Browsing by Subject "Nrf2"
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Item Astaxanthin mitigates diabetic cardiomyopathy and nephropathyin HF/HFr/STZ diabetic rats via modulating NOX4, fractalkine, Nrf2, and AP-1 pathways(Springer Nature, 2025-06-20) El-Nasr, Nesma M. E. Abo; Hussien, Yosra A.; El-Baset, Marawan Abd; Shabana, Marwa E.; Saleh, Dalia O.; Neurology, School of MedicineThis study investigated the effects of astaxanthin (ASTA) on diabetic cardiomyopathy (DCM) and nephropathy (DN) in rats. Type 2 diabetes was induced through a high-fat/high-fructose (HF/HFr) diet followed by a sub-diabetogenic dose streptozotocin injection. Diabetic rats were treated with ASTA at a dose of 100 mg/kg for four weeks. Serum markers of renal and cardiac function, oxidative stress parameters, and electrocardiographic (ECG) measurements were assessed. Diabetic control rats exhibited significant impairment in renal and cardiac functions, heightened oxidative stress, and altered ECG parameters. Treatment with ASTA (100 mg/kg) markedly improved these conditions, proven by reduction in serum urea, creatinine, cardiac creatine phosphokinase-MB (CK-MB), and LDH levels. Additionally, oxidative stress markers such as MDA, GSH, SOD, and NOX4 were restored in both heart and kidney tissues. Furthermore, ASTA was able to increase the cardiac and renal Fractalkine chemokine as well as attenuate the elevated Nrf2 and AP-1. ECG abnormalities were partially reversed, with enhancements in the QTc interval and ST segment height. The histopathological examination of cardiac and renal tissues confirmed these results. Finally, the forementioned promising observations suggest that ASTA may offer therapeutic potential in mitigating DCM and DN via modulation of NOX4, Fractalkine, Nrf2, and AP-1 Pathway, warranting further research into its mechanisms and clinical applicability.Item Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2(Elsevier, 2021-05-04) Stenvinkel, Peter; Chertow, Glenn M.; Devarajan, Prasad; Levin, Adeera; Andreoli, Sharon P.; Bangalore, Sripal; Warady, Bradley A.; Pediatrics, School of MedicineDespite recent advances in the management of chronic kidney disease (CKD), morbidity and mortality rates in these patients remain high. Although pressure-mediated injury is a well-recognized mechanism of disease progression in CKD, emerging data indicate that an intermediate phenotype involving chronic inflammation, oxidative stress, hypoxia, senescence, and mitochondrial dysfunction plays a key role in the etiology, progression, and pathophysiology of CKD. A variety of factors promote chronic inflammation in CKD, including oxidative stress and the adoption of a proinflammatory phenotype by resident kidney cells. Regulation of proinflammatory and anti-inflammatory factors through NF-κB– and nuclear factor, erythroid 2 like 2 (Nrf2)–mediated gene transcription, respectively, plays a critical role in the glomerular and tubular cell response to kidney injury. Chronic inflammation contributes to the decline in glomerular filtration rate (GFR) in CKD. Whereas the role of chronic inflammation in diabetic kidney disease (DKD) has been well-elucidated, there is now substantial evidence indicating unresolved inflammatory processes lead to fibrosis and eventual end-stage kidney disease (ESKD) in several other diseases, such as Alport syndrome, autosomal-dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS). In this review, we aim to clarify the mechanisms of chronic inflammation in the pathophysiology and disease progression across the spectrum of kidney diseases, with a focus on Nrf2.Item Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich’s Ataxia(MDPI, 2024-12-13) Vo, Anh T. T.; Khan, Uffaf; Liopo, Anton V.; Mouli, Karthik; Olson, Kenneth R.; McHugh, Emily A.; Tour, James M.; Manoj, Madhavan Pooparayil; Derry, Paul J.; Kent, Thomas A.; Anatomy, Cell Biology and Physiology, School of MedicineHarsh acid oxidation of activated charcoal transforms an insoluble carbon-rich source into water-soluble, disc structures of graphene decorated with multiple oxygen-containing functionalities. We term these