Appraisal of Chitosan-Coated Lipid Nano-Combination with Miltefosine and Albendazole in the Treatment of Murine Trichinellosis: Experimental Study with Evaluation of Immunological and Immunohistochemical Parameters.

PURPOSE: Resistance and adverse consequences of albendazole (ABZ) in treating trichinellosis urged demand for secure and effective new drugs. The current study aimed to assess the effect of chitosan-coated lipid nano-combination with albendazole and miltefosine (MFS) in treating experimental murine trichinellosis and evaluating pathological and immunological changes of trichinellosis. MATERIALS AND METHODS: One hundred twenty Swiss albino mice were divided into six groups. Each group was subdivided into a and b subgroups based on the scarification time, which was 7- and 40-days post-infection (PI), respectively. The treatment efficacy was evaluated using parasitological, histopathological, serological (interleukin (IL)-12 and IL-4 serum levels), immunohistochemical (GATA3, glutathione peroxidase1 (GPX1) and caspase-3), and scanning electron microscopy (SEM) methods. RESULTS: The most effective drug was nanostructured lipid carriers (NLCs) loaded with ABZ (G5), which showed the most significant reduction in adults and larval count (100% and 92.39%, respectively). The greatest amelioration in histopathological changes was reported in G4 treated with MFS. GATA3 and caspase-3 were significantly reduced in all treated groups. GPX1 was significantly increased in G6 treated with MFS + NLCs. The highest degenerative effects on adults and larvae by SEM were documented in G6. CONCLUSION: Loading ABZ or MFS on chitosan-coated NLCs enhanced their efficacy against trichinellosis. Although ABZ was better than MFS, their combination should be considered as MFS caused a significant reduction in the intensity of infection. Furthermore, MFS showed anti-inflammatory (↓GATA3) and antiapoptotic effects (↓caspase-3), especially in the muscular phase. Also, when loaded with NLCS, it showed an antioxidant effect (↑GPX1).

Antioxidant Defence in Labeo rohita to Biotic and Abiotic Stress: Insight from mRNA Expression, Molecular Characterization and Recombinant Protein-Based ELISA of Catalase, Glutathione Peroxidase, CuZn Superoxide Dismutase, and Glutathione S-Transferase.

Fish possess numerous enzymatic antioxidant systems as part of their innate immunity. These systems have been poorly studied in Labeo rohita (rohu). The present study characterized and investigated the role of antioxidant genes in the defence mechanisms against two types of stressors, including infection and ammonia stress. Four key genes associated with antioxidant activity-catalase, glutathione peroxidase, glutathione S-transferase, and CuZn superoxide dismutase were successfully cloned and sequenced. These genes were found to be expressed in different tissues and developmental stages of rohu. The expression levels of these antioxidant genes in the liver and anterior kidney tissues of rohu juveniles were modulated in response to bacterial infection (Aeromonas hydrophila), parasite infection (Argulus siamensis), poly I:C stimulation and ammonia stress. Additionally, the recombinant proteins derived from these genes exhibited significant antioxidant and antibacterial activities. These proteins also demonstrated a protective effect against A. hydrophila infection in rohu and had an immunomodulatory role. Furthermore, indirect ELISA assay systems were developed to measure these protein levels in healthy as well as A. hydrophila and ammonia-induced rohu serum. Overall, this study characterized and emphasised the importance of the antioxidant mechanism in rohu's defence against oxidative damage and microbial diseases.

LncRNA VPS9D1-AS1 promotes cell proliferation in acute lymphoblastic leukemia through modulating GPX1 expression by miR-491-5p and miR-214-3p evasion.

Alterations in messenger RNAs (mRNAs) of protein-coding genes can influence the malignant behaviors of acute lymphoblastic leukemia (ALL) cells. According to the prediction from The Cancer Genome Atlas (TCGA) database, we discovered that glutathione peroxidase 1 (GPX1) was up-regulated in acute myeloid leukemia (LAML) tissues, which pushed us to explore the feasible role and its related modulatory mechanism of GPX1 in ALL. In this research, we first proved the high expression of GPX1 in ALL cells compared with normal cells. Functional assays further revealed that the proliferation was obstructed and the apoptosis was facilitated in ALL cells with silenced GPX1. Then, both miR-491-5p and miR-214-3p that were down-regulated in ALL cells were affirmed to target GPX1. Subsequently, VPS9D1 antisense RNA 1 (VPS9D1-AS1) was recognized as the upstream regulator of miR-491-5p-miR-214-3p/GPX1 axis in a competing endogenous RNA (ceRNA) model. Importantly, we proved that VPS9D1-AS1 served as a tumor promoter in ALL through elevating GPX1. In conclusion, VPS9D1-AS1 contributed to ALL cell proliferation through miR-491-5p-miR-214-3p/GPX1 axis, hinting an optional choice for the treatment of ALL.

