SOD1 Protein Research Articles

The role of Sod-2 in different types of neuronal damage and behavioral changes induced by polystyrene nanoplastics in Caenorhabditis elegans

Polystyrene nanoplastics (PS-NPs) have been demonstrated to accumulate in organisms especially from soil and exhibit neurotoxicity. However, the specific mechanisms by which PS-NPs caused neurotoxic effects remain largely unexplored. In this study, we employed PS-NPs with a diameter of 50 nm as the toxicant and used estimated exposure concentrations which are similar to those found in Chinese agricultural soil (i.e., 0, 1, 5 and 10 μg/mL). We found that PS-NPs induced significant neurotoxicity and behavioral damage in nematodes. Taking advantage of neuronal-specific reporter nematodes, we unveiled the order of neuronal damage induced by PS-NPs being DAergic neurons, followed by Achergic neurons and GABAergic neurons. Additionally, PS-NPs significantly reduced the neurotransmitter levels corresponding to these three types of neurons, with the order of reduction being Ach followed by DA and GABA. Moreover, we demonstrated that PS-NPs led to an increase in ROS production, the activation of gst-4 and a decrease in Sod-2 protein content. Furthermore, we unveiled that Sod-2 could suppress the generation of ROS induced by PS-NPs. Then we proved that the pretreatment with mitochondrial ROS scavenger Mitoquinone (Mito Q) was able to alleviate PS-NPs-induced neurotoxic effects and behavioral damage by scavenging ROS and subsequently regulating Sod-2 protein expression. In summary, we have demonstrated for the first time that ROS-mediated reduction of Sod-2 protein plays a crucial role in PS-NPs-induced neurotoxicity and behavioral damage. Furthermore, Mito Q shows potential therapeutic value in alleviating the toxic effects of PS-NPs, providing new insights for the prevention and treatment of PS-NPs-induced neurotoxicity.

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility

IntroductionSkeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative stress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2).Methods: iSOD2 KD and control (CON) animals were administered doxycycline for 3- or 12- weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery. ResultsMaximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were no significant differences in antioxidant or mitochondrial biogenesis genes between groups. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not. ConclusionWe use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

Mitigating Hyperglycaemic Oxidative Stress in HepG2 Cells: The Role of Carica papaya Leaf and Root Extracts in Promoting Glucose Uptake and Antioxidant Defence

Background/Objectives: Diabetes often goes undiagnosed, with 60% of people in Africa unaware of their condition. Type 2 diabetes mellitus (T2DM) is associated with insulin resistance and is treated with metformin, despite the undesirable side effects. Medicinal plants with therapeutic potential, such as Carica papaya, have shown promising anti-diabetic properties. This study explored the role of C. papaya leaf and root extracts compared to metformin in reducing hyperglycaemia-induced oxidative stress and their impact on liver function using HepG2 as a reference. Methods: The cytotoxicity was assessed through the MTT assay. At the same time, glucose uptake and metabolism (ATP and ∆Ψm) in HepG2 cells treated with C. papaya aqueous leaf and root extract were evaluated using a luminometry assay. Additionally, antioxidant properties (SOD2, GPx1, GSH, and Nrf2) were measured using qPCR and Western blot following the detection of MDA, NO, and iNOS, indicators of free radicals. Results: The MTT assay showed that C. papaya extracts did not exhibit toxicity in HepG2 cells and enhanced glucose uptake compared to the hyperglycaemic control (HGC) and metformin. The glucose levels in C. papaya-treated cells increased ATP production (p < 0.05), while the ∆Ψm was significantly increased in HGR1000-treated cells (p < 0.05). Furthermore, C. papaya leaf extract upregulated GPx1 (p < 0.05), GSH, and Nrf2 gene (p < 0.05), while SOD2 and Nrf2 proteins were reduced (p > 0.05), ultimately lowering ROS (p > 0.05). Contrarily, the root extract stimulated SOD2 (p > 0.05), GPx1 (p < 0.05), and GSH levels (p < 0.05), reducing Nrf2 gene and protein expression (p < 0.05) and resulting in high MDA levels (p < 0.05). Additionally, the extracts elevated NO levels and iNOS expression (p < 0.05), suggesting potential RNS activation. Conclusion: Taken together, the leaf extract stimulated glucose metabolism and triggered ROS production, producing a strong antioxidant response that was more effective than the root extract and metformin. However, the root extract, particularly at high concentrations, was less effective at neutralising free radicals as it did not stimulate Nrf2 production, but it did maintain elevated levels of SOD2, GSH, and GPx1 antioxidants.

