Vitamin E is an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) but associated with hemorrhagic complications when used for other indications. We aimed to determine the risk of developing iron deficiency during treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) with vitamin E. Iron status was monitored prospectively in 20 people with MASLD treated with 200 - 800 IU/d vitamin E (https://clinicaltrials.gov/study/NCT01792115). To gain mechanistic insights liver histology, hepatic gene expression, hepatic 4-hydroxynonenal, haptoglobin genotype and plasma vitamin E levels were assessed. We found iron deficiency to occur in 11/20 subjects (55%) after a median 11 weeks (range 4-13) of vitamin E treatment, and anemia to occur in 6 of the 11 (30% of study population) after 23 weeks (16-36). Ferritin (84.5 ± 85.2 to 47.8 ± 54.9μg/L, p < 0.001) and mean corpuscular volume (MCV, 86.2 ± 4.9 to 84.3±4.3fL, p = 0.003) significantly decreased, with a concomitant rise in red-cell distribution width (RDW, 13.4 ± 1.3 to 14.4 ± 1.9%, p = 0.003). A gastrointestinal bleeding source was found in 75% of subjects with complete work-up. Iron deficiency occurred in all diabetics vs. 47% of non-diabetics (p 0.007). Iron deficiency risk was not associated with cirrhosis, platelet count, prothrombin time, haptoglobin genotype, or plasma vitamin E level. Changes in hepatic gene expression and oxidative stress were suggestive of an extrahepatic effect. Iron deficiency resolved with appropriate care even with continued vitamin E treatment. We conclude that occult gastrointestinal bleeding and iron deficiency were frequently observed during vitamin E treatment, possibly reflecting an effect on platelet function. Close monitoring is warranted during the first months of treatment, especially in diabetics and subjects with risk factors for gastrointestinal bleeding.

Background/Objectives: While previous study results have suggested an elevated risk of type 2 diabetes with potato consumption, limited and inconsistent results are available on the association of potato consumption with the risk of cardiovascular disease (CVD) and hypertension (HTN). We assessed the associations of (i) total potato consumption with the risk of CVD and HTN as the primary aim and (ii) fried potatoes and combined baked, boiled, and mashed potatoes with the risk of CVD and HTN as the secondary aim. Methods: We conducted a meta-analysis using data from seven cohorts for CVD (n = 110,063) and five cohorts for HTN (n = 67,146). Cox regression was used to estimate multivariable adjusted hazard ratios separately in each cohort and the cohort-specific results were meta-analyzed using an inverse-variance weighted method. Results: The mean age ranged from 25 to 72 years, 65% of the respondents were women, and the mean consumption of total potatoes ranged from 1.9 to 4.3 times per week. In the primary analysis, total potato intake was not associated with the risk of either CVD or HTN: multivariable adjusted HR (95% CI) comparing 5+ servings/week to no potato intake: 0.96 (0.89-1.04) for CVD and 1.04 (0.99-1.08) for HTN. In secondary analyses, the consumption of combined baked, boiled, and mashed potatoes was not associated with CVD or HTN; while fried potato consumption was not associated with CVD risk, there was a 10% higher risk of HTN (95% CI: 4% to 17%) comparing 1+ servings/week to no fried potato intake. Conclusions: While the consumption of total potato was not associated with the risk of CVD or HTN risk, a modest elevated risk of HTN but not CVD was observed only with fried potato consumption.

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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

Physical activity (PA) can improve cancer survival; however, whether the timing of PA differentially affects mortality risk is unclear. We evaluated the association between PA levels pre- and post-diagnosis and mortality risk in the Women's Health Study (WHS), Physicians' Health Study (PHS)-I, and PHS-II prospective cohorts.

We categorized PA pre- and post-diagnosis as active (WHS: ≥ 7.5 metabolic equivalent (MET)-h/week; PHS: vigorous PA ≥ 2-4 times/week) or inactive. We analyzed changes in pre- and post-diagnosis PA levels as four joint categories: (1) Inactive → Inactive, (2) Active → Inactive, (3) Inactive → Active, and (4) Active → Active, on mortality risk using multivariable Cox proportional hazards regression.

We identified 10,541 participants with incident cancer and 3,696 deaths during follow-up. Compared to maintaining inactivity in both periods, remaining active pre- and post-diagnosis observed lower all-cause (Hazard Ratio [95% confidence interval]: WHS: 0.55 [0.47-0.64]; PHS-I: 0.77 [0.67-0.88]), cancer (WHS: 0.55 [0.45-0.67]; PHS-I: 0.75; [0.61-0.92]) and non-cancer/cardiovascular disease (CVD) mortality risks (WHS: 0.49 [0.38-0.65]). Similarly, becoming active post-diagnosis was associated with lower all-cause (WHS: 0.60 (0.48-0.75]; PHS-I: 0.72 [0.61-0.88]), cancer (WHS: 0.65 [0.49-0.86]; PHS-I: 0.64 [0.49-0.84]), and non-cancer/CVD mortality risk (WHS: 0.49 [0.33-0.75]). Being active pre- and post-diagnosis was associated with lower mortality risks in separate analyses, although significance differed by cohort and outcome.

Remaining active pre- and post-diagnosis and becoming active post-diagnosis may be associated with improvements in cancer survival, however, research is needed across diverse cancer populations.

