1 and GPx1 increased. Overall, NaAsO(2) exposure could induce oxidative stress liver injury and low expression of PSMB5 in L-02 cells, and PSMB5 might play an important role in the regulation of oxidative stress by regulating the expression of SOD1 and Gpx1.

Ochratoxin A (OTA) is a potent nephrotoxin. Selenium (Se) is an essential micronutrient for humans and animals, and plays a key role in antioxidant defense. To date, little is known about the effect of Se on OTA-induced DNA damage. In this study, the protective effects of Se (from selenomethionine) against OTA-induced cytotoxicity and DNA damage were investigated by using PK15 cells as a model. The results showed that OTA at 4.0 μg/mL induced cytotoxicity and DNA damage. Se at 0.5, 1, 2 and 4 μM significantly blocked OTA-induced cytotoxicity and DNA damage. Furthermore, Se blocked the increases of DNMT1, DNMT3a and HDAC1 mRNA and protein expression, reversed the decreases of glutathione peroxidase 1 (GPx1) mRNA and protein expression, and promoted the increases of SOCS3 mRNA and protein expression induced by OTA. Overexpression of GPx1 by pcDNA3.1-GPx1 inhibited the OTA-induced DNMT1 expression, promoted OTA-induced SOCS3 expression, and prevented the OTA-induced cytotoxicity and DNA damage. In contrast, knock-down of GPx1 by using a GPx1-specific siRNA had the opposite effects. The results suggest that GPx1-mediated DNMT1 expression is involved in the blocking effects of selenium on OTA-induced cytotoxicity and DNA damage.

Numerous statistical methods have been developed to explore genomic imprinting and maternal effects by identifying parent-of-origin patterns in complex human diseases. However, because most of these methods only use available locus-specific genotype data, it is sometimes impossible for them to infer the distribution of parental origin of a variant allele, especially when some genotypes are missing. In this article, we propose a two-step approach, LIMEhap, to improve upon a recent partial likelihood inference method. In the first step, the distribution of the missing genotypes is inferred through the construction of haplotypes by using information from nearby loci. In the second step, a partial likelihood method is applied to the inferred data. To substantiate the validity of the proposed procedures, we simulated data in a genomic region of gene GPX1. The results show that, by borrowing genetic information from nearby loci, the power of the proposed method can be close to that with complete genotype data at the locus of interest. Since the inference on the genotype distribution is made under the assumption of Hardy-Weinberg Equilibrium (HWE), we further studied the robustness of LIMEhap to violation of HWE. Finally, we demonstrate the utility of LIMEhap by applying it to an autism dataset.

This study is aimed at investigating the effect of different exercise loads on the reproductive function of obese male mice and the underlying mechanisms. Male mice with high-fat diet-induced obesity were divided into obesity control (OC), obesity moderate-load exercise (OME), and obesity high-load exercise (OHE) groups. The OME and OHE groups were subjected to swimming exercise 5 days per week over a duration of 8 weeks, with the exercise load progressively increased to 2 h per day in the OME group and 2 h twice per day in the OHE group. In the OC group mice without exercise regimen, we observed a decrease in mRNA expression of antioxidant enzymes, increase in free radical products, upregulation of mRNA and protein expression of nuclear factor-κB and proinflammatory cytokines, inhibition of mRNA and protein expression of testosterone synthases, decrease in the serum testosterone level and sperm quality, and increase in sperm apoptosis. Although both moderate-load exercise and high-load exercise reduced body fat, only moderate-load exercise effectively alleviated obesity-induced oxidative stress, downregulated the expression of nuclear factor-κB and proinflammatory cytokines, and reversed the decrease in mRNA and protein expression of testosterone synthases, serum testosterone level, and sperm quality. These changes were not observed in the OHE group mice. Obesity-induced testicular oxidative stress and inflammatory response decreased testosterone synthesis and sperm quality. Moderate-load exercise alleviated the negative effect of obesity on male reproductive function by decreasing testicular oxidative stress and inflammatory responses. Although high-load exercise effectively reduced body fat, its effects on alleviating oxidative stress and improving male reproductive function were limited.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, p. 1

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney, and its diagnosis and prognosis still lack reliable biomarkers. Glutathione peroxidase 1 (GPX1) has been identified to be highly expressed in a variety of human malignancies. However, few studies have studied the expression of GPX1 and its biological functions in RCC. We attempted to assess the potential of GPX1 as a promising biomarker for RCC diagnosis and prognosis. In this study, we analyzed and explored the public cancer databases (TCGA and ONCOMINE) to conclude that GPX1 is highly expressed in RCC. Meanwhile, we evaluated the expression of GPX1 at the levels of RCC cells and tissues to verify the results of the database. Moreover, high GPX1 levels were positively correlated with short overall survival time, distant metastasis, lymphatic metastasis, and tumor stage. Receiver operating characteristic curve (ROC) analysis showed that high GPX1 levels could distinguish RCC patients from normal subjects (p < 0.0001). Kaplan-Meier curve analysis revealed that high GPX1 levels predicted shorter overall survival time (p = 0.0009). Finally, the functional roles of GPX1 were examined using a GPX1 sh-RNA knockdown method in RCC cell lines. In summary, our results suggest that GPX1 may have the potential to serve as a diagnostic and prognostic biomarker for RCC patients. Moreover, targeting GPX1 may represent as a new therapeutic strategy and direction for RCC patients.

