The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of antioxidant responses in mammals, where it plays a critical role in detoxification, maintaining cellular homeostasis, combating inflammation and fibrosis, and slowing disease progression. Kelch-like ECH-associated protein 1 (Keap1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, serves as a critical sensor of oxidative and electrophilic stress, regulating Nrf2 activity by sequestering it in the cytoplasm, leading to its proteasomal degradation and transcriptional repression. However, the clinical potential of targeting the Keap1-dependent Nrf2 regulatory pathway has been limited. This is evidenced by early postnatal lethality in Keap1 knockout mice, as well as significant adverse events after pharmacological blockade of Keap1 in human patients with Alport syndrome as well as in those with type 2 diabetes mellitus and chronic kidney disease. The exact underlying mechanisms remain elusive, but may involve non-specific and systemic activation of the Nrf2 antioxidant response in both injured and normal tissues. Beyond Keap1-dependent regulation, Nrf2 activity is modulated by Keap1-independent mechanisms, including transcriptional, epigenetic, and post-translational modifications. In particular, GSK3β has emerged as a critical convergence point for these diverse signaling pathways. Unlike Keap1-dependent regulation, GSK3β-mediated Keap1-independent Nrf2 regulation does not affect basal Nrf2 activity but modulates its response at a delayed/late phase of cellular stress. This allows fine-tuning of the inducibility, magnitude, and duration of the Nrf2 response specifically in stressed or injured tissues. As one of the most metabolically active organs, the kidney is a major source of production of reactive oxygen and nitrogen species and also a vulnerable organ to oxidative damage. Targeting the GSK3β-mediated Nrf2 regulatory pathway represents a promising new approach for the treatment of kidney disease.

Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.

While the antioxidative potential of certain vitamins and minerals in cardio-protection has garnered increasing interest, their ability to attenuate associations between air pollution exposure and cardiometabolic diseases (CMDs) remains unexplored. This study examined the associations of air pollution (particulate matter including ultrafine particles (UFP), and nitrogen oxides, including NO2 and NOx) and six dietary antioxidants with incident non-fatal CMDs in 30,519 EPIC-NL study participants. Data on CMD incidence (total cardiovascular disease (CVD), acute myocardial infarction (AMI), coronary heart disease (CHD) and heart failure (HF)) and Type 2 Diabetes Mellitus (T2DM) diagnoses were obtained from medical registries. Annual average ambient concentrations of air pollutants at the participants' baseline residential addresses were predicted using land use regression models. Dietary intake of antioxidants was assessed via a food frequency questionnaire. Multivariable Cox regression models were used to explore associations. Exposures to NO2 and UFP were associated with elevated HF risk (Hazard Ratio (HR) (95 % CI): 1.24 (1.00, 1.54) and 1.69 (1.04, 2.76), respectively). Higher beta-carotene intake was associated with reduced risk of total CVD and CHD incidence (HR (95 % CI): 0.94 (0.89, 0.99) and 0.92 (0.84, 0.99), respectively), whereas, in general, antioxidant intake was positively associated with incident T2DM. Interaction analyses indicated some variability in CMD risk by antioxidant intake, but none of these interactions remained significant after correcting for multiple comparisons. These findings indicate that the associations of air pollution with incident CMD do not differ by dietary antioxidant intake.

This study aims to elucidate the effects of oral nutritional supplements on inflammatory factors and antioxidant status in patients undergoing hemodialysis through a meta-analysis of previous research.

This study conducted literature databases from inception to November 2024, including PubMed, Embase, Cochrane, Wanfang, and China National Knowledge Infrastructure (CNKI), to identify all published randomized controlled trials assessing the impact of oral nutritional supplementation on inflammation and oxidative stress in patients on maintenance hemodialysis. Heterogeneity was assessed using the Chi-square test. Subgroup analyses and sensitivity analyses were performed to explore the sources of heterogeneity. Publication bias was evaluated using funnel plots and the Egger test.

Supplementation with unsaturated fatty acids did not significantly affect serum CRP levels in patients undergoing hemodialysis (MD = - 0.93, 95% CI [- 2.53, 0.68], Z = 1.13, P = 0.26). The total antioxidant capacity in the antioxidant group was higher than that in the control group (MD = 0.09, 95% CI [0.05, 0.14], Z = 4.41, P < 0.0001). The MDA levels in the antioxidant group were lower than those in the control group (MD = - 2.28, 95% CI [- 2.75, - 1.80], Z = 9.42, P < 0.0001), while the difference in IL-6 levels between the antioxidant group and the control group was not statistically significant (MD = - 0.10, 95% CI [- 0.56, 0.36], Z = 0.41, P = 0.68).