pleiotropic nano-enzymes as "pleozymes". A broad redox potential spans many crucial redox reactions including the oxidation of hydrogen sulfide (H2S) to polysulfides and thiosulfate, dismutation of the superoxide radical (O2-*), and oxidation of NADH to NAD+. The oxidation of H2S is predicted to enhance protein persulfidation-the attachment of sulfur to cysteine residues. Persulfidated proteins act as redox intermediates, and persulfidation protects proteins from irreversible oxidation and ubiquitination, providing an important means of signaling. Protein persulfidation is believed to decline in several neurological disorders and aging. Importantly, and consistent with the role of persulfidation in signaling, the master antioxidant transcription factor Nrf2 is regulated by Keap1's persulfidation. Here, we demonstrate that pleozymes increased overall protein persulfidation in cells from apparently healthy individuals and from individuals with the mitochondrial protein mutation responsible for Friedreich's ataxia. We further find that pleozymes specifically enhanced Keap1 persulfidation, with subsequent increased accumulation of Nrf2 and Nrf2's antioxidant targets.Item Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver(Taylor & Francis, 2014-08-01) Hu, Min; Zou, Yuhong; Nambiar, Shashank Manohar; Lee, Joonyong; Yang, Yan; Dai, Guoli; Department of Biology, School of ScienceKeap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.Item Mechanotransduction in Living Bone: Effects of the Keap1-Nrf2 Pathway(2019-08) Priddy, Carlie; Li, Jiliang; Dai, Guoli; Wallace, Joseph M.The Keap1-Nrf2 pathway regulates a wide range of cytoprotective genes, and has been found to serve a protective and beneficial role in many body systems. There is limited information available, however, about its role in bone homeostasis. While Nrf2 activation has been suggested as an effective method of increasing bone mass and quality, there have been conflicting reports which associate Keap1 deficiency with detrimental phenotypes. As Keap1 deletion is a common method of Nrf2 activation, further study should address the impacts of various methods of regulating Nrf2 expression. Also, little research has been conducted on the specific pathways by which Nrf2 activation improves bone quality. In this study, the effects of alterations to Nrf2 activation levels were explored in two specific and varied scenarios. In the first experiment, moderate Nrf2 activation was achieved via partial deletion of its sequestering protein, Keap1, in an aging mouse model. The hypothesis tested here is that moderate Nrf2 activation improves bone quality by affecting bone metabolism and response to mechanical loading. The results of this first experiment suggest a subtle, sex-specific effect of moderate Nrf2 activation in aging mice which improves specific indices of bone quality to varying degrees, but does not affect loading-induced bone formation. It is likely that the overwhelming phenotypic impacts associated with aging or the systemic effects of global Keap1 deficiency may increase the difficulty in parsing out significant effects that can be attributed solely to Nrf2 activation. In the second experiment, a cell-specific knockout of Nrf2 in the osteocytes was achieved using a Cre/Lox breeding system. The hypothesis tested here is that osteocyte-specific deletion of Nrf2 impairs bone quality by affecting bone metabolism and response to mechanical loading. The results of this experiment suggest an important role of Nrf2 in osteocyte function which improves certain indices of bone quality, which impacts male and female bones in different 7 ways, but did not significantly impact loading-induced bone formation. Further studies should modify the method of Nrf2 activation in an effort to refine the animal model, allowing the effects of Nrf2 to be isolated from the potential systemic effects of Keap1 deletion. Future studies should also utilize other conditional knockout models to elucidate the effects of Nrf2 in other specific cell types.Item Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice(Nature Research, 2020-01-15) Yin, Yukun; Corry, Kylie