Uncontrolled hyperglycemia in people with diabetes is an established risk of premature cardiovascular disease. Repeated hypoglycemic events are also associated with increased cardiovascular mortality. Both hyperglycemia and hypoglycemia induce cellular stress, notably endoplasmic reticulum (ER) stress, a known promoter of cardiovascular disease. Contemporary anti-hyperglycemic drugs such as glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors simultaneously inhibit oxidative stress and ER stress in human coronary artery endothelial cells. Similarly, other known cardioprotective drugs, such as statins and inhibitors of the renin-angiotensin-aldosterone system (RAAS) share a common pleiotropic effect of reducing cellular stress. Antioxidants reduce oxidative stress but may aggravate ER stress. This dichotomy of antioxidant effects may underline the unfavorable outcomes of clinical trials with antioxidant vitamin use. The aim of this review is to highlight the potential role of cellular stress reduction in cardioprotective effects of contemporary diabetes drugs. Future clinical trials are needed to test the hypothesis that cellular stress is the fundamental culprit in cardiovascular disease.

High-sensitivity C-reactive protein (CRP), low-density lipoprotein (LDL) cholesterol, and lipoprotein(a) levels contribute to 5-year and 10-year predictions of cardiovascular risk and represent distinct pathways for pharmacologic intervention. More information about the usefulness of these biomarkers for predicting cardiovascular risk over longer periods of time in women is needed because early-life intervention represents an important risk-reduction method.

We measured high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels at baseline in 27,939 initially healthy U.S. women who were subsequently followed for 30 years. The primary end point was a first major adverse cardiovascular event, which was a composite of myocardial infarction, coronary revascularization, stroke, or death from cardiovascular causes. We calculated the adjusted hazard ratios and 95% confidence intervals across quintiles of each biomarker, along with 30-year cumulative incidence curves adjusted for age and competing risks.

The mean age of the participants at baseline was 54.7 years. During the 30-year follow-up, 3662 first major cardiovascular events occurred. Quintiles of increasing baseline levels of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) all predicted 30-year risks. Covariable-adjusted hazard ratios for the primary end point in a comparison of the top with the bottom quintile were 1.70 (95% confidence interval [CI], 1.52 to 1.90) for high-sensitivity CRP, 1.36 (95% CI, 1.23 to 1.52) for LDL cholesterol, and 1.33 (95% CI, 1.21 to 1.47) for lipoprotein(a). Findings for coronary heart disease and stroke appeared to be consistent with those for the primary end point. Each biomarker showed independent contributions to overall risk. The greatest spread for risk was obtained in models that incorporated all three biomarkers.

A single combined measure of high-sensitivity CRP, LDL cholesterol, and lipoprotein(a) levels among initially healthy U.S. women was predictive of incident cardiovascular events during a 30-year period. These data support efforts to extend strategies for the primary prevention of atherosclerotic events beyond traditional 10-year estimates of risk. (Funded by the National Institutes of Health; Women's Health Study ClinicalTrials.gov number, NCT00000479.).

Our bodies are constantly exposed to or producing free radicals nearly on a daily basis. These highly reactive molecules are generated through a variety of internal and external processes and pathways within the body. If these free radicals are not neutralized by antioxidants, they can lead to a state of oxidative stress, which has been linked to a wide range of severe and debilitating disorders affecting various systems in the human body. This involves neurodegenerative diseases, diabetes, atherosclerosis, fatty liver, inflammation, and aging. Thankfully, the human body is armed with a repertoire of powerful antioxidants with different natures and modes of action. The recent decades witnessed the publication of enormous papers proving antioxidant activity of a novel synthesized compound, plant extract, or a purified drug in vitro, in vivo, and even on human beings. However, the efficacy of antioxidant therapies in clinical trials, including selenium, vitamin C, vitamin E, and vitamin A, has been notably inconsistent. This inconsistency can be primarily ascribed to different factors related to the nature of free radical generation, purpose and the specific type of therapy employed, and the intricate oxidative stress connected network, among others. Collectively, these factors will be explored in this review article to decipher the observed shortcomings in the application of antioxidant therapies within clinical settings.

Increased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.

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.

Vitamin D may prevent the development of hypertension through down-regulation of renin-angiotensin system. However, epidemiologic studies assessing the interrelation of vitamin D-related biomarkers with hypertension are sparse.

We examined the prospective associations between vitamin D-related biomarkers and the risk of hypertension in a nested case-control study. In each of the Women's Health Study (WHS) and Physicians' Health Study (PHS) II, 500 incident hypertension cases and 500 age and race-matched controls were randomly selected. Baseline plasma 25(OH)-vitamin D [25(OH)D], parathyroid hormone (PTH), and total renin concentrations were measured.

Among controls, 25(OH)D and PTH were inversely correlated, but neither was correlated with total renin. In the crude model, there was a trend of association between increasing quintiles of 25(OH)D and lower risk of hypertension in women, with relative risks and 95% CIs of 1.00, 1.24 (0.84-1.83), 0.82 (0.53-1.25), 0.75 (0.48-1.16), and 0.81 (0.52-1.27) (P, trend: .07). Adjustment for body mass index and other hypertension risk factors eliminated this association (relative risk of 5th quintile: 1.03). No associations were found in men. Baseline PTH and ratio of 25(OH)D to PTH were not associated with the risk of hypertension in women or men. When men and women were included in the same model, vitamin D insufficiency (defined as 25(OH)D <20 ng/mL) also was not associated with an increased risk of hypertension. No interactions were found across subgroups.

Our study found no association of baseline plasma 25(OH)D or PTH with the risk of hypertension or total renin concentration in middle-aged and older men and women.

Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R.

Data on the relation of potato consumption with risk of type 2 diabetes (T2D) are limited and inconsistent. It is unclear whether the plant-based diet index (PDI), which is a novel and comprehensive tool to assess overall dietary pattern, modifies the association of potato intake with T2D.

We examined the association of total, combined baked, boiled, and mashed potatoes and fried potatoes with risk of T2D and test the interaction between PDI score and potato consumption on T2D risk.

We conducted a de novo, harmonized, individual-level data from 7 United States cohorts (N = 105,531). Cox regression was used to estimate hazard ratios (HRs) separately in each cohort adjusting for anthropometric, demographic, and lifestyle factors and cohort-specific results were pooled using an inverse-variance weighted method.

Mean age ranged from 25 to 72 y, 65% women, and mean consumption of total potatoes ranged from 1.9 to 4.3 times per week. In the primary analysis, total potato intake was not associated with T2D risk: multivariable adjusted HR of 1.01 (95% confidence interval [CI]: 0.95, 1.08) for consumption of 1-2 servings/wk; 1.01 (95% CI: 0.93, 1.10) for >2-3 servings/wk; 1.05 (95% CI: 0.99, 1.12) for >3 to <5 servings/wk; and 1.07 (95% CI: 0.99, 1.16) for 5+ servings/wk compared with no potato intake. In secondary analyses, consumption of combined baked, boiled, and mashed potatoes was not associated with T2D risk, whereas fried potato consumption was positively associated with T2D risk: HR were 1 (ref), 1.07 (95% CI: 1.02, 1.12), and 1.12 (95% CI: 1.03, 1.22) for intake frequency of 0/wk, >0 to 1/wk, and >1/wk, respectively (P-trend = 0.04). There was no significant interaction between PDI score and potato consumption on T2D risk.

Although consumption of total potato is not associated with T2D risk, a modest elevated risk of T2D is observed with fried potato consumption.

Migraine and Parkinson disease (PD) are common neurologic disorders, which are hypothesized to share some pathophysiologic mechanisms. However, data on the association between migraine and risk of developing PD are sparse. We estimate the effect of migraine, migraine subtypes, and migraine episode frequency on the risk of developing PD in middle-aged and older women.

We used data from the Women's Health Study, a United States-based cohort of women in health professions aged 45 years and older at baseline (1992-1995). Only women with complete self-reported information on migraine and headache and no history of PD were included. Participants were followed up for self-reported physician-diagnosed PD through December 31, 2021. We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and corresponding 95% CIs of the association between migraine, migraine subtypes, and migraine episode frequency and the risk of developing PD.

A total of 39,312 women were included in the analyses. Among those, 7,321 women (18.6%) reported any migraine at baseline, of whom 2,153 (5.5%) reported a history of migraine, 2,057 (5.2%) reported migraine with aura, and 3,111 (7.9%) reported migraine without aura. During a mean follow-up of 22.0 years, 685 PD cases were reported. Of those, 128 (18.7%) were reported by women who also reported any migraine and 557 (81.3%) by women without any migraine. After adjusting for confounding, the HR for the association of any migraine on the risk of PD was 1.07 (0.88-1.29). Compared with women without migraine, the HRs (95% CI) for PD were 0.87 (0.59-1.27) for migraine with aura, 1.21 (0.93-1.58) for migraine without aura, and 1.05 (0.76-1.45) for history of migraine. Compared with those with a migraine frequency of less than monthly, the HRs were 1.09 (0.64-1.87) for a monthly frequency and 1.10 (0.44-2.75) for a weekly or greater frequency.

In this large cohort of women, the risk of developing PD was not elevated among those experiencing migraine, irrespective of migraine subtypes or the frequency of migraine. The generalizability of our findings to other populations, such as men, should be further investigated.

ClinicalTrials.gov Identifier: NCT00000479.

The exploration of targeted therapy has proven to be a highly promising avenue in the realm of drug development research. The human body generates a substantial amount of free radicals during metabolic processes, and if not promptly eliminated, these free radicals can lead to oxidative stress, disrupting homeostasis and potentially contributing to chronic diseases and cancers. Before the development of contemporary medicine with synthetic pharmaceuticals and antioxidants, there was a long-standing practice of employing raw, natural ingredients to cure a variety of illnesses. This practice persisted even after the active antioxidant molecules were known. The ability of natural antioxidants to neutralise excess free radicals in the human body and so prevent and cure a wide range of illnesses. The term "natural antioxidant" refers to compounds derived from plants or other living organisms that have the ability to control the production of free radicals, scavenge them, stop free radical-mediated chain reactions, and prevent lipid peroxidation. These compounds have a strong potential to inhibit oxidative stress. Phytochemicals (antioxidants) derived from plants, such as polyphenols, carotenoids, vitamins, and others, are central to the discussion of natural antioxidants. Not only may these chemicals increase endogenous antioxidant defenses, affect communication cascades, and control gene expression, but they have also shown strong free radical scavenging properties. This study comprehensively summarizes the primary classes of natural antioxidants found in different plant and animal source that contribute to the prevention and treatment of diseases. Additionally, it outlines the research progress and outlines future development prospects. These discoveries not only establish a theoretical groundwork for pharmacological development but also present inventive ideas for addressing challenges in medical treatment.

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.

Accumulating more steps/day is associated with a lower risk of cancer mortality and composite cancer outcomes. However, less is known about the relationship of steps/day with the risk of multiple site-specific cancers.

This study included >22,000 women from the Women's Health Accelerometry Collaboration Cohort (2011-2022), comprised of women from the Women's Health Study and Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Steps/day and step intensity were collected with accelerometry. Incident cancer cases and deaths were adjudicated. Stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of steps/day and step intensity with incident breast, colon, endometrial, lung, and ovarian cancers, a composite of 13 physical activity-related cancers, total invasive cancer, and fatal cancer.

On average, women were 73.4 years old, accumulated 4993 steps/day, and had 7.9 years of follow-up. There were small nonsignificant inverse associations with the risks of colon cancer (HR = 0.94, 95% CI: 0.83, 1.05), endometrial cancer (HR = 0.91, 95% CI: 0.82, 1.01), and fatal cancer (HR = 0.95 95% CI: 0.90, 1.00) per 1000 steps/day. More minutes at ≥40 steps/min and a faster peak 10- and 30-min step cadence were associated with a lower risk of endometrial cancer, but findings were attenuated after adjustment for body mass index and steps/day.

Among women 62-97 years, there were small nonsignificant inverse associations of colon, endometrial, and fatal cancer with more steps/day. Epidemiologic studies with longer follow-up and updated assessments are needed to further explore these associations.

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.

A previous study showed that vitamin E is effective in reducing the incidence of myocardial infarction only when it is taken in the absence of other antioxidants. It is unclear if it also reduces the incidence of stroke.

The aim of this meta-analysis is to compare the effect of vitamin E supplementation alone or combined with other antioxidants on the incidence of stroke.

A search was performed in the following databases: PubMed, ISI Web of Science, SCOPUS, and Cochrane Library.

Sixteen randomized controlled trials were selected to evaluate the effect of vitamin E supplementation on stroke.

The range of vitamin E doses used was 33-800 IU. The follow-up period ranged from 6 months to 9.4 years. Compared with controls, when vitamin E was given alone it did not reduce the incidence of ischemic and hemorrhagic stroke. Conversely, compared with controls, supplementation of vitamin E with other antioxidants reduced ischemic stroke (random effects, RR: 0.91; 95% CI: 0.84-0.99; P = 0.02) but with a significant increase in hemorrhagic stroke (random effects, RR: 1.22; 95% CI: 1.0-1.48; P = 0.04).

Supplementation with vitamin E alone is not associated with stroke reduction. Instead, supplementation of vitamin E with other antioxidants reduces the incidence of ischemic stroke but increases the risk of hemorrhagic stroke, cancelling any beneficial effect derived. Thus, vitamin E is not recommended in stroke prevention.

PROSPERO registration no. CRD42022258259.

Current US physical activity (PA) guidelines prescribe moderate to vigorous PA (MVPA) time of at least 150 minutes per week for health. An analogous step-based recommendation has not been issued due to insufficient evidence.

To examine the associations of MVPA time and step counts with all-cause mortality and cardiovascular disease (CVD).

This cohort study analyzed data from an ongoing follow-up study of surviving participants of the Women's Health Study, a randomized clinical trial conducted from 1992 to 2004 in the US to evaluate use of low-dose aspirin and vitamin E for preventing cancer and CVD. Participants were 62 years or older who were free from CVD and cancer, completed annual questionnaires, and agreed to measure their PA with an accelerometer as part of a 2011-2015 ancillary study. Participants were followed up through December 31, 2022.

Time spent in MVPA and step counts, measured with an accelerometer for 7 consecutive days.

The associations of MVPA time and step counts with all-cause mortality and CVD (composite of myocardial infarction, stroke, and CVD mortality) adjusted for confounders. Cox proportional hazards regression models, restricted mean survival time differences, and area under the receiver operating characteristic curve (AUC) were used to evaluate the associations.

A total of 14 399 women (mean [SD] age, 71.8 [5.6] years) were included. The median (IQR) MVPA time and step counts were 62 (20-149) minutes per week and 5183 (3691-7001) steps per day, respectively. During a median (IQR) follow-up of 9.0 (8.0-9.9) years, the hazard ratios (HR) per SD for all-cause mortality were 0.82 (95% CI, 0.75-0.90) for MVPA time and 0.74 (95% CI, 0.69-0.80) for step counts. Greater MVPA time and step counts (top 3 quartiles vs bottom quartile) were associated with a longer period free from death: 2.22 (95% CI, 1.58-2.85) months and 2.36 (95% CI, 1.73-2.99) months at 9 years follow-up, respectively. The AUCs for all-cause mortality from MVPA time and step counts were similar: 0.55 (95% CI, 0.52-0.57) for both metrics. Similar associations of these 2 metrics with CVD were observed.

Results of this study suggest that among females 62 years or older, MVPA time and step counts were qualitatively similar in their associations with all-cause mortality and CVD. Step count-based goals should be considered for future guidelines along with time-based goals, allowing for the accommodation of personal preferences.

Previous researches examining the impact of dietary nutrition on mortality risk have mainly focused on individual nutrients, however the interaction of these nutrients has not been considered. The purpose of this study was to identify of nutrient deficiencies patterns and analyze their potential impact on mortality risk in older adults with hypertension.

We included participants from the National Health and Nutrition Examination Survey (NHANES) study. The latent class analysis (LCA) was applied to uncover specific malnutrition profiles within the sample. Risk of the end points across the phenogroups was compared using Kaplan-Meier analysis and Cox proportional hazard regression model. Multinomial logistic regression was used to determine the influencing factors of specific malnutrition profiles.

A total of 6924 participants aged 60 years or older with hypertension from NHANES 2003-2014 was followed until December 31, 2019 with a median follow-up of 8.7 years. Various nutrients included vitamin A, vitamin B1, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, fiber, folate, calcium, magnesium, zinc, copper, iron, and selenium, and LCA revealed 4 classes of malnutrition. Regarding all-cause mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.42 from 1.19 to 1.70) compared with "Adequate Nutrient" group, followed by "Inadequate Nutrient" group (1.29 from 1.10 to 1.50), and "Low Fiber, Magnesium, and Vit E" group (1.17 from 1.02 to 1.35). For cardiovascular mortality, "Nutrient Deprived" group showed the strongest hazard ratio (1.61 from 1.19 to 2.16) compared with "Adequate Nutrient" group, followed by "Low Fiber, Magnesium, and Vit E" group (1.51 from 1.04 to 2.20), and "Inadequate Nutrient" group (1.37 from 1.03 to 1.83).

The study revealed a significant association between nutrients deficiency patterns and the risk of all-cause and cardiovascular mortality in older adults with hypertension. The findings suggested that nutrients deficiency pattern may be an important risk factor for mortality in older adults with hypertension.

Bovine dairy milk is a nutrient-rich matrix, but consumption of full-fat dairy food varieties has been claimed historically to be associated with poorer cardiometabolic health, a notion often attributed to the saturated fat content. However, continued investigation that includes observational studies and randomized controlled trials (RCTs) provide evidence that favorably supports full-fat dairy foods and their bioactive components on cardiometabolic health. This review addresses this controversy by examining the evidence surrounding full-fat dairy foods and their implications for human health. Dairy foods are heterogeneous, not just in their fat content but also in other compositional aspects within and between fermented (e.g., yogurt, cheese) and nonfermented products (e.g., milk) that could differentially influence cardiometabolic health. Drawing from complementary lines of evidence from epidemiological studies and RCTs, this review describes the health effects of dairy foods regarding their fat content, as well as their polar lipids that are concentrated in the milk fat globule fraction. Observational studies have limitedly supported the consumption of full-fat dairy to protect against cardiometabolic disorders. However, this framework has been disputed by RCTs indicating that dairy foods, regardless of their fat content or fermentation, are not detrimental to cardiometabolic health and may instead alleviate certain cardiometabolic risk factors. As dietary recommendations evolve, which currently indicate to avoid full-fat dairy foods, it is essential to consider the totality of evidence, especially from RCTs, while also recognizing that investigation is needed to evaluate the complexity of dairy foods within diverse dietary patterns and their impacts on cardiometabolic health.

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.

Stroke represents a significant public health challenge, necessitating the exploration of preventive measures. This network meta-analysis aimed to assess the efficacy of different vitamin treatments compared to a placebo in preventing stroke.

A systematic electronic search in databases including PubMed, EmBASE, Web of Science, clinicaltrials.gov, and Google Scholar until 31 May 2023 was conducted, to identify published studies investigating the association between vitamin intake and the risk of stroke. Pooled risk ratio (RR) with 95% confidence intervals (CIs) was calculated using a frequentist network meta-analysis. Furthermore, we ranked vitamins based on p-scores, facilitating a comparative assessment of their effectiveness in preventing stroke.

A total of 56 studies, including 17 randomized controlled trials (RCTs) and 39 cohort studies were analyzed. Direct estimates obtained from network meta-analysis, we found that vitamin A (RR: .81 [.72-.91]), vitamin B-complex (RR: .85 [.74-.97]), vitamin B6 (RR: 79 [.68-.92]), folate (RR: .86 [.75-.97]), vitamin C (RR: .77 [.70-.85]) and vitamin D (RR: .73 [.64-.83]) were significantly associated with a decreased stroke risk. However, no significant association was observed for vitamin B2, vitamin B12, and vitamin E. Subsequent to network meta-analysis, vitamins were ranked in decreasing order of their efficacy in stroke prevention based on p-score, with vitamin D (p-score = .91), vitamin C (p-score = .79), vitamin B6 (p-score = .70), vitamin A (p-score = .65), vitamin B-complex (p-score = .53), folate (p-score = .49), vitamin B2 (p-score = .39), vitamin E (p-score = .28), vitamin B12 (.13) and placebo (.10).

Our study has established noteworthy connections between vitamin A, vitamin B-complex, vitamin B6, folate, vitamin C, and vitamin D in the realm of stroke prevention. These findings add substantial weight to the accumulating evidence supporting the potential advantages of vitamin interventions in mitigating the risk of stroke. However, to solidify and validate these observations, additional research is imperative. Well-designed clinical trials or cohort studies are needed to further explore these associations and formulate clear guidelines for incorporating vitamin supplementation into effective stroke prevention strategies.

