Article

Curcuminoids Target Decreasing Serum Adipocyte-fatty Acid Binding Protein Levels in Their Glucose-lowering Effect in Patients with Type 2 Diabetes

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Abstract

Whether supplementation of curcuminoids decreases serum adipocyte-fatty acid binding protein (A-FABP) level and whether this decrease benefits glucose control is unclear. One-hundred participants (n=50 administered curcuminoids, n=50 administered placebo) from our previous report on the effect of curcuminoids on type 2 diabetes in a 3-month intervention were assessed for levels of serum A-FABP, oxidative stress, and inflammatory biomarkers. Curcuminoids supplementation led to significant decreases in serum A-FABP, C-reactive protein (CRP), tumor necrosis factor-α, and interleukin-6 levels. Curcuminoids supplementation also significantly increased serum superoxide dismutase (SOD) activity. The change in serum A-FABP levels showed positive correlations with changes in levels of glucose, free fatty acids (FFAs), and CRP in subjects supplemented with curcuminoids. Further stepwise regression analysis showed that A-FABP was an independent predictor for levels of FFAs, SOD, and CRP. These results suggest that curcuminoids may exert anti-diabetic effects, at least in part, by reductions in serum A-FABP level. A-FABP reduction is associated with improved metabolic parameters in human type 2 diabetes.

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... The clinical trials used different doses of curcumin. Two studies investigated curcumin 300 mg/day [25,26], three studies investigated curcumin 1 g/day [27][28][29] and two studies investigated curcumin 1.5 g/day [4,30]. The range of intervention periods was from four weeks [7] up to three months [26]. ...
... Two studies investigated curcumin 300 mg/day [25,26], three studies investigated curcumin 1 g/day [27][28][29] and two studies investigated curcumin 1.5 g/day [4,30]. The range of intervention periods was from four weeks [7] up to three months [26]. Study design of all included studies was parallel-group, except one which was cross-over design [28]. ...
... Study design of all included studies was parallel-group, except one which was cross-over design [28]. Selected studies enrolled subjects with obesity [26,28], type 2 diabetes [25,26], type 2 diabetic nephropathy [30], major depressive disorder [27], knee osteoarthritis [4], metabolic syndrome [5], and sulfur mustard-exposed veterans [7]. Demographic and biochemical characteristics of the evaluated studies are presented in Table 1. ...
Article
Background: Tumor necrosis factor-α (TNF-α) is a key inflammatory mediator and its reduction is a therapeutic target in several inflammatory diseases. Curcumin, a bioactive polyphenol from turmeric, has been shown in several preclinical studies to block TNF-α effectively. However, clinical evidence has not been fully conclusive. Objective: The aim of the present meta-analysis was to evaluate the efficacy of curcumin supplementation on circulating levels of TNF-α in randomized controlled trials (RCTs). Methods: The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to September 21, 2015, to identify RCTs investigating the impact of curcumin on circulating TNF-α concentration. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Results: Eight RCTs comprising nine treatment arms were finally selected for the meta-analysis. There was a significant reduction of circulating TNF-α concentrations following curcumin supplementation (WMD: -4.69pg/mL, 95% CI: -7.10, -2.28, p<0.001). This effect size was robust in sensitivity analysis. Meta-regression did not suggest any significant association between the circulating TNF-α-lowering effects of curcumin with either dose or duration (slope: 0.197; 95% CI: -1.73, 2.12; p=0.841) of treatment. Conclusion: This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating TNF-α concentration.
... Data were pooled from 9 eligible studies [41][42][43][44][45][46][47][48][49] comprising 10 treatment arms which included 609 subjects, with 305 in the curcuminoids arm and 304 in the control arm (participants enrolled from the cross-over trial were considered in both arms). Included studies were published between 2008 and 2015. ...
... The dose of curcuminoids used changed in the various trials. One study reported effects of curcuminoids 200 mg/day [41], two studies reported effects of curcuminoids 300 mg/day [42,43], three studies of curcuminoids 1 g/day [44][45][46], two studies of curcuminoids 1.5 g/day [47,48], and one study curcuminoids 6 g/day [49]. The range of intervention periods was from 2 weeks [49] up to 8 months [41]. ...
... One study reported effects of curcuminoids 200 mg/day [41], two studies reported effects of curcuminoids 300 mg/day [42,43], three studies of curcuminoids 1 g/day [44][45][46], two studies of curcuminoids 1.5 g/day [47,48], and one study curcuminoids 6 g/day [49]. The range of intervention periods was from 2 weeks [49] up to 8 months [41]. Study design of almost all included studies was parallelgroup, except one which was cross-over design [44]. ...
