Uncontrolled Oxidative Stress Research Articles

Berberine Alleviates Uterine Inflammation in Rats via Modulating the TLR-2/p-PI3K/p-AKT Axis

Uterine inflammation affects 8% of women in the United States and 32% in developing nations, often caused by uncontrolled inflammation and oxidative stress. This condition significantly impacts women’s health, productivity, and quality of life, and increases the risk of related morbidities leading to higher healthcare costs. Research now focuses on natural antioxidants and anti-inflammatory, particularly berberine (BBR), an isoquinoline alkaloid known for its antioxidant, anti-inflammatory, and antiapoptotic activities. The present study sought to examine the potential therapeutic efficacy of BBR against uterine inflammation induced by the intrauterine infusion of an iodine (I2) mixture in an experimental setting. Female Sprague Dawley rats (n = 6) were divided into five groups, control, sham, I2, I2 and BBR 10 mg/kg, and I2 and BBR 25 mg/kg-treated groups. Compared to I2 infusion, BBR treatment effectively restored normal uterine histopathology and reduced inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor- kappa B (NF-κB), monocyte chemoattractant protein 1 (MCP1), and myeloperoxidase (MPO). It lowered oxidative markers like malondialdehyde (MDA), and increased antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). It balanced apoptotic genes by upregulating B-cell lymphoma 2 (Bcl-2) and downregulating Bcl-2-associated X protein (Bax). Furthermore, BBR reduced the expression of Toll-like receptor 2 (TLR-2), phosphorylated phosphatidylinositol 3‑kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) in the rats treated with intrauterine I2. Ultimately, the therapeutic benefits of BBR can be attributed, to some extent, to its antioxidant, anti-inflammatory, and antiapoptotic properties, in addition to its ability to modulate the TLR-2/p-PI3K/p-AKT axis.

Puerarin-Loaded Liposomes Co-Modified by Ischemic Myocardium-Targeting Peptide and Triphenylphosphonium Cations Ameliorate Myocardial Ischemia-Reperfusion Injury.

Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.

Epigenetic modifications in the ferroptosis pathway in cord blood cells from newborns of smoking mothers and their influence on fetal growth

Maternal smoking during pregnancy increases oxidative stress and decreases antioxidant capacity in newborns. Uncontrolled oxidative stress plays a role in fetal development disorders and in adverse perinatal outcomes. In order to identify molecular pathways involved in low fetal growth, epigenetic modifications in newborns of smoking and non-smoking mothers were examined. Low birth weight newborns of mothers who smoked more than 10 cigarettes per day during the first trimester of pregnancy and normal birth weight newborns of mothers who did not smoke during pregnancy were included in the study. DNA was extracted from umbilical cord blood of term newborns. 125 differentially methylated regions were identified by MeDIP-Seq. Functional analysis revealed several pathways, such as ferroptosis, that were enriched in differentially methylated genes after prenatal smoke exposure. GPX4 and PCBP1 were found to be hypermethylated and associated with low fetal growth. These epigenetic modifications in ferroptosis pathway genes in newborns of smoking mothers can potentially contribute to intrauterine growth restriction through the induction of cell death via lipid peroxidation of cell membranes. The identification of epigenetic modifications in the ferroptosis pathway sheds light on the potential mechanisms underlying the pathophysiology of low birth weight in infants born to smoking mothers.

Oxidative stress–mediated proapoptosis signaling: A novel theory on the mechanism underlying the pathogenesis of burning mouth syndrome