Premature coronary heart disease (CHD) is a major cause of death in women. We aimed to characterize biomarker profiles of women who developed CHD before and after age 65 years.

In the Women's Health Study (median follow-up 21.5 years), women were grouped by age and timing of incident CHD: baseline age <65 years with premature CHD by age 65 years (25 042 women; 447 events) and baseline age ≥65 years with nonpremature CHD (2982 women; 351 events). Associations of 44 baseline plasma biomarkers measured using standard assays and a nuclear magnetic resonance (NMR)-metabolomics assay were analyzed using Cox models adjusted for clinical risk factors.

Twelve biomarkers showed associations only with premature CHD and included lipoprotein(a), which was associated with premature CHD [adjusted hazard ratio (HR) per SD: 1.29 (95% CI 1.17-1.42)] but not with nonpremature CHD [1.09(0.98-1.22)](Pinteraction = 0.02). NMR-measured lipoprotein insulin resistance was associated with the highest risk of premature CHD [1.92 (1.52-2.42)] but was not associated with nonpremature CHD (Pinteraction <0.001). Eleven biomarkers showed stronger associations with premature vs nonpremature CHD, including apolipoprotein B. Nine NMR biomarkers showed no association with premature or nonpremature CHD, whereas 12 biomarkers showed similar significant associations with premature and nonpremature CHD, respectively, including low-density lipoprotein (LDL) cholesterol [1.30(1.20-1.45) and 1.22(1.10-1.35)] and C-reactive protein [1.34(1.19-1.50) and 1.25(1.08-1.44)].

In women, a profile of 12 biomarkers was selectively associated with premature CHD, driven by lipoprotein(a) and insulin-resistant atherogenic dyslipoproteinemia. This has implications for the development of biomarker panels to screen for premature CHD.

Altered metabolic function has many detrimental effects on the body that can manifest as cardiovascular and liver diseases. Traditional approaches to understanding and treating metabolic dysfunction-associated disorders have been organ-centered, leading to silo-type disease care. However, given the broad impact that systemic metabolic dysfunction has on the human body, approaches that simultaneously involve multiple medical specialists need to be developed and encouraged to optimize patient outcomes. In this review, we highlight how several of the treatments developed for cardiac care may have a beneficial effect on the liver and vice versa, suggesting that there is a need to target the disease process, rather than specifically target the cardiovascular or liver specific sequelae of metabolic dysfunction.

Higher adherence to the Mediterranean diet has been associated with reduced risk of all-cause mortality, but data on underlying molecular mechanisms over long follow-up are limited.

To investigate Mediterranean diet adherence and risk of all-cause mortality and to examine the relative contribution of cardiometabolic factors to this risk reduction.

This cohort study included initially healthy women from the Women's Health Study, who had provided blood samples, biomarker measurements, and dietary information. Baseline data included self-reported demographics and a validated food-frequency questionnaire. The data collection period was from April 1993 to January 1996, and data analysis took place from June 2018 to November 2023.

Mediterranean diet score (range, 0-9) was computed based on 9 dietary components.

Thirty-three blood biomarkers, including traditional and novel lipid, lipoprotein, apolipoprotein, inflammation, insulin resistance, and metabolism measurements, were evaluated at baseline using standard assays and nuclear magnetic resonance spectroscopy. Mortality and cause of death were determined from medical and death records. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for Mediterranean diet adherence and mortality risk, and mediation analyses were used to calculate the mediated effect of different biomarkers in understanding this association.

Among 25 315 participants, the mean (SD) baseline age was 54.6 (7.1) years, with 329 (1.3%) Asian women, 406 (1.6%) Black women, 240 (0.9%) Hispanic women, 24 036 (94.9%) White women, and 95 (0.4%) women with other race and ethnicity; the median (IQR) Mediterranean diet adherence score was 4.0 (3.0-5.0). Over a mean (SD) of 24.7 (4.8) years of follow-up, 3879 deaths occurred. Compared with low Mediterranean diet adherence (score 0-3), adjusted risk reductions were observed for middle (score 4-5) and upper (score 6-9) groups, with HRs of 0.84 (95% CI, 0.78-0.90) and 0.77 (95% CI, 0.70-0.84), respectively (P for trend < .001). Further adjusting for lifestyle factors attenuated the risk reductions, but they remained statistically significant (middle adherence group: HR, 0.92 [95% CI, 0.85-0.99]; upper adherence group: HR, 0.89 [95% CI, 0.82-0.98]; P for trend = .001). Of the biomarkers examined, small molecule metabolites and inflammatory biomarkers contributed most to the lower mortality risk (explaining 14.8% and 13.0%, respectively, of the association), followed by triglyceride-rich lipoproteins (10.2%), body mass index (10.2%), and insulin resistance (7.4%). Other pathways, including branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension, had smaller contributions (<3%).

In this cohort study, higher adherence to the Mediterranean diet was associated with 23% lower risk of all-cause mortality. This inverse association was partially explained by multiple cardiometabolic factors.

Describing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population.

To describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women.

Women from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other.

In unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at ≥40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB.

Several sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.

Despite the various anticancer activities of tocopherols, little is known about tocopherols associated with lung cancer risk among low-income African Americans (AA) and European Americans (EA) who are disproportionately affected by the disease.

We conducted a nested case-control study that included 209 incident lung cancer cases and 406 matched controls within the Southern Community Cohort Study. Using biospecimens collected at cohort enrollment, plasma levels of α-, β/γ-, δ-, and total-tocopherols were measured by high-performance liquid chromatography with photodiode array detection. Conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI) for lung cancer risk after adjusting for potential confounders. Stratified analyses were also conducted.

Plasma levels of total-tocopherols were inversely associated with lung cancer risk overall [OR (95% CI) for the highest vs. lowest tertile = 0.51 (0.30-0.90)]. The inverse association remained significant among EAs [0.20 (0.06-0.65)], men [0.43 (0.21-0.90)], current smokers [0.49 (0.26-0.93)], and cases diagnosed within 2 years of blood draw [0.36 (0.15-0.86)], though we did not find a significant risk reduction among AAs [0.75 (0.39-1.45)]. Notably, we found significant interactions between α-tocopherol and race after controlling the FDR to correct for multiple comparisons (Pinteraction = 0.02).

Our results indicate that plasma total-tocopherols are inversely associated with lung cancer risk, but the association may differ across specific isomeric forms of tocopherols, race, or other individuals' characteristics. Further large-scale studies are warranted to confirm our findings.

Recommendations on tocopherols for lung cancer prevention should take isomers, race, and smoking behaviors into consideration.

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.

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.

Qing Gan Zi Shen Decoction (QGZS) is a traditional Chinese formula. It has been extensively used for decades in the treatment of hypertension combined with metabolic diseases, but its cardioprotective effects and underlying mechanisms are poorly understood.

To explore the cardioprotective effects and potential mechanisms of QGZS in an animal model of obese hypertension.

In this study, spontaneously hypertensive rats (SHRs) were utilized as an animal model to examine the effects of a high-fat diet and two concentrations of QGZS. Echocardiography, hematoxylin eosin (H&E) staining, and wheat germ agglutinin (WGA) staining were employed to assess the cardiac structure and function of the SHRs throughout a 16-week therapy period. Furthermore, Western blotting (WB) and immunofluorescence (IF) were employed to identify the levels of Nrf2 expression in the mitochondria, cytoplasm, and nucleus of the myocardium. Additionally, transmission electron microscopy and enzyme-linked immunosorbent assay (ELISA) were utilized to measure mitochondrial morphology and pro-inflammatory cytokine levels, respectively. Furthermore, Western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) techniques were employed to quantify the levels of marker proteins associated with myocardial fibrosis, cardiac inflammation, oxidative stress, and mitochondrial dysfunction.

QGZS inhibited weight gain and depressed systolic and mean arterial pressures in high-fat-fed SHRs. Echocardiographic results demonstrated that QGZS prevented the increase in left ventricular mass, restricted the growth of left ventricular diameter, and improved ejection fraction (EF), fractional shortening (FS), and the ratio of early diastolic peak velocity of transmitral flow (E) to late diastolic peak velocity (A) in high-fat-fed SHRs. This suggested that QGZS prevented ventricular remodeling and protected cardiac systolic and diastolic functions. H&E and WGA staining showed that QGZS improved cardiomyocyte disorders and restricted cardiomyocyte hypertrophy. The underlying mechanisms, QGZS attenuated the oxidative stress state, including reducing the generation of reactive oxygen species (ROS) in the myocardium, revitalizing the antioxidant enzyme system, and protecting mitochondrial function. Moreover, QGZS alleviated the pro-inflammatory state in high-fat-fed SHRs. What's more, QGZS significantly increased the expression level of Nrf2 in nuclei and mitochondria in rat heart tissues, exerting a proximate Nrf2 agonist effect.

QGZS exerted cardioprotective effects, in part due to its increasing expression of Nrf2 protein in the heart, which promoted Nrf2 nuclear expression.

The number of adults aged ≥ 65 years with cancer is rapidly increasing. Older adults with cancer are susceptible to treatment-related acute and chronic adverse events, resulting in loss of independence, reduction in physical function, and decreased quality of life. Nevertheless, evidence-based interventions to prevent or treat acute and chronic adverse events in older adults with cancer are limited. Several promising blood-based biomarkers related to inflammation and epigenetic modifications are available to identify older adults with cancer who are at increased risk of accelerated aging and physical, functional, and cognitive impairments caused by the cancer and its treatment. Inflammatory changes and epigenetic modifications can be reversible and targeted by lifestyle changes and interventions. Here we discuss ways in which changes in inflammatory and epigenetic pathways influence the aging process and how these pathways can be targeted by interventions aimed at reducing inflammation and aging-associated biological markers. As the number of older adults with cancer entering survivorship continues to increase, it is becoming progressively more important to understand ways in which the benefit from treatment can be enhanced while reducing the effects of accelerated aging.

Maintaining an appropriate concentration of vitamin D is essential for the proper functioning of the body, regardless of age. Nowadays, there are more and more indications that vitamin D supplementation at higher than standard doses may show protective and therapeutic effects. Our study identified differences in the body's response to long-term supplementation with cholecalciferol at an increased dose. Two groups of pigs were used in the experiment. The first group received a standard dose of cholecalciferol (grower, 2000 IU/kg feed, and finisher, 1500 IU/kg feed), and the second group received an increased dose (grower, 3000 IU/kg feed, and finisher, 2500 IU/kg feed). After slaughter, lung samples were collected and used for RRBS and mRNA sequencing. Analysis of the methylation results showed that 2349 CpG sites had significantly altered methylation patterns and 1116 (47.51%) identified DMSs (Differentially Methylated Sites) were related to genes and their regulatory sites. The mRNA sequencing results showed a significant change in the expression of 195 genes. The integrated analysis identified eleven genes with DNA methylation and mRNA expression differences between the analyzed groups. The results of this study suggested that an increased vitamin D intake may be helpful for the prevention of lung cancer and pulmonary fibrosis. These actions may stem from the influence of vitamin D on the expression of genes associated with collagen production, such as SHMT1, UGT1A6, and ITIH2.The anti-cancer properties of vitamin D are also supported by changes in KLHL3 and TTPA gene expression.

Fat-soluble vitamins (vitamin A, D, E, and K) assume a pivotal role in maintaining human homeostasis by virtue of their enzymatic functions. The daily inclusion of these vitamins is imperative to the upkeep of various physiological processes including vision, bone health, immunity, and protection against oxidative stress. Current research highlights fat-soluble vitamins as potential therapeutics for human diseases, especially cancer. Fat-soluble vitamins exert their therapeutic effects through multiple pathways, including regulation of matrix metalloproteinases' (MMPs) expression and enzymatic activity. As MMPs have been reported to be involved in the pathology of various diseases, such as cancers, cardiovascular diseases, and neurological disorders, regulating the expression and/or activity of MMPs could be considered as a potent therapeutic strategy. Here, we summarize the properties of fat-soluble vitamins and their potential as promising candidates capable of effectively modulating MMPs through multiple pathways to treat human diseases.

The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D.

We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier.

The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition.

We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Higher consumption of Mediterranean diet (MED) intake has been associated with reduced risk of all-cause mortality but limited data are available examining long-term outcomes in women or the underlying molecular mechanisms of this inverse association in human populations. We aimed to investigate the association of MED intake with long-term risk of all-cause mortality in women and to better characterize the relative contribution of traditional and novel cardiometabolic factors to the MED-related risk reduction in morality.

In a prospective cohort study of 25,315 initially healthy women from the Women's Health Study, we assessed dietary MED intake using a validated semiquantitative food frequency questionnaire according to the usual 9-category measure of MED adherence. Baseline levels of more than thirty cardiometabolic biomarkers were measured using standard assays and targeted nuclear magnetic resonance spectroscopy, including lipids, lipoproteins, apolipoproteins, inflammation, glucose metabolism and insulin resistance, branched-chain amino acids, small metabolites, and clinical factors. Mortality and cause of death was ascertained prospectively through medical and death records.

During a mean follow-up of 25 years, 3,879 deaths were ascertained. Compared to the reference group of low MED intake (0-3, approximately the bottom tertile), and adjusting for age, treatment, and energy intake, risk reductions were observed for the middle and upper MED groups with respective HRs of 0.84 (95% CI 0.78-0.90) and 0.77 (95% CI 0.70-0.84), p for trend <0.0001. Further adjusting for smoking, physical activity, alcohol intake and menopausal factors attenuated the risk reductions which remained significant with respective HRs of 0.92 (95% CI 0.85-0.99) and 0.89 (95% CI 0.82-0.98), p for trend 0.0011. Risk reductions were generally similar for CVD and non-CVD mortality. Small molecule metabolites (e.g., alanine and homocysteine) and inflammation made the largest contributions to lower mortality risk (accounting for 14.8% and 13.0% of the benefit of the MED-mortality association, respectively), followed by triglyceride-rich lipoproteins (10.2%), adiposity (10.2%) and insulin resistance (7.4%), with lesser contributions (<3%) from other pathways including branched-chain amino acids, high-density lipoproteins, low-density lipoproteins, glycemic measures, and hypertension.

In the large-scale prospective Women's Health Study of 25,315 initially healthy US women followed for 25 years, higher MED intake was associated with approximately one fifth relative risk reduction in mortality. The inverse association was only partially explained by known novel and traditional cardiometabolic factors.

Evidence suggests that individuals diagnosed with Parkinson's Disease (PD) spend less time in moderate-to-vigorous intensity physical activity (MVPA) compared to those without PD. However, prior studies primarily included men and did not consider movement across the entire intensity spectrum. To address these gaps, the association of PD status with total volume physical activity and time spent in sedentary, low light-intensity physical activity (LLPA), high light-intensity physical activity (HLPA), and MVPA among older women was examined. This is a cross-sectional analysis of 17,466 ambulatory women enrolled in the Women's Health Study (WHS) with a median (IQR) age of 70 (67-75) years who were asked to wear an accelerometer for 7 days from 2011 to 2015 for the ancillary study. Reported PD status was assessed via annual mail-in questionnaires prior to device wear. Compared to those without PD (n = 16,661), PD (n = 80) was associated with 98,400 fewer vector magnitude (VM) counts per day and with spending an average of 23.2 more minutes per day sedentary and 10.5 more minutes per day in LLPA. Further, PD was associated with spending 6.4 and 27.3 fewer minutes per day in HLPA and MVPA, respectively, compared to women without PD. PD in women is associated with more daily sedentary time and less time spent in health-enhancing physical activity. Prevention strategies to promote physical activity should be emphasized to enhance health and limit progression of disability in women living with PD.