Oxidative Medicine and Cellular Longevity最新文献

Numerous cellular and animal studies demonstrated the ability of redox-active Mn(III) N-alkyl- and N-alkoxyalkylpyridyporphyrins (MnPs) to protect normal tissue while suppressing tumor growth. The mechanism primarily involves the modulation of NF-кB and Nrf2 signaling pathways via catalysis of MnP/H₂O₂-driven protein thiol oxidation. Such differential protection/suppression effects have paved the way of Mn porphyrins (commonly known as mimics of superoxide dismutase) into clinical trials, therefore introducing new line of therapeutics that are affecting cellular redox status/oxidative stress, rather than specific proteins. The most clinically advanced Mn porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethyl-2-pyridyl) porphyrin (MnTnBuOE-2-PyP⁵⁺, BMX-001) has progressed into five Phase II clinical trials, two of those related to the injuries of central nervous system. Currently, no efficient treatment for chemotherapy-induced neuropathy is available in clinics. We therefore employed BMX-001 to assess its effect on paclitaxel (PTX)-induced neuropathy. Mechanical (Von-Frey filaments) and thermal (hot plate) stimulation, toxicity (body weight), muscular coordination and general physical condition (rotarod) of female CD-1 mice were evaluated over 3 weeks with 2 mg/kg daily dosing and also at clinically relevant dosing of 0.8 mg/kg given subcutaneously (SC) twice weekly after 1.6 mg/kg loading dose. Data revealed a significant ability of BMX-001 to suppress peripheral neuropathy and neuroinflammation. Importantly, while protecting peripheral tissue, BMX-001 suppressed the tumor growth of CAOV2 high-grade serous ovarian cancer in a mouse subcutaneous xenograft model. Previously, the strong anticancer effect was only seen when Mn porphyrins were combined with radiation, chemotherapy, and ascorbate (Asc). Our data further demonstrate that high-grade serous ovarian cancer is the first in vivo cancer thus far studied where redox-active Mn porphyrin, as a single agent, exhibits strong anticancer effect, comparable to that of PTX. The effect is presumably due to high tumor levels of BMX-001 and high oxidative stress specific to the aggressive chemoresistant CAOV2 cell line. Such a strong anticancer effect of BMX-001 would allow for lowering the dosing of PTX and reducing the neuropathy. The combined neuropathy protection and anticancer efficacy demonstrate, therefore, strong therapeutic potential of BMX-001 for gynecological cancers. Moreover, the ability of BMX-001 to suppress neuropathy may be relevant for all types of cancer where chemotherapeutics that induce neuropathy are used as a standard-of-care.

[This corrects the article DOI: 10.1155/2019/3649808.].

[This retracts the article DOI: 10.1155/2023/3492480.].

[This retracts the article DOI: 10.1155/2021/8877691.].

The present study aimed to evaluate the protective effects of aqueous and ethanol extracts of Tabernaemontana stapfiana (T. stapfiana) on cognitive disability induced by aluminum chloride (AlCl₃) in Wistar rats. Forty-five Wistar rats were distributed in different groups of five animals each. Test groups were daily given AlCl₃ (100 mg/kg) following by the doses of the extracts for 21 days. At the end of treatment period, rats were sacrificed and the brain homogenate and serum were prepared and used to evaluate oxidative stress in brain and serum cytokines using colorimetric tests and ELISA, respectively. The findings of this study showed that reduced brain, body weight, and antioxidant enzymes (reduced glutathione [GSH], catalase [CAT], and superoxide dismutase [SOD]), while it increases oxidant biomarkers (malondiadehyde (MDA), nitric oxide (NO) and inflammatory cytokines (IL-10, TNF-α, IL-1β, and IL-6). Therefore, the administration of aqueous or ethanol extracts of T. stapfiana stem bark significantly (p  < 0.001) reduced the IL-10, TNF-α, IL-1β, and IL-6 levels in AlCl₃-treated rats compared to non treated rats. Moreover, the extracts significantly (p  < 0.001) changed the oxidant-antioxidant balance by reducing the MDA and NO levels, while increasing SOD and GSH concentrations caused and NO in AlCl₃-treated rats as compared to nontreated rats. Conclusively, aqueous or ethanol extracts of T. stapfiana stem bark prevented the oxidative stress and inflammation in brain, which made the brain to be not change after administration of the causative agent of cognitive impairment (CI), AlCl₃.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a prevalent enzymopathy, predisposes individuals to hemolytic anemia upon exposure to various medications. This literature review explores the molecular underpinnings of drug-induced hemolytic anemia (DIHA) in G6PD-deficient patients, focusing on dapsone, amoxicillin, and primaquine. These drugs are essential for treating infections such as leprosy and malaria. However, they can damage red blood cell (RBC) membranes through complex mechanisms distinct from traditional immune-mediated pathways. Evidence suggests that drug metabolites, such as dapsone hydroxylamine and 5-hydroxyprimaquine, induce oxidative stress and disrupt RBC membrane integrity. The band 3 protein, a critical component of the RBC cytoskeleton, emerges as a key player in this process, undergoing tyrosine phosphorylation and aggregation, leading to membrane remodeling and instability. This review underscores the need for further research to elucidate the precise molecular interactions involved in drug-induced hemolysis in G6PD deficiency. Understanding these mechanisms may pave the way for developing targeted therapies, including adjuvant treatments and novel drug formulations, to mitigate the risk of hemolytic anemia in this vulnerable population.