Unsaturated fatty acids do not have a significant effect on serum CRP levels in patients undergoing hemodialysis. The antioxidants (vitamin E and polyphenols) can enhance the antioxidant capacity and reduce MDA levels in these patients; however, their impact on IL-6 levels is not significant. Further high-quality randomized controlled trials are needed to validate these conclusions.

The presence of a substantial necrotic core in atherosclerotic plaques markedly heightens the risk of rupture, a consequence of elevated iron levels that exacerbate oxidative stress and lipid peroxidation, thereby sustaining a detrimental cycle of ferroptosis and inflammation. Concurrently targeting both ferroptosis and inflammation is crucial for the effective treatment of vulnerable plaques. In this study, we introduce gallium hexacyanoferrate nanoabsorption catalysts (GaHCF NACs) designed to disrupt this pathological cycle. GaHCF NACs function as highly efficient iron chelators with robust antiferroptosis properties. Through in situ capture of iron within atherosclerotic plaques, these catalysts enhance reactive oxygen species scavenging, initiating an amplified therapeutic response. GaHCF NACs significantly advance plaque regression, stabilization, and vascular functional recovery by inhibiting MAPK13 (p38-δ MAPK) signaling, a key mediator of inflammation and cell death. Importantly, the in situ iron capture process generates a detectable photoacoustic signal, offering a notable diagnostic advantage that allows real-time monitoring of plague status. This multifunctional nanocatalytic platform in situ transforms toxic iron within atherosclerotic plaques into both a therapeutic and diagnostic agent, adapting dynamically to the microenvironment and representing a promising strategy for reducing plaque vulnerability and preventing rupture.

The balance of redox states is crucial for maintaining physiological homeostasis. For decades, the focus has been mainly on the concept of oxidative stress, which is involved in the mechanism of almost all diseases. However, robust evidence has highlighted that reductive stress, the other side of the redox spectrum, plays a pivotal role in the development of various diseases, particularly those related to metabolism and cardiovascular health.

In this review, we present an extensive array of evidence for the occurrence of reductive stress and its significant implications mainly in metabolic and cardiovascular diseases.

Reductive stress is defined as a shift in the cellular redox balance towards a more reduced state, characterized by an excess of endogenous reductants (such as NADH, NADPH, and GSH) over their oxidized counterparts (NAD+, NADP+, and GSSG). While oxidative stress has been the predominant mechanism studied in obesity, metabolic disorders, and cardiovascular diseases, growing evidence underscores the critical role of reductive stress. This review discusses how reductive stress contributes to metabolic and cardiovascular pathologies, emphasizing its effects on key cellular processes. For example, excessive NADH accumulation can disrupt mitochondrial function by impairing the electron transport chain, leading to decreased ATP production and increased production of reactive oxygen species. In the endoplasmic reticulum (ER), an excess of reductive equivalents hampers protein folding, triggering ER stress and activating the unfolded protein response, which can lead to insulin resistance and compromised cellular homeostasis. Furthermore, we explore how excessive antioxidant supplementation can exacerbate reductive stress by further shifting the redox balance, potentially undermining the beneficial effects of exercise, impairing cardiovascular health, and aggravating metabolic disorders, particularly in obese individuals. This growing body of evidence calls for a reevaluation of the role of reductive stress in disease pathogenesis and therapeutic interventions.

Inflammaging refers to chronic, low-grade inflammation that becomes more common with age and plays a central role in the pathophysiology of various vascular diseases. Key inflammatory mediators involved in inflammaging contribute to endothelial dysfunction and accelerate the progression of atherosclerosis. In addition, specific pathological mechanisms and the role of inflammasomes have emerged as critical drivers of immune responses within the vasculature. A comprehensive understanding of these processes may lead to innovative treatment strategies that could significantly improve the management of age-related vascular diseases. Emerging therapeutic approaches, including cytokine inhibitors, senolytics, and specialized pro-resolving mediators, aim to counteract inflammaging and restore vascular health. This review seeks to provide an in-depth exploration of the molecular pathways underlying vascular inflammaging and highlight potential therapeutic interventions.

The very high energy demand of the heart is primarily met by adenosine triphosphate (ATP) production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure [including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved EF (HFpEF), and diabetic cardiomyopathies] is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signalling and post-translational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.

Prostate cancer (PCa), a highly prevalent cancer in men worldwide, is projected to rise in the coming years. As emerging data indicate the carcinogenic effects of fine particulate matter (PM2.5) in lung cancer and other site-specific cancers, there is an urgent need to evaluate the relationship between this environmental risk factor and PCa as a potential target for intervention. The present review provides up-to-date evidence about the impact of airborne PM2.5 pollution on the initiation and progression of PCa. Examining the composition and characteristics of PM2.5 reveals its ability to induce toxic effects, inflammatory injuries, and oxidative damages. Additionally, PM2.5 can attach to endocrine-disrupting chemicals implicated in prostatic carcinogenesis. Considering the potential significance of oxidative stress in the risk of the disease, our review underlines the protective strategies, such as antioxidant-based approaches, for individuals exposed to increased PM2.5 levels. Moreover, the findings call for further research to understand the associations and mechanisms linking PM2.5 exposure to PCa risk as well as to suggest appropriate measures by policymakers, scientific researchers, and healthcare professionals in order to address this global health issue.

Epidemiological evidence indicates that trace elements are significantly associated with cardiovascular health. However, its causality and underlying mechanisms remain unclear. Therefore, this study aimed to investigate the causal relationship between trace elements and cardiovascular disease, as well as their potential mechanism of action.

Two-sample Mendelian randomization (MR) analyses along with mediated and multivariate MR analyses were employed. These analyses utilized 13 trace elements as exposure variables and 20 cardiovascular diseases as outcome variables, with 4907 circulating plasma proteins, 1400 serum metabolites, 731 immune cell phenotypes, and 473 intestinal flora as potential mediators. The Bayesian weighted MR method was used to validate the MR results, and linkage disequilibrium score regression (LDSC) was applied to explore the genetic correlation between trace elements and cardiovascular disease.

Our findings indicated a positive or negative causal relationship between genetically predicted trace elements and cardiovascular disease. An analysis using the Bayesian weighted MR method demonstrated that our causal inference results were reliable. The results of the mediated MR analyses indicate that potassium may reduce the risk of ischemic heart disease by influencing the expression of the plasma proteins BDH2 and C1R. Vitamin B12 may increase the risk of coronary atherosclerosis and cardiovascular death by reducing the levels of VPS29 and PSME1 proteins, while vitamin C may mitigate the risk of cardiac arrest by inhibiting the expression of the TPST2 protein. In addition, potassium can reduce the risk of ischemic heart disease by lowering 4-methoxyphenyl sulfate levels. None of the instrumental variables exhibited pleiotropy in the MR analysis. A sensitivity analysis using the leave-one-out method further confirmed the robustness of our findings. LDSC results indicated a genetic correlation between multiple trace elements and various cardiovascular diseases.

This study uncovered the true causal relationship between trace elements and cardiovascular disease risk using genetic methods, and revealed the significant mediating role of specific plasma proteins and metabolites in this relationship.

Natural forms of vitamin E include four tocopherols and four tocotrienols (α, β, γ, and δ), which are essential as lipophilic antioxidants. Among these eight isoforms, α-tocopherol (αT), the predominant form of vitamin E found in tissues, has traditionally received the most attention in disease prevention research due to its robust antioxidant activity. However, recent studies suggest that other forms of vitamin E exhibit distinct and potentially more potent beneficial activities in disease prevention and treatment. These non-αT forms of vitamin E are metabolized in vivo, producing various metabolites, including 13'-carboxychromanol, though their biological roles remain largely unknown. Notably, sphingolipids, known for their significant roles in cancer biology, may be involved in the anticancer effects of vitamin E through the modulation of sphingolipid metabolism. This review focuses on the diverse biological activities of different vitamin E forms and their metabolites, particularly their anticancer effects, while highlighting the underlying mechanisms, including their novel impact on regulating sphingolipid pathways. By elucidating these interactions, we aim to provide a deeper understanding on the multifaceted roles of vitamin E in cancer prevention and therapy.

Urinary 8-hydroxydeoxyguanosine (8-OHdG) level is an oxidative stress marker in patients with cancer; however, little is currently known about the clinical relevance of urinary 8-OHdG levels in patients with prostate cancer at diagnosis. Voided urine samples were collected from patients at the time of prostate biopsy and stored at -80˚C after centrifugation. All of the patients were classified according to histology of the biopsy. Once the patients were diagnosed with prostate cancer, the standard of care and treatments were administered according to the standard guidelines. The association between clinicopathological parameters and urinary 8-OHdG and N-terminal telopeptide (NTx) levels were explored. A total of 409 patients received prostate biopsy, of which 190 were benign, 41 were diagnosed with prostatitis and 178 were diagnosed with prostate cancer. The urinary 8-OHdG/creatinine ratio was marginally associated with prostate size (P=0.052) but not with serum prostate-specific antigen levels (P=0.707). With correction for prostate size, the ratio of urinary 8-OHdG/creatinine was significantly higher in patients with prostate cancer than those without malignancy (P=0.004). Moreover, urinary 8-OHdG levels were weakly associated with urinary NTx levels (r2=0.04, P=0.009). In conclusion, urinary 8-OHdG levels normalized for prostate volume may reflect prostate cancer risk and could be used to predict prostate cancer aggressiveness.

Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS-MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5-2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting.

In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function. The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues. In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.

The association between vitamin E and the risk of kidney disease is well documented in observational studies, but the role of vitamin E in kidney disease remain inconclusive. Here, we evaluated the causal effect of vitamin E on the risk of multiple kidney diseases, including chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis.

We conducted a two-sample Mendelian randomization analysis from large-scale trans-ancestry genome-wide association studies to determine whether there was a significant causal relationship between vitamin E and multiple kidney diseases in European, American, and Asian ancestry. Instrumental genetic variants associated with vitamin E were selected, and summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were conducted. Pleiotropy and sensitivity were assessed.

We obtained 87 instrumental genetic variants in European ancestry and found no causal relationship between vitamin E and chronic kidney disease, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and dialysis with no heterogeneity and pleiotropy. We obtained 18 instrumental genetic variants in Asian ancestry and vitamin E had no causal relationship with membranous nephropathy, diabetic nephropathy, and IgA nephropathy with no heterogeneity and pleiotropy. In African ancestry, 25 instrumental genetic variants were obtained and no causal relationship was identified with no heterogeneity and pleiotropy.

Our study first suggested plausible non-causal associations between vitamin E and multiple kidney diseases among different ancestry.

Vitamins are known to affect the regulation of several biochemical and metabolic pathways that influence cellular function. Adequate amounts of both hydrophilic and lipophilic vitamins are required for maintaining normal cardiac and vascular function, but their deficiencies can contribute to cardiovascular abnormalities. In this regard, a deficiency in the lipophilic vitamins, such as vitamins A, D, and E, as well as in the hydrophilic vitamins, such as vitamin C and B, has been associated with suboptimal cardiovascular function, whereas additional intakes have been suggested to reduce the risk of atherosclerosis, hypertension, ischemic heart disease, arrhythmias, and heart failure. Here, we have attempted to describe the association between low vitamin status and cardiovascular disease, and to offer a discussion on the efficacy of vitamins. While there are inconsistencies in the impact of a deficiency in vitamins on the development of cardiovascular disease and the benefits associated with supplementation, this review proposes that specific vitamins may contribute to the prevention of cardiovascular disease in individuals at risk rather than serve as an adjunct therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the main cause of chronic liver disease in children and adolescents. Indeed, epidemiological studies have shown that MASLD affects up to 40% of children with obesity. Despite the recent approval of medications that target weight loss in adolescents that could have benefits on pediatric MASLD, lifestyle interventions, such as diet and exercise, remain the mainstay of our therapeutic approach. More specifically, studies on diet alone have focused on the possible role of carbohydrate or fat restriction, albeit without a definite answer on the best approach. Weight loss after dietary intervention in children with obesity and MASLD has a beneficial effect, regardless of the diet used. In relation to the role of exercise in MASLD reversal, indirect evidence comes from studies showing that a sedentary lifestyle leading to poor fitness, and low muscle mass is associated with MASLD. However, research on the direct effect of exercise on MASLD in children is scarce. A combination of diet and exercise seems to be beneficial with several studies showing improvement in surrogate markers of MASLD, such as serum alanine aminotransferase and hepatic fat fraction, the latter evaluated with imaging studies. Several dietary supplements, such as vitamin E, probiotics, and omega-3 fatty acid supplements have also been studied in children and adolescents with MASLD, but with equivocal results. This review aims to critically present available data on the effects of lifestyle interventions, including diet, exercise, and dietary supplements, on pediatric MASLD, thus suggesting a frame for future research that could enhance our knowledge on pediatric MASLD management and optimize clinicians' approach to this vexing medical condition.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for vitamin E. As α-tocopherol is recognised as the only essential form of vitamin E, the Panel restricted its evaluation to α-tocopherol. Systematic reviews of the literature were conducted to assess evidence on priority adverse health effects of excess intake of vitamin E, namely risk of impaired coagulation and bleeding, cardiovascular disease and prostate cancer. The effect on blood clotting and associated increased risk of bleeding is considered as the critical effect to establish an UL for vitamin E. No new evidence has been published that could improve the characterisation of a dose-response. The ULs for vitamin E from all dietary sources, which were previously established by the Scientific Committee on Food, are retained for all population groups, i.e. 300 mg/day for adults, including pregnant and lactating women, 100 mg/day for children aged 1-3 years, 120 mg/day for 4-6 years, 160 mg/day for 7-10 years, 220 mg/day for 11-14 years and 260 mg/day for 15-17 years. A UL of 50 mg/day is established for infants aged 4-6 months and a UL of 60 mg/day for infants aged 7-11 months. ULs apply to all stereoisomeric forms of α-tocopherol. ULs do not apply to individuals receiving anticoagulant or antiplatelet medications (e.g. aspirin), to patients on secondary prevention for CVD or to patients with vitamin K malabsorption syndromes. It is unlikely that the ULs for vitamin E are exceeded in European populations, except for regular users of food supplements containing high doses of vitamin E.

Obstructive sleep apnea (OSA) is a common clinical problem that is associated with adverse cardiovascular outcomes attributed to the oxidative stress due to sympathetic overstimulation. Treatment approaches targeting oxidative stress have been tried by multiple investigators. This systematic review and meta-analysis evaluated the efficacy and safety of such approaches.

Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA.

A total of six studies (five randomized trials and one case-control study) were included, including 160 patients with OSA using N-acetyl cysteine, vitamin C, carbocysteine, superoxide dismutase, vitamin E, allopurinol, and their combinations. There was a significant improvement in flow-mediated dilatation (FMD) following antioxidants, with the pooled effect being 2.16 % (95% CI 1.65-2.67) using the random-effects model (I2 = 0% and p<0.001). It was also associated with a significant reduction in malondialdehyde levels and an increase in reduced glutathione (GSH) levels. There was also a significant improvement in the Epworth sleepiness scale, oxygen desaturation index, and minimum oxygen saturation during sleep without any significant adverse effects.

Antioxidant therapy in patients with OSA is associated with improved endothelial function, reduced oxidative stress, and improved sleep parameters. These results call for future multicentre studies with longer follow-ups to assess the utility of antioxidant therapy in patients with OSA.

The vitamin E family contains α-tocopherol (αT), βT, γT, and δT and α-tocotrienol (TE), βTE, γTE, and δTE. Research has revealed distinct roles of these vitamin E forms in prostate cancer (PCa). The ATBC trial showed that αT at a modest dose significantly decreased PCa mortality among heavy smokers. However, other randomized controlled trials including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) indicate that supplementation of high-dose αT (≥400 IU) does not prevent PCa among nonsmokers. Preclinical cell and animal studies also do not support chemopreventive roles of high-dose αT and offer explanations for increased incidence of early-stage PCa reported in the SELECT. In contrast, accumulating animal studies have demonstrated that γT, δT, γTE, and δTE appear to be effective for preventing early-stage PCa from progression to adenocarcinoma in various PCa models. Existing evidence also support therapeutic roles of γTE and its related combinations against advanced PCa. Mechanistic and cell-based studies show that different forms of vitamin E display varied efficacy, that is, δTE ≥ γTE > δT ≥ γT >> αT, in inhibiting cancer hallmarks and enabling characteristics, including uncontrolled cell proliferation, angiogenesis, and inflammation possibly via blocking 5-lipoxygenase, nuclear factor κB, hypoxia-inducible factor-1α, modulating sphingolipids, and targeting PCa stem cells. Overall, existing evidence suggests that modest αT supplement may be beneficial to smokers and γT, δT, γTE, and δTE are promising agents for PCa prevention for modest-risk to relatively high-risk population. Despite encouraging preclinical evidence, clinical research testing γT, δT, γTE, and δTE for PCa prevention is sparse and should be considered.

There is a "popular" belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their "harmful" effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically "inactive" organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the "pathogenic" role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.

Cardiovascular diseases (CVD) are the leading cause of death worldwide. From this perspective, the role of vitamin E and its metabolites in preventing CVD has been studied, being supported by the findings that low vitamin E concentrations are associated with an increased risk of cardiovascular events. Despite this, no studies have analysed the co-existence of vitamin E deficiency (VED) and CVD on the basis of population studies. Facing that, this study summarises information on the relationship between vitamin E status and CVD, providing a basis for understanding the determining and protective factors for its development. VED may be a public health problem since it has been observed to vary from 0·6% to 55·5% worldwide, with higher percentages in Asia and Europe, where CVD mortality rates stand out. Intervention studies with α-tocopherol supplementation do not confirm cardioprotective action of vitamin E, which may reflect that α-tocopherol alone does not provide cardiovascular protection to individuals, but the consumption of all isomers found in food. Considering that low concentrations of α-tocopherol can lead to a higher susceptibility to diseases involving oxidative stress in the population, in addition to the high and growing prevalence of CVD and VED, it is essential to investigate or reinterpret the mechanisms of action of vitamin E and its metabolites in the cardiovascular process to better understand the co-existence of CVD and VED. It is also important to implement public health policies and programmes aimed at promoting the consumption of natural food sources of vitamin E and healthy fats.

Dry eye disease (DED) represents a prevalent ocular surface disease. The development of effective nutritional management strategies for DED is crucial due to its association with various factors such as inflammation, oxidative stress, deficiencies in polyunsaturated fatty acids (PUFAs), imbalanced PUFA ratios, and vitamin insufficiencies. Extensive research has explored the impact of oral nutritional supplements, varying in composition and dosage, on the symptoms of DED. The main components of these supplements include fish oils (Omega-3 fatty acids), vitamins, trace elements, and phytochemical extracts. Beyond these well-known nutrients, it is necessary to explore whether novel nutrients might contribute to more effective DED management. This review provides a comprehensive update on the therapeutic potential of nutrients and presents new perspectives for combination supplements in DED treatment.

The excessive production of various reactive oxidant species over endogenous antioxidant defense mechanisms leads to the development of a state of oxidative stress, with serious biological consequences. The consequences of oxidative stress depend on the balance between the generation of reactive oxidant species and the antioxidant defense and include oxidative damage of biomolecules, disruption of signal transduction, mutation, and cell apoptosis. Accumulating evidence suggests that oxidative stress is involved in the physiopathology of various debilitating illnesses associated with chronic inflammation, including cardiovascular diseases, diabetes, cancer, or neurodegenerative processes, that need continuous pharmacological treatment. Oxidative stress and chronic inflammation are tightly linked pathophysiological processes, one of which can be simply promoted by another. Although, many antioxidant trials have been unsuccessful (some of the trials showed either no effect or even harmful effects) in human patients as a preventive or curative measure, targeting oxidative stress remains an interesting therapeutic approach for the development of new agents to design novel anti-inflammatory drugs with a reliable safety profile. In this regard, several natural antioxidant compounds were explored as potential therapeutic options for the treatment of chronic inflammatory diseases. Several metalloenzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, are among the essential enzymes that maintain the low nanomolar physiological concentrations of superoxide (O2•-) and hydrogen peroxide (H2O2), the major redox signaling molecules, and thus play important roles in the alteration of the redox homeostasis. These enzymes have become a striking source of motivation to design catalytic drugs to enhance the action of these enzymes under pathological conditions related to chronic inflammation. This review is focused on several major representatives of natural and synthetic antioxidants as potential drug candidates for the treatment of chronic inflammatory diseases.

The intricate relationship between cancer and cardiovascular diseases (CVD), notably heart failure (HF), is gaining attention in the medical field. This literature review explores the intricate interplay between cancer and CVD, particularly HF, emphasizing their significant impact on global mortality and comorbidity. While preventive measures have contributed to reducing their incidence, challenges persist in predicting and managing cancer-related complications. This review article delves into various risk factors associated with both cancer and HF, including lifestyle factors, genetic predispositions, and immune system dysregulation. It highlights emerging evidence suggesting a direct interaction between cancer and HF, with studies indicating an elevated risk of mortality from cancer in patients with HF and vice versa. Pathological mechanisms such as inflammation, oxidative stress, and tissue hypoxia are implicated in cancer-induced cardiac dysfunction, underscoring the need for comprehensive clinical investigations and ethical considerations in patient care. The review also discusses the potential role of biomarkers in risk assessment, early detection of cardiotoxicity, and understanding common pathophysiological links between cancer and HF, paving the way for multifaceted preventive and therapeutic approaches.

Endometriosis (EMT) a common gynecological condition in women, an inflammatory disease characterized by the presence of endometrial tissue on organs and tissues in the pelvis, and is mainly associated with chronic pelvic pain and infertility. As the etiology has not been fully elucidated, current treatment is limited to surgery, hormones and painkillers, with more side effects and difficulty in achieving long-term relief. Oxidative stress manifests itself as an overproduction of reactive oxygen species, which has an integral impact in the pathology of female reproductive disorders. In this review, we evaluate the mechanisms of iron overload-induced oxidative stress and ferroptosis in EMT and their pathophysiological implications.

Because the etiology has not been fully elucidated, current treatments are limited to surgery, hormones, and painkillers, which have many side effects and are difficult to achieve long-term relief.

We interpreted that antioxidants as well as ferroptosis inducers show promising results in the treatment of EMT, but their application in this population needs to be further investigated.

In combination with the interpretation of previous studies, it was shown that iron overload is present in the peritoneal fluid, endometriotic lesions, peritoneum and macrophages in the abdominal cavity. However, the programmed cellular ferroptosis associated with iron overload is resisted by endometriotic foci, which is critical to the pathophysiology of EMT with local iron overload and inflammation.

Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.

