Curcumin and Ferroptosis: a Promising Target for Disease Prevention and Treatment.

Ferroptosis is a recently identified form of cell death characterized by iron accumulation and lipid peroxidation. Unlike apoptosis, necrosis, and autophagy, ferroptosis operates through a distinct molecular pathway. Curcumin, derived from turmeric rhizomes, is a natural compound with diverse therapeutic benefits, including neuroprotective, anti-metabolic syndrome, anti-inflammatory, and anti-cancer properties. Growing evidence suggests that curcumin possesses both pro-oxidant and antioxidant properties, which can vary depending on the cell type. In this review, we explore the relationship between the effects of curcumin and the molecular mechanisms underlying the ferroptosis signaling pathway, drawing from current in vivo and in vitro research. Curcumin has been found to induce ferroptosis in cancer cells while acting as an inhibitor of ferroptosis in tissue injuries. Notably, curcumin treatment leads to alterations in key ferroptosis markers, underscoring its significant impact on this process. Nonetheless, further research focused on elucidating this important attribute of turmeric is crucial for advancing disease treatment.

Regulatory effects of curcumin on nitric oxide signaling in the cardiovascular system.

The continuously rising prevalence of cardiovascular disease (CVD) globally substantially impacts the economic growth of developing countries. Indeed, one of the leading causes of death worldwide is unfavorable cardiovascular events. Reduced nitric oxide (NO) generation is the pathogenic foundation of endothelial dysfunction, which is regarded as the first stage in the development of a number of CVDs. Nitric oxide exerts an array of biological effects, including vasodilation, the suppression of vascular smooth muscle cell proliferation and the functional control of cardiac cells. Numerous treatment strategies aim to increase NO synthesis or upregulate downstream NO signaling pathways. The major component of Curcuma longa, curcumin, has long been utilized in traditional medicine to treat various illnesses, especially CVDs. Curcumin improves CV function as well as having important pleiotropic effects, such as anti-inflammatory and antioxidant, through its ability to increase the bioavailability of NO and to positively impact NO-related signaling pathways. In this review, we discuss the scientific literature relating to curcumin's positive effects on NO signaling and vascular endothelial function.

The Effect of Curcumin on the Gut-Brain Axis: Therapeutic Implications.

The gut-brain axis describes the bidirectional communication between the gut, the enteric nervous system, and the central nervous system. The gut-brain axis has attracted increasing attention owing to its regulatory effect on dysbiosis and a wide range of related diseases. Several types of nutrients, such as curcumin, have been proposed as regulators of the dysbiotic state, and preclinical experiments have suggested that curcumin is not only beneficial but also safe. This review focuses on the interplay between curcumin and the gut microbiota. Moreover, it provides a comprehensive review of the crosstalk between the gut-brain axis and disease, whilst also discussing curcumin-mediated gut-brain axis-dependent and -independent signaling about modulation of gut microbiota dysbiosis. This will help to define the utility of curcumin as a novel therapeutic agent to regulate intestinal microflora dysbiosis.

Impact of curcumin on p38 MAPK: therapeutic implications.

Curcumin (diferuloylmethane) is a herbal remedy which possesses numerous biological attributes including anti-inflammatory, anti-oxidant and anti-cancer properties. Curcumin has been shown to impact a number of signaling pathways including nuclear factor kappa B (NF-KB), reactive oxygen species (ROS), Wingless/Integrated (Wnt), Janus kinase-signal transducer and activator of mitogen-activated protein kinase (MAPK) and transcription (JAK/STAT). P38 belongs to the MAPKs, is known as a stress-activated MAPK and is involved in diverse biological responses. P38 is activated in various signaling cascades. P38 plays a role in inflammation, cell differentiation, proliferation, motility and survival. This cascade can serve as a therapeutic target in many disorders. Extensive evidence confirms that curcumin impacts the P38 MAPK signaling pathway, through which it exerts anti-inflammatory, neuroprotective, and apoptotic effects. Hence, curcumin can positively affect inflammatory disorders and cancers, as well as to increase glucose uptake in cells. This review discusses the pharmacological and therapeutic effects of curcumin as effected through p38 MAPK.

The effect of medicinal plants on cirrhosis: A systematic review of clinical trials.

