Mitochondrial Antioxidant Defense Research Articles

Cannabidiol Enhances Mitochondrial Metabolism and Antioxidant Defenses in Human Intestinal Epithelial Caco-2 Cells.

The reintroduction of hemp production has resulted in increased consumption of cannabidiol (CBD) products, particularly CBD oil, yet their effects on intestinal health are not fully understood. Proper mitochondrial function and antioxidant defenses are vital for maintaining the intestinal epithelial barrier. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC)1α are key mediators of mitochondrial metabolism. Using Caco-2 cells, we found that CBD oil promoted AMPK phosphorylation, upregulated differentiation markers, and enhanced PGC1α/SIRT3 mitochondrial signaling. CBD oil reduced reactive oxygen species production and increased antioxidant enzymes. Moreover, CBD oil also increased levels of citrate, malate, and succinate-key metabolites of the tricarboxylic acid cycle-alongside upregulation of pyruvate dehydrogenase and isocitrate dehydrogenase 1. Similarly, pure CBD induced metabolic and antioxidant signaling. CBD enhances mitochondrial metabolic activity and antioxidant defense in Caco-2 cells, making it a promising candidate for treating intestinal dysfunction.

Copper and Colorectal Cancer.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30-40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer.

Mitochondrial resilience and antioxidant defence against HIV-1: unveiling the power of Asparagus racemosus extracts and Shatavarin IV.

Asparagus racemosus (AR), an Ayurvedic botanical, possesses various biological characteristics, yet its impact on HIV-1 replication remains to be elucidated. This study aimed to investigate the inhibitory effects of AR root extracts and its principal bioactive molecule, Shatavarin IV (Shatavarin), on HIV-1 replication and their role in mitigating mitochondrial dysfunction during HIV-1 infection, utilizing both in vitro and in silico methodologies. The cytotoxicity of the extracts was evaluated using MTT and ATPlite assays. In vitro anti-HIV-1 activity was assessed in TZM-bl cells against X4 and R5 subtypes, and confirmed in peripheral blood mononuclear cells using HIV-1 p24 antigen capture ELISA and viral copy number assessment. Mechanistic insights were obtained through enzymatic assays targeting HIV-1 Integrase, Protease and Reverse Transcriptase. Shatavarin's activity was also validated via viral copy number and p24 antigen capture assays, along with molecular interaction studies against key HIV-1 replication enzymes. HIV-1 induced mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species (ROS), calcium accumulation, mitochondrial potential, and caspase activity within the infected cells. Non-cytotoxic concentrations of both aqueous and hydroalcoholic extracts derived from Asparagus racemosus roots displayed dose-dependent inhibition of HIV-1 replication. Notably, the hydroalcoholic extract exhibited superior Reverse Transcriptase activity, complemented by moderate activity observed in the Protease assay. Molecular interaction studies revealed that Shatavarin IV, the key bioactive constituent of AR, formed hydrogen bonds within the active binding pocket site residues crucial for HIV replication enzyme catalysis, suggesting its potential in attenuating HIV-1 infection. Mitochondrial dysfunction induced by HIV-1 infection, marked by increased oxidative stress, mitochondrial calcium overload, loss of mitochondrial membrane potential, and elevated caspase activity, was effectively mitigated by treatment with AR extracts and Shatavarin IV. These findings underscore the potential of AR extracts and Shatavarin IV as antiviral agents, while enhancing mitochondrial function during HIV-1 infection. In conclusion, Asparagus racemosus extracts, particularly Shatavarin IV, demonstrate promising inhibitory effects against HIV-1 replication while concurrently ameliorating mitochondrial dysfunction induced by the virus. These findings suggest the therapeutic potential of AR extracts and Shatavarin in combating HIV-1 infection and improving mitochondrial health.