Article
The aim of this meta-analysis was to evaluate the efficacy of curcuminoids supplementation on circulating concentrations of IL-6 in randomized controlled trials (RCTs). The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to November 01, 2015, to identify RCTs investigating the impact of curcuminoids on circulating IL-6 concentrations. Nine RCTs comprising 10 treatment arms were found to be eligible for the meta-analysis. There was a significant reduction of circulating IL-6 concentrations following curcuminoids supplementation (WMD: -0.60pg/mL, 95% CI: -1.06, -0.14, p=0.011). Meta-regression did not suggest any significant association between the circulating IL-6 lowering effects of curcuminoids with either dose or duration of treatment. There was a significant association between the IL-6-lowering activity of curcumin and baseline IL-6 concentration (slope: -0.51; 95% CI: -0.80, -0.23; p=0.005). This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating IL-6 concentrations. This effect appears to be more evident in patients with higher degrees of systemic inflammation.
... In 20 investigations, a variety of curcuminoid preparations were administered to subjects with T2DM. [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] For those trials evaluating raw turmeric powder or curcuminoid fractions, no consistent effects were noted for measures of FBG, HbA 1c , lipid profiles, antioxidant status, and IR. Doses administered were from 66 mg/d to 1.3 g/d for periods of 4 weeks to 6 months. ...
... Powdered turmeric or C-fraction: inconsistent or no effect on BG, BP, serum lipids, leptin, body fat, blood oxidative stress markers (↓IR measured from only 1 study) C-fraction + piperine: inconsistent or no effect on serum lipids, cytokines [68][69][70][71][72][73][74][75][76][77] Prediabetes, hypercholesterolemia Powdered turmeric or C-fraction: inconsistent or no effect on BG, BP, BMI, HbA 1c , IR, serum lipids, blood oxidative stress markers; ↓serum cytokines C-fraction + hypoglycemics vs hypoglycemics: drug-dependent improvements in serum lipids or BG C-fraction + piperine: (↓TC, ↓HbA 1c , ↓Lp(a), ↓leptin, ↓MDA, ↑adiponectin, ↑SOD measured from only 1 study) Lipidated C-fraction: ↓foot microangiopathy, ↓retinal edema, ↑retinal systolic flow, ↑visual acuity, ↑microcirculation Nanoparticles of C-fraction: inconsistent or no effect on BG, serum lipids; ↓HbA 1c , ↓neuropathy [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] MetS Dose range 400 mg/d to 2.4 g/d Treatment lengths 1-12 mo ...
... Based on the meta-analysis of Azhdari et al 126 of MetS RCTs, [104][105][106][107]116,127 curcuminoid intake was associated with improvements in FBG, TG, and high-density lipoprotein (HDL) levels and diastolic blood pressure. Another meta-analysis 128 of prediabetes and T2DM trials, which were typically of 2-to 3-month duration, 78,83,85,88,89,92,93,129 found that curcuminoids significantly decreased HbA 1c levels in prediabetes and T2DM and decreased FBG levels in T2DM, but no significant improvement in lipid profiles was observed. It is worth noting that in this meta-analysis these authors conducted a separate sensitivity analysis to assess the statistical robustness of their findings. ...
Article
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For centuries, Curcuma longa (turmeric) was used as a spice in Asian cuisine and as a medicinal herb for treatment of inflammation, pain, wound healing, and digestive disorders, to name a few. Considerable preclinical research found that turmeric and its bioactive curcuminoid polyphenols can affect a variety of chronic conditions. Poor oral bioavailability of these curcuminoids hindered human trials investigating the efficacy of oral turmeric and its curcuminoids in treating various diseases and disorders. However, with the development of absorption-enhanced curcuminoid formulations in the past decade, dozens of clinical studies were conducted examining this spice's actions toward inflammatory conditions and glucose/lipid dysregulation. This narrative review of human trials addresses the scientific evidence for potential health benefits of turmeric and its curcuminoids in the treatment of arthritis, diabetes, and the metabolic syndrome and discusses recommendations for future research.
... Antidiabetic effects of curcumin is well established using human subjects in recent years [19,65,22,23] . According to Thota ]et al. [19] , curcumin significantly decreased the post prandial glycemia. ...
... According to Thota ]et al. [19] , curcumin significantly decreased the post prandial glycemia. In brief, there was a reduction in the body weight, BMI, blood glucose levels [22,23,64,65] . Moreover, curcumin significantly reduced glycated hemoglobin (HbA1C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) levels, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in subjects within 8 weeks [22] . ...
... Elburki et al [102] has recently determined that curcumin caused a significant reduction in pathologically excessive levels of inducible MMPs, local and systemic inflammation and prevented from hyperglycemia-and bacteria-induced connective tissue which is unfavorable for wound healing. Curcuminoids has shown to possess significant anti-inflammatory, antioxidant, anti-carcinogenic, anticoagulant, anti-infective and anti-diabetic effects [65,77,103] . ...