Medicinal plants with minimal side effects, low cost, and liver-protective effects can be a suitable treatment option for cirrhosis. Therefore, this systematic review aimed to determine the effectiveness of herbal medicines on cirrhosis, a life-threatening liver disease. PubMed, Scopus, Web of Science, and Google Scholar were systematically searched for clinical trials that investigated the effect of medicinal plants on cirrhosis. This review includes 11 clinical trials, of which eight studies including 613 patients assessed the effect of silymarin on cirrhosis. Three of six studies showed the beneficial effects of silymarin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Two studies including 118 patients investigated the effect of curcumin on cirrhosis, one showing improvement in quality of life and the other showing improvements in alkaline phosphatase (ALP), bilirubin, prothrombin time (PT), and the international normalized ratio (INR). An article including four patients investigated the effect of ginseng on cirrhosis; two patients reported improvement in the Child-Pugh score, and ascites decreased in two. All studies included here reported no or negligible side effects. Results showed that medicinal plants including silymarin, curcumin, and ginseng have beneficial effects on cirrhosis. However, due to the limited number of studies, further high-quality studies are warranted.

Relationship between total vitamin D metabolites and complications in patients with type 2 diabetes.

In our previous study, it was shown that endogenous vitamin D3 and its metabolites are associated with diabetic microvascular complications and cardiovascular risk factors. The aim of the present study was to determine if the relationship between total vitamin D (vitamin D2 supplements plus endogenous vitamin D3) was a better predictor of complications in type 2 diabetes (T2DM). A total of 460 patients with T2DM participated in the present cross-sectional study. Plasma levels of total vitamin D and its metabolites (1,25-dihydroxyvitamin D (1,25(OH)D), 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)D) were measured by isotope-dilution liquid chromatography tandem mass spectrometry analysis. 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 were associated with diabetic retinopathy and coronary artery disease, but total 1,25-dihydroxyvitamin D and total 25-hydroxyvitamin D levels were not statistically associated with any complications. Total 1,25-dihydroxyvitamin D showed the same positive association as 1,25-dihydroxyvitamin D3 for hypertension and dyslipidemia, and total 25-hydroxyvitamin D showed the same positive association as 25-hydroxyvitamin D3 for dyslipidemia. Total 24,25-dihydroxyvitamin D showed the same positive association only with dyslipidemia as did 24,25-dihydroxyvitamin D3. However, total 25-hydroxyvitamin D was associated with hypertension, whereas 25-hydroxyvitamin D3 was not. Vitamin D3 metabolites were associated with diabetic retinopathy, whereas total vitamin D levels were not, suggesting that endogenous vitamin D3 metabolites are a better measure of diabetic microvascular complications. However, both total vitamin D and vitamin D3 metabolites were associated with cardiovascular risk factors in patients with type 2 diabetes.

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications.

BACKGROUND: Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications. RESEARCH DESIGN AND METHODS: Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. RESULTS: An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05). CONCLUSIONS: In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.

Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications.

BACKGROUND: Epidemiological studies have suggested that vitamin D deficiency is associated with the development of type 2 diabetes (T2DM) and is related to diabetes complications. This study was undertaken to determine the relationship between diabetes complications and cardiovascular risk factors with vitamin D3 and its metabolites: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 25-hydroxyvitamin D3 (25(OH)D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3); and 25-hydroxy-3epi-vitamin D3 (3epi25(OH)D3). METHODS: 750 Qatari subjects, 460 (61.3%) with and 290 (38.7%) without T2DM, who were not taking vitamin D3 supplements, participated in this cross-sectional, observational study. Plasma concentrations of vitamin D3 and its metabolites were measured by liquid chromatography tandem mass spectrometry analysis. RESULTS: T2DM subjects had lower concentrations of all vitamin D3 metabolites (p < 0.001) except 3epi25(OH)D3 (p < 0.071). Males had higher concentrations of all vitamin D3 metabolites (p < 0.001). In the T2DM subjects, lower 25(OH)D3 was associated with retinopathy (p < 0.03) and dyslipidemia (p < 0.04), but not neuropathy or vascular complications; lower 1,25(OH)2D3 was associated with hypertension (p < 0.009), dyslipidemia (p < 0.003) and retinopathy (p < 0.006), and coronary artery disease (p < 0.012), but not neuropathy; lower 24,25(OH)2D3 concentrations were associated with dyslipidemia alone (p < 0.019); 3epi25(OH)D3 associated with diabetic neuropathy alone (p < 0.029). In nondiabetics, 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3 were associated with dyslipidemia (p < 0.001, p < 0.001, p < 0.015, respectively) and lower 1,25(OH)2D3 was associated with hypertension (p < 0.001). Spearman's correlation showed 1,25(OH)2D3 to be negatively correlated to age and diabetes duration. CONCLUSIONS: Different diabetes complications were associated with differing vitamin D parameters, with diabetic retinopathy related to lower 25(OH)D3 and 1,25(OH)2D3 levels, hypertension significantly associated with lower 1,25(OH)2D3, while dyslipidemia was associated with lower 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3. While 25(OH)D metabolites were lower in females, there was not an exaggeration in complications.