Pyrroroquinoline Quinone (PQQ) Improves the Quality of Holstein Bull Semen during Cryopreservation.

Cryopreserved semen is extensively utilized in the artificial insemination (AI) of domestic animals; however, suboptimal conception rates due to oxidative damage following AI continue to pose a challenge. The present study investigated the effects of Pyrroroquinoline Quinone (PQQ), a novel antioxidant, on the semen quality of Holstein bulls during cryopreservation, as well as its potential molecular mechanisms. Semen samples were diluted with varying concentrations of PQQ (0, 50 μmol/L, 100 μmol/L, 150 μmol/L) prior to cryopreservation. Following the freeze-thaw process, a comprehensive evaluation was conducted to assess sperm motility, plasma membrane integrity, acrosome integrity, and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP). Western blot analysis was employed to examine the levels of proteins including PGAM2, CAPZB, CAT, SOD1, and GPX1. Notably, the inclusion of 100 μmol/L PQQ significantly enhanced sperm motility, membrane integrity, and acrosome integrity post freeze-thawing (p < 0.05). Furthermore, the group treated with 100 μmol/L PQQ exhibited reduced levels of MDA and ROS (p < 0.05), while ATP levels were significantly elevated (p < 0.05). Interestingly, treatment with 100 μmol/L PQQ resulted in decreased consumption of PGAM2, CAPZB, CAT, SOD1, and GPX1 proteins in sperm after freeze-thawing, compared to the control group (p < 0.05). These findings indicate that PQQ treatment enhances the quality of bull semen, mitigates oxidative stress damage, and ultimately improves the efficacy of sperm cryopreservation.

In silico assessment of antioxidant activity and toxicity profiling of bioactive molecules from Murraya koenigii

The antioxidant activity of curry leaves is of interest because oxidative stress is implicated in a variety of diseases, including cancer, heart disease, and neurodegenerative disorders. By scavenging free radicals and inhibiting lipid peroxidation, antioxidants can help protect cells from damage and reduce the risk of these diseases. Overall, in-silico studies suggest that curry leaves and their bioactive compounds have potent antioxidant activity. The objective of the study was to assess the antioxidant activity of the bioactive molecules from Murraya koenigii and anticipate the toxicity by in-silico research. iGEMDOCK software was used to assess the antioxidant activity. ProTox II software was used to conduct the toxicity investigations. Osthol (− 81.4863, − 81.9046 kcal/mol), mukoenineA (− 81.0417, − 78.9941 kcal/mol), murrayone(− 80.0731, − 78.9453 kcal/mol), kaempferol (− 97.0774, − 89.3534 kcal/mol), and apigenin (− 89.5291, − 108.704 kcal/mol) were found to have the highest binding energies with SOD and GPx proteins, respectively, when compared with standard (ascorbic acid; − 81.132, − 98.917 kcal/mol). All the mentioned compounds have low levels of hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. The bioactive molecules of Murraya koenigii have a potent antioxidant effect and low level of toxicity that gives valuable insight for optimizing lead molecules to combat free radical generation or oxidation.