Autism is a severe neurodevelopmental disorder leading to deficits in social interaction, communication, and several activities. An increasing number of evidence suggests a role of oxidative stress in the etiology of autism spectrum disorder (ASD). Indeed, impaired antioxidant mechanisms may lead to the inadequate removal of H

Background Melatonin, as a free radical scavenger exhibiting genomic actions, regulates the antioxidant genes expression and apoptosis mechanisms. In polycystic ovary syndrome (PCOS) patients, an imbalance between free radicals and antioxidants in follicular fluid leads to oxidative stress, aberrant folliculogenesis, and intrinsic defects in PCOS oocytes. In this experimental mouse model study, oocytes of PCOS and the control groups were cultured in different melatonin concentrations (10− 5, 10− 6, and 10− 7 M) to investigate the expression of oocyte maturation-related genes (Gdf9/Bmp15), antioxidant-related genes (Gpx1/Sod1), apoptotic biomarkers (Bcl2/Bax) and total intracellular ROS levels. Results Gdf9 and Bmp15, Gpx1 and Sod1 were up-regulated in PCOS and control oocytes cultured in all melatonin concentrations compared to those cultured in IVM basal medium (P Bcl2 and decreased Bax gene expression in PCOS and control oocytes compared to non-treated oocytes. Conclusions Melatonin increased antioxidant gene expression and regulated the apoptosis pathway, effectively reducing the adverse effects of culture conditions on PCOS oocytes. Furthermore, it influenced the expression of oocyte maturation-related genes in PCOS, providing valuable support during the IVM process.

Acute myeloid leukemia (AML) has been characterized by the swift development of abnormal cells in the bone marrow. This research aimed to examine the impacts of the miR-185-5p-GPX1 axis on AML progression and differentiation. Findings indicated that miR-185-5p and GPX1 levels were significantly reduced and elevated, respectively. The upregulation of miR-185-5p was observed to restrict the proliferation and invasion abilities of AML cells, and promote differentiate and apoptosis. Moreover, the overexpression of GPX1 was noticed to enhance the growth of AML cells. In conclusion, this research suggested that by targeting GPX1, miR-185-5p inhibited AML progression and downregulated AML cells' proliferation and invasion.

Glutathione peroxidase 1 (GPX1) and catalase are expressed in the lens epithelial cells and cortical fiber cells, where they detoxify H2O2 to reduce oxidative stress, which is a major cause for cataractogenesis. We sought to find out, between these two enzymes, which is critical for transparency and homeostasis in the aging lens by investigating alterations in the lens's refractive property, transparency, and gap junction coupling (GJC) resistance.Wild-type (C57BL/6J), GPX1 knockout (GPX1In contrast to wild-type (WT) and CATChanges in the refractive and physiological properties of the lens occurred before cataract formation in GPX1

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.

We were very pleased that our finding of an association between coronavirus disease 2019 (COVID-19) outcome in China and selenium status (1) was endorsed by Seale and colleagues, based on their understanding of the likely mechanism by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the selenoprotein, cytosolic glutathione peroxidase (GPX1) (2).

Preeclampsia (PE) is a serious pregnancy complication whose etiology is not fully understood. However, previous reports have suggested that oxidative stress and genetic variants may contribute to the development of PE. This study aimed to examine the relationship between the Glutathione peroxidase-1(GPx-1) and Manganese Superoxide dismutase (MnSOD) polymorphisms and preeclampsia (PE) risk in Iranian women. Genotyping of the studied women, including 179 preeclamptic cases and 202 controls, for GPx-1 rs1050450 and MnSOD rs4880 polymorphisms was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our results showed a 1.7- to 1.6-fold increased risk of PE in the rs1050450 CT and CT + TT (dominant model) genotypes compared to CC genotype (OR = 1.7, 95%CI 1.1-2.7; P = 0.01 and OR = 1.6, 95%CI 1.1-2.4; P = 0.02; respectively). We also found a marked correlation between TC and CC genotypes of MnSOD rs4880 polymorphism and a 1.9- to 2.3-fold increase risk of PE (OR = 1.9, 95%CI 1.2-2.9; P = 0.005 and OR = 2.3, 95%CI 1-5.1; P = 0.04, respectively). The rs4880 MnSOD polymorphism was correlated with increased risk of PE in the allelic and dominant models (OR = 1.8, 95% CI 1.2-2.5, P = 0.002; OR = 1.9, 95%CI 1.3-3, P = 0.002, respectively). High frequency of TC/CC genotype of MnSOD rs4880 and CT genotypes of rs1050450 polymorphism in PE patients compared to controls showed the contribution of these variants to PE susceptibility.