Association of vitamin D2 and D3 with type 2 diabetes complications.

AIMS: Vitamin D measurement is a composite of vitamin D2 (25(OH)D2) and D3 (25(OH)D3) levels, and its deficiency is associated with the development of type 2 diabetes (T2DM) and diabetic complications; vitamin D deficiency may be treated with vitamin D2 supplements. This study was undertaken to determine if vitamin D2 and D3 levels differed between those with and without T2DM in this Middle Eastern population, and the relationship between diabetic microvascular complications and vitamin D2 and vitamin D3 levels in subjects with T2DM. METHODS: Four hundred ninety-six Qatari subjects, 274 with and 222 without T2DM participated in the study. Plasma levels of total vitamin D2 and D3 were measured by LC-MS/MS analysis. RESULTS: All subjects were taking vitamin D2 and none were taking D3 supplements. Vitamin D2 levels were higher in diabetics, particularly in females, and higher levels were associated with hypertension and dyslipidemia in the diabetic subjects (p < 0.001), but were not related to diabetic retinopathy or nephropathy. Vitamin D3 levels measured in the same subjects were lower in diabetics, particularly in females (p < 0.001), were unrelated to dyslipidemia or hypertension, but were associated with retinopathy (p < 0.014). Neither vitamin D2 nor vitamin D3 were associated with neuropathy. For those subjects with hypertension, dyslipidemia, retinopathy or neuropathy, comparison of highest with lowest tertiles for vitamin D2 and vitamin D3 showed no difference. CONCLUSIONS: In this Qatari cohort, vitamin D2 was associated with hypertension and dyslipidemia, whilst vitamin D3 levels were associated with diabetic retinopathy. Vitamin D2 levels were higher, whilst vitamin D3 were lower in diabetics and females, likely due to ingestion of vitamin D2 supplements.

Curcumin as a therapeutic agent in leukemia.

Leukemia comprises a group of hematological malignancies responsible for 8% of all cancers and is the most common cancer in children. Despite significant improvements in leukemia treatment, the efficacy of conventional chemotherapeutic agents is low and the disease carries a poor prognosis with frequent relapses and high mortality. Curcumin is a yellow polyphenol compound with diverse pharmacological actions including anticancer, antioxidant, antidiabetic, anti-inflammatory, immunomodulatory, hepatoprotective, lipid-regulating, antidepressant, and antiarthritic. Many cellular and experimental studies have reported the benefits of curcumin in treating leukemia. Curcumin's anticancer effects are exerted via various mechanisms. Here, we review the effects of curcumin on various types of leukemia whilst considering its mechanisms of action.

Protective effects of plant-derived natural products on renal complications.

Diabetic nephropathy is the leading cause of renal failure worldwide. This debilitating disorder has several underlying pathophysiologic mechanisms, and therefore a variety of pharmacologic agents have been developed to prevent or treat diabetic nephropathy; however, synthetic drugs may possess unfavorable side effects. In response to this, the global use of herbal-based pharmacologic agents is increasing among diabetic patients. Numerous studies have reported therapeutic benefits of herbal-based compounds against diabetes-induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.

Curcumin as a therapeutic candidate for multiple sclerosis: Molecular mechanisms and targets.