Anti-osteoporotic Activity of Ethyl Cinnamate from Coix lacryma-jobi Targeting SOD and GPx Proteins

Anti-osteoporotic Activity of Ethyl Cinnamate from Coix lacryma-jobi Targeting SOD and GPx Proteins

GPX5-Enriched Exosomes Improve Sperm Quality and Fertilization Ability

Semen preservation quality affects the artificial insemination success rate, and seminal exosomes are rich in various proteins that are transferable to sperm and conducive to sperm-function preservation during storage. However, the specific effects of these proteins remain unclear. In this study, the specific effects of these proteins on semen preservation quality and fertilization capacity were investigated through a proteomic analysis of seminal exosomes from boars with high conception rates (HCRs) and low conception rates (LCRs). The results revealed significant differences in the expression of 161 proteins between the two groups, with the GPX5 level being significantly higher in the HCR group (p &lt; 0.05). The role of GPX5 was further investigated by constructing engineered exosomes enriched with GPX5 (Exo-GPX5), which could successfully transfer GPX5 to sperm. Compared to the control group, Exo-GPX5 could significantly improve sperm motility on storage days 4 and 5 and enhance the acrosome integrity on day 5 (p &lt; 0.05). Additionally, Exo-GPX5 increased the total antioxidant capacity (T-AOC) of sperm, reduced the malondialdehyde (MDA) level, and decreased the expression of antioxidant proteins SOD1 and CAT (p &lt; 0.05). In simulated fertilization experiments, Exo-GPX5-treated sperm exhibited higher capacitation ability and a significant increase in the acrosome reaction rate (p &lt; 0.05). Overall, Exo-GPX5 can improve boar semen quality under 17 °C storage conditions and enhance sperm fertilization capacity.

Regulation of the SIRT3/SOD2 Signaling Pathway by a Compound Mixture from Polygonum orientale L. for Myocardial Damage

Background: Polygonum orientale L. (PO) has demonstrated notable efficacy in treating coronary heart disease. Previous research identified eight key active components in PO for cardiomyocyte protection, but the underlying mechanisms remained unclear; Methods: Network pharmacology and molecular docking were used to identify potential target proteins of PO’s active components. Experimental models assessed the cardioprotective effects and mechanisms; Results: Network analysis and molecular docking revealed that the active components exhibited the highest binding affinity with SOD2, indicating it as a key element in the cardiac protection of PO. In vivo, PO extract improved myocardial structure and function, and increased SOD2 protein levels. In vitro, the active components of PO (Mixture) mitigated oxidative stress and apoptosis, upregulating SIRT3 and decreasing acetylated SOD2, leading to increased SOD2 and reduced ROS levels. The observed effects were reversed by a SIRT3 inhibitor, indicating the involvement of the SIRT3/SOD2 signaling pathway; Conclusions: This comprehensive approach elucidated the critical mechanisms underlying the cardioprotective properties of PO’s bioactive constituents, highlighting the regulation of the SIRT3/SOD2 signaling pathway as a new mechanism for PO’s anti-cardiovascular disease effects, and suggesting the Mixture’s potential as a promising drug candidate.

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.

Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative distress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of more flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2). iSOD2 KD and control (CON) animals were administered doxycycline for 3- or 12- weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery. Maximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were minimal changes in gene expression between KD and CON muscle. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not. We use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

Increased susceptibility of human limbal aniridia fibroblasts to oxidative stress

Aniridia-associated keratopathy originates from a haploinsufficiency of the transcription factor PAX6 (PAX6+/−). In the corneal epithelium of PAX6+/− mice, a significant increase in oxidized proteins was observed, accompanied by impaired compensation for elevated oxidative stress (OS). The extent to which limbal fibroblast cells (LFCs) are affected by an increased susceptibility to OS in cases of congenital aniridia (AN) has not been determined, yet. Our aim was to examine the impact of OS on antioxidant enzyme expression in normal and AN-LFCs. Following isolation and culture of primary LFCs (n = 8) and AN-LFCs (n = 8), cells were treated with cobalt chloride for 48 h to chemically induce hypoxic conditions and OS. Subsequently, HIF-1α/-2α, PHD1/2, Nrf2, CAT, SOD1, PRDX6, and GPX1 gene expression was examined by qPCR. SOD1, PRDX6, and GPX1 protein levels were assessed from the cell lysate by Western blot. The induction of hypoxia led to reduced HIF-1α gene expression in both fibroblast groups (p≤0.008), while the decrease in PHD1 was limited to AN-LFCs (p = 0.0007). On the other hand, under hypoxic conditions, PHD2 showed higher mRNA expression in AN-LFCs compared to normal LFCs (p = 0.013). As a result of OS, the mRNA levels of Nrf2 (p<0.0001) and the antioxidant enzymes CAT (p = 0.005), SOD1 (p = 0.005), GPX1 (p = 0.002) decreased in AN-LFCs. This was accompanied by an increased protein expression of SOD1 (p = 0.019) and PRDX6 (p=0.0009). In the normal LFC group, the induced extent of OS had no impact on the gene (p≥0.151) and protein expression (p ≥ 0.629) of antioxidant enzymes, except for the GPX1 mRNA level (p = 0.027). AN-LFCs exhibit higher susceptibility to OS than normal LFCs. Therefore, in AN-LFCs, there are sustained alterations in gene and protein expression of antioxidative enzymes even after 48 h of CoCl2 treatment.

Amyotrophic Lateral Sclerosis and swim training affect copper metabolism in skeletal muscle in a mouse model of disease.

Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice. SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild-type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined. ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p = .0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p = .0021) and 34% (p = .0372), while the CTR1 protein (copper importer) decreased by 45% (p = .002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles. The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life.

O07 RENAL DENERVATION IMPROVES RIGHT VENTRICULAR FUNCTION, RESTORES MYOCARDIAL NOREPINEPHRINE LEVELS AND REVERSES VENTRICULAR SPECIFICITY OF SELECTED MARKERS IN HYPERTENSIVE RATS WITH HEART FAILURE INDUCED BY VOLUME OVERLOAD

Background and objective: Despite the known anti-hypertensive effect of renal denervation (RDN), its influence on the cardiac function, particularly of the right ventricle (RV) and the cardiac sympathetic nervous system in heart failure (HF) is poorly understood. This study aimed to investigate the effect of RDN on RV function, myocardial norepinephrine (NE), and left versus right ventricular (LV/RV) dominance of HF markers in HF induced by aorto-caval fistula (ACF). Methods: ACF was created in hypertensive Ren-2 transgenic rats. RDN was performed by phenol application. Cardiac function was measured by echocardiography and pressure-volume analysis. NE levels were measured using an ELISA kit, protein expression was assessed by western blotting, gene expression by TaqMan PCR assay, and ROS by Amplex Red assay. Results: RDN in ACF rats decreased RV hypertrophy and dilatation, decreased RV end-systolic pressure and end-diastolic pressure, improved RV function (Ees +45%, FAC +20%), decreased HF gene markers Nppa, Tgm2, Myh7/6 ratio, and increased SOD2 protein expression. RDN decreased plasmatic NE levels, increased NE in RV, and decreased monoamine oxidase (MAO-A) in RV. NE levels and SOD2 were more dominant in RV than LV in control (sham/intact) rats and ACF changed their specificity towards RV dominance, while RDN had no effect in these parameters in ACF on ventricular specificity. In sham/intact rats dominant for LV were hemodynamic parameters Ees, EDPVR, and molecular markers Mao-a, ROS production by MAO-A, Nppa, Myh7, Myh7/6 ratio, Tgm2, Uchl1, and Beta1/Chrm2 ratio. ACF changed the dominance of these selected markers from LV to RV. Interestingly, RDN reversed dominance back towards LV in gene markers Mao-a, Nppa, Myh7, Tgm2, Uchl1, and Beta1/Chrm2 ratio. Conclusions: RDN decreased RV ESP and EDP, improved RV systolic function, restored NE levels, decreased RV gene expression of selected HF markers, and reversed their RV/LV dominance, probably by reduction of central sympathetic nerve drive and alternations of the cardiac sympathetic nervous system.