BackgroundBurning mouth syndrome (BMS) is a chronic oral pain disorder characterized by a generalized burning sensation in the oral mucosa without apparent medical or dental causes. Despite various hypotheses proposed to explain BMS pathogenesis, a clear understanding of the cellular-level events and associated histologic and molecular findings is lacking. Advancing our understanding of BMS pathogenesis could facilitate the development of more targeted therapeutic interventions. Types of Studies ReviewedThe authors conducted an extensive literature search and review of cellular mechanisms, focusing on evidence-based data that support a comprehensive hypothesis for BMS pathogenesis. The authors explored novel and detailed mechanisms that may account for the characteristic features of BMS. ResultsThe authors proposed that BMS symptoms arise from the uncontrolled activation of proapoptotic transmembrane calcium permeable channels expressed in intraoral mucosal nerve fibers. Elevated levels of reactive oxygen species or dysfunctional antiapoptosis pathways may lead to uncontrolled oxidative stress–mediated apoptosis signaling, resulting in upregulation of transmembrane transient receptor potential vanilloid type 1 and P2X 3 calcium channels in nociceptive fibers. Activation of these channels can cause nerve terminal depolarization, leading to generation of action potentials that are centrally interpreted as pain. Conclusions and Practical ImplicationsThe authors present a novel hypothesis for BMS pathogenesis, highlighting the role of proapoptotic transmembrane calcium permeable channels and oxidative stress–mediated apoptosis signaling in the development of BMS symptoms. Understanding these underlying mechanisms could provide new insights into the development of targeted therapeutic interventions for BMS. Additional research is warranted to validate this hypothesis and explore potential avenues for effective management of BMS.

β-Nicotinamide Mononucleotide Alleviates Hydrogen Peroxide-Induced Cell Cycle Arrest and Death in Ovarian Granulosa Cells.

Maintaining normal functions of ovarian granulosa cells (GCs) is essential for oocyte development and maturation. The dysfunction of GCs impairs nutrition supply and estrogen secretion by follicles, thus negatively affecting the breeding capacity of farm animals. Impaired GCs is generally associated with declines in Nicotinamide adenine dinucleotide (NAD+) levels, which triggers un-controlled oxidative stress, and the oxidative stress, thus, attack the subcellular structures and cause cell damage. β-nicotinamide mononucleotide (NMN), a NAD+ precursor, has demonstrated well-known antioxidant properties in several studies. In this study, using two types of ovarian GCs (mouse GCs (mGCs) and human granulosa cell line (KGN)) as cell models, we aimed to investigate the potential effects of NMN on gene expression patterns and antioxidant capacity of both mGCs and KGN that were exposed to hydrogen peroxide (H2O2). As shown in results of the study, mGCs that were exposed to H2O2 significantly altered the gene expression patterns, with 428 differentially expressed genes (DEGs) when compared with those of the control group. Furthermore, adding NMN to H2O2-cultured mGCs displayed 621 DEGs. The functional enrichment analysis revealed that DEGs were mainly enriched in key pathways like cell cycle, senescence, and cell death. Using RT-qPCR, CCK8, and β-galactosidase staining, we found that H2O2 exposure on mGCs obviously reduced cell activity/mRNA expressions of antioxidant genes, inhibited cell proliferation, and induced cellular senescence. Notably, NMN supplementation partially prevented these H2O2-induced abnormalities. Moreover, these similar beneficial effects of NMN on antioxidant capacity were confirmed in the KGN cell models that were exposed to H2O2. Taken together, the present results demonstrate that NMN supplementation protects against H2O2-induced impairments in gene expression pattern, cell cycle arrest, and cell death in ovarian GCs through boosting NAD+ levels and provide potential strategies to ameliorate uncontrolled oxidative stress in ovarian GCs.

Exploring the therapeutic potential of the mitochondrial transfer-associated enzymatic machinery in brain degeneration.

Mitochondrial dysfunction is a central event in the pathogenesis of several degenerative brain disorders. It entails fission and fusion dynamics disruption, progressive decline in mitochondrial clearance, and uncontrolled oxidative stress. Many therapeutic strategies have been formulated to reverse these alterations, including replacing damaged mitochondria with healthy ones. Spontaneous mitochondrial transfer is a naturally occurring process with different biological functions. It comprises mitochondrial donation from one cell to another, carried out through different pathways, such as the formation and stabilization of tunneling nanotubules and Gap junctions and the release of extracellular vesicles with mitochondrial cargoes. Even though many aspects of regulating these mechanisms still need to be discovered, some key enzymatic regulators have been identified. This review summarizes the current knowledge on mitochondrial dysfunction in different neurodegenerative disorders. Besides, we analyzed the usage of mitochondrial transfer as an endogenous revitalization tool, emphasizing the enzyme regulators that govern this mechanism. Going deeper into this matter would be helpful to take advantage of the therapeutic potential of mitochondrial transfer.

Heme Interactions as Regulators of the Alternative Pathway Complement Responses and Implications for Heme-Associated Pathologies.