All vitamins play essential roles in various aspects of body function and systems. Patients with chronic kidney disease (CKD), including those receiving dialysis, may be at increased risk of developing vitamin deficiencies due to anorexia, poor dietary intake, protein energy wasting, restricted diet, dialysis loss, or inadequate sun exposure for vitamin D. However, clinical manifestations of most vitamin deficiencies are usually subtle or undetected in this population. Testing for circulating levels is not undertaken for most vitamins except folate, B12, and 25-hydroxyvitamin D because assays may not be available or may be costly to perform and do not always correlate with body stores. The last systematic review through 2016 was performed for the Kidney Disease Outcome Quality Initiative (KDOQI) 2020 Nutrition Guideline update, so this article summarizes the more recent evidence. We review the use of vitamins supplementation in the CKD population. To date there have been no randomized trials to support the benefits of any vitamin supplementation for kidney, cardiovascular, or patient-centered outcomes. The decision to supplement water-soluble vitamins should be individualized, taking account the patient's dietary intake, nutritional status, risk of vitamins deficiency/insufficiency, CKD stage, comorbid status, and dialysis loss. Nutritional vitamin D deficiency should be corrected, but the supplementation dose and formulation need to be personalized, taking into consideration the degree of 25-hydroxyvitamin D deficiency, parathyroid hormone levels, CKD stage, and local formulation. Routine supplementation of vitamins A and E is not supported due to potential toxicity. Although more trial data are required to elucidate the roles of vitamin supplementation, all patients with CKD should undergo periodic assessment of dietary intake and aim to receive various vitamins through natural food sources and a healthy eating pattern that includes vitamin-dense foods.

Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.

Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.

Vitamin E is a lipid-soluble nutrient found mainly in vegetable oils and oilseeds. It is divided into eight homologous compounds; however, only α-tocopherol exhibits vitamin activity. Many advantages are related to these compounds, including cellular protection through antioxidant and anti-inflammatory activity, and improving lipid metabolism. Physiopathology of many diseases incepts with reduced antioxidant defense, characterized by an increased reactive oxygen species production and activation of transcription factors involved in inflammation, such as nuclear factor-kappa B (NF-κB), that can be linked to oxidative stress. Moreover, disorders of lipid metabolism can increase the risk of cardiovascular diseases. In addition, intestinal dysbiosis plays a vital role in developing chronic non-communicable diseases. In this regard, vitamin E can be considered to mitigate those disorders, but data still needs to be more conclusive. This narrative review aims to elucidate the mechanisms of action of vitamin E and if supplementation can be beneficial in a disease scenario regarding non-communicable diseases.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

Inflammation is a major component of heart failure (HF), causing peripheral vasculopathy and cardiac remodeling. High levels of circulating inflammatory cytokines in HF patients have been well recognized. The hallmark of the inflammatory imbalance is the insufficient production of anti-inflammatory mediators, a condition that leads to dysregulated cytokine activity. The condition progresses because of the pathogenic consequences of the cytokine imbalance, including the impact of endothelial dysfunction and adrenergic responsiveness deterioration, and unfavorable inotropic effects on the myocardium. Hence, to develop possible anti-inflammatory treatment options that will enhance the outcomes of HF patients, it is essential to identify the potential pathophysiological mechanisms of inflammation in HF. Inflammatory mediators, such as cytokines, adhesion molecules, and acute-phase proteins, are elevated during this process, highlighting the complex association between inflammation and HF. Therefore, these inflammatory markers can be used in predicting prognosis of the syndrome. Various immune cells impact on myocardial remodeling and recovery. They lead to stimulation, release of alarmins and risk-related molecule patterns. Targeting key inflammatory mechanisms seems a quite promising therapy strategy in HF. Cytokine modulation is only one of several possible targets in the fight against inflammation, as the potential molecular targets for therapy in HF include immune activation, inflammation, oxidative stress, alterations in mitochondrial bioenergetics, and autophagy.

Vascular calcification (VC), an actively regulated process, has been recognized as an independent and strong predictor of cardiovascular disease (CVD) and mortality worldwide. Diet has been shown to have a major role in the progression of VC. Oxidative stress (OS), a common pro-calcification factor, is closely related to VC, and evidence strongly suggests that dietary antioxidants directly prevent VC. Herein, we provided an overview of OS and its key role in VC and underlined the mechanisms of harmful effects of OS on VC. Furthermore, we introduced dietary antioxidants, and discussed about surrounding the challenges of dietary antioxidants in VC management. This review will benefit future research about the effects of dietary antioxidants on cardiovascular health.

Cardiac allograft vasculopathy (CAV) is a progressive fibroproliferative disease which occurs after heart transplantation and is associated with significant long-term morbidity and mortality. Currently available strategies including statins, mammalian target of rapamycin (mTOR) inhibitors, and revascularization, have limited overall effectiveness in treating this pathology once the disease process is established. mTOR inhibitors, while effective when used early in the disease process, are not well tolerated, and hence not routinely used in post-transplant care.