Multiple sclerosis (MS) is a disease that has shown a considerable increase in prevalence in recent centuries. Current knowledge about its etiology is incomplete, and therefore it cannot be managed optimally utilizing targeted therapeutic regimens at each stage of the disease. MS progresses in different stages, beginning with a cascade of inflammation. The pivotal spark to initiate this cascade seems to be the migration of Th17 into the central nervous system across the blood-brain barrier (BBB) through the disrupted tight junctions. Coupling of interleukin (IL)-17 and IL-22 to their receptors in the BBB layer facilitates this migration. Subsequently, axon degeneration and the various manifestations of nerve-muscle disorders appear. Curcumin, a major component of turmeric, is derived from Curcuma longa, which belongs to the Zingiberaceae family. Numerous properties of curcumin have been identified recently, some of which can be effective in the treatment of MS, particularly the anti-inflammatory properties via inhibition of secretion of proinflammatory cytokines. In this paper, we will review the various properties and key effects of curcumin for the treatment of MS.

Antidiabetic potential of saffron and its active constituents.

The prevalence of diabetes mellitus is growing rapidly worldwide. This metabolic disorder affects many physiological pathways and is a key underlying cause of a multitude of debilitating complications. There is, therefore, a critical need for effective diabetes management. Although many synthetic therapeutic glucose-lowering agents have been developed to control glucose homeostasis, they may have unfavorable side effects or limited efficacy. Herbal-based hypoglycemic agents present an adjunct treatment option to mitigate insulin resistance, improve glycemic control and reduce the required dose of standard antidiabetic medications. Saffron (Crocus sativus L.), whilst widely used as a food additive, is a natural product with insulin-sensitizing and hypoglycemic effects. Saffron contains several bioactive ß carotenes, which exert their pharmacological effects in various tissues without any obvious side effects. In this study, we discuss how saffron and its major components exert their hypoglycemic effects by induction of insulin sensitivity, improving insulin signaling and preventing ß-cell failure, all mechanisms combining to achieve better glycemic control.

Evidence of curcumin and curcumin analogue effects in skin diseases: A narrative review.

Curcumin, a natural polyphenolic and yellow pigment obtained from the spice turmeric, has strong antioxidative, anti-inflammatory, and antibacterial properties. Due to these properties, curcumin has been used as a remedy for the prevention and treatment of skin aging and disorders such as psoriasis, infection, acne, skin inflammation, and skin cancer. Curcumin has protective effects against skin damage caused by chronic ultraviolet B radiation. One of the challenges in maximizing the therapeutic potential of curcumin is its low bioavailability, limited aqueous solubility, and chemical instability. In this regard, the present review is focused on recent studies concerning the use of curcumin for the treatment of skin diseases, as well as offering new and efficient strategies to optimize its pharmacokinetic profile and increase its bioavailability.

Therapeutic use of curcumin-encapsulated and curcumin-primed exosomes.

Curcumin, the bioactive pigment of turmeric which has polyphenolic-hydrophobic components, has been used for the treatment of a variety of diseases. However, due to its insignificant intestinal-liver metabolism, low stability, quick systemic elimination and its hydrophobic property with low solubility, curcumin has limited bioavailability. Exosomes are nanovesicles (30-100 nm) released from diverse cell types into extracellular and, ultimately, into bio-fluids in a tightly regulated manner. Exosomes are capable of transferring lipids, proteins, RNAs and DNAs, both with and without direct cell-to-cell contact. Curcumin-encapsulated exosomes are highly bioavailable, soluble and safe, and can reach high concentrations in the blood; they, therefore, have therapeutic potential without toxic effects and immune stimulation. Thus, curcumin-encapsulated exosomes could be superior to other synthetic nanoparticles as a carrier of curcumin. The aim of the current review is to offer an overview of the in vitro, in vivo and clinical studies pertaining to the role of curcumin-primed and curcumin-encapsulated exosomes in the treatment of cancer, oxidative stress, brain disorders, cholesterol, and endothelial dysfunction.

Therapeutic potential of curcumin in diabetic complications.