Granulosa cell insight: unraveling the potential of menstrual blood-derived stem cells and their exosomes on mitochondrial mechanisms in polycystic ovary syndrome (PCOS)

BackgroundPolycystic ovary syndrome (PCOS) presents a significant challenge in women’s reproductive health, characterized by disrupted folliculogenesis and ovulatory dysfunction. Central to PCOS pathogenesis are granulosa cells, whose dysfunction contributes to aberrant steroid hormone production and oxidative stress. Mitochondrial dysfunction emerges as a key player, influencing cellular energetics, oxidative stress, and steroidogenesis. This study investigates the therapeutic potential of menstrual blood-derived stem cells (MenSCs) and their exosomes in mitigating mitochondrial dysfunction and oxidative stress in PCOS granulosa cells.MethodsUsing a rat model of PCOS induced by letrozole, granulosa cells were harvested and cultured. MenSCs and their exosomes were employed to assess their effects on mitochondrial biogenesis, oxidative stress, and estrogen production in PCOS granulosa cells.ResultsResults showed diminished mitochondrial biogenesis and increased oxidative stress in PCOS granulosa cells, alongside reduced estrogen production. Treatment with MenSCs and their exosomes demonstrated significant improvements in mitochondrial biogenesis, oxidative stress levels, and estrogen production in PCOS granulosa cells. Further analysis showed MenSCs' superior efficacy over exosomes, attributed to their sustained secretion of bioactive factors. Mechanistically, MenSCs and exosomes activated pathways related to mitochondrial biogenesis and antioxidative defense, highlighting their therapeutic potential for PCOS.ConclusionsThis study offers insights into granulosa cells mitochondria’s role in PCOS pathogenesis and proposes MenSCs and exosomes as a potential strategy for mitigating mitochondrial dysfunction and oxidative stress in PCOS. Further research is needed to understand underlying mechanisms and validate clinical efficacy, presenting promising avenues for addressing PCOS complexity.

Berberine Attenuates Acetamiprid Exposure-Induced Mitochondrial Dysfunction and Apoptosis in Rats via Regulating the Antioxidant Defense System.

Acetamiprid (ACMP) is a neonicotinoid insecticide that poses a significant threat to the environment and mankind. Oxidative stress and mitochondrial dysfunction are considered prime contributors to ACMP-induced toxic effects. Meanwhile, berberine (BBR) a natural plant alkaloid, is a topic of interest because of its therapeutic and prophylactic actions. Therefore, this study evaluated the effects of BBR on ACMP-mediated alterations in mitochondrial functions and apoptosis in rat liver tissue. Male Wistar rats were divided into four groups: (I) control, (II) BBR-treated, (III) ACMP-exposed, and (IV) BBR+ACMP co-treated groups. The doses of BBR (150 mg/kg b.wt) and ACMP (1/10 of LD50, i.e., 21.7 mg/kg b.wt) were given intragastrically for 21 consecutive days. The results showed that the administration of ACMP diminished mitochondrial complex activity, downregulated complex I (ND1 and ND2) and complex IV (COX1 and COX4) subunit mRNA expression, depleted the antioxidant defense system, and induced apoptosis in rat liver. BBR pre-treatment significantly attenuated ACMP-induced mitochondrial dysfunction by maintaining mitochondrial complex activity and upregulating ND1, ND2, COX1, and COX4 mRNA expression. BBR reversed ACMP-mediated apoptosis by diminishing Bax and caspase-3 and increasing the Bcl-2 protein level. BBR also improved the mitochondrial antioxidant defense system by upregulating mRNA expression of PGC-1α, MnSOD, and UCP-2 in rat liver tissue. This study is the first to evaluate the protective potential of BBR against pesticide-induced mitochondrial dysfunction in liver tissue. In conclusion, BBR offers protection against ACMP-induced impairment in mitochondrial functions by maintaining the antioxidant level and modulating the apoptotic cascade.

Gut microbiota-derived indole-3-propionic acid alleviates diabetic kidney disease through its mitochondrial protective effect via reducing ubiquitination mediated-degradation of SIRT1

IntroductionGut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown. ObjectivesThis study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD. MethodsMetagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury. ResultsAlterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin–proteasome degradation, restoring SIRT1′s role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense. ConclusionOur findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.

Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5’-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

Mitochondria-targeted antioxidant, mitoQ protects hepatic tissue from N-nitrosodiethylamine-induced damage by modulating mitochondrial function and redox status

BackgroundTargeting mitochondrial oxidative stress can be a promising strategy for the prevention of hepatocellular carcinoma (HCC). In the current study, we investigated the modulatory effect of mitochondria-targeted antioxidant, mitoQ against N-nitrosodiethylamine (NDEA)-induced hepatic damage in mouse. MethodsBALB/c mice were administered NDEA (10 mg/kg b. w., single dose, intraperitoneally) and the hepatoprotective effect of mitoQ was studied by administering mitoQ (0.125 mg/kg b. w., orally once a week) to the animals. The administration of mitoQ started two weeks prior the NDEA administration. The animals were sacrificed 24 h following NDEA administration after which the blood samples and hepatic tissues were collected. Serum was used for the estimation of liver injury markers and hepatic tissues were analyzed for histopathological changes, antioxidant defense status, mitochondrial functional status, level of mitochondrial reactive oxygen species (mtROS) and mitochondrial lipid peroxidation (mtLPO). ResultsMitoQ treatment to the NDEA-challenged group normalized liver injury markers, level of mtROS and mtLPO. MitoQ treatment also improved the status of mitochondrial antioxidant defense system, mitochondrial complex enzymes. ConclusionOur findings indicate that mito-Q significantly protected against NDEA-induced hepatic damage by modulating mitochondrial function and redox status which may be one of the causes of its purported chemopreventive effect.

Mitochondrial oxidative stress-mediated ferroptosis as a contributing factor of refrigerated beef tenderness: From mitochondrial biochemistry and proteomics perspective

This study aimed to investigate the mechanism of ferroptosis mediated by mitochondrial oxidative stress and its potential associations with tenderness of beef during refrigeration. Results showed that mitochondrial reactive oxygen species (ROS) reached a maximum at day 3 (116.67 ± 8.50 mg protein), the degree of mitochondrial swelling, mitochondrial membrane permeability increased with the increase of refrigeration time, and mitochondrial free iron content increased significantly (p < 0.05), while mitochondria showed the morphological features of ferroptosis. In addition, the decreased levels of reduced glutathione, total antioxidant capacity and the activity of glutathione peroxidase, and the accumulation of malondialdehyde reflected an imbalance in mitochondrial antioxidant defense system, presenting the physiological characteristics of ferroptosis. Furthermore, mitochondrial TMT quantitative proteomics identified 7 differentially expressed proteins (DEPs) enriched to the ferroptosis pathway, including ACSL1, LOC788801, ACSL4, PRNP, VDAC2, ACSL3 and LPCAT3, which were primarily involved in lipid metabolism pathway and were the major mitochondrial pathway involved in ferroptosis during beef refrigeration. Besides, ROS and lipid peroxidation from mitochondrial oxidative stress-mediated ferroptosis attacked tissue myofibril structure and increased myofibrillar fragmentation index, which promoted the improvement of postmortem meat tenderness. These findings provided new perspectives on the role of mitochondria in cell death and the effect of ferroptosis on muscle tenderization.

Cardiovascular and muscular plasticity in an endurance‐master athlete following 12 weeks of detraining and retraining: a case study

AbstractBackgroundThis study examined the cardiorespiratory and muscular adaptations of a 53‐year‐old endurance master athlete following 12 weeks of detraining and retraining.MethodsData were collected before and after detraining, and after retraining. Maximal oxygen uptake (VO2max) was evaluated during maximal cycling exercise. Proteins involved in muscle contraction, mitochondrial function and glycolysis were investigated using western blot analysis.ResultsVO2max decreased by 7% after detraining and was 5% greater than baseline after retraining. Detraining induced an important increase in the ryanodine receptor type 1 protein levels (RyR1, +44%) with a decrease in the protein levels of its stabilizer FKBP12 (−24%). We observed a 138% increase in the sarco‐endoplasmic reticulum ATPase 1 protein and a 42% increase in the myosin heavy chain fast‐twitch protein in response to detraining. This was associated with depressed levels of the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) proteins, while the expression of the mitochondrial dynamic proteins appeared stimulated. Twelve weeks of retraining reversed almost all the alterations observed in muscle proteins, but specifically increased mitochondrial biogenesis, OXPHOS and antioxidant defence proteins as well as the glucose transporter 4 (Glut‐4, +36%) and hexokinase (+100%) proteins levels above the baseline. The mitochondrial dynamic proteins were further increased with the retraining.ConclusionsThese data provide novel information on cardiorespiratory and muscular plasticity, suggesting that highly endurance‐trained athletes might show substantial muscular adaptations while retrained after a detraining period and call for more extensive clinical trials.

Climate change consequences on the systemic heart of female Octopus maya: oxidative phosphorylation assessment and the antioxidant system.

There is evidence that indicates that temperature modulates the reproduction of the tropical species Octopus maya, through the over- or under-expression of many genes in the brain. If the oxygen supply to the brain depends on the circulatory system, how temperature affects different tissues will begin in the heart, responsible for pumping the oxygen to tissues. The present study examines the impact of heat stress on the mitochondrial function of the systemic heart of adult O. maya. The mitochondrial metabolism and antioxidant defense system were measured in the systemic heart tissue of female organisms acclimated to different temperatures (24, 26, and 30°C). The results show that acclimation temperature affects respiratory State 3 and State 4o (oligomycin-induced) with higher values observed in females acclimated at 26°C. The antioxidant defense system is also affected by acclimation temperature with significant differences observed in superoxide dismutase, glutathione S-transferase activities, and glutathione levels. The results suggest that high temperatures (30°C) could exert physical limitations on the circulatory system through the heart pumping, affecting nutrient and oxygen transport to other tissues, including the brain, which exerts control over the reproductive system. The role of the cardiovascular system in supporting aerobic metabolism in octopus females is discussed.

2,4,6-trinitrotoluene causes mitochondrial toxicity in Caenorhabditis elegans by affecting electron transport

As a typical energetic compound widely used in military activities, 2,4,6-trinitrotoluene (TNT) has attracted great attention in recent years due to its heavy pollution and wide distribution in and around the training facilities, firing ranges, and demolition sites. However, the subcellular targets and the underlying toxic mechanism of TNT remain largely unknown. In this study, we explored the toxic effects of TNT biological reduction on the mitochondrial function and homeostasis in Caenorhabditis elegans (C. elegans). With short-term exposure of L4 larvae, 10–1000 ng/mL TNT reduced mitochondrial membrane potential and adenosine triphosphate (ATP) content, which was associated with decreased expression of specific mitochondrial complex involving gas-1 and mev-1 genes. Using fluorescence-labeled transgenic nematodes, we found that fluorescence expression of sod-3 (muls84) and gst-4 (dvls19) was increased, suggesting that TNT disrupted the mitochondrial antioxidant defense system. Furthermore, 10 ng/mL TNT exposure increased the expression of the autophagy-related gene pink-1 and activated mitochondrial unfolded protein response (mt UPR), which was indicated by the increased expression of mitochondrial stress activated transcription factor atfs-1, ubiquitin-like protein ubl-5, and homeobox protein dve-1. Our findings demonstrated that TNT biological reduction caused mitochondrial dysfunction and the development of mt UPR protective stress responses, and provided a basis for determining the potential risks of energetic compounds to living organisms.

Effects of chronic hydrogen peroxide exposure on mitochondrial oxidative stress genes, ROS production and lipid peroxidation in HL60 cells

Hydrogen peroxide (H2O2) is a reactive species that is also involved in the redox regulation of cells because of it is relative stability. In numerous pathological situations, a chronic increase in the production of reactive species is observed, which is related to oxidative stress and cellular damage. This study aimed to evaluate the effects of long-term exposure to different H2O2 concentrations on oxidative stress biomarkers and mitochondrial dynamics in HL60 cells. HL60 cells were treated with a sustained production (0.1, 1.0 and 10.0 nM/s) of H2O2 for one hour. H2O2 production and malondialdehyde (MDA) levels, as a lipid peroxidation marker, increased progressively in HL60 cells in accordance with higher H2O2 exposure, with significant differences between the 10 nM/s H2O2 group and the control and 0.1 nM/s groups. Similarly, progressive increased expression in genes related to the mitochondrial antioxidant defences and mitochondrial dynamics were also observed. Significantly increased gene expression in the 10 nM/s H2O2 with respect to the control group was observed for manganese superoxide dismutase (MnSOD), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG1α), nuclear respiratory factor 2 (Nrf2), mitochondrial transcription factor A (Tfam), mitofusins 1 and 2 (Mfn1 and Mfn2) and uncoupling protein 3 (UCP3), whereas no significant changes were observed in the cytochrome c oxidase subunit IV (COXIV) gene expression. In conclusion, exposure to different sustained production of H2O2 is related to a progressive increase in the gene expression of mitochondrial dynamics and redox processes in HL60 cells, but also to oxidative damage at higher H2O2 production levels.

Post-thaw sperm morphokinetics and mitochondrial genes profile of buck semen supplemented with selenium in two different forms

Background The quality characteristics of semen is a determinant factor for improving fertility of rabbit. Objectives The current investigation was done to evaluate post-thaw sperm morphokinetics and mitochondrial genes expression profile of buck semen supplemented with selenium in two different forms. Materials and methods Sexually mature bucks (n=16) that aged three months on average were used for collecting two ejaculates which were evaluated using computer assisted semen analysis (CASA) program. The semen samples of all experimental animals which recorded progressive motility greater than or equal to 70% were pooled for cryopreservation. The pooled semen was divided into three groups that were supplemented with selenium nanoparticles and selenium in normal form in addition to the control group. Morphological characteristics as well as CASA parameters were assessed after freezing for 1 week. Moreover, enzymatic activity assays were performed to measure the antioxidant capacity of cryopreserved buck semen. Transcriptional profile of mitochondrial activity and antioxidant defense regulating genes was conducted using quantitative real-time polymerase chain reaction (PCR). Results and conclusion The addition of selenium in normal and Nano forms has significantly (P ≤0.05) enhanced some of CASA parameters such as DCL (µm), DAP (µm), DSL (µm), VCL (µm/s), VAP (µm/s), Amplitude of lateral head (ALH) (µ), BCF (Hz), and VSL (µm/s) during prefreezing period compared with control group. Moreover, the data presented in the present study indicated a significant (P ≤0.05) improvement of post-thaw total and progressive sperm motility in the two groups supplemented with normal and Nano compared with control group. The post-thaw level of total antioxidant capacity (TAC) and percentage of live sperm were higher in the two groups supplemented with selenium and Nano selenium than the control group. The expression profile of candidate genes regulating mitochondrial activity (ATP Synthase F1 Subunit Alpha (ATP5A1), NADH dehydrogenase subunit1 (ND1), NADH dehydrogenase subunit2 (ND2), and Carnitine palmitoyltransferase (CPT2)) was increased significantly (P ≤0.05) in semen supplemented with selenium in normal and Nano forms compared with the control group. In conclusion, the data of this investigation demonstrated enhancement of CASA parameters during pre-freezing post thaw total and progressive sperm motility in the two groups supplemented with normal and nano selenium. The proportion of sperm viability and the level of total antioxidant capacity were enhanced in the two groups supplemented with selenium which was coupled with up-regulation of mitochondrial transcripts. It seems the both two forms shared the same mechanism on improving post-thaw physical and molecular qualities of rabbit sperm.

Copper and Melanoma Risk: Results from NHANES 2007-2018 and Mendelian Randomization Analyses.

Copper is an essential trace element obtained from food. There is a paucity of observational or prospective studies that have investigated the relationship between copper and melanoma risk. Copper serves as a cofactor for pivotal enzymes involved in mitochondrial respiration, antioxidant defense, and neurotransmitter synthesis. Undoubtedly, copper plays an indispensable role in the initiation and progression of tumors, particularly melanoma; however, further investigations are warranted to elucidate the underlying mechanisms linking copper and melanoma risk. Given the availability of dietary copper and serum copper data in the NHANES database, we conducted an investigation into the association between dietary copper intake and serum copper levels with melanoma risk. We enrolled 26,401 individuals with dietary copper data in the 2007-2018 NHANES database. To mitigate confounding variables, a propensity score matching (PSM) was performed. To assess the association between dietary copper intake and melanoma risk, we employed a multivariate logistic regression analysis before and after PSM. The restricted cubic spline analysis was utilized to determine whether there is a non-linear relationship between dietary copper intake and melanoma risk, with subgroup analysis conducted to determine beneficiaries. Then, those with blood copper data from the enrolled population with dietary copper intake were screened out, and subsequently, multivariate logistic regression models were subsequently constructed to investigate the association between serum copper levels and melanoma risk after PSM. Mendelian analysis was further utilized to validate the results of the NHANES database using serum copper as the exposure factor and melanoma as the outcome variable. The study found that melanoma risk was associated with dietary copper intake before and after PSM, demonstrated by multiple logistic regression. The relationship between dietary copper intake and melanoma risk was non-linear, with a reduced risk observed above approximately 2.5mg/day, as shown by the RCS. The evidence suggests that an increased intake of copper is linked to a decreased risk of melanoma. To clarify the mechanism behind the increased risk of melanoma due to higher dietary copper intake, we analyzed the population data from the NHANES database on serum copper and dietary copper intake. Our results indicated that there is no causal relationship between serum copper and melanoma risk. Mendelian randomization analysis of multi-database data sources confirmed the conclusion of the NHANES database analysis. Dietary copper is a protective factor against melanoma, and serum copper or blood copper is not associated with melanoma risk. This suggests that serum or blood copper is not responsible for the protective effect of dietary copper intake on melanoma risk, and the mechanisms need to be further investigated.

Cardiovascular and muscular plasticity in an endurance-master athlete following 12 weeks of detraining and retraining: A case study.

Introduction&#x0D; This study aimed at examining the cardiorespiratory and muscular adaptations following 12 weeks of detraining and retraining in a 53-year-old endurance master athlete.&#x0D; Methods&#x0D; Data were collected before and after detraining and after retraining. Maximal oxygen uptake (VO2max) was evaluated during maximal cycling exercise. Proteins involved in muscle contraction, mitochondrial function and glycolysis were investigated using western blot analysis.&#x0D; Results&#x0D; VO2max decreased by 7% after detraining and was 5% greater than baseline after retraining. Detraining induced an important increase in the ryanodine receptor type 1 protein levels (RyR1, +44%) with a decrease in the protein levels of its stabilizer FKBP12 (-24%). We observed a 138% increase in the sarco-endoplasmic reticulum ATPase 1 protein and a 42% increase in the myosin heavy chain fast-twitch protein in response to detraining, suggesting transformation towards a more glycolytic phenotype. This was associated with depressed levels of the mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) proteins, while the expression of the mitochondrial dynamic proteins appeared stimulated. Twelve weeks of retraining reversed almost all the alterations observed in muscle proteins, but specifically increased mitochondrial biogenesis, OXPHOS and antioxidant defense proteins as well as the glucose transporter 4 (Glut -4, +36%) and hexokinase (+100%) proteins levels compared to baseline. The mitochondrial dynamic proteins were further increased with the retraining.&#x0D; Discussion/Conclusion&#x0D; These data provide novel information on cardiorespiratory and muscular plasticity suggesting that highly endurance-trained athletes might show substantial muscular adaptations while retrained after a detraining period and call for more extensive clinical trials.

Role of Mitochondrial ROS for Calcium Alternans in Atrial Myocytes.

Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation-contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS production is enhanced during CaT alternans, measured by fluorescence microscopy. Exogenous ROS (tert-butyl hydroperoxide) enhanced CaT alternans, whereas ROS scavengers (dithiothreitol, MnTBAP, quercetin, tempol) alleviated CaT alternans. While the inhibition of cellular NADPH oxidases had no effect on CaT alternans, interference with mitochondrial ROS (ROSm) production had profound effects: (1) the superoxide dismutase mimetic MitoTempo diminished CaT alternans and shifted the pacing threshold to higher frequencies; (2) the inhibition of cyt c peroxidase by SS-31, and inhibitors of ROSm production by complexes of the electron transport chain S1QEL1.1 and S3QEL2, decreased the severity of CaT alternans; however (3) the impairment of mitochondrial antioxidant defense by the inhibition of nicotinamide nucleotide transhydrogenase with NBD-Cl and thioredoxin reductase-2 with auranofin enhanced CaT alternans. Our results suggest that intact mitochondrial antioxidant defense provides crucial protection against pro-arrhythmic CaT alternans. Thus, modulating the mitochondrial redox state represents a potential therapeutic approach for alternans-associated arrhythmias, including AF.

Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system

Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in β-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves β-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves β-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved β-cell function and survival under high-glucose conditions via the glutathione redox balance.

Advances in exercise to alleviate sarcopenia in older adults by improving mitochondrial dysfunction.

Sarcopenia is a chronic degenerative disease affecting primarily older adults. A growing aging population is gradually increasing the number of patients suffering from sarcopenia, placing increasing financial pressure on patients' families and society in general. There is a strong link between mitochondrial dysfunction and sarcopenia pathogenesis. As a result, treating sarcopenia by improving mitochondrial dysfunction is an effective strategy. Numerous studies have demonstrated that exercise has a positive effect on mitochondrial dysfunction when treating sarcopenia. Exercise promotes mitochondrial biogenesis and mitochondrial fusion/division to add new mitochondria or improve dysfunctional mitochondria while maintaining mitochondrial calcium homeostasis, mitochondrial antioxidant defense system, and mitochondrial autophagy to promote normal mitochondrial function. Furthermore, exercise can reduce mitochondrial damage caused by aging by inhibiting mitochondrial oxidative stress, mitochondrial DNA damage, and mitochondrial apoptosis. Exercise effectiveness depends on several factors, including exercise duration, exercise intensity, and exercise form. Therefore, Moderate-intensity exercise over 4weeks potentially mitigates sarcopenia in older adults by ameliorating mitochondrial dysfunction. HIIT has demonstrated potential as a viable approach to addressing sarcopenia in aged rats. However, further investigation is required to validate its efficacy in treating sarcopenia in older adults.

Nicotinamide enhances osteoblast differentiation through activation of the mitochondrial antioxidant defense system

Although the normal physiological level of oxidative stress is beneficial for maintaining bone homeostasis, imbalance between reactive oxygen species (ROS) production and antioxidant defense can cause various bone diseases. The purpose of this study was to determine whether nicotinamide (NAM), an NAD+ precursor, can support the maintenance of bone homeostasis by regulating osteoblasts. Here, we found that NAM enhances osteoblast differentiation and mitochondrial metabolism. NAM increases the expression of antioxidant enzymes, which is due to increased FOXO3A transcriptional activity via SIRT3 activation. NAM has not only a preventive effect against weak and chronic oxidative stress but also a therapeutic effect against strong and acute exposure to H2O2 in osteoblast differentiation. Collectively, the results indicate that NAM increases mitochondrial biogenesis and antioxidant enzyme expression through activation of the SIRT3-FOXO3A axis, which consequently enhances osteoblast differentiation. These results suggest that NAM could be a potential preventive or therapeutic agent for bone diseases caused by ROS.