Recent work on rodent models have given us a novel mechanistic understanding of effects of ascorbic acid in preventing CAV. TET methyl cytosine dioxygenase2 (TET2) reduces vascular smooth muscle cell (VSMC) apoptosis and intimal thickening. TET2 is repressed by interferon γ (IFNγ) in the setting of CAV. Ascorbic acid has been shown to promote TET2 activity and attenuate allograft vasculopathy in animal models and CAV progression in a small clinical trial.

CAV remains a challenging disease process and needs better preventative strategies. Ascorbic acid improves endothelial dysfunction, reduces reactive oxygen species, and prevents development of intimal hyperplasia by preventing smooth muscle cell apoptosis and hyperproliferation. Further large-scale randomized control studies of ascorbic acid are needed to establish the role in routine post-transplant management.

To summarize the effect of vitamin E-coated dialyzer membranes (VEMs) treatment or oral vitamin E intake on antioxidant molecules, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), and total antioxidant level in patients receiving dialysis.

A literature search of PubMed, Embase, CNKI, and the Cochrane Library databases is performed from inception to July 1, 2023, with no language nor country restrictions. Twenty-four experimental studies involving 512 patients undergoing dialysis are selected for meta-analysis. The levels of antioxidant markers in the blood of patients receiving hemodialysis (HD) improve with long-term VEMs treatment (p = 0.016). According to the findings of each antioxidant index, there is a significant increase in the levels of erythrocyte-derived SOD (p = 0.047), CAT (p = 0.029), and plasma-derived total antioxidant level (p < 0.001). The antioxidant marker levels in patients receiving HD are significantly increased by oral vitamin E intake (p < 0.001). Erythrocyte-derived SOD (p = 0.003), GPX (p < 0.001), and CAT (p = 0.001) substantially improves after 2-6 months of intervention with oral vitamin E preparation. The antioxidant index of patients receiving peritoneal dialysis (PD) is unaffected by oral vitamin E treatment (p = 0.945).

Vitamin E therapy has a favorable effect on the retention of antioxidant compounds in patients undergoing dialysis.

This paper summarizes the biochemistry, metabolism, and dietary needs of vitamins in patients with chronic kidney disease (CKD) and kidney transplant recipients. Evidence indicates that the dietary intake, in vivo synthesis, urinary excretion or metabolism of different vitamins may be substantially altered in kidney failure. There are discrepancies in vitamin status assessment depending on whether the assay is functional or measuring the blood vitamin level. Whether vitamin supplements should be routinely prescribed for patients with CKD is controversial. Because low dietary intake and compounds that interfere with vitamin activity are not uncommon in patients with CKD, and water-soluble vitamin supplements appear safe and not costly, the authors recommend that supplements of the water-soluble vitamins should be routinely offered to these individuals. More research is needed to assess vitamin nutrition and function and to determine the daily vitamin needs for all patients with CKD.

Diabetic cardiomyopathy describes decreased myocardial function in diabetic patients in the absence of other heart diseases such as myocardial ischemia and hypertension. Recent studies have defined numerous molecular interactions and signaling events that may account for deleterious changes in mitochondrial dynamics and functions influenced by hyperglycemic stress. A metabolic switch from glucose to fatty acid oxidation to fuel ATP synthesis, mitochondrial oxidative injury resulting from increased mitochondrial ROS production and decreased antioxidant capacity, enhanced mitochondrial fission and defective mitochondrial fusion, impaired mitophagy, and blunted mitochondrial biogenesis are major signatures of mitochondrial pathologies during diabetic cardiomyopathy. This review describes the molecular alterations underlying mitochondrial abnormalities associated with hyperglycemia and discusses their influence on cardiomyocyte viability and function. Based on basic research findings and clinical evidence, diabetic treatment standards and their impact on mitochondrial function, as well as mitochondria-targeted therapies of potential benefit for diabetic cardiomyopathy patients, are also summarized.

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide, affecting up to 30% of adults. Progression to non-alcoholic steatohepatitis (NASH) is a key risk factor for cirrhosis, hepatocellular carcinoma and cardiovascular events. Alterations in reproductive hormones are linked to the development and/or progression of NAFLD/NASH in women. Women with polycystic ovary syndrome and those with oestrogen deficiency are at increased risk of NAFLD/NASH, with higher mortality rates in older women compared to men of similar ages. NAFLD/NASH is currently the leading indication for liver transplantation in women without hepatocellular carcinoma. Therefore, a better understanding of NAFLD in women is needed to improve outcomes. In this review, we discuss the hormonal and non-hormonal factors that contribute to NAFLD development and progression in women. Furthermore, we highlight areas of focus for clinical practice and for future research.