Article
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Background: Diabetes mellitus, remains a metabolic disorder which is alarmingly rising in the world. It is characterized by hyperglycemia, and associates relative or absolute insulin deficiency or resistance. Disruption of the metabolism may cause lot of micro and macro vascular complications mostly affecting vital organs like kidneys, heart, eyes, and nerves. Objective: To discuss the potential of C. longa and its constituent curcumin in treatment of diabetes mellitus and its complications. Method: An electronic search was performed using Science Direct, Scopus, Springer link, PubMed, Google scholar and collected articles in English up to 2020 August 15 relating to C. longa and curcumin in treatment of diabetes mellitus and its complications. Results: C. longa root or rhizome is an indigenous herb used as a spice in Asian cuisine for thousand years and known to have various therapeutic, medicinal applications for various diseases including diabetes. Curcumin is the major polyphenolic constituent of, C. longa. Human and animal researches conducted using C. longa and curcumin have proven that, the usage of C. longa is beneficial for the treatment of diabetes mellitus including diabetic complications. Curcumin has been reported to prevent the development of diabetes by exerting its cellular effects via various molecular mechanisms. Therapeutic potential of curcumin has been reported against various diabetic complications such as nephropathy, retinopathy, cardiac myopathy, etc. in numerous preclinical and clinical studies. Conclusion: These findings might enable to design and practice novel treatment strategies for diabetes mellitus and its complications, and promote inclusion of C. longa in clinical practice for the treatment of diabetes mellitus and diabetes related diseases. Furthermore, C. longa clinically proven ailment for many diseases including diabetes could be consumed as a safe ingredient of healthy diet. More attention should be extended towards conducting further research on this valuable molecule to utilize it as a therapeutic agent for the treatment of diabetes mellitus and other human diseases.
... In the treatment of diabetes, there is also evidence to support curcumin as a part of the diabetes treatment program [14,15]. At present, many randomized controlled trials (RCTs) on the treatment of T2DM with curcumin have been published [11,[16][17][18][19][20][21][22], but there is still no systematic review and meta-analysis to assess the effects and safety of curcumin. erefore, we decide to perform a systematic review and meta-analysis for the first time to evaluate the clinical effects of curcumin on T2DM. ...
... Twelve records met the inclusion criteria [11,[16][17][18][19][20][21][22][31][32][33][34] 3.3.1. Sequence Generation. ...
... Panahi et al. [16][17][18][19] and Khajehdehi et al. [22] failed to describe the method of randomization, and we therefore rated it as having an unclear risk of bias. Na et al. [20,21], Chuengsamarn et al. [11], and ota et al. [33] utilized a computer-generated random list, and Asadi et al. [31,32] and Adibian et al. [34] utilized block randomization, so they were thought to have low risks of bias. Studies included in quantitative synthesis (meta-analysis) (n = 12) Evidence-Based Complementary and Alternative Medicine ...
Article
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Background: Diabetes is a major public health concern. In addition, there is some evidence to support curcumin as part of a diabetes treatment program. Methods: Data from randomized controlled trials were obtained to assess the effects of curcumin versus placebo or western medicine in patients with type 2 diabetes mellitus (T2DM). The study's registration number is CRD42018089528. The primary outcomes included homeostasis model assessment-insulin resistance (HOMA-IR), glycosylated hemoglobin (HbAlc), total cholesterol (TC), and triglyceride (TG). Results: Four trials involving 453 patients were included. The HOMA-IR of curcumin group is lower in Asia (WMD: -2.41, 95% CI: -4.44 to -0.39, P=0.02) and the Middle East subgroups (WMD: -0.60, 95% CI: -0.74 to -0.46, P < 0.00001). The HbAlc in the curcumin group is lower than that in the control group (WMD: -0.69; 95% CI: -0.91, -0.48; P < 0.0001). The TC and TG levels of the curcumin group are lower in the Asia subgroup (TC: WMD: -23.45, 95% CI: -40.04 to -6.84, P=0.006; TG: WMD: -54.14, 95% CI: -95.71 to -12.57, P=0.01), while in the Middle East the difference was of not statistically significant (TC: WMD: 22.91, 95% CI: -16.94 to 62.75, P=0.26; TG: WMD: -4.56, 95% CI: -19.28 to 10.16, P=0.54). Conclusion: Based on the current evidence, curcumin may assist in improving the insulin resistance, glycemic control, and decreased TG and TC in patients with T2DM.
... There have been at least 8 studies conducted on the efficacy of curcumin supplements on type 2 diabetes mellitus [27][28][29][30][31][32][33][34], as summarized in Table 2. Included studies were placebo controlled and randomized clinical trials. The average duration of curcumin intake ranged from 4 to 36 weeks. ...
... A total of five studies reported significantly improved clinical outcomes in the curcumin group [27,[30][31][32]34]. Six studies reported three or more improved laboratory measures [27][28][29][30]33,34]. Three included studies assessed the effect of curcumin supplementation on sequelae associated with T2DM such as atherosclerosis [27] and diabetic microangiopathy [31,32]. ...
... In 2014, Na LX et al. investigated the role of serum adipocyte fatty acid binding protein (A-FABP) in regulating fatty acid metabolism and metabolic syndrome in patients taking curcumin [28]. A-FABP is a cytoplasmic protein implicated in intracellular fatty acid trafficking. ...
Article
Full-text available
Over recent decades, many clinical trials on curcumin supplementation have been conducted on various autoimmune diseases including osteoarthritis, type 2 diabetes, and ulcerative colitis patients. This review attempts to summarize the highlights from these clinical trials. The efficacy of curcumin either alone or in conjunction with existing treatment was evaluated. Sixteen clinