Reduction Of Oxidative Stress Research Articles

Phytoconstituents-Based Nanotherapeutic Approach for the Effective Management of Joint Inflammatory Condition: Arthritis.

Arthritis, a prevalent inflammatory joint condition, presents challenges for effective therapeutic interventions, with conventional treatments often limited in efficacy and associated with adverse effects. Recent years have witnessed a growing interest in exploring natural compounds, particularly phytoconstituents, renowned for their anti-inflammatory and joint-protective properties. This review aims to illuminate the potential of employing nanotherapeutic approaches with phytoconstituents for enhanced arthritis management. The integration of nanotechnology with phytoconstituents emerges as a promising strategy, addressing limitations in traditional arthritis treatments. Nanocarriers like liposomes and nanoparticles provide a platform for targeted drug delivery, improving the bioavailability of phytoconstituents. Furthermore, the combined effects of phytoconstituents can be leveraged to target multiple pathways in arthritis pathogenesis, including inflammation, oxidative stress, and cartilage degradation. Key phytoconstituents, such as curcumin, resveratrol, and quercetin, exhibit anti-inflammatory and immunomodulatory properties. Nevertheless, their therapeutic potential is often impeded by challenges like poor solubility, stability, and bioavailability. Nanocarriers offer solutions by enhancing pharmacokinetics and enabling sustained release, thereby boosting overall therapeutic efficacy. The review explores the mechanisms underlying the anti-arthritic effects of phytoconstituents and their nanoformulations, including the modulation of pro-inflammatory cytokines, inhibition of matrix metalloproteinases, and reduction of oxidative stress. In summary, the integration of phytoconstituents with nanotechnology presents a promising avenue for developing targeted and effective arthritis therapies. This comprehensive review serves as a valuable resource for researchers, clinicians, and pharmaceutical developers seeking innovative approaches to address the intricate challenges associated with arthritis management.

Chronic Administration of Red Yeast Rice Mitigates Endothelial Dysfunction in Spontaneously Hypertensive Rats by Inhibiting Oxidative Stress and Endothelial Nitric Oxide Synthase Uncoupling.

Hypertension is associated with endothelial dysfunction. An imbalance in the production of Nitric Oxide (NO) and Reactive Oxygen Species (ROS), leading to impaired NO-cyclic Guanosine Monophosphate (cGMP) pathway, contributes to this disorder. Red Yeast Rice (RYR), produced from the fermentation of rice with Monascus purpureus, is a traditional functional food originating from China. Although recognized for its anti-dyslipidemia properties, there has been growing evidence regarding the anti-hypertensive effects of RYR. However, these studies only focused on its direct and short-term effects. This study aims to investigate the vasoprotective effects of chronic oral RYR administration using Spontaneously Hypertensive Rats (SHR). SHR were randomly divided into 3 groups: SHR - Control; SHR - RYR extract (100 mg/kg/day); SHR - lovastatin (10 mg/kg/day). Wistar-Kyoto Rats (WKY) were used as normotensive controls. All animals were treated for 12 weeks by oral gavage. Systolic Blood Pressure (SBP) was measured weekly (tail-cuff method). Vascular reactivity was determined using isolated rat aortic rings in an organ bath. Aortic ROS, NO, tetrahydrobiopterin (BH4), and cGMP levels were evaluated. Administration of RYR attenuated SBP elevation and enhanced endothelium-dependent vasodilation in aortic rings. In addition, RYR decreased ROS production and significantly improved the level of vascular NO, BH4, and cGMP. In an SHR model, treatment with RYR for 12 weeks exerts an SBP lowering effect that can be attributed to improved vascular function via reduction of oxidative stress, decreased endothelial NO Synthase (eNOS) uncoupling and enhanced NO-cGMP pathway.

Effect of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on ischemia-reperfusion injury in a rat model.

Despite advancements in reconstructive procedures, ischemia-reperfusion (I/R) injury remains a significant challenge in reconstructive surgery, with mitochondrial dysfunction playing a pivotal role. Mitochondrial transplantation has emerged as a promising therapeutic strategy to address this issue. This study aims to evaluate the impact of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on skin flap I/R models in rats. Twenty male rats underwent I/R injury on skin flaps, with or without mitochondrial transplantation administered via intravenous or subcutaneous routes. Analysis encompassed histopathology, inflammatory, apoptotic, oxidative stress, and hypoxia markers. Results revealed a reduction in inflammation, apoptosis, oxidative stress, and hypoxia in the transplantation group compared to controls. The findings suggest that umbilical cord mesenchymal stem cell-derived mitochondrial transplantation shows promise in enhancing flap viability and attenuating I/R injury, offering valuable insights for improved outcomes in reconstructive surgery. However, further exploration in larger animal models and refinement of delivery methods and dosage are warranted to fully elucidate its clinical translatability.

Myrtenol-Loaded Fatty Acid Nanocarriers Protect Rat Brains Against Ischemia-Reperfusion Injury: Antioxidant and Anti-Inflammatory Effects.

This research investigated the preventive effects of myrtenol (MYR), fatty acid nanocarriers (FANC), and myrtenol-loaded FANC (MYR + FANC) on neurological disturbance, stroke volume, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and tumor necrosis factor-alpha (TNF-α) in the brain with ischemia-reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in rats. Seventy two Wistar male rats were divided into six main groups. The groups were sham, ischemia-reperfusion group (MACO), MACO-MYR (50 mg/kg), MACO-FANC (50 and 100 mg/kg), and MACO-MYR + FANC (50 mg/kg). Stroke volume, neurological deficit scores, and the brain levels of MDA, SOD, and TNF-α were examined with TTC staining, observation, and ELISA, respectively. Pretreatment with MYR, FANC (100 mg/kg), and MYR + FANC reduced the neurological deficit score and cerebral infarction volume. MYR, FANC (100 mg/kg), and MYR + FANC pretreatment increased and decreased brain SOD and MDA levels compared to MACO group, respectively. The TNF-α level decreased in the MYR + FANC group compared to MCAO and MCAO-MYR groups in the brain. The use of FANC (100 mg/kg), MYR, and MYR + FANC has protective effects against oxidative stress and ischemia-reperfusion injury. FANC probably improve the bioavailability of MYR, as MYR+ FANC had more therapeutic effects on the reduction of ischemia-reperfusion injuries, inflammation, and oxidative stress.

Guanylate cyclase promotes osseointegration by inhibiting oxidative stress and inflammation in aged rats with iron overload.

This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation. In this study, 60 rats were included in a titanium rod implantation model and underwent subsequent guanylate cyclase treatment. Imaging, histology, and biomechanics were used to evaluate the osseointegration of rats in each group. First, the impact of VIT on bone integration in aged rats with iron overload was investigated. Subsequently, VIT was employed to modulate the differentiation of MC3T3-E1 cells and RAW264.7 cells under conditions of iron overload. Utilizing an OVX rat model, we observed significant alterations in bone mass and osseointegration due to VIT administration in aged rats with iron overload. The observed effects were concomitant with reductions in bone metabolism, oxidative stress, and inflammation. To elucidate whether these effects are associated with osteoclast and osteoblast activity, we conducted in vitro experiments using MC3T3-E1 cells and RAW264.7 cells. Our findings indicate that iron accumulation suppressed the activity of MC3T3-E1 while enhancing RAW264.7 function. Furthermore, iron overload significantly decreased oxidative stress levels; however, these detrimental effects can be mitigated by VIT treatment. Collectively, our data provide compelling evidence that VIT has the potential to reverse the deleterious consequences of iron overload on osseointegration and bone mass during ageing.

A Butyrate-Yielding Dietary Supplement Prevents Acute Alcoholic Liver Injury by Modulating Nrf2-Mediated Hepatic Oxidative Stress and Gut Microbiota.

Alcoholic liver disease (ALD) is a globally prevalent form of liver disease for which there is no effective treatment. Recent studies have found that a significant decrease in butyrate was closely associated with ALD development. Given the low compliance and delivery efficiency associated with oral-route butyrate administration, a highly effective butyrate-yielding dietary supplement, butyrylated high-amylose maize starch (HAMSB), is a good alternative approach. Here, we synthesized HAMSB, evaluated the effect of HAMSB on acute ALD in mice, compared its effect with that of oral administration of butyrate, and further studied the potential mechanism of action. The results showed HAMSB alleviated acute ALD in mice, as evidenced by the inhibition of hepatic-function impairment and the improvement in liver steatosis and lipid metabolism; in these respects, HAMSB supplementation was superior to oral sodium butyrate administration. These improvements can be attributed to the reduction of oxidative stress though the regulation of Nrf2-mediated antioxidant signaling in the liver and the improvement in the composition and function of microbiota in the intestine. In conclusion, HAMSB is a safe and effective dietary supplement for preventing acute ALD that could be useful as a disease-modifying functional food or candidate medicine.

