Oxid Med Cell Longev
· 2025 · PMID 41113998
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Epilepsy is a neurological brain disease characterized by multiple seizures with short intervals and becomes drug-resistant when it causes oxidative stress and inflammation in the brain. Ferulic acid (FA) is a plant phen...Epilepsy is a neurological brain disease characterized by multiple seizures with short intervals and becomes drug-resistant when it causes oxidative stress and inflammation in the brain. Ferulic acid (FA) is a plant phenolic substance with antioxidant, anti-inflammatory, and neuroprotective effects that is used in the treatment of neurodegenerative diseases in traditional medicine. This study evaluated the effect of FA (20 or 80 mg/kg) alone and then FA (20 mg/kg) combined with valproate (VPA) or carbamazepine (CBZ) on maximal electroshock-induced seizures (MESs) in mice associated with interleukin-1β (IL-1β) concentrations and total antioxidant capacity (TAC) assessment in the hippocampus. Male NMRI mice (weight 25-30 g) were injected intraperitoneally with saline (1 mL/kg), FA (20 or 80 mg/kg), diazepam (D) (20 mg/kg), VPA (200 mg/kg), CBZ (10 mg/kg), FA (20 mg/kg) + VPA (200 mg/kg), and FA (20 mg/kg) + CBZ (10 mg/kg) before application of MES. Duration of tonic hind limb extension (HLE), and chimney climbing time and grip-strength were also recorded. Then, mice scarified and hippocampus removed and homogenized. The level of IL-1β and TAC were determined. FA (20 and 80 mg/kg) significantly reduced the HLE duration and prevented seizure-induced hippocampal IL-1β increase and antioxidant capacity decrease. In addition, FA (20 mg/kg) enhanced the anticonvulsant efficacy of VPA and CBZ by regulating hippocampal IL-1β and antioxidant capacity. The finding suggest that FA possessed anticonvulsant effect and improved VPA and CBZ efficacy by regulating of IL-1β and antioxidant capacity in the hippocampus.
Oxid Med Cell Longev
· 2025 · PMID 41049128
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Pulmonary neutrophilic inflammation (PNI) is the recruitment and activation of neutrophils in the microvasculature with the release of myeloperoxidase (MPO) in the airways. Bystander epithelial cells can take up MPO, whe...Pulmonary neutrophilic inflammation (PNI) is the recruitment and activation of neutrophils in the microvasculature with the release of myeloperoxidase (MPO) in the airways. Bystander epithelial cells can take up MPO, where it can generate HOCl. HOCl can react with DNA, generating DNA radicals, which then decay to produce several mutagenic end-oxidation products, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo). Herein, we aimed to test whether HOCl-induced DNA radicals precede DNA oxidation and mutagenesis in A549 human lung epithelial cells as an in vitro model that resembles PNI. Interestingly, by trapping HOCl-induced DNA radicals, the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) blocks the formation of 8-oxo-dGuo and possibly other end-oxidation products, forming DNA-DMPO nitrone adducts. By preventing DNA oxidation, DMPO reduces the mutation of the hypoxanthine phosphoribosyl transferase () gene, one of the genes most sensitive to oxidative damage. The transcription factor p53 is known as the master regulator of the cell response to genomic damage. By trapping DNA radicals, DMPO also blocks the translocation of p53 to the cell nucleus, suggesting that by trapping DNA radicals with DMPO, end-oxidation products are prevented, and the cell response to genomic damage is blunted. Trapping DNA radicals to reduce the accumulation of HOCl-induced mutagenic end-oxidation products will provide new therapeutic avenues to reduce genotoxic damage during PNI.
Oxid Med Cell Longev
· 2025 · PMID 41031329
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Exposure to hyperoxia lasting either a few days at normobaria or a few hours at hyperbaria induces pulmonary oxygen toxicity. Cellular functional changes resulting from oxygen toxicity include alterations in both mitocho...Exposure to hyperoxia lasting either a few days at normobaria or a few hours at hyperbaria induces pulmonary oxygen toxicity. Cellular functional changes resulting from oxygen toxicity include alterations in both mitochondrial dynamics and bioenergetics. The primary goal of this study was to quantify the prophylactic effects of three compounds, caffeine, MitoQ, and γ-aminobutyric acid (GABA), to protect human pulmonary cells in vitro from mitochondrial alterations induced by normobaric- and hyperbaric-hyperoxic conditions. Using cultured lung microvascular and pulmonary artery endothelial cells as well as A549 cells, we examined mitochondrial dynamic and bioenergetics function following exposure to normobaric-hyperoxic (5% CO and 95% O for 72 h) and hyperbaric-hyperoxic (~5% CO equivalent and remainder O at pressure of 4.8 atmosphere absolute (ATA) for 4 h) conditions in the presence of the drugs. Mitochondrial respiration parameters, inner membrane potential, motility, intracellular distribution, and size were measured, along with quantitation of respiration complex levels. Redistribution of intracellular ATP-linked respiration was determined. Comparisons of results were made to controls under normobaric-normoxic conditions. Effects of the drugs under control conditions were also measured. Presence of the drugs resulted in differential effects on hyperoxia-induced alterations in cellular respiration function, stability of mitochondrial potential, and distribution of ATP-linked respiration within the cell. Inclusion of these drugs also produced unique signatures for respiration complex protein levels. Moreso for caffeine than for MitoQ and GABA, its inclusion in the face of hyperoxic exposure served to preserve mitochondrial bioenergetics function, primarily by promoting intracellular redistribution of mitochondrial volume to the perinuclear space. These results indicate a potential role for pharmacologic prophylaxis via therapeutics targeted to support mitochondrial function as a means of protecting the lung from hyperoxia-induced pulmonary cellular oxygen toxicity.
Cappellini F, Zorzan D, Tomay F
… +6 more, Toccaceli M, Marinelli A, Mancini M, Bucchi A, Tonelli C, Petroni K
Oxid Med Cell Longev
· 2025 · PMID 41018278
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Doxorubicin (Doxo) is an anthracycline widely used as a chemotherapeutic agent for many solid and hematological cancers. Its clinical use is limited due to a cumulative dose-dependent and irreversible cardiotoxicity that...Doxorubicin (Doxo) is an anthracycline widely used as a chemotherapeutic agent for many solid and hematological cancers. Its clinical use is limited due to a cumulative dose-dependent and irreversible cardiotoxicity that can cause progressive cardiomyopathy and congestive heart failure. A cardioprotective therapy that can decrease heart damage without reducing the anticancer efficacy during Doxo therapy is of utmost importance. Anthocyanins (ACNs) are renowned cardioprotective agents thanks to their antioxidant and anti-inflammatory properties. An ACN-rich diet from purple corn, which mainly contains cyanidin 3-glucoside (C3G) and its acetylated derivatives, has been previously shown to be effective in reducing Doxo-induced cardiotoxicity in mice. Aiming at unveiling the molecular mechanisms involved in ACN protection, we considered the fibroblast growth factor 21/AMP-activated protein kinase/SIRTUIN1 (FGF21/AMPK/SIRT1)/p53 pathway in murine HL-1 cardiomyocytes treated with Doxo in the presence or absence of purple corn extract (RED). Our work shows that Doxo-induced AMPK activation is restored to control levels by the RED extract. p53 acetylation was increased by the RED extract and upon Sirt1 silencing, indicating that p53 acetylation is SIRT1-dependent and suggesting that the RED extract may affect SIRT1 activity through AMPK. Notably, increased p53 acetylation led to decreased levels of cleaved-caspase 3 and Puma and p21 transcript levels, indicating a reduced level of apoptosis. The RED-induced cardioprotection and p53 acetylation were confirmed in mouse primary cardiomyocytes. In conclusion, the RED extract may prevent cardiomyocytes apoptosis through the modulation of AMPK and acetylation of p53.
Spasojevic I, Huang Z, da Silva WTA
… +11 more, Duan W, Du L, Chen C, Cao J, Zhang S, Lee H, Lo G, Tovmasyan A, Sheng H, Batinic-Haberle I, Secord AA
Oxid Med Cell Longev
· 2025 · PMID 40900760
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Numerous cellular and animal studies demonstrated the ability of redox-active Mn(III) -alkyl- and -alkoxyalkylpyridyporphyrins (MnPs) to protect normal tissue while suppressing tumor growth. The mechanism primarily invol...Numerous cellular and animal studies demonstrated the ability of redox-active Mn(III) -alkyl- and -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/HO-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) -tetrakis(-n-butoxyethyl-2-pyridyl) porphyrin (MnTnBuOE-2-PyP, 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.
Ngenteh ML, Sanda KA, Neng TP
… +4 more, Fubi BBL, Nchang NR, Nsah KB, Mahamat O
Oxid Med Cell Longev
· 2025 · PMID 40821960
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The present study aimed to evaluate the protective effects of aqueous and ethanol extracts of () on cognitive disability induced by aluminum chloride (AlCl) in Wistar rats. Forty-five Wistar rats were distributed in dif...The present study aimed to evaluate the protective effects of aqueous and ethanol extracts of () on cognitive disability induced by aluminum chloride (AlCl) in Wistar rats. Forty-five Wistar rats were distributed in different groups of five animals each. Test groups were daily given AlCl (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 stem bark significantly ( < 0.001) reduced the IL-10, TNF-α, IL-1β, and IL-6 levels in AlCl-treated rats compared to non treated rats. Moreover, the extracts significantly ( < 0.001) changed the oxidant-antioxidant balance by reducing the MDA and NO levels, while increasing SOD and GSH concentrations caused and NO in AlCl-treated rats as compared to nontreated rats. Conclusively, aqueous or ethanol extracts of 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), AlCl.
Oxid Med Cell Longev
· 2025 · PMID 40799291
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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...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.