Diabetes mellitus is an extremely prevalent endocrine disease and a major global public health concern. Diabetic complications, such as retinopathy, nephropathy, neuropathy and cardiovascular disease, are common and majorly impact a patient's quality of life. Curcumin, the major active component of turmeric, possesses extensive known pharmacological properties, including anti-inflammatory, antioxidant, and antitumor effects. Increasing evidence suggests that curcumin may offer protection against diabetic complications. The current review focuses on the possible molecular targets and pathways involved in diabetic complications and, in particular, the multi-target approach of curcumin in attenuating diabetic nephropathy, retinopathy, and neuropathy.

Impact of curcumin on sirtuins: A review.

Curcumin is a bioactive phytochemical that modulates several physiological and cellular processes leading to therapeutic effects against different diseases. Sirtuins are highly conserved nicotine adenine dinucleotide-dependent proteins that regulate the activity of target enzymes and transcription factors by deacetylation. Curcumin possesses both antioxidant and anti-inflammatory properties and has been shown to increase sirtuin-1 (SIRT1) by activating small molecules. Upregulation of SIRT1 by curcumin has been reported to confer protective effects against a range of neurological disorders including glutamate excitotoxicity, ß-amyloid-induced cell death in cortical neurons, cerebral ischemic damage, and stroke. Activation of AMPK and SIRT1 by curcumin has also been noted to mediate the protective effects of curcumin against ischemia/reperfusion injury, cardiac fibrosis, diabetes, and lipid metabolism abnormalities. These protective effects of SIRT1 activation are partly mediated by the deacetylation of p53 and reduction of apoptosis. In this review, we summarize the role of SIRT1 in mediating the pharmacological effects of curcumin in several diseases.

The protective role of curcumin in myocardial ischemia-reperfusion injury.

Coronary artery disease (CAD) is a well-known pathological condition that is characterized by high morbidity and mortality. The main pathological manifestation of CAD is myocardial injury due to ischemia-reperfusion (I-R). Currently, no efficacious treatment of protecting the heart against myocardial I-R exists. Hence, it is necessary to discover or develop novel strategies to prevent myocardial-reperfusion injury to improve clinical outcomes in patients with CAD. A large body of experimental evidence supports cardioprotective properties of curcumin and the ability of this phytochemical to modify some cardiovascular risk factors. However, the detailed effects of curcumin in myocardial I-R injury are still unclear and there is a lack of evidence concerning which curcumin regimen may be ideal for myocardial I-R injury. This paper presents a brief review of the pathophysiology of myocardial I-R injury and the mechanisms of action of curcumin in reducing myocardial I-R injury.

The versatile role of curcumin in cancer prevention and treatment: A focus on PI3K/AKT pathway.

Despite significant advances in treatment modalities, millions of cancer-related deaths continue to occur annually, often as a consequence of developing resistance against the range of available chemotherapeutic drugs. Furthermore, available anti-cancer chemotherapeutic agents show limited efficacy, often have severe side effects, and are expensive. Thus, the discovery of pharmacological agents that do not have these disadvantages is necessary. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa L.), is one such agent that has been widely studied for its anti-inflammatory and/or anti-cancer effects. Curcumin exerts its anti-cancer effect by suppressing the initiation, progression, and metastasis of a variety of cancers and appears to inhibit carcinogenesis by affecting two main processes: angiogenesis and tumor growth. These anti-cancer effects are largely mediated via negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. The PI3K/AKT pathway is commonly activated in cancer initiation and progression. Considered to be the key signaling pathway, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway therefore represents a key target for cancer therapeutics. In the current review, we focus upon curcumin's targeting of PI3K/AKT in different malignancies to effect inhibition of cancer development and progression.

Curcumin in heart failure: A choice for complementary therapy?

Heart failure is a major public health concern and one of the most common reasons for a cardiac hospital admission. Heart failure may be classified as having a reduced or preserved ejection fraction and its severity is based on the symptom score. Given the aging population, it is predicted that admissions with heart failure will increase. Whilst pharmacological therapy has improved the associated morbidity and mortality, there is a need for additional therapies to improve the clinical outcome as the death rate remains high. Curcumin is a natural product derived from turmeric that appears to have cardiovascular benefit through a number of mechanisms. In this review, we have assessed the mechanisms by which curcumin may exert its effects in different models of heart failure and show that it has promise as a complementary treatment in heart failure.