Non-thermal atmospheric pressure plasma has been widely used for preclinical studies in areas such as wound healing, blood coagulation, and cancer therapy. We previously developed plasma-activated medium (PAM) and plasma-activated Ringer’s lactate solutions (PAL) for cancer treatments. Many in vitro and in vivo experiments demonstrated that both PAM and PAL exhibit anti-tumor effects in several types of cancer cells such as ovarian, gastric, and pancreatic cancer cells as well as glioblastoma cells. However, interestingly, PAM induces more intracellular reactive oxygen species in glioblastoma cells than PAL. To investigate the differences in intracellular molecular mechanisms of the effects of PAM and PAL in glioblastoma cells, we measured gene expression levels of antioxidant genes such as CAT, SOD2, and GPX1. Microarray and quantitative real-time PCR analyses revealed that PAM elevated stress-inducible genes that induce apoptosis such as GADD45α signaling molecules. PAL suppressed genes downstream of the survival and proliferation signaling network such as YAP/TEAD signaling molecules. These data reveal that PAM and PAL induce apoptosis in glioblastoma cells by different intracellular molecular mechanisms.

The aim of this study was to investigate whether the glutathione peroxidase-1 gene (GPx-1) affects cocaine-induced conditioned place preference (CPP) using a mouse model. Cocaine-induced CPP was accompanied by an increase in the level of σ-1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx-1 gene knockout (GPx-1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ-1 receptor were much less pronounced in GPx-1-overexpressing transgenic (GPx-1 TG) mice than non-transgenic (non-TG) mice. Treatment of the mice with BD1047, a σ-1 receptor antagonist, significantly attenuated both cocaine-induced CPP and c-Fos-immunoreactivity (c-Fos-IR) in WT and GPx-1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine-induced CPP and c-Fos in non-TG mice, there were no additional protective effects in cocaine-treated GPx-1 TG mice, indicating that the σ-1 receptor is a critical target for GPx-1-mediated psychoprotective activity. Overall, our results suggest that GPx-1 attenuates cocaine-induced CPP via inhibition of σ-1 receptor expression.

Selenium is an essential trace element, and its deficiency can cause cardiomyopathy, arrhythmias and increased susceptibility to infection. Such clinical symptoms are considered primarily attributed to decreased expression of some of the 25 selenocysteine-containing selenoproteins in humans. Conversely, a selenium-excessive diet can cause acute poisoning and chronic symptoms with unknown mechanisms. To reveal the impact of selenium deficiency and excess on selenoprotein expression in vivo, mice (that possess 24 selenoproteins) were fed with selenium-deficient or selenomethionine-excessive diets for up to 4 weeks, and the expression levels of nine representative selenoproteins [glutathione peroxidase (Gpx) 1/2/3/4, thioredoxin reductase 1/2, deiodinase 1, and selenoprotein P/S] were measured in 10 organs (brain, heart, liver, lung, kidney, pancreas, spleen, testis, skeletal muscle and thymus). We observed a time-dependent decrease in the selenium content of most organs (except testis) of selenium-deficient mice but not in the expression levels of the nine selenoproteins, with the exceptions of Gpx1/2 in the heart/liver/kidney/pancreas/spleen and Gpx3 in the pancreas/spleen. Serum lipid peroxidation levels were up-regulated in response to Se deficiency because of the decreased expression/activity of Gpx3, a plasma-type Gpx. In contrast, a time-dependent increase was observed in the selenium content of all organs but not the expression levels of the nine selenoproteins in most organs of selenomethionine-excessive mice; however, markedly elevated protein-bound selenium levels were observed in the liver/kidney. These results suggest that the systemic response to selenium deficiency and selenomethionine excess involves the down-regulation of some selenoproteins such as Gpx1/Gpx3 and up-regulation of selenium-containing proteins (not selenoproteins), respectively.

Since reproductive toxicity is associated with oxidative stress, nuclear factor κB (NFκB), a redox-sensitive transcription factor, may be involved in the reproductive dysfunction induced by the abusive drug, such as cocaine. In the present study, we investigated whether NFκB mediates cocaine-induced reproductive dysfunction in male mice, and whether glutathione peroxidase (GPx)-1, a well-known enzymatic antioxidant, modulates NFκB activity to affect this reproductive dysfunction. Cocaine treatment significantly increased nuclear translocation of NFκB and its DNA binding activity in the testis of mice. Treatment with cocaine resulted in a significant increase in sperm abnormality, and in significant decreases in the sperm viability and sperm level. Furthermore, cocaine significantly reduced hypothalamic gonadotropin-releasing-hormone expression and plasma testosterone level. These alterations were more pronounced in the GPx-1 knockout (GPx-1 KO) than wild type (WT) mice, and they were less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than in non-transgenic (non-TG) mice. Pyrrolidine dithiocarbamate (PDTC), an NFκB inhibitor, was more effective in attenuating cocaine-induced reproductive toxicity in GPx-1 KO than in WT mice. Although PDTC treatment was also significantly protective against the reproductive toxicity in non-TG mice, PDTC did not show additional positive effects against the protective potential mediated by GPx-1 overexpression in mice. Therefore, our results suggest that GPx-1 gene is a protective factor in response to reproductive dysfunction induced by cocaine in male mice, and that NFκB is a critical mediator of protective activity of GPx-1 gene in our experimental conditions.