Medical management of vitiligo: a narrative review

Vitiligo is a chronic cutaneous disease presenting with asymptomatic depigmented macular lesions without any signs of inflammation. Since time immemorial, treatment has been sought for this disorder due to the substantial stigma associated with it, more so in patients with skin of color. Vitiligo can be divided into two major clinical types − segmental vitiligo (SV) and non-segmental vitiligo (NSV). The pathophysiological basis for the loss of functional melanocytes resulting in vitiligo includes genetic predisposition, autoimmune mechanisms, and oxidative stress, among others. Thus, combination therapies targeting the autoimmune nature of disease, activation of melanocytes, and reduction of oxidative stress often yield a successful treatment response. There are very few FDA-approved options for vitiligo, and certain recently introduced modalities may modify the way vitiligo is conventionally treated. This review summarizes the conventional as well as the newer medical treatment options for different clinical types of vitiligo.

Role of nutraceuticals in viral infections as immunomodulators: A comprehensive review

AbstractNutraceuticals are dietary supplements produced from food sources that are intended to improve health through immune system modulation or by helping to prevent and treat a variety of ailments. Their anti‐inflammatory, immunomodulatory, and antioxidant qualities are well recognized. In certain instances, they even show direct microbiological efficacy against viral infections. Because of their special capacity, they may be able to help slow the spread and effects of very infectious illnesses, such as pandemics like COVID‐19. Nutraceuticals work well against viral infections because of a number of intricate processes. Reducing the harm that infections do to the immune system is one of the main effects. Nutraceuticals have the power to stimulate and activate the immune system, improving the body's capacity to identify and eliminate infections. Additionally, they are essential in reducing oxidative damage, which can result in serious consequences and is frequently intensified during viral infections. Nutraceuticals also strengthen immunity by promoting regulatory T cell differentiation and proliferation, which is crucial for preserving immune system homeostasis and limiting hyperinflammatory reactions. They control the production of proinflammatory cytokines, which helps to avoid cytokine storms during viral infections that may seriously harm tissue. This regulation lowers the danger of hyperinflammation and enhances overall results by supporting a balanced immune response. Through a number of biochemical mechanisms, nutraceuticals can strengthen the body's defenses against viral infections. They promote a more effective and efficient immune response by regulating immune cell activities, oxidative stress reduction, and antioxidant pathway activation. Furthermore, by interacting with different cellular signaling pathways, nutraceuticals can affect the synthesis and function of important immune components. This study clarifies the molecular processes behind the immunomodulatory effects of nutraceuticals, highlighting their crucial role in both treating and preventing viral infections.

LFHP-1c improves cognitive function after TBI in mice by reducing oxidative stress through the PGAM5-NRF2-KEAP1 ternary complex

Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI.

Resolvin D5 Protects Female Hairless Mouse Skin from Pathological Alterations Caused by UVB Irradiation.

Resolvin D5 (RvD5) is a lipid mediator that has been reported to present anti-inflammatory and pro-resolution properties. Evidence also supports its capability to enhance reactive oxygen species (ROS) production during bacterial infections, which would be detrimental in diseases driven by ROS. The biological activity of RvD5 and mechanisms against UVB irradiation skin pathology have not been investigated so far. Female hairless mice were treated intraperitoneally with RvD5 before UVB stimulus. RvD5 reduced skin edema in a dose-dependent manner as well as oxidative stress by increasing antioxidants (endogenous tissue antioxidant scavenging of cationic radical, iron reduction, catalase activity and reduced glutathione levels) and decreasing pro-oxidants (superoxide anion and lipid peroxidation). RvD5 antioxidant activity was accompanied by enhancement of Nrf2, HO-1 and NQO1 mRNA expression. RvD5 reduced the production of IL-1β, TNF-α, TGF-β, and IL-10. RvD5 also reduced the inflammatory cell counts, including mast cells and neutrophils/macrophages. The reduction of oxidative stress and inflammation resulted in diminished matrix metalloproteinase 9 activity, collagen degradation, epidermal thickening and sunburn cell development. Therefore, this study demonstrates, to our knowledge, the first body of evidence that RvD5 can be used to treat UVB skin pathology and unveils, at least in part, its mechanisms of action.

Insights into trehalose mediated physiological and biochemical mechanisms in Zea mays L. under chromium stress

BackgroundChromium (Cr) toxicity significantly threatens agricultural ecosystems worldwide, adversely affecting plant growth and development and reducing crop productivity. Trehalose, a non-reducing sugar has been identified as a mitigator of toxic effects induced by abiotic stressors such as drought, salinity, and heavy metals. The primary objective of this study was to investigate the influence of exogenously applied trehalose on maize plants exposed to Cr stress.ResultsTwo maize varieties, FH-1046 and FH-1453, were subjected to two different Cr concentrations (0.3 mM, and 0.5 mM). The results revealed significant variations in growth and biochemical parameters for both maize varieties under Cr-induced stress conditions as compared to the control group. Foliar application of trehalose at a concentration of 30 mM was administered to both maize varieties, leading to a noteworthy reduction in the detrimental effects of Cr stress. Notably, the Cr (0.5 mM) stress more adversely affected the shoot length more than 0.3mM of Cr stress. Cr stress (0.5 mM) significantly reduced the shoot length by 12.4% in FH-1046 and 24.5% in FH-1453 while Trehalose increased shoot length by 30.19% and 4.75% in FH-1046 and FH-1453 respectively. Cr stress significantly constrained growth and biochemical processes, whereas trehalose notably improved plant growth by reducing Cr uptake and minimizing oxidative stress caused by Cr. This reduction in oxidative stress was evidenced by decreased production of proline, SOD, POD, MDA, H2O2, catalase, and APX. Trehalose also enhanced photosynthetic activities under Cr stress, as indicated by increased values of chlorophyll a, b, and carotenoids. Furthermore, the ameliorative potential of trehalose was demonstrated by increased contents of proteins and carbohydrates and a decrease in Cr uptake.ConclusionsThe study demonstrates that trehalose application substantially improved growth and enhanced photosynthetic activities in both maize varieties. Trehalose (30 mM) significantly increased the plant biomass, reduced ROS production and enhanced resilience to Cr stress even at 0.5 mM.

Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Exploring the therapeutic potential of Modafinil in mitigating renal ischemia-reperfusion injury in rats.

Renal ischemia reperfusion injury (IRI) is a post-ischemic event, which can lead to subsequent acute kidney injury (AKI), transplant failure, renal dysfunction and fibrosis via heightened oxidative stress and production of inflammatory cytokines and chemokines. This study aims to assess the effect of Modafinil, a wake-promoting agent with previously proven anti-inflammatory and anti-oxidative properties, on ameliorating renal IRI. A total of 30 male Wistar rats were divided into five groups: Sham-operated group, ischemia reperfusion (I/R) control group and Modafinil pre-treated groups (at different doses of 50, 100 and 150 mg/kg). IRI was induced by means of bilaterally clamping the renal arteries for 45 min, followed by 24 h of reperfusion. Tissue pathological assessments demonstrated a reduction of glomerular, vascular and interstitial injury at doses of 50 and 100 mg/kg of Modafinil. The biochemical studies showed a significant decrease in tissue pro-inflammatory factors, including tumor necrosis factor alpha (TNF-α), Interleukin-18 (IL-18) and lactate dehydrogenase (LDH). Moreover, an elevation was observed in levels of super oxide dismutase (SOD) and catalase, indicating the reduction of oxidative stress. Furthermore, the levels of creatinine (Cr), urea and neutrophil gelatinase-associated lipocalin (NGAL) were declined, indicating the improvement in renal function at effective doses of Modafinil (50 and 100 mg/kg) compared to the I/R control group without Modafinil pre-treatment. Our findings suggest that Modafinil holds promise as an effective therapeutic agent to address the clinical challenges associated with kidney IRI reducing the need for hospitalization and potentially alleviating related morbidities.

Renal Protective Effect of Boeravinone B against Diabetic Nephropathy Rats via Inhibition of The Inflammatory and JAK2/STAT3 Signalling Pathway.

Chronic inflammation is a common feature in diabetes, especially when blood sugar levels are poorly controlled. This chronic low-grade inflammation can affect various organs, including the kidneys. Podocyte damage play a key role in the development of diabetic nephropathy (DN). The aim of the study was to evaluate the nephroprotective effect of Boeravinone B (BB) against streptozotocin (STZ) induced DN in rats and explore the underlying mechanism. In this experimental study, the rats received intraperitoneal injections of STZ (60 mg/kg) to induce DN. Various doses of BB (2.5, 5, and 7.5 mg/kg) were administered orally. Glucose levels, body weights, and organ weights (hepatic and renal) were assessed. Renal, histomorphological, antioxidant, hepatic, and cytokine levels were determined, as were the mRNA expression levels of JAK2 and STAT3. At end of the experimental study, the rats were sacrificed and their renal tissues were removed for histopathological assessment. BB treatment decreased glucose levels and increased body weights. This treatment suppressed hepatic weights, increased renal tissue weights, and also decreased renal parameters like uric acid, urea, bilirubin, creatinine (Cr) and, albumin. There was a decrease (P<0.001) in histomorphological parameters such as kidney hypertrophy index (KHI), mean glomerular volume (MGV), foot process fusion ratio (FPFR), and glomerular basement membrane thickness (GBMT) after treatment with BB. In addition, this treatment improved the levels of renal podocin, renal CD2- associated protein (CD2AP) and suppressed hepatic parameter levels. BB treatment (P<0.001) altered antioxidant parameters and cytokine levels, and suppressed mRNA expressions of JAK2, STAT3, RAGE, KIM-1, NAGL, and S100A8. Administration of BB showed renal protective effects against STZ-induced DN in rats via the reduction of oxidative stress and inflammatory reactions.

An Anti-Inflammatory Diet and Its Potential Benefit for Individuals with Mental Disorders and Neurodegenerative Diseases-A Narrative Review.

This narrative review synthesizes current evidence regarding anti-inflammatory dietary patterns and their potential benefits for individuals with mental disorders and neurodegenerative diseases. Chronic low-grade inflammation is increasingly recognized as a key factor in the etiology and progression of these conditions. The review examines the evidence for the anti-inflammatory and neuroprotective properties of dietary components and food groups, focusing on whole foods rather than specific nutrients or supplements. Key dietary components showing potential benefits include fruits and vegetables (especially berries and leafy greens), whole grains, legumes, fatty fish rich in omega-3, nuts (particularly walnuts), olive oil, and fermented foods. These foods are generally rich in antioxidants, dietary fiber, and bioactive compounds that may help modulate inflammation, support gut health, and promote neuroprotection. Conversely, ultra-processed foods, red meat, and sugary beverages may be harmful. Based on this evidence, we designed the Brain Anti-Inflammatory Nutrition (BrAIN) diet. The mechanisms of this diet include the modulation of the gut microbiota and the gut-brain axis, the regulation of inflammatory pathways, a reduction in oxidative stress, and the promotion of neuroplasticity. The BrAIN diet shows promise as an aid to manage mental and neurodegenerative disorders.

Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) Ameliorate Heart Failure through Reductions in Oxidative Stress: A Systematic Review and Meta-Analysis.

The objectives of this study were to explore the role that eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) plays in heart failure (HF), highlighting the potential connection to oxidative stress pathways. Following PRISMA guidelines, we conducted electronic searches of the literature in MEDLINE and EMBASE focusing on serum EPA and/or DHA and EPA and/or DHA supplementation in adult patients with heart failure or who had heart failure as an outcome of this study. We screened 254 studies, encompassing RCTs, observational studies, and cohort studies that examined HF outcomes in relation to either serum concentrations or dietary supplementation of EPA and/or DHA. The exclusion criteria were pediatric patients, non-HF studies, abstracts, editorials, case reports, and reviews. Eleven studies met our criteria. In meta-analyses, high serum concentrations of DHA were associated with a lower rate of heart failure with a hazard ratio of 0.74 (CI = 0.59-0.94). High serum concentrations of EPA also were associated with an overall reduction in major adverse cardiovascular events with a hazard ratio of 0.60 (CI = 0.46-0.77). EPA and DHA, or n3-PUFA administration, were associated with an increased LVEF with a mean difference of 1.55 (CI = 0.07-3.03)%. A potential explanation for these findings is the ability of EPA and DHA to inhibit pathways by which oxidative stress damages the heart or impairs cardiac systolic or diastolic function producing heart failure. Specifically, EPA may lower oxidative stress within the heart by reducing the concentration of reactive oxygen species (ROS) within cardiac tissue by (i) upregulating nuclear factor erythroid 2-related factor 2 (Nrf2), which increases the expression of antioxidant enzyme activity, including heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain, and manganese superoxide dismutase (SOD), (ii) increasing the expression of copper-zinc superoxide dismutase (MnSOD) and glutathione peroxidase, (iii) targeting Free Fatty Acid Receptor 4 (Ffar4), (iv) upregulating expression of heme-oxygenase-1, (v) lowering arachidonic acid levels, and (vi) inhibiting the RhoA/ROCK signaling pathway. DHA may lower oxidative stress within the heart by (i) reducing levels of mitochondrial-fission-related protein DRP-1(ser-63), (ii) promoting the incorporation of cardiolipin within the mitochondrial membrane, (iii) reducing myocardial fibrosis, which leads to diastolic heart failure, (iv) reducing the expression of genes such as Appa, Myh7, and Agtr1α, and (v) reducing inflammatory cytokines such as IL-6, TNF-α. In conclusion, EPA and/or DHA have the potential to improve heart failure, perhaps mediated by their ability to modulate oxidative stress.

Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis

Cytochrome P450 F3 (CYP4F3) is recognized as a disease-associated immune response initiator that is involved in the synthesis of cholesterol, steroids, and lipids. This study identified the upregulation of CYP4F3 expression in colorectal cancer (CRC) and its association with poor patient prognosis through a comparative analysis between CRC tumor tissues with normal tissues from public databases. The overexpression of CYP4F3 in CT26.wt and SW620, promoted cell proliferation and migration, a reduction of cellular oxidative stress, an up-regulation of the oxidative stress-related pathway NRF2, and an inhibition of cellular ferroptosis. Additionally, inhibition of NRF2 activity stimulated cellular ferroptosis when CYP4F3 was overexpressed. Ferroptosis, characterized by iron-dependent lipid peroxidation, is a non-apoptotic way of cell death with a critical role in cancer development. When given a ferroptosis agonist to CYP4F3-overexpression CRC cells, NRF2 was activated, and cell proliferation and migration were reduced. Furthermore, the mice subcutaneously injected with CYP4F3-overexpression CT26.wt cells formed significantly larger tumors compared to the CYP4F3-vector CT26.wt cell group. This study systematically identified an important role of CYP4F3 in CRC development as a regulator of CRC cells to escape ferroptosis via NRF2, highlighting the significance of CYP4F3 as a potential therapeutic target for CRC.

Celastrus orbiculatus Thunb. extracts and celastrol alleviate NAFLD by preserving mitochondrial function through activating the FGF21/AMPK/PGC-1α pathway.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease globally, characterized by the accumulation of lipids, oxidative stress, and mitochondrial dysfunction in the liver. Celastrus orbiculatus Thunb. (COT) and its active compound celastrol (CEL) have demonstrated antioxidant and anti-inflammatory properties. Our prior research has shown the beneficial effects of COT in mitigating NAFLD induced by a high-fat diet (HFD) in guinea pigs by reducing hepatic lipid levels and inhibiting oxidative stress. This study further assessed the effects of COT on NAFLD and explored its underlying mitochondria-related mechanisms. COT extract or CEL was administered as an intervention in C57BL/6J mice fed a HFD or in HepG2 cells treated with sodium oleate. Oral glucose tolerance test, biochemical parameters including liver enzymes, blood lipid, and pro-inflammatory factors, and steatosis were evaluated. Meanwhile, mitochondrial ultrastructure and indicators related to oxidative stress were tested. Furthermore, regulators of mitochondrial function were measured using RT-qPCR and Western blot. The findings demonstrated significant reductions in hepatic steatosis, oxidative stress, and inflammation associated with NAFLD in both experimental models following treatment with COT extract or CEL. Additionally, improvements were observed in mitochondrial structure, ATP content, and ATPase activity. This improvement can be attributed to the significant upregulation of mRNA and protein expression levels of key regulators including FGF21, AMPK, PGC-1α, PPARγ, and SIRT3. These findings suggest that COT may enhance mitochondrial function by activating the FGF21/AMPK/PGC-1α signaling pathway to mitigate NAFLD, which indicated that COT has the potential to target mitochondria and serve as a novel therapeutic option for NAFLD.

Ameliorative effects of mesenchymal stromal cells on senescence associated phenotypes in naturally aged rats

BackgroundAging is a multifaceted process that affects all organ systems. With the increasing trend of population aging, aging-related diseases have resulted in significant medical challenges and socioeconomic burdens. Mesenchymal stromal cells (MSCs), due to their antioxidative stress, immunoregulatory, and tissue repair capabilities, hold promise as a potential anti-aging intervention.MethodsIn this study, we transplanted MSCs into naturally aged rats at 24 months, and subsequently examined levels of aging-related factors such as β-galactosidase, superoxide dismutase, p16, p21 and malondialdehyde in multiple organs. Additionally, we assessed various aging-related phenotypes in these aged rats, including immune senescence, lipid deposition, myocardial fibrosis, and tissue damage. We also conducted a 16 S ribosomal ribonucleic acid (rRNA) analysis to study the composition of gut microbiota.ResultsThe results indicated that MSCs significantly reduced the levels of aging-associated and oxidative stress-related factors in multiple organs such as the heart, liver, and lungs of naturally aging rats. Furthermore, they mitigated chronic tissue damage and inflammation caused by aging, reduced levels of liver lipid deposition and myocardial fibrosis, alleviated aging-associated immunodeficiency and immune cell apoptosis, and positively influenced the gut microbiota composition towards a more youthful state. This research underscores the diverse anti-aging effects of MSCs, including oxidative stress reduction, tissue repair, metabolic regulation, and improvement of immune functions, shedding light on the underlying anti-aging mechanisms associated with MSCs.ConclusionsThe study confirms that MSCs hold great promise as a potential anti-aging approach, offering the possibility of extending lifespan and improving the quality of life in the elderly population.

Abstract Tu128: p22 phox is a critical factor for the prevention of oxidation and stabilization of SERCA2a in the heart.

Introduction: Elevated oxidative stress linked with heart failure is a major cause for the downregulation of sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase 2a (SERCA2a). NADPH oxidase (NOX) complexes are a key source of reactive oxygen species (ROS) in cardiomyocytes. p22 phox , a transmembrane partner of NOX1-4, plays an essential role in mediating ROS production in multiple NOX complexes. We investigated the role of p22 phox in oxidative stress and SERCA2a levels during pressure overload (PO). Question: Does loss of p22 phox alleviate heart failure through reduction of oxidative stress and stabilization of SERCA2a levels during PO? Methods/approach: Cardiac-specific p22 phox knockout ( p22 phox -cKO) mice were subjected to sham operation or transverse aortic constriction (TAC). The p22 phox interactome was analyzed by co-immunoprecipitation and mass spectrometry. Protein cysteine oxidation was probed by biotinylated-iodoacetamide (BIAM) labelling. Results: The p22 phox -cKO mouse heart showed a 30% reduction in Dityrosine levels compared to WT after 4-week TAC (p&lt;0.05) and 50% lower total tissue H 2 O 2 levels compared to WT after 1-week TAC (p&lt;0.01). Unexpectedly, p22 phox -cKO mice had higher mortality (+20%, p&lt;0.05), lung congestion (2-fold, p&lt;0.05), and fibrosis (&gt;40%, p&lt;0.01) and a lower (40%, p&lt;0.01) left ventricle ejection fraction than WT after TAC. p22 phox directly interacted with SERCA2a. Lack of p22 phox led to oxidation of SERCA2a (50% reduction in BIAM labelling, p&lt;0.01) at cysteine 498 and promoted proteasome-mediated degradation of SERCA2a. The relative SERCA2a ATPase activity was unaltered in both WT and p22 phox -cKO mice. Furthermore, in the absence of p22 phox , SERCA2a interacted strongly with HMG-CoA reductase degradation protein 1 (Hrd1), an endoplasmic reticulum-associated degradation (ERAD)-specific E3 ubiquitin ligase. Knockdown of Hrd1 in the presence of p22 phox knockdown restored SERCA2a to 70% of WT levels (ns and p&lt;0.5 vs p22 phox knockdown). SERCA2a C498S knock-in mice exhibited better cardiac function and stable SERCA2a protein levels after TAC compared to WT mice. Conclusion: The loss of p22 phox exacerbated heart failure through increased SERCA2a cysteine 498 oxidation and degradation through ERAD.