Heme (Fe2+-protoporphyrin IX) is a pigment of life, and as a prosthetic group in several hemoproteins, it contributes to diverse critical cellular processes. While its intracellular levels are tightly regulated by networks of heme-binding proteins (HeBPs), labile heme can be hazardous through oxidative processes. In blood plasma, heme is scavenged by hemopexin (HPX), albumin and several other proteins, while it also interacts directly with complement components C1q, C3 and factor I. These direct interactions block the classical pathway (CP) and distort the alternative pathway (AP). Errors or flaws in heme metabolism, causing uncontrolled intracellular oxidative stress, can lead to several severe hematological disorders. Direct interactions of extracellular heme with alternative pathway complement components (APCCs) may be implicated molecularly in diverse conditions at sites of abnormal cell damage and vascular injury. In such disorders, a deregulated AP could be associated with the heme-mediated disruption of the physiological heparan sulphate-CFH coat of stressed cells and the induction of local hemostatic responses. Within this conceptual frame, a computational evaluation of HBMs (heme-binding motifs) aimed to determine how heme interacts with APCCs and whether these interactions are affected by genetic variation within putative HBMs. Combined computational analysis and database mining identified putative HBMs in all of the 16 APCCs examined, with 10 exhibiting disease-associated genetic (SNPs) and/or epigenetic variation (PTMs). Overall, this article indicates that among the pleiotropic roles of heme reviewed, the interactions of heme with APCCs could induce differential AP-mediated hemostasis-driven pathologies in certain individuals.

Potential Benefits of Omega-3 Polyunsaturated Fatty Acids (N3PUFAs) on Cardiovascular Health Associated with COVID-19: An Update for 2023.

The accumulating literature demonstrates that omega-3 polyunsaturated fatty acid (n-3 polyunsaturated fatty acid, N3PUFA) can be incorporated into the phospholipid bilayer of cell membranes in the human body to positively affect the cardiovascular system, including improving epithelial function, decreasing coagulopathy, and attenuating uncontrolled inflammatory responses and oxidative stress. Moreover, it has been proven that the N3PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of some potent endogenous bioactive lipid mediators that mediate some favorable effects attributed to their parent substances. A dose-response relationship between increased EPA and DHA intake and reduced thrombotic outcomes has been reported. The excellent safety profile of dietary N3PUFAs makes them a prospective adjuvant treatment for people exposed to a higher risk of cardiovascular problems associated with COVID-19. This review presented the potential mechanisms that might contribute to the beneficial effects of N3PUFA and the optimal form and dose applied.

Early adaptive responses in the skeletal muscle of young mice with hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is characterized by iron overload that can cause multiple organ dysfunction primarily due to uncontrolled iron-mediated oxidative stress. Although HH leads to muscular weakness, disorder, and fatigue, the mechanism by which HH affects skeletal muscle physiology is largely unknown. Using Hfe knockout mice (6-7months old), a well-defined mouse model of HH, we examined iron status in the skeletal muscle, as well as other organs. As mitochondria are key organelle for muscular function, this study also explored how molecular markers for mitochondrial function and related systems are regulated in the HH skeletal muscle using western blots. Although iron overload was evident at the systemic level, only mild iron overload was observed in the skeletal muscle of HH. Of note, mitochondrial electron transport chain complex I was upregulated in the HH skeletal muscle, which was accompanied by enhanced autophagy. However, these molecular changes were not associated with oxidative stress, suggesting altered mitochondrial metabolism in the muscle in response to iron overload. These early adaptive responses may be important for supporting mitochondrial health before fully developing skeletal muscle dysfunction in HH. More studies are needed to determine the role of autophagy in the HH-related muscle mitochondrial dysfunction.

Attenuation of the Severity of Acute Respiratory Distress Syndrome by Pomiferin through Blocking Inflammation and Oxidative Stress in an AKT/Foxo1 Pathway-Dependent Manner.

Acute respiratory distress syndrome (ARDS) gives rise to uncontrolled inflammatory response and oxidative stress, causing very high mortality globally. Pomiferin is a kind of prenylated isoflavonoid extracted from Maclura pomifera, owning anti-inflammatory and antioxidant properties. However, the functions and possible mechanisms of pomiferin in lipopolysaccharide- (LPS-) induced ARDS remain unknown. C57BL/6 mice were injected with LPS (5 mg/kg) intratracheally to induce an in vivo ARDS model while RAW264.7 macrophages were stimulated with LPS (100 ng/ml) to induce an in vitro model. Our data demonstrated that pomiferin (20 mg/kg) significantly improved pulmonary function and lung pathological injury in mice with ARDS, apart from increasing survival rate. Meanwhile, pomiferin treatment also inhibited LPS-induced inflammation as well as oxidative stress in lung tissues. LPS stimulation significantly activated AKT/Foxo1 signal pathway in lung tissues, which could be reversed after pomiferin treatment. In vitro experiments further showed that 10, 20, and 50 μM of pomiferin could enhance cell viability of RAW264.7 macrophages stimulated with LPS. What is more, 3-deoxysappanchalcone (3-DE), one AKT agonist, was used to active AKT in RAW264.7 macrophages. The results further showed that 3-DE could abolish pomiferin-elicited protection in LPS-treated RAW264.7 macrophages, evidenced by activated inflammation and oxidative stress. Taken together, our study showed that pomiferin could exert an ARDS-protective effect by blocking the AKT/Foxo1 signal pathway to inhibit LPS-induced inflammatory response and oxidative injury, which may serve as a potential candidate for the treatment of ARDS in the future.

Anti-inflammatory and anti-oxidant properties of Ipomoea nil (Linn.) Roth significantly alleviates cigarette smoke (CS)-induced acute lung injury via possibly inhibiting the NF-κB pathway

Acute respiratory distress syndrome (ARDS), a serious manifestation of acute lung injury (ALI), is a debilitating inflammatory lung disease that is caused by multiple risk factors. One of the primary causes that can lead to ALI/ARDS is cigarette smoke (CS) and its primary mode of action is via oxidative stress. Despite extensive research, no appropriate therapy is currently available to treat ALI/ARDS, which means there is a dire need for new potential approaches. In our study we explored the protective effects of 70 % methanolic-aqueous extract of Ipomoea nil (Linn.) Roth, named as In.Mcx against CS-induced ALI mice models and RAW 264.7 macrophages because Ipomoea nil has traditionally been used to treat breathing irregularities. Male Swiss albino mice (20–25 ± 2 g) were subjected to CS for 10 uninterrupted days in order to establish CS-induced ALI murine models. Dexamethasone (1 mg/kg), In.Mcx (100 200, and 300 mg/kg) and normal saline (10 mL/kg) were given to respective animal groups, 1 h before CS-exposure. 24 h after the last CS exposure, the lungs and bronchoalveolar lavage fluid (BALF) of all euthanized mice were harvested. Altered alveolar integrity and elevated lung weight-coefficient, total inflammatory cells, oxidative stress, expression of pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (KC) were significantly decreased by In.Mcx in CS-exposed mice. In.Mcx also revealed significant lowering IL-1β, IL-6 and KC expression in CSE (4 %)-activated RAW 264.7 macrophage. Additionally, In.Mcx showed marked enzyme inhibition activity against Acetylcholinesterase, Butyrylcholinesterase and Lipoxygenase. Importantly, In.Mcx dose-dependently and remarkably suppressed the CS-induced oxidative stress via not only reducing the MPO, TOS and MDA content but also improving TAC production in the lungs. Accordingly, HPLC analysis revealed the presence of many important antioxidant components. Finally, In.Mcx showed a marked decrease in the NF-κB expression both in in vivo and in vitro models. Our findings suggest that In.Mcx has positive therapeutic effects against CS-induced ALI via suppressing uncontrolled inflammatory response, oxidative stress, lipoxygenase and NF-κB p65 pathway.

Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner.

Neuropathic pain (NPP) is a debilitating clinical condition that presently has few effective treatments. NPP is caused by uncontrolled central oxidative stress and inflammation. Preliminary studies indicate that dexmedetomidine (DEX), an agonist of the alpha-2 adrenergic receptor, is beneficial for treating NPP. In this paper, the effects of administering DEX around injured nerves in a chronic constriction injury- (CCI-) induced neuropathic pain mouse model are investigated. According to the results, the perineural DEX significantly reversed the decline in the mechanical threshold and thermal latency in CCI mice (p < 0.001). In the peripherally affected ischiadic nerve, the perineuronal DEX upregulated the expressions of pAMPK, OPA1, and SNPH but not Drp1 or KIF5B. The aforementioned effects of administering DEX can be partially reversed by compound C, a selective and reversible inhibitor of AMP-activated protein kinase (AMPK). Furthermore, it was found that perineural DEX significantly inhibited the CCI-induced upregulation of the immediate early gene c-Fos, overexpression of the inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), attenuation of the NADH dehydrogenase complexes I, II, III, and IV, and the repression of ATP, SOD, and GSH in the dorsal horn of the spinal cord (DHSC) (p < 0.01). These findings indicate that perineuronal DEX protected the injured ischiadic nerves and attenuated neuropathic pain via AMPK activation to improve energy supply in the peripheral injured nerves, alleviate the inflammatory factor release, and inhibit oxidative stress in the DHSC.

Mechanisms of Kwashiorkor-Associated Immune Suppression: Insights From Human, Mouse, and Pig Studies.

Malnutrition refers to inadequate energy and/or nutrient intake. Malnutrition exhibits a bidirectional relationship with infections whereby malnutrition increases risk of infections that further aggravates malnutrition. Severe malnutrition (SM) is the main cause of secondary immune deficiency and mortality among children in developing countries. SM can manifest as marasmus (non-edematous), observed most often (68.6% of all malnutrition cases), kwashiorkor (edematous), detected in 23.8% of cases, and marasmic kwashiorkor, identified in ~7.6% of SM cases. Marasmus and kwashiorkor occur due to calorie-energy and protein-calorie deficiency (PCD), respectively. Kwashiorkor and marasmic kwashiorkor present with reduced protein levels, protein catabolism rates, and altered levels of micronutrients leading to uncontrolled oxidative stress, exhaustion of anaerobic commensals, and proliferation of pathobionts. Due to these alterations, kwashiorkor children present with profoundly impaired immune function, compromised intestinal barrier, and secondary micronutrient deficiencies. Kwashiorkor-induced alterations contribute to growth stunting and reduced efficacy of oral vaccines. SM is treated with antibiotics and ready-to-use therapeutic foods with variable efficacy. Kwashiorkor has been extensively investigated in gnotobiotic (Gn) mice and piglet models to understand its multiple immediate and long-term effects on children health. Due to numerous physiological and immunological similarities between pigs and humans, pig represents a highly relevant model to study kwashiorkor pathophysiology and immunology. Here we summarize the impact of kwashiorkor on children’s health, immunity, and gut functions and review the relevant findings from human and animal studies. We also discuss the reciprocal interactions between PCD and rotavirus—a highly prevalent enteric childhood pathogen due to which pathogenesis and immunity are affected by childhood SM.

Verapamil attenuates oxidative stress and inflammatory responses in cigarette smoke (CS)-induced murine models of acute lung injury and CSE-stimulated RAW 264.7 macrophages via inhibiting the NF-κB pathway

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), severe form of ALI, are characterized by overwhelming of lung inflammation, and no treatment is currently available to treat ALI/ARDS. Cigarette smoke (CS) is one of the prime causes to induce ALI/ARDS via oxidative stress. Despite extensive research, no appropriate therapy is currently available to treat ALI/ARDS. Hence, new potential approaches are needed to treat ALI/ARDS. Consequently, this project was designed to explore the protective effects of verapamil against CS-induced ALI by in vivo and in vitro method. In vivo data obtained from respiratory mechanics, pulmonary morphometric analyses and lung histopathology revealed that verapamil dose-dependently and strikingly decreased the lung weight coefficient, attenuated the albumin exudation into lungs, minimized the infiltration of macrophages and neutrophils into lungs, reduced the pro-inflammatory cytokines (tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and keratinocyte chemoattractant (KC)) production, and improved the hypoxemia and lung histopathological changes. Similarly, verapamil also reduced the production of TNF-α, IL-6 and KC from cigarette smoke extract (CSE)-stimulated RAW 264.7 macrophage. Importantly, verapamil dose-dependently and remarkably suppressed the CS-induced oxidative stress via not only reducing the myeloperoxidase (MPO) activity of lungs, total oxidative stress (TOS) and malondialdehyde (MDA) content in the lungs and supernatant of RAW 264.7 macrophage but also improving total antioxidant capacity (TAC) and superoxide dismutase (SOD) production. Finally, verapamil strikingly decreased the NF-κB expression both in in vivo and in vitro models. Hence, verapamil has positive therapeutic effects against CS-induced ALI via suppressing uncontrolled inflammatory response, oxidative stress and NF-κB p65 signaling.

Cadmium and Cadmium/BDE (47 or 209) Exposure Affect Mitochondrial Function, DNA Damage/Repair Mechanisms and Barrier Integrity in Airway Epithelial Cells

Heavy metals and Brominated diphenyl ether flame-retardants (BDEs) often coexist in the environment and are capable of inducing injury, cytotoxicity or genotoxicity in human epithelial cells of the lung. We studied the effects of single Cadmium chloride (CdCl2) or CdCl2/BDE (47 or 209) mixtures in airway epithelial cells, using A549 cell line cultured at submerged conditions and air–liquid interface (ALI) (an in vitro model described as physiologically relevant in vivo-like). We evaluated cell viability, oxidative stress, apoptosis, DNA damage/repair (Comet assay, γH2AX phosphorylation ser139), mitochondrial redox balance (NOX-4, Nrf2 and TFAM) and cell barrier integrity (TEER, ZO-1, Claudin-1, E-cadherin-1) in A549 cells exposed to CdCl2 (1 nM to 10 µM), or to CdCl2 (100 nM)/BDEs (47 or 209) (100 nM). CdCl2 (10 μM) reduced cell viability and increased apoptosis. CdCl2 (100 nM) significantly affected DNA-damage/repair (Olive Tail length production), γH2AX phosphorylation and oxidative stress (ROS/JC-1 production) in submerged cell cultures. CdCl2 (100 nM) decreased viability, TEER, ZO-1, Claudin-1 and E-cadherin-1 mRNA expression, and Nrf2 and TFAM while increased NOX-4, in ALI culture of cells. In both cell culture approaches, the cells stimulated with Cadmium/BDEs mixtures did not show a significant increase in the effects observed in the cells treated with CdCl2 alone. CdCl2 inhalation might exert cytotoxicity and genotoxicity, playing a pivotal role in the uncontrolled oxidative stress, damaging DNA and gene expression in airway epithelial cells. No additional or synergistic adverse effects of CdCl2/BDEs mixture were observed in comparison to CdCl2 alone in lung epithelium.

Calcitriol confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

BackgroundThe present study aimed to further explore the potential interaction between oxidative stress and autophagy in the progression of traumatic brain injury (TBI) and therapeutic mechanism of calcitriol, the active form of vitamin D (VitD).MethodsNeuroprotective effects of calcitriol were examined following TBI. We further evaluated the impacts of TBI and calcitriol treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling.ResultsWe found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. In support, we further found that chloroquine (CQ) treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of calcitriol against both TBI-induced neurological deficits and neuronal apoptosis.ConclusionsTherefore, our work demonstrated a neuroprotective role of calcitriol in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

Antioxidant Therapy and Antioxidant-Related Bionanomaterials in Diabetic Wound Healing.

Ulcers are a lower-extremity complication of diabetes with high recurrence rates. Oxidative stress has been identified as a key factor in impaired diabetic wound healing. Hyperglycemia induces an accumulation of intracellular reactive oxygen species (ROS) and advanced glycation end products, activation of intracellular metabolic pathways, such as the polyol pathway, and PKC signaling leading to suppression of antioxidant enzymes and compounds. Excessive and uncontrolled oxidative stress impairs the function of cells involved in the wound healing process, resulting in chronic non-healing wounds. Given the central role of oxidative stress in the pathology of diabetic ulcers, we performed a comprehensive review on the mechanism of oxidative stress in diabetic wound healing, focusing on the progress of antioxidant therapeutics. We summarize the antioxidant therapies proposed in the past 5 years for use in diabetic wound healing, including Nrf2- and NFκB-pathway-related antioxidant therapy, vitamins, enzymes, hormones, medicinal plants, and biological materials.