Paternal exercise induces antioxidant defenses by α-Klotho/Keap1 pathways in the skeletal muscle of offspring exposed to a high fat-diet without changing telomere length

Although previous studies demonstrated that the ancestral lifestyle can enhance the metabolic health of offspring exposed to an obesogenic diet, the specific connections between these positive effects in redox state and telomere length are unknown. We investigated the impact of paternal resistance training (RT) on stress-responsive signaling and the pathways involved in telomere homeostasis in skeletal muscle. This investigation encompassed both the fathers and first-generation litter exposed to a long-term standard diet (24 weeks) and high fat diet (HFD). Wistar rats were randomized into sedentary or trained fathers (8 weeks of resistance training). The offspring were obtained by mating with sedentary females. Upon weaning, male offspring were divided into four groups: offspring of sedentary or trained fathers exposed to either a control diet or HFD. The gastrocnemius was prepared for reverse transcription-quantitative polymerase chain reaction, immunoblotting, ELISA, and electron paramagnetic resonance spectroscopy. RT upregulated shelterin mRNA levels and antioxidant protein, preserving muscle telomere in fathers. Conversely, HFD induced a disturbance in the redox balance, which may have contributed to the offspring telomere shortening from sedentary fathers. Preconceptional paternal RT downregulates Kelch-like ECH-associated protein 1 (Keap1) mRNA levels in the skeletal muscle of progeny exposed to HFD, driving an increase in Glutathione reductase mRNA levels, Sod1 and Catalase protein levels to mitigate ROS production. Also, paternal exercise upregulates α-Klotho protein levels, mediating antioxidative responses without altering shelterin mRNA levels and telomere length. We provide the first in-depth analysis that the offspring's redox state seems to be directly associated with the beneficial effects of paternal exercise.

Polyphenolic metacyclophane as a radical scavenger for therapeutic activation: a computational study

Modeling antioxidants for improved human health is a prime area of research. Inclusion complexes exhibit antioxidant activity. Supramolecular scaffolds like calixtyrosol are anticipated to have considerable antioxidant and therapeutic activity. In this study, we have designed 30 polyphenolic metacyclophanes and investigated their antioxidant properties. Exceptional O─H bond dissociation energy of 44 kcal/mol is reported for a metacyclophane with acyl urea linkage. This may be explained through a cooperative effect of localization of spin density distribution and an intramolecular hydrogen bonding of the corresponding radical. Further, the pharmacokinetics and toxicity analysis screened eight drug-like candidates. The interaction of the eight screened molecules with the Lysozyme transport protein and SOD protein has been studied using the molecular docking approach. Lastly, the MD simulations are performed to analyze the conformational changes of the transport protein after complexation with the proposed molecules. Comprehensive analyses including density functional studies of physiological parameters, favorable pharmacokinetics, toxicity, molecular docking, and MD simulations affirmed polyphenolic metacyclophane XXI as a radical scavenging and drug-like candidate.

Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by progressive axonopathy, jointly leading to the dying back of the motor neuron, disrupting both nerve signaling and motor control. In this review, we highlight the roles of axonopathy in ALS progression, driven by the interplay of multiple factors including defective trafficking machinery, protein aggregation, and mitochondrial dysfunction. Dysfunctional intracellular transport, caused by disruptions in microtubules, molecular motors, and adaptors, has been identified as a key contributor to disease progression. Aberrant protein aggregation involving TDP-43, FUS, SOD1, and dipeptide repeat proteins further amplifies neuronal toxicity. Mitochondrial defects lead to ATP depletion, oxidative stress, and Ca2+ imbalance, which are regarded as key factors underlying the loss of neuromuscular junctions and axonopathy. Mitigating these defects through interventions including neurotrophic treatments offers therapeutic potential. Collaborative research efforts aim to unravel ALS complexities, opening avenues for holistic interventions that target diverse pathological mechanisms.

Insights into Dysregulated Neurological Biomarkers in Cancer.

The link between neurodegenerative diseases (NDs) and cancer has generated greater interest in biomedical research, with decades of global studies investigating neurodegenerative biomarkers in cancer to better understand possible connections. Tau, amyloid-β, α-synuclein, SOD1, TDP-43, and other proteins associated with nervous system diseases have also been identified in various types of solid and malignant tumors, suggesting a potential overlap in pathological processes. In this review, we aim to provide an overview of current evidence on the role of these proteins in cancer, specifically examining their effects on cell proliferation, apoptosis, chemoresistance, and tumor progression. Additionally, we discuss the diagnostic and therapeutic implications of this interconnection, emphasizing the importance of further research to completely comprehend the clinical implications of these proteins in tumors. Finally, we explore the challenges and opportunities in targeting these proteins for the development of new targeted anticancer therapies, providing insight into how to integrate knowledge of NDs in oncology research.

Isorhamnetin Improves Oocyte Maturation by Activating the Pi3k/Akt Signaling Pathway.

Isorhamnetin is a natural flavonoid with various pharmacological activities, which can be widely and continuously ingested by humans and animals through their daily diet. The aim of this study is to explore the benefits and molecular mechanisms of isorhamnetin on oocyte maturation. Oocytes are incubated with isorhamnetin (5, 10, 20, and 30µM) for 44h. Isorhamnetin (10µM) increases the polar body extrusion rate of oocytes. Furthermore, isorhamnetin alleviates oxidative stress by inhibiting reactive oxygen species levels and stimulating SOD2 protein expression. The changes in intracellular mitochondrial autophagy and apoptosis-related proteins (Bcl-2, Bax/Bcl-2, and C-Casp3) indicate that isorhamnetin inhibits oocyte apoptosis. Isorhamnetin inhibits endoplasmic reticulum stress by reducing the protein expression of CHOP and GRP78 and improving the normal distribution rate of endoplasmic reticulum. Mechanistic studies show that isorhamnetin activates the PI3K/Akt signaling pathway. Isorhamnetin promotes oocyte maturation by inhibiting oxidative stress, mitochondrial dysregulation, apoptosis, and endoplasmic reticulum stress, which have important potential for improving oocyte quality and treating female infertility.

RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2-3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene lowering a promising approach, supported by preclinical data and the 2023 FDA approval of the GapmeR ASO targeting SOD1, tofersen. Despite the approval of an ASO and the optimism it brings to the field, the pharmacodynamics and pharmacokinetics of therapeutic SOD1 modulation can be improved. Here, we developed a chemically stabilized divalent siRNA scaffold (di-siRNA) that effectively suppresses SOD1 expression in vitro and in vivo. With optimized chemical modification, it achieves remarkable CNS tissue permeation and SOD1 silencing in vivo. Administered intraventricularly, di-siRNASOD1 extended survival in SOD1-G93A ALS mice, surpassing survival previously seen in these mice by ASO modalities, slowed disease progression, and prevented ALS neuropathology. These properties offer an improved therapeutic strategy for SOD1-mediated ALS and may extend to other dominantly inherited neurological disorders.

Molecular insights to in vitro biocompatibility of endodontic Pulpotec with macrophages determined by oxidative stress and apoptosis

Pulp therapy has been emerged as a one of the efficient therapies in the field of endodontics. Among different types of new endodontic materials, pulpotec has been materialized as a recognized material for vital pulp therapy. However, its efficacy has been challenged due to lack of information about its cellular biocompatibility. This study evaluates the mechanistic biocompatibility of pulpotec cement with macrophage cells (RAW 264.7) at cellular and molecular level. The biocompatibility was evaluated using experimental and computational techniques like MTT assay, oxidative stress analysis and apoptosis analysis through flow cytometry and fluorescent microscopy. The results showed concentration-dependent cytotoxicity of pulpotec cement extract to RAW 264.7 cells with an LC 50 of X/10-X/20. The computational analysis depicted the molecular interaction of pulpotec cement extract components with metabolic proteins like Sod1 and p53. The study revealed the effects of Pulpotec cement's extract, showing a concentration-dependent induction of oxidative stress and apoptosis. These effects were due to influential structural and functional abnormalities in the Sod1 and p53 proteins, caused by their molecular interaction with internalized components of Pulpotec cement. The study provided a detailed view on the utility of Pulpotec in endodontic applications, highlighting its biomedical aspects.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.