A.; Loughran, John P.; Li, Jiliang; Biology, School of ScienceKeap1 is a negative controller of the transcription factor Nrf2 for its activity. The Keap1/Nrf2 signaling pathway has been considered as a master regulator of cytoprotective genes, and exists in many cell types including osteoblasts and osteoclasts. Our previous study shows Nrf2 deletion decreases bone formation. Recent studies show hyperactivation of Nrf2 causes osteopenia in Keap1−/− mice, and Keap1−/− osteoblasts have significantly less proliferative potential than Keap1+/− osteoblasts. We aimed to examine if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism. We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice. Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5a in cultured primary osteoblasts compared to WT control. In male mice, compared with their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone formation rate (+30.7%, P = 0.0029), but did not change the ultimate force (P < 0.01). The osteoclast cell numbers (−32.45%, P = 0.01) and surface (−32.58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice. Compared to male WT mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased. Our data suggest that moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling in male mice.Item Neutrophil NADPH oxidase promotes bacterial eradication and regulates NF-κB-Mediated inflammation via NRF2 signaling during urinary tract infections(Elsevier, 2025) Cotzomi-Ortega, Israel; Rosowski, Emily E.; Wang, Xin; Sanchez-Zamora, Yuriko I.; Lopez-Torres, Jeimy M.; Sanchez-Orellana, Gamaliel; Han, Rachel; Vásquez-Martínez, Gabriela; Andrade, Gabriel Mayoral; Ballash, Gregory; Cortado, Hanna; Li, Birong; Ali, Yusuf; Rascon, Raul; Robledo-Avila, Frank; Partida-Sanchez, Santiago; Pérez-Campos, Eduardo; Olofsson-Sahl, Peter; Zepeda-Orozco, Diana; Spencer, John David; Becknell, Brian; Ruiz-Rosado, Juan de Dios; Pediatrics, School of MedicineThe precise role of neutrophil-derived reactive oxygen species (ROS) in combating bacterial uropathogens during urinary tract infections (UTI) remains largely unexplored. In this study, we elucidate the antimicrobial significance of NADPH oxidase 2 (NOX2)-derived ROS, as opposed to mitochondrial ROS, in facilitating neutrophil-mediated eradication of uropathogenic Escherichia coli (UPEC), the primary causative agent of UTI. Furthermore, NOX2-derived ROS regulate NF-κB-mediated inflammatory responses in neutrophils against UPEC by inducing the release of nuclear factor erythroid 2-related factor 2 (Nrf2) from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1). Consistently, the absence of NOX2 (Cybb-/-) in mice led to uncontrolled bacterial infection associated with increased NF-κB signaling, heightened neutrophilic inflammation, and increased bladder pathology during cystitis. These findings underscore a dual role for neutrophil NOX2 in both eradicating UPEC and mitigating neutrophil-mediated inflammation in the urinary tract, revealing a previously unrecognized effector and regulatory mechanism in the control of UTI.Item Nrf2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age(Plos, 2017-02-02) Pellegrini, Gretel Gisela; Cregor, Meloney; McAndrews, Kevin; Morales, Cynthya Carolina; McCabe, Linda Doyle; McCabe, George P.; Peacock, Munro; Burr, David; Weaver, Connie; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of MedicineAccumulation of reactive oxygen species (ROS) is an important pathogenic mechanism underling the loss of bone mass and strength with aging and other conditions leading to osteoporosis. The transcription factor erythroid 2-related factor2 (Nrf2) plays a central role in activating the cellular response to ROS. Here, we examined the endogenous response of bone regulated by Nrf2, and its relationship with bone mass and architecture in the male and female murine skeleton. Young (3 month-old) and old (15 month-old) Nrf2 knockout (KO) mice of either sex exhibited the expected reduction in Nrf2 mRNA expression compared to wild type (WT) littermates. Nrf2 deletion did not lead to compensatory increase in Nrf1 or Nrf3, other members of this