Prenatal ethanol (EtOH) exposure is known to induce adverse effects on fetal brain development. Docosahexaenoic acid (DHA) has been shown to alleviate these effects by up-regulating antioxidant mechanisms in the brain. The liver is the first organ to receive enriched blood after placental transport. Therefore, it could be negatively affected by EtOH, but no studies have assessed the effects of DHA on fetal liver. This study examined the effects of maternal DHA intake on DHA status and gene expression of key enzymes of the glutathione antioxidant system in the fetal liver after prenatal EtOH exposure. Pregnant Sprague–Dawley dams were intubated with EtOH for the first 10 days of pregnancy, while being fed a control or DHA-supplemented diet. Fetal livers were collected at gestational day 20, and free fatty acids and phospholipid profile, as well as glutathione reductase (GR) and glutathione peroxidase-1 (GPx1) gene expressions, were assessed. Prenatal EtOH exposure increased fetal liver weight, whereas maternal DHA supplementation decreased fetal liver weight. DHA supplementation increased fetal liver free fatty acid and phospholipid DHA independently of EtOH. GR and GPx1 messenger RNA (mRNA) expressions were significantly increased and decreased, respectively, in the EtOH-exposed group compared with all other groups. Providing DHA normalized GR and GPx1 mRNA expression to control levels. This study shows that maternal DHA supplementation alters the expression of fetal liver genes involved in the glutathione antioxidative system during prenatal EtOH exposure. The fetal liver may play an important role in mitigating the signs and symptoms of fetal alcohol spectrum disorders in affected offspring.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute lung failure in critically sick patients, which severely compromises the function of multiple organs, including the brain. Although, the optic nerve and the retina are a part of the central nervous system, the effects of ARDS on these ocular structures are completely unknown. Thus, the major goal of this study was to test the hypothesis that ARDS affects vascular function in the eye. ARDS was induced in anesthetized pigs by intratracheal injection of lipopolysaccharide (LPS). Sham-treated animals served as controls. Pigs were monitored for 8 h and then sacrificed. Subsequently, retinal arterioles and short posterior ciliary arteries were isolated and cannulated with micropipettes to measure vascular responses by videomicroscopy. Levels of reactive oxygen species (ROS) were quantified in isolated vessels using dihydroethidium (DHE). Messenger RNA expression of hypoxic, inflammatory, prooxidative, and antioxidative genes was assessed by real-time PCR. When group-dependent differences in mRNA expression levels were found for a particular gene, immunostainings were conducted. Strikingly, responses to the endothelium-dependent vasodilator, bradykinin, were markedly impaired in retinal arterioles of LPS-treated pigs, but no differences were seen between ciliary arteries of LPS- and sham-treated animals. ROS levels were increased in retinal arterioles but not in ciliary arteries of LPS-treated pigs. Messenger RNA levels for HIF-1α, VEGF-A and NOX2 were markedly increased in retinal arterioles of LPS-treated pigs, whereas ciliary arteries had only negligible mRNA level changes. Pronounced immunoreactivity for HIF-1α, VEGF-A and NOX2 was seen in the endothelium of retinal arterioles from LPS-treated pigs. Histologically, massive edema was seen especially in the retinal nerve fiber layer of pigs treated with LPS. Our study provides the first evidence that ARDS induced by intratracheal LPS application evokes endothelial dysfunction in porcine retinal arterioles together with retinal edema, indicative of vascular leakage. In contrast, ciliary arteries appear to be resistant to intratracheal LPS application.

Fil: Costilla, Melisa. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Fil: Costilla, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Macri Delbono, Rodrigo. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Macri Delbono, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Klecha, Alicia Juana. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Klecha, Alicia Juana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Klecha, Alicia Juana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cremaschi, Graciela A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Laboratorio de Radioisotopos; Argentina Fil: Barreiro Arcos, María Laura. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Barreiro Arcos, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Barreiro Arcos, María Laura. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Abstract: Hyperthyroidism is an endocrine disorder characterized by excessive secretion of thyroid hormones T3 and T4. Thyroid hormones exert pleiotropic actions on numerous tissues and induce an overall increase in metabolism, with an increase in energy demand and oxygen consumption. Therefore, the purpose of this study was to investigate the effects of hyperthyroidism on the production of reactive oxygen species (ROS) in lymph node and spleen cells of euthyroid and hyperthyroid mice, analyzing antioxidant mechanisms involved in the restitution of the cellular redox state. For this, thirty female Balb/c (H-2d) mice were randomly divided into two groups: euthyroid (by treatment with placebo) and hyperthyroid (by treatment with 12 mg/l of T4 in drinking water for 30 days). We found a significant increase in ROS and an increase in the genomic and protein expression of the antioxidant enzymes catalase (CAT) and glutathione peroxidase-1 (GPx-1) in lymph node and spleen cells of hyperthyroid mice. In vitro treatment with H2O2 (250 μM) of the lymphoid cells of euthyroid mice increased the expression levels of CAT and GPx-1. The hyperthyroidism increased the phosphorylation levels of Nrf2 (nuclear factor erythroid 2-related factor) and the kinase activity of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). Additionally, we found an increase in the expression of the classic isoenzymes of PKCα, β and γ. In conclusion, these results indicated that the increase in ROS found in the hyperthyroid state induces the antioxidant enzyme transcription through the activation of the Nrf-2 factor in lymphoid tissues. This shows the influence of hyperthyroidism on the regulation of the cellular antioxidant system.

Background: Diabetes is the seventh most common disease leading to death with a global estimate of 425 million diabetics, expected to be 629 million in 2045. The role of reactive metabolites and antioxidants, such as glutathione, glutathione peroxidase, superoxide dismutase and catalase in type 2 diabetes mellitus (T2DM) provides an opportunity for identifying gene variants and risk genotypes. We hypothesised that certain antioxidant gene-gene interactions are linked with T2DM and can model disease risk prediction.Materials and methods: Genotyping of single nucleotide polymorphisms (SNPs) in antioxidant genes for glutathione (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) was performed in 558 T2DMs and 410 age and sex matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), routine lab indices by standard techniques.Results: The null/null allele combination of GSTM1del and GSTT1del increased disease risk up to 1.7-fold. The combination of SNPs in GSTM1del, GSTT1del, GSTP1 + 313A/G and in CAT-21A/T, SOD2 + 47C/T, GPx1 + 599C/T increased the risk of diabetes 13.5 and 2.1-fold, respectively. Interaction of SNPs GSTM1del, GSTT1del, GSTP1 + 313A/G (105Ile/Val), CAT-21A/T, SOD2 + 47C/T, GPx1 + 599C/T were significantly linked with disease risk >5 × 103 fold.Conclusion: As the number of gene combinations increase, there is a rise in the odds ratio of disease risk, suggesting that gene-gene interaction plays an important role in T2DM susceptibility. Individuals who possess the GSTM1del, GSTT1del, GSTP1 105I/V(+313A/G), CAT-21A/T, SOD2 + 47C/T and GPx1 + 599C/T are at very high risk of developing T2DM.

Organophosphate esters (OPEs) are frequently used as replacements for the banned polybrominated diphenyl ether (PBDEs). Since OPEs are structurally similar to organophosphate pesticides, exposure and toxicity of these compounds is of significant societal and scientific interest. Cytotoxicity (MTT), biotransformation (cyp1a1) and oxidative stress responses (gpx1, gr, gsta2, cat) were investigated in H4IIE cells exposed for 48 h to four different OPEs (tributyl phosphate (TBP), tris(2-butoxyethyl) phosphate (TBOEP), tris-(2-chloroethyl) phosphate (TCEP) and triphenyl phosphate (TPP)). MTT assay revealed a dose-dependent decrease of cell viability following exposure to TBP, TBOEP, TCEP and TPP. Cells treated with TBP and TBOEP exhibited significant increase of cyp1a1 at the highest tested concentration, at transcriptional and enzymatic (MROD) levels. Significant increases of oxidative stress markers were observed after exposure to TBP and TBOEP. On the other hand, cells treated with TCEP and TPP showed opposite trends between cyp1a1 mRNA and enzymatic activities. Furthermore, exposure to TCEP increased gst and cat especially at the highest concentration tested, whereas TPP produced significant changes only for gr and cat at the highest concentration. In conclusion, OPEs produced compound and concentration-specific effects on biotransformation and oxidative stress processes. Overall, our results suggest the participation of multiple mechanisms of detoxification in defense of OPEs exposure with different modes of action depending on their chemical structure.

Microglia, the brain’s resident immune cells, exhibit constitutive expression of the ionized calcium binding adaptor molecule 1 (IBA1), a cytoplasmic protein with actin and calcium-binding functions involved in membrane ruffling. Microglia are long-lived cells that exhibit a senescent morphology (dystrophy) with aging, which may be indicative of cell dysfunction. It has been reported that dystrophy of IBA1-positive microglia is exacerbated in obese humans. Our own preliminary studies of microglia in the medial temporal lobe of obese subjects have revealed another microglial abnormality, which is the loss of IBA1 immunoreactivity that can create large areas in the brain seemingly devoid of all microglial cells. Here, we systematically compared microglial appearance in human hippocampi derived from obese individuals compared to controls (nobese = 33, nnon-obese = 30). In both groups, we found areas that were negative for IBA1, but contained P2YR12 and glutathione-peroxidase 1 (GPX)-positive microglia. The number and extent of IBA1-negative regions was increased in obese cases. Since some cases of non-obese individuals also exhibited loss of IBA-1 immunoreactivity, we searched for possible confounders and found that hepatic dysfunction strongly impacts the distribution of microglial cells: By computational analysis of scanned IBA1-stained sections, we detected increased Mean Empty Space distances (p = 0.016) and IBA1-negative areas (p = 0.090) which were independent from the cause of liver dysfunction, but also from aging. Thus, we report on a novel type of microglia pathological change, i.e. localized loss of IBA1 that is linked, at least in part, to obesity and hepatic dysfunction.

Compelling evidence indicates that oxidative stress contributes to cocaine neurotoxicity. The present study was performed to elucidate the role of the glutathione peroxidase-1 (GPx-1) in cocaine-induced kindling (convulsive) behaviors in mice. Cocaine-induced convulsive behaviors significantly increased GPx-1 , p-IkB, and p-JAK2/STAT3 expression, and oxidative burdens in the hippocampus of mice. There was no significant difference in cocaine-induced p-IkB expression between non-transgenic (non-TG) and GPx-1 overexpressing transgenic (GPx-1 TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1 TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1 TG mice. Triple-labeling immunocytochemistry indicated that GPx-1-, p-STAT3-, and GFAP-immunoreactivities were co-localized in the same cells. AG490, a JAK2/STAT3 inhibitor, but not pyrrolidone dithiocarbamate, an NFκB inhibitor, significantly counteracted GPx-1-mediated protective potentials (i.e., anticonvulsant-, antioxidant-, antiapoptotic-effects). Genetic overexpression of GPx-1 significantly attenuated proliferation of Iba-1-labeled microglia induced by cocaine in mice. However, AG490 or astrocytic inhibition (by GFAP antisense oligonucleotide and α-aminoadipate) significantly increased Iba-1-labeled microglial activity and M1 phenotype microglial mRNA levels, reflecting that proinflammatory potentials were mediated by AG490 or astrocytic inhibition. This microglial activation was less pronounced in GPx-1 TG than in non-TG mice. Furthermore, either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, our results suggest that astrocytic modulation between GPx-1 and JAK2/STAT3 might be one of the underlying mechanisms for protecting against convulsive neurotoxicity induced by cocaine.

The objective of this study was to evaluate the effect of organic, inorganic, and selenium nanoparticle supplements at the final stage of pregnancy on selenium, zinc, copper, and iron concentrations of goats and placental, colostrum, and milk transfer of these trace minerals from goats to their kids. Forty pregnant Khalkhali goats (30 ± 5 kg) were randomly allocated to four treatments including (1) no supplement (control), 0.6 mg Se head−1 day−1 of selenomethionine (SM), 0.6 mg Se head−1 day−1 of selenium nanoparticles (SN), and 0.6 mg Se head−1 day−1 of sodium selenite (SS), from 4 weeks before the expected day of delivery to delivery day. Blood samples were taken from the goats 4 weeks before the expected day of delivery and on the kidding day. Colostrum samples were collected from the goats immediately after kidding. Instantly after delivery, newborn kids were taken apart from their dams and their blood samples were collected from the jugular vein, before they drank their first colostrums and at 7, 14, 21, and 28 after birthday. The results demonstrated that the whole blood and serum Se concentration was greater in Se-supplemented goats compared with the control (P

Objective In obese patients undergoing caloric restriction, there are several potential mechanisms involved in the improvement of metabolic outcomes. The present study further explores whether caloric restriction can modulate endoplasmic reticulum (ER) stress and mitochondrial function, as both are known to be mechanisms underlying inflammation and insulin resistance (IR) during obesity. Methods A total of 64 obese patients with BMI ≥35 kg/m2 underwent a dietary program consisting of 6 weeks of a very-low-calorie diet followed by 18 weeks of low-calorie diet. We evaluated changes in the metabolic and inflammatory markers -TNFα, hsCRP, complement component 3 (C3c), and retinol binding protein 4 (RBP4)-, in the ER stress markers and modulators -eIF2α-P, sXBP1, ATF6, JNK-P, CHOP, GRP78, and SIRT1-, and in mitochondrial function parameters -mitochondrial reactive oxygen species (mROS), glutathione peroxidase 1 (GPX1), cytosolic Ca2+, and mitochondrial membrane potential. Results The dietary intervention produced an 8.85% weight loss associated with enhanced insulin sensitivity, a less marked atherogenic lipid profile, and a decrease in systemic inflammation (TNFα, hsCRP) and adipokine levels (RBP4 and C3c). Chronic ER stress was significantly reduced (ATF6-CHOP, JNK-P) and expression levels of SIRT1 and GRP78 – a Ca2+-dependent chaperone – were increased and accompanied by the restoration of Ca2+ depots. Furthermore, mROS production and mitochondrial membrane potential improvement were associated with the up-regulation of the antioxidant enzyme GPX1. Conclusions Our data provide evidence that moderate weight loss attenuates systemic inflammation and IR and promotes the amelioration of ER stress and mitochondrial dysfunction, increasing the expression of chaperones, SIRT1 and antioxidant GPX1.

Deoxynivalenol (DON) is a cytotoxic mycotoxin that can cause cell damages. The main effect is to inhibit protein synthesis. Oxidative stress is one of the effects of DON. Selenium (Se) can ameliorate the cell damage caused by DON-induced oxidative stress, but it is unclear whether through selenoprotein glutathione peroxidase 1 (GPX1). We established GPX1-knockdown porcine spleen lymphocytes, and treated them with DON and Se. Untransfected porcine splenic lymphocytes (group P) and transfected cells (group M, GPX1 knockdown) were treated with or without DON (0.824, 0.412, 0.206, or 0.103 μg/mL, group D1-4), Se (Na2SeO3, 2 μM, group Se), or both (group SD1–4) for 6, 12, or 24 h. The cells were collected and the activities of SOD and CAT, levels of GSH, H2O2, malonaldehyde (MDA), total antioxidant capacity (T-AOC), and the inhibition of free hydroxyl radicals were determined. Levels of ROS were measured at 24 h. Compared with group P, the antioxidant capacity of group M was reduced. DON caused greater oxidative damage to the GPX1-knockdown porcine splenic lymphocytes than to the normal control cells. When Na2SeO3 was combined with DON, it reduced the damage in the GPX1-knockdown porcine splenic lymphocytes, but less effectively than in the normal porcine splenic lymphocytes.

Val-Asn-Pro (VNP) was identified from the raw material of baijiu distillation (Jiupei) and exhibit antioxidant activity in vitro. In this study, residue after baijiu distillation (Jiuzao) was used to seek the antioxidant peptide VNP with the methods reported inthe previous study. Its potential antioxidant mechanism in vivo was further assessed. Gene and protein expressions of Nrf2/Keap1-p38MAPK/PI3K-MafK signaling pathway and downstream enzymes (i.e., CAT, GPX1, SOD1, and HO-1) in AAPH-induced oxidative stress Sprague-Dawley (SD) rats were investigated. Influence of VNP on baijiu characteristics was also investigated. Based on the results, VNP was identified with a content of 5.25 mg/g Jiuzao. VNP significantly mitigated excess oxidative stress via activation of Nrf2/Keap1-p38MAPK/PI3K-MafK signaling pathway and activated downstream antioxidant enzymes. Furthermore, VNP showed unconspicuous influence on the flavor and taste of baijiu when added into baijiu and the content remained stable during storage. These results indicated that VNP is a potent antioxidant component isolated from Jiuzao that can be used in baijiu to enhance its antioxidant effect without affecting the main flavor and taste. The utilization of these functional components can also increase the added value of Jiuzao.

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C–C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor – N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1–3, and protects hippocampal neurons from ROS as well as improves memory function after trauma., Graphical abstract Image 1

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.

Exploration of long-term in vivo effects of nanomaterials, particularly those with potential biomedical applications, is quite important for better understanding and evaluating their biosafety. Selenium nanoparticles (SeNPs) has been considered as a good candidate in biomedical applications due to its high bioavailability, considerable biological activity, and low toxicity. However, its long-term biological effects and biosafety remain unknown. Our previous study demonstrated that 8-week supplementation with SeNPs (50 μg Se/kg/day) was safe and had an anti-atherosclerotic activity in apolipoprotein E-deficient (ApoE-/-) mice, a well-known animal model of atherosclerosis. As a chronic disease, atherosclerosis needs long-term drug therapy. The aim of this study is to investigate the long-term effects of SeNPs with different sizes on atherosclerotic lesions and their biosafety in ApoE-/- mice fed with a high fat diet. Unexpectedly, the results showed that 24-week administration of SeNPs even at a low dose (50 μg Se/kg/day) aggravated atherosclerotic lesions. Furthermore, SeNPs exacerbated oxidative stress by inhibiting the activities of antioxidant enzymes and the expression of antioxidant selenoenzymes. SeNPs also exacerbated hyperlipidaemia by inducing hepatic lipid metabolic disorder. In the meanwhile, SeNPs aggravated organ injury, especially liver and kidney injury. The above adverse effects of SeNPs were size dependent: SeNPs with the size of 40.4 nm showed the highest adverse effects among the SeNPs with three sizes (23.1 nm, 40.4 nm, and 86.8 nm). In conclusion, the present work shows that long-term administration of low-dose SeNPs aggravated atherosclerotic lesions by enhancing oxidative stress and hyperlipidaemia in ApoE-/- mice, indicative of cardiovascular toxicity. Moreover, long-term administration of SeNPs led to injury to liver and kidney. These results offer novel insights for better understanding the biosafety of SeNPs and other biomedical nanomaterials.