[This retracts the article DOI: 10.1155/2020/7126976.].

As we age, cerebral endothelial cells (CECs) are less efficient in maintaining genome integrity and accumulate DNA damage. DNA damage in the brain endothelium can lead to the impairment of the blood-brain barrier (BBB), which is a major factor in brain dysfunction and dementia. Thus, identifying factors that regulate DNA repair in the brain endothelium can prevent brain dysfunction associated with aging. E2F1 is a transcription factor that regulates the expression of genes associated with DNA repair, among other functions. We hypothesize that E2F1 is downregulated in the brain vasculature of mice with aging and that E2F1 upregulation can improve cognitive function. We found that in the brain endothelium, E2F1 was significantly less phosphorylated, which is associated with its transcriptional activity, in the brain vasculature of aged mice and cultured CEC derived from aged mice compared with those from young mice. We found that E2f1 overexpression reduced DNA damage in cultured CEC, and targeting the brain vasculature to overexpress E2f1 improved cognition and increased the expression of genes associated with BBB integrity in aged mice. From RNA sequencing data from cultured CEC, we found that E2f1 overexpression significantly upregulated Acod1, which codes for aconitate decarboxylase-1 (ACOD1), an enzyme that produces itaconate. We also found that 4-octyl itaconate (4-OI), a derivative of itaconate, reduced DNA damage, promoted cell proliferation, and restored endothelial barrier function from oxidative stress in cultured CEC. Thus, our study identifies the E2F1-ACOD1 axis as a molecular pathway that can protect the brain endothelium from oxidative stress and aging.

Introduction: Diabetic nephropathy (DN), a major complication of diabetes mellitus (DM) and a leading cause of end-stage renal disease (ESRD) globally, is characterized by oxidative stress (OS), chronic inflammation, and progressive fibrosis. Despite existing treatment options, disease progression remains a challenge. This study evaluates the therapeutic potential of vitamin D, alone and in combination with metformin, in mitigating DN progression in streptozotocin (STZ) induced diabetic rats. Methods: Male Wister rats were induced with diabetes using a single intraperitoneal injection of STZ and randomized into seven groups. Treatment regimens included vitamin D (5000 or 8000 IU), metformin (250 mg), or a combination, administered over 12 or 21 weeks. Fasting blood glucose (FBG), lipid profiles, renal function markers, and OS indicators were assessed. Renal tissues were examined via histopathological analysis to assess structural changes, and immunohistochemistry (IHC) was performed to evaluate the expression of key proteins involved in inflammation (transforming growth factor-beta [TGF-β]), fibrosis (VEGF), and OS (nuclear factor erythroid 2-related factor 2 [Nrf2]), and vitamin D receptor (VDR) signaling. Results: Vitamin D treatment caused a dose-dependent decrease in FBG, with the vitamin D and metformin combination therapy achieving the greatest decrease (-49.8%) by week 21. Triglyceride levels were significantly reduced (-50%), while HDL levels remained stable. Combination therapy significantly reduced hydrogen peroxide (H₂O₂) (-36.84%) and nitric oxide (NO) (-14.29%) and enhanced antioxidant enzyme activity: glutathione reductase (GR) (+250%), Superoxide dismutase (SOD) (+11.33%), and Glutathione peroxidase (GPx) (+62.83%). Histological analysis revealed preserved renal architecture and reduced fibrosis in treated groups, particularly in those receiving combination therapy. IHC showed increased VDR and Nrf2 expression, reduced VEGF and TGF-β levels, reflecting attenuation of inflammation, fibrosis, and oxidative damage. Conclusion: Vitamin D, particularly in combination with metformin, significantly attenuates DN progression by enhancing metabolic control, reducing OS, and preserving renal function. These findings support its potential as an effective adjunctive therapy in DN management and provide a foundation for future clinical investigations.

Mammary gland epithelial dysfunction is one of the serious consequences of subchronic dietary vitamin A deficiency (VAD). However, the underlying mechanism of this process is incompletely known. Consequently, we utilized a virgin rat model of dietary VAD (3 and 6 months) and subsequently intervened with a vitamin A sufficient (VAS) diet (0.5 or 1 month) prior to treatment completion. This experimental model allowed us to investigate the underlying molecular mechanism of mammary gland tissue dysfunction caused by VAD. Dietary VAD for 3 and 6 months caused increased inflammatory cell infiltration in the mammary gland parenchyma and glandular cells, with increased inflammation and apoptosis and reduced cell proliferation. These changes can be reversed with a VAS diet. Imbalances between the NF-κB and retinoic acid (RA) signaling pathways underlie mammary gland dysfunction following subchronic VAD. Nulliparous rats fed a VAD diet experience mammary gland epithelial dysfunction because of inflammation, apoptosis, and impaired cell growth.