transcription factor family; and instead, Nrf1 expression was lower in KO mice. Compared to the respective WT littermate controls, female KO mice, young and old, exhibited lower expression of both detoxifying and antioxidant enzymes; young male KO mice, displayed lower expression of detoxifying enzymes but not antioxidant enzymes; and old male KO mice showed no differences in either detoxifying or antioxidant enzymes. Moreover, old male WT mice exhibited lower Nrf2 levels, and consequently lower expression of both detoxifying and antioxidant enzymes, compared to old female WT mice. These endogenous antioxidant responses lead to delayed rate of bone acquisition in female KO mice and higher bone acquisition in male KO mice as quantified by DXA and μCT, demonstrating that Nrf2 is required for full bone accrual in the female skeleton but unnecessary and even detrimental in the male skeleton. Therefore, Nrf2 regulates the antioxidant endogenous response and bone accrual differently depending on sex and age. These findings suggest that therapeutic interventions that target Nrf2 could be developed to enhance the endogenous antioxidant response in a sex- and age-selective manner.Item Protective role of remogliflozin against experimental liver fibrosis by activating AMPK/SIRT1/Nrf2 and suppressing NF-κB pathways(Frontiers Media, 2025-06-09) ALSuhaymi, Naif; Alsugoor, Mahdi H.; Shokry, Aya A.; Fayed, Hany M.; Mohamed, Bassim M. S. A.; Afifi, Sherif M.; Esatbeyoglu, Tuba; Korany, Reda M. S.; Elbaset, Marawan A.; Neurology, School of MedicineLiver fibrosis is considered an epidemic health problem since it can lead to several insults that can be fatal. Remogliflozin (Remo), an inhibitor of the sodium-glucose cotransporter 2 (SGLT2) protein, is one of the most recently developed antidiabetic drugs for treating type 2 diabetes mellitus (T2DM). The antidiabetic and antioxidant impacts of Remo have been demonstrated in numerous animal models; however, its antifibrotic activity remains unclear. Therefore, we planned this study to clarify the preventive activity of Remo against thioacetamide (TAA)-induced liver fibrosis in male rats, along with its anticipated pathways. Four groups of rats (n = 6) were used in our investigation: the control group; the TAA group, which received 100 mg/kg b.wt IP twice a week for 6 weeks; and the TAA + Remo groups, which were given two doses of Remo at 25 and 50 mg/kg b.wt orally, respectively, for 4 weeks in addition to TAA injections. The TAA group showed a marked increase in liver enzymes, lipid peroxidation, and proinflammatory cytokines, along with a marked decrease in albumin and cellular antioxidant status. Additionally, the TAA group showed a marked increase in nuclear factor-κB (NF-κB) and a marked decrease in AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels and expressions. The harmful effects of TAA were significantly mitigated by Remo therapy, which improved the aforementioned parameters. Histopathological findings corroborated the biochemical results. The results of our study suggest that Remo has anti-inflammatory and antioxidant properties that protect against TAA-induced liver fibrosis by inhibiting the NF-κB pathway and activating the AMPK/SIRT1/Nrf2 pathway.Item Role of Nrf2 in bone metabolism(BioMed Central, 2015-10-29) Sun, Yong-Xin; Xu, Ai-Hua; Yang, Yang; Li, Jiliang; Department of Biology, School of ScienceNuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor expressed in many cell types, including osteoblasts, osteocytes, and osteoclasts. Nrf2 has been considered a master regulator of cytoprotective genes against oxidative and chemical insults. The lack of Nrf2 can induce pathologies in multiple organs. Nrf2 deficiency promotes osteoclast differentiation and osteoclast activity, which leads to an increase in bone resorption. The role of Nrf2 in osteoblast differentiation and osteoblast activity is more complex. Nrf2 mediates anabolic effects within an ideal range. Nrf2 deletion suppresses load induced bone formation and delays fracture healing. Overall, Nrf2 plays an important role in the regulation of bone homeostasis in bone cells.