ABSTRACT
Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.
Subject(s)
Ferroptosis , Infarction, Middle Cerebral Artery , Mice, Inbred C57BL , NF-E2-Related Factor 2 , Neuroprotective Agents , Oxidative Stress , Reperfusion Injury , Thiones , Thiophenes , Animals , Ferroptosis/drug effects , Oxidative Stress/drug effects , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Thiones/pharmacology , Thiones/therapeutic use , PC12 Cells , NF-E2-Related Factor 2/metabolism , Mice , Male , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Thiophenes/pharmacology , Thiophenes/therapeutic use , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Rats , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Disease Models, Animal , Brain Ischemia/drug therapy , Brain Ischemia/metabolism , Brain/drug effects , Brain/pathology , Brain/metabolism , PyrazinesABSTRACT
BACKGROUND: The excessive and frequent intake of refined sugar leads to caries. However, the relationship between the amount of sugar intake and the risk of caries is not always consistent. Oral microbial profile and function may impact the link between them. This study aims to identify the plaque microbiota characteristics of caries subjects with low (CL) and high (CH) sugar consumption, and of caries-free subjects with low (FL) and high sugar (FH) consumption. METHODS: A total of 40 adolescents were enrolled in the study, and supragingival plaque samples were collected and subjected to metagenomic analyses. The caries status, sugar consumption, and oral-health behaviors of the subjects were recorded. RESULTS: The results indicate that the CL group showed a higher abundance of several cariogenic microorganisms Lactobacillus, A. gerencseriae, A. dentails, S. mutans, C. albicans, S. wiggsiae and P. acidifaciens. C. gingivalis, and P. gingivalis, which were enriched in the FH group. In terms of gene function, the phosphotransferase sugar uptake system, phosphotransferase system, and several two-component responses-regulator pairs were enriched in the CL group. CONCLUSION: Overall, our data suggest the existence of an increased cariogenic microbial community and sugar catabolism potential in the CL group, and a healthy microbial community in the FH group, which had self-stabilizing functional potential.
Subject(s)
Dental Caries , Microbiota , Adolescent , Candida albicans , Dental Caries/etiology , Dietary Sugars/adverse effects , Humans , Lactobacillus , Phosphotransferases , Streptococcus mutans , SugarsABSTRACT
Sepsis-induced cardiomyopathy (SIC) is a common complication of sepsis and is the main reason for the high mortality in sepsis patients. More recent studies have indicated that activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling plays a protective role in SIC. As a potent activator of Nrf2, Omaveloxolone plays a pivotal role in defending against oxidative stress and the inflammatory response. Thus, we examined the efficacy of omaveloxolone in SIC. In the present study, the mice were injected intraperitoneally with a single dose of LPS (10 mg/kg) for 12 h to induce SIC. The data in our study indicated that omaveloxolone administration significantly improved cardiac injury and dysfunction in LPS-induced SIC. In addition, omaveloxolone administration reduced SIC-related cardiac oxidative stress, the inflammatory response and cardiomyocyte apoptosis in mice. In addition, omaveloxolone administration also improved LPS-induced cardiomyocyte injury in an in vitro model using H9C2 cells. Moreover, knockdown of Nrf2 by si-Nrf2 abolished the omaveloxolone-mediated cardioprotective effects. In conclusion, omaveloxolone has potent cardioprotective potential in treating sepsis and SIC via activation of the Nrf2 signaling pathway.