MicroRNA-30d-5p ameliorates lipopolysaccharide-induced acute lung injury via activating AMPKα

Objectives Acute lung injury (ALI) is a devastating lung disease characterized by uncontrolled pulmonary inflammation and oxidative stress. Currently, no effective therapeutic strategies are available for ALI and its prognosis remains poor. The present study aims to investigate the role and potential mechanism of microRNA-30d-5p (miR-30d-5p) in the progression of ALI. Methods Mice were intravenously treated with miR-30d-5p agomir, antagomir or their respective controls for 3 consecutive days and then were exposed to a single intratracheal injection of lipopolysaccharide (LPS) for 12 h at a dosage of 5 mg/kg to induce ALI. To inhibit adenosine monophosphate-activated protein kinase α (AMPKα) or phosphodiesterase 4 D (PDE4D), compound C (CpC) and rolipram were used. Results miR-30d-5p expression in the lungs was significantly inhibited by LPS treatment. miR-30d-5p agomir significantly alleviated, while miR-30d-5p antagomir aggravated pulmonary inflammation, oxidative damage, and dysfunction in ALI mice. Besides, we found that miR-30d-5p agomir ameliorated LPS-induced ALI via activating AMPKα and that the inhibition of AMPKα by CpC completely abolished these beneficial effects of miR-30d-5p agomir. Further findings validated that PDE4D downregulation was required for the activation of AMPKα by miR-30d-5p agomir. Conclusion miR-30d-5p ameliorates LPS-induced ALI via activating AMPKα and it is a valuable therapeutic candidate in the treatment of ALI.

A Point Mutation in the Transcriptional Repressor PerR Results in a Constitutive Oxidative Stress Response in Clostridioides difficile 630Δerm.

ABSTRACTThe human pathogen Clostridioides difficile has evolved into the leading cause of nosocomial diarrhea. The bacterium is capable of spore formation, which even allows survival of antibiotic treatment. Although C. difficile features an anaerobic lifestyle, we determined a remarkably high oxygen tolerance of the laboratory reference strain 630Δerm. A mutation of a single nucleotide (single nucleotide polymorphism [SNP]) in the DNA sequence (A to G) of the gene encoding the regulatory protein PerR results in an amino acid substitution (Thr to Ala) in one of the helices of the helix-turn-helix DNA binding domain of this transcriptional repressor in C. difficile 630Δerm. PerR is a sensor protein for hydrogen peroxide and controls the expression of genes involved in the oxidative stress response. We show that PerR of C. difficile 630Δerm has lost its ability to bind the promoter region of PerR-controlled genes. This results in a constitutive derepression of genes encoding oxidative stress proteins such as a rubrerythrin (rbr1) whose mRNA abundance under anaerobic conditions was increased by a factor of about 7 compared to its parental strain C. difficile 630. Rubrerythrin repression in strain 630Δerm could be restored by the introduction of PerR from strain 630. The permanent oxidative stress response of C. difficile 630Δerm observed here should be considered in physiological and pathophysiological investigations based on this widely used model strain.IMPORTANCE The intestinal pathogen Clostridioides difficile is one of the major challenges in medical facilities nowadays. In order to better combat the bacterium, detailed knowledge of its physiology is mandatory. C. difficile strain 630Δerm was generated in a laboratory from the patient-isolated strain C. difficile 630 and represents a reference strain for many researchers in the field, serving as the basis for the construction of insertional gene knockout mutants. In our work, we demonstrate that this strain is characterized by an uncontrolled oxidative stress response as a result of a single-base-pair substitution in the sequence of a transcriptional regulator. C. difficile researchers working with model strain 630Δerm should be aware of this permanent stress response.

Dynamics of Toll-like Receptors Signaling in Skeletal Muscle Atrophy.

Skeletal muscle atrophy has been characterized as a state of uncontrolled inflammation and oxidative stress that escalates protein catabolism. Recent advancement supports impinging signaling molecules in the muscle fibers controlled through toll-like receptors (TLR). Activated TLR signaling pathways have been identified as inhibitors of muscle mass and provoke the settings for muscle atrophy. Among them, mainly TLR2 and TLR4 manifest their presence to exacerbate the release of the pro-inflammatory cytokine to deform the synchronized muscle programming. The present review enlightens the TLR signaling mediated muscle loss and the interplay between inflammation and skeletal muscle growth.