We suggested that selenium-dependent glutathione peroxidase (GPx) plays a protective role against methamphetamine (MA)-induced dopaminergic toxicity. We focused on GPx-1, a major selenium-dependent enzyme and constructed a GPx-1 gene-encoded adenoviral vector (Ad-GPx-1) to delineate the role of GPx-1 in MA-induced dopaminergic neurotoxicity. Exposure to Ad-GPx-1 significantly induced GPx activity and GPx-1 protein levels in GPx-1-knockout (GPx-1-KO) mice. MA-induced dopaminergic impairments [i.e., hyperthermia; increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) DNA-binding activity; and decreased dopamine levels, TH activity, and behavioral activity] were more pronounced in GPx-1-KO mice than in WT mice. In contrast, exposure to Ad-GPx-1 significantly attenuated MA-induced dopaminergic loss in GPx-1-KO mice. The protective effect exerted by Ad-GPx-1 was comparable to that exerted by pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor against MA insult. Consistently, GPx-1 overexpression significantly attenuated MA dopaminergic toxicity in mice. PDTC did not significantly impact the protective effect of GPx-1 overexpression, suggesting that interaction between NF-κB and GPx-1 is critical for dopaminergic protection. Thus, NF-κB is a potential therapeutic target for GPx-1-mediated dopaminergic protective activity. This study for the first time demonstrated that Ad-GPx-1 rescued dopaminergic toxicity in vivo following MA insult. Furthermore, GPx-1-associated therapeutic interventions may be important against dopaminergic toxicity.

Background: Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference. Methods: Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian randomization to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells. Results: Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in Mendelian randomization. In multivariable Mendelian randomization, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages ( GPX1 , C4orf3 ) and involved in ligand-receptor interactions ( CCR5 ). Conclusions: We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations, and single-cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

The discovery of effective therapeutic agents against neurodegenerative diseases (NDDs) remains challenging. Neurotoxicity, inflammations, and oxidative stress are associating factors of NDDs. Sodium butyrate (NaB) is a short-chain fatty acid found in diet and produced in the gut that reportedly protects cancer, inflammation, obesity and so on. Previously, SH-SY5Y cells were studied as in vitro models of cerebral diseases. We have investigated the neuroprotective effects of NaB in SH-SY5Y cells stimulated with TNF-α. The expression of inflammatory mediators, including iNOS, COX-2, and mitogen-activated protein kinases (MAPK) and the apoptotic regulators, including P-53, Bcl-2 associated X (BAX) Protein, and caspase-3 were analyzed by western blot analysis. The anti-apoptotic gene Bcl-2 and the pro-apoptotic gene BAX translocation were also investigated. Our results showed that NaB attenuated cell death and inhibited the NO production and decreased the expression of iNOS and COX-2 in TNF-α-stimulated SH-SY5Y cells. NaB notably ameliorated apoptotic regulatory proteins p-53, Caspase-3 and caspase-1 level, and reversed phosphorylation of extracellular signal-regulated kinases and p-38 proteins. NaB ameliorated Glucocorticoid receptor and NLRP3 inflammasome expressions. NaB also suppressed the BAX nuclear translocation and modulated Nrf-2, HO-1 and MnSOD expression in neuroblastoma cells. In addition, NaB substantially reversed the reactive oxygen species in H2O2 induced SH-SY5Y cells. Altogether, our results suggest that sodium butyrate has potential therapeutic effects against NDDs.

The lectin of Bauhinia forficata (nBfL) is a protein able to bind reversibly to N-acetylgalactosamine, performing several functions and one of them is the antiproliferative activity in tumor cells, but its effects have not yet been evaluated in female gametes. The objective of the present study was to determine the additional effect of B. forficata recombinants lectins in the medium of maturation in vitro of bovine oocytes in expression of genes related to oxidative stress pathways. To get the proteins, the gene for this recombinant lectin (rBfL) and its truncated isoform (rtBfL) were cloned and expressed in Escherichia coli (E.coli). The oocytes obtained through follicular puncture were incubated in IVM medium for 24 h containing concentrations of 10 μg/mL, 50 μg/mL and 100 μg/mL of nBfL, rBfL and rtBfL, and a no treated group as a control. In the groups treated with the concentration of 100 μg / mL, the gene expression of genes involved in oxidative stress SOD2, CAT, GPX-1, GSR, NOS2 and apoptosis BAX, CASP3 were evaluated. The rtBfL increased the expression of the SOD2, GSR and NOS2 genes and all the tested lectins increased the expression of the CASP3 gene compared to the control group. These findings indicate that the tested concentrations of the B. forficata recombinants lectins probably influence the expression of oxidative stress genes and increase the expression of the apoptotic gene CASP3 during in vitro maturation of bovine oocytes.