Expression and prognostic potential of GPX1 in human cancers based on data mining.

BACKGROUND: Glutathione peroxidase-1 (GPX1) is a member of the GPX family, which considered an enzyme that interacts with oxidative stress. GPX1 differential expression is closely correlated with carcinogenesis and disease progression. In this study, we used bioinformatics analysis to investigate GPX1 expression level and explore the prognostic information in different human cancers. METHODS: Expression was analyzed via the Oncomine database and Gene Expression Profiling Interactive Analysis tool, and potential prognostic analysis was evaluated using the UALCAN, GEPIA, and DriverDBv3 databases. Then, the UALCAN database was used to find the promoter methylation of GPX1 in defied cancer types. While GPX1 related functional networks were found within the GeneMANIA interactive tool and Cytoscape software. Moreover, Metascape online website was used to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: We found that GPX1 was commonly overexpressed in most human cancers. High expression of GPX1 could lead to poor outcomes in Brain Lower Grade Glioma, while GPX1 over expression was correlated with better prognosis in Kidney renal papillary cell carcinoma (KIPP). High GPX1 expression was marginally associated with poor prognosis in acute myeloid leukemia (AML). Gene regulation network suggested that GPX1 mainly involved in pathways including the glutathione metabolism, ferroptosis, TP53 regulates metabolic genes, reactive oxygen species (ROS) metabolic process, and several other signaling pathways. CONCLUSIONS: Our findings revealed that GPX1 showed significant expression differences among cancers and served as a prognostic biomarker for defined cancer types. The data mining effectively revealed useful information about GPX1 expression, prognostic values, and potential functional networks in cancers, thus providing researchers with an available way to further explore the mechanism underlying carcinogenesis of genes of interest in different cancers.

Comprehensive analysis of glutathione peroxidase-1 (GPX1) expression and prognostic value in three different types of renal cell carcinoma.

BACKGROUND: Glutathione peroxidase-1 (GPX1) is generally expressed in tissues with high oxygen tension such as the kidneys and lungs, and its main function is to degrade reactive oxygen species (ROS) and protect cells from oxidative stress. Studies have shown that GPX1 is upregulated in many tumor tissues and is closely related to tumor progression and metastasis. This study aimed to explore the possibility of GPX1 as a biomarker for kidney chromophobe cell carcinoma (KICH), kidney renal papillary cell carcinoma (KIRP), and kidney renal clear cell carcinoma (KIRC). METHODS: The Oncomine and GEPIA databases were used to analyze the GPX1 expression differences between tumor and normal tissues, and the UALCAN, GEPIA and DriverDBv3 databases were used to perform the survival analyses. The GeneMANIA interactive tool was then used to find the GPX1-related protein-protein interaction (PPI). Following this, the LinkedOmics database was used for the enrichment analysis of GPX1, and the Timer database was used to estimate the abundance of immune infiltration. Finally, quantitative polymerase chain reaction (qPCR) was performed on patient specimens collected in the clinic to confirm the database findings. RESULTS: In our study, we found that the expression of GPX1 in three types of renal cell carcinoma (RCC) were upregulated, and the high expression of GXP1 was related to the poor prognosis of patients with KICH and KIRC. On the contrary, KIRP patients with a high expression of GPX1 had a better prognosis. In addition, GPX1 was related to the abundance of immune cell infiltration. The results of the qPCR analysis confirmed that the expression of GPX1 in RCC was increased compared with the control group (P<0.05). CONCLUSIONS: Our results indicate that the expression of GPX1 is related to the prognosis of three types of RCC. As such, GPX1 expression could be a reliable diagnostic and prognostic biomarker for RCC and, more importantly, may provide a new direction for therapeutic strategies.

Selenium-binding protein 1 is down-regulated in malignant melanoma.

Selenium-binding protein 1 (SELENBP1) expression is reduced in various epithelial cancer entities compared to corresponding normal tissue and has already been described as a tumor suppressor involved in the regulation of cell proliferation, senescence, migration and apoptosis. We identified SELENBP1 to be down-regulated in cutaneous melanoma, a malignant cancer of pigment-producing melanocytes in the skin, which leads to the assumption that SELENBP1 also functions as tumor suppressor in the skin, as shown by others e.g. for prostate or lung carcinoma. However, in vitro analyses indicate that SELENBP1 re-expression in human melanoma cell lines has no impact on cell proliferation, migration or tube formation of the tumor cells themselves when compared to control-transfected cells. Interestingly, supernatant taken from melanoma cell lines transfected with a SELENBP1 re-expression plasmid led to suppression of vessel formation of HMEC cells. Furthermore, SELENBP1 re-expression alters the sensitivity of melanoma cells for Vemurafenib treatment. The data also hint to a functional interaction of SELENBP1 with GPX1 (Glutathione peroxidase 1). Low SELENBP1 mRNA levels correlate inversely with GPX1 expression in melanoma. The re-expression of SELENBP1 combined with down-regulation of GPX1 expression led to reduction of the proliferation of melanoma cells. In summary, SELENBP1 influences the tumor microenvironment and SELENBP1 action is functionally influenced by GPX1.

Neurochemical and motor changes in mice with combined mutations linked to Parkinson's disease.

Considerable evidence suggests that oxidative stress plays a role in the pathogenesis of Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder. Reduced expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), enzymes that function to detoxify aldehydes and hydroxyl radicals, respectively, has been reported in the substantia nigra of patients who died with PD. To determine whether deficiency in these two genes contributes to the pathogenesis of PD, mice were generated with homozygous null mutations of both Aldh1a1 (the murine homolog of ALDH1) and Gpx1 genes [knockout (KO) mice]. At 6 and 18 months of age, KO mice showed a significantly decreased latency to fall in the automated accelerating rotarod test and increased time to complete the pole test opamine levels were not altered; however, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were significantly reduced at 18 months of age. Proteins adducted with 4-hydroxynonenal, the end-product of lipid peroxidation, were increased in the. midbrain and striatum of KO mice at 6 and 18 months. In conclusion, dual mutations in Gpx1 and Aldh1a1 genes are associated with motor deficits and increased lipid peroxidation in adult mice.

Lack of association between glutathione peroxidase1 (GPx1) activity, Pro198Leu polymorphism and stenosis of coronary arteries: A population-based prediction.

BACKGROUND: We studied the association between erythrocyte glutathione peroxidase1 (GPx1) activity and rs1050450 (Pro198Leu) site with the stenosis of coronary arteries and, evaluated the Pro/Leu position within the predicted tertiary structure. METHODS: Subjects were recruited from who underwent coronary angiography (controls; n = 55, Stenosis < 5% and Patients; n = 95, Stenosis ≥ 50%). The GPx1 activity and rs1050450 C/T variants were determined using enzyme assay and RFLP-PCR techniques, respectively. The conserved regions and GPx1 tertiary structure were predicted using bioinformatics tools. RESULTS: We did not find significant association between GPx1 activity (P = 0.96), rs1050450 genotype distribution and coronary artery disease (adjusted OR = 0.79; 95%CI 0.28-2.2, P = 0.6). The polymorphic variants were not located at the predicted structural and functional domains so that it had not the significant role on the GPx1stability and function. CONCLUSIONS: In agreement with the results predicted from bioinformatics tools, we suggested that the GPx1 activity and rs1050450 (Pro198Leu) site are not involved in the development of stenosis of coronary arteries in the study population.

Homozygous Deletion of Glutathione Peroxidase 1 and Aldehyde Dehydrogenase 1a1 Genes Is Not Associated with Schizophrenia-Like Behavior in Mice.

Much evidence suggests that oxidative stress plays a role in schizophrenia pathogenesis. Major oxidative stress sources include hydrogen peroxide and biogenic aldehydes that are mainly cleared in vivo by glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), respectively. Both enzymes are richly expressed in brain. Schizophrenia patients have significantly increased plasma levels of malondialdehyde and glutathione, combined with decreased GPX activity and ALDH1 mRNA levels in the ventral tegmental area. Absence of Aldh1a1 (murine homolog of ALDH1) gene causes increased basal extracellular dopamine concentrations, a common characteristic of schizophrenia. Studies investigating association between gene polymorphisms of GPX1 (the most abundant form of GPX) or ALDH1A1 with schizophrenia also have not clearly demonstrated whether ALDH1A1 or GPX1 is involved in pathogenesis of schizophrenia. To investigate possible contributions of ALDH and GPX to pathological behaviors associated with schizophrenia, we generated mice with both Aldh1a1 and Gpx1 gene deletions (KO). Aldh1a1/Gpx1 KO and wild type (WT) mice had similar number of novel entry and alteration in Y-maze test, suggesting no cognition deficit in KO. Furthermore, KO and WT displayed similar social interaction and novelty preferences in three chambered tests. Overall, KO and WT had similar activity levels, as indicated by their entries in the Y-maze and sociability tests. Furthermore both genotypes buried a similar percentage of marbles in a 30 min marble-burying task. In summary, homozygous deletion of Gpx1 and Aldh1a1 genes was not associated with schizophrenia-like behavioral phenotypes including anxiety, hyperactivity, cognitive deficit or social disability. Our findings suggest that constitutive absence of these genes alone is unlikely to give rise to common behavioral schizophrenia symptoms. However, these mice may be highly sensitive to oxidative challenges during critical stages of prenatal or juvenile brain development.