Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases

Nutraceutical therapies for atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed

Statins for the primary prevention of cardiovascular disease.

BACKGROUND: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of CVD is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with CVD. The case for primary prevention was uncertain when the last version of this review was published (2011) and in light of new data an update of this review is required. OBJECTIVES: To assess the effects, both harms and benefits, of statins in people with no history of CVD. SEARCH METHODS: To avoid duplication of effort, we checked reference lists of previous systematic reviews. The searches conducted in 2007 were updated in January 2012. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2022, Issue 4), MEDLINE OVID (1950 to December Week 4 2011) and EMBASE OVID (1980 to 2012 Week 1).There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of statins versus placebo or usual care control with minimum treatment duration of one year and follow-up of six months, in adults with no restrictions on total, low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data. Outcomes included all-cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non-fatal CHD, CVD and stroke events), revascularisation, change in total and LDL cholesterol concentrations, adverse events, quality of life and costs. Odds ratios (OR) and risk ratios (RR) were calculated for dichotomous data, and for continuous data, pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated. We contacted trial authors to obtain missing data. MAIN RESULTS: The latest search found four new trials and updated follow-up data on three trials included in the original review. Eighteen randomised control trials (19 trial arms; 56,934 participants) were included. Fourteen trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (OR 0.86, 95% CI 0.79 to 0.94); as was combined fatal and non-fatal CVD RR 0.75 (95% CI 0.70 to 0.81), combined fatal and non-fatal CHD events RR 0.73 (95% CI 0.67 to 0.80) and combined fatal and non-fatal stroke (RR 0.78, 95% CI 0.68 to 0.89). Reduction of revascularisation rates (RR 0.62, 95% CI 0.54 to 0.72) was also seen. Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no evidence of any serious harm caused by statin prescription. Evidence available to date showed that primary prevention with statins is likely to be cost-effective and may improve patient quality of life. Recent findings from the Cholesterol Treatment Trialists study using individual patient data meta-analysis indicate that these benefits are similar in people at lower (< 1% per year) risk of a major cardiovascular event. AUTHORS' CONCLUSIONS: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins

The Effect of Curcumin on Reducing Atherogenic Risks in Obese Patients with Type 2 Diabetes: A Randomized Controlled Trial

Curcumin, derived from turmeric root, exhibits notable anti-inflammatory effects. These anti-inflammatory properties might also provide advantages in reducing cardiovascular complications, such as atherosclerosis. This study aimed to evaluate the efficacy of curcumin in reducing the risk of atherogenesis in obese patients with type 2 diabetes. The study employed a randomized, double-blind, placebo-controlled trial design with 227 participants diagnosed with type 2 diabetes. The parameters used to assess atherogenic risk reduction included pulse wave velocity and metabolic profiles, including low-density lipoprotein cholesterol and small dense low-density lipoprotein cholesterol. Measurements were recorded at baseline and at 3-, 6-, 9-, and 12-month intervals. After 12 months, participants receiving curcumin exhibited a significant reduction in pulse wave velocity (p &lt; 0.001). This group showed significantly reduced levels of cardiometabolic risk biomarkers, including low-density lipoprotein cholesterol and small dense low-density lipoprotein cholesterol, all with p values less than 0.001. High-sensitivity C-reactive protein, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were also significantly lower in the curcumin group, with p values less than 0.001. The curcumin intervention significantly reduced pulse wave velocity and improved cardiometabolic risk profiles. These findings suggest that curcumin treatment may effectively reduce atherogenic risks in type 2 diabetes patients with obesity

Curcumin Attenuates Liver Steatosis via Antioxidant and Anti-Inflammatory Pathways in Obese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial

Liver steatosis, the hallmark component of metabolic dysfunction-associated steatotic liver disease (MASLD), is particularly common among individuals with type 2 diabetes mellitus (T2DM). Shared mechanisms such as insulin resistance, oxidative stress, and chronic inflammation contribute to the coexistence of these conditions and accelerate disease progression, emphasizing the need for effective therapeutic strategies. In this 12-month, randomized, double-blind, placebo-controlled trial, 227 obese individuals with T2DM were assigned to receive either 1500 mg of curcumin daily or placebo. Curcumin significantly reduced liver fat content, liver stiffness, and glycated hemoglobin (HbA1c) compared with placebo (all p &lt; 0.001). Improvements were also noted in inflammatory mediators, including interleukin-1 beta (IL-1&beta;) and tumor necrosis factor-alpha (TNF-&alpha;) (all p &lt; 0.001), reflecting curcumin&rsquo;s anti-inflammatory effects. Antioxidant benefits were evident, as total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase (SOD) increased, while malondialdehyde levels decreased (all p &lt; 0.001). Systematic safety assessments, including liver and kidney function tests, revealed no clinically significant abnormalities. Mild gastrointestinal discomfort was the most common non-serious adverse event. Overall, these findings support curcumin as a safe and effective adjunctive therapy for improving liver steatosis in obese patients with T2DM

Curcumin extract improves beta cell functions in obese patients with type 2 diabetes: a randomized controlled trial

Abstract Background Type 2 diabetes mellitus (T2DM) is a chronic condition characterized by insulin resistance and impaired insulin production, leading to elevated blood glucose levels. Curcumin, a polyphenolic compound from Curcuma longa, has shown potential in improving insulin sensitivity and reducing blood glucose levels, which may help mitigate type 2 diabetes progression. Objective To assess the efficacy of improving type 2 diabetes (T2DM). Study design This randomized, double-blind, placebo-controlled trial included subjects (n = 272) with criteria for type 2 diabetes. Methods All subjects were randomly assigned to receive curcumin (1500 mg/day) or placebo with blind labels for 12 months. To assess the improvement of T2DM after curcumin treatments body weight and body mass index, fasting plasma glucose, glycosylated hemoglobin A1c, β-cell function (homeostasis model assessment [HOMA-β]), insulin resistance (HOMA-IR), insulin, adiponectin, and leptin were monitored at the baseline and at 3-, 6-, 9-, and 12-month visits during the course of intervention. Results After 12 months of treatment, the curcumin-treated group showed a significant decrease in fasting blood glucose (115.49 vs.130.71; P < 0.05), HbA1c (6.12 vs. 6.47; P < 0.05). In addition, the curcumin-treated group showed a better overall function of β-cells, with higher HOMA-β (136.20 vs. 105.19; P < 0.01) The curcumin-treated group showed a lower level of HOMA-IR (4.86 vs. 6.04; P < 0.001) and higher adiponectin (14.51 vs. 10.36; P < 0.001) when compared to the placebo group. The curcumin-treated group also showed a lower level of leptin (9.42 vs. 20.66; P < 0.001). Additionally, body mass index was lowered (25.9 4 vs.29.34), with a P value of 0.001. Conclusions A 12-month curcumin intervention in type 2 diabetes patients shows a significant glucose-lowering effect. Curcumin treatment appeared to improve the overall function of β-cells and reduce both insulin resistance and body weight, with very minor adverse effects. Curcumin intervention in obese patients with type 2 diabetes may be beneficial. Trial registration Thai clinical trials regentrify no.20140303003

Curcumin Reduces Depression in Obese Patients with Type 2 Diabetes: A Randomized Controlled Trial

Type 2 diabetes and depression co-occur in a bidirectional manner. Curcumin supplements exhibit antidepressant effects that may mitigate depression by modulating neurotransmitters and reducing inflammatory and oxidative stress pathways. This study aimed to evaluate the efficacy of curcumin in improving depression severity in obese type 2 diabetes patients. The study employed a randomized, double-blind, placebo-controlled trial design with 227 participants. The primary end-point was depression severity assessed using the Patient Health Questionnaire-9. Biomarkers were measured at baseline and at 3-, 6-, 9-, and 12-month intervals. The biomarkers assessed were serotonin levels, pro-inflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha), antioxidant activities (total antioxidant status, glutathione peroxidase, and superoxide dismutase), and malondialdehyde. After 12 months, the curcumin group exhibited significantly improved depression severity (p = 0.000001). The curcumin group had higher levels of serotonin (p &lt; 0.0001) but lower levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p &lt; 0.001 for all) than the placebo group. Total antioxidant status, glutathione peroxidase activity, and superoxide dismutase activity were elevated in the curcumin group, whereas malondialdehyde levels were greater in the placebo group (p &lt; 0.001 for all). These findings suggest curcumin may have antidepressant effects on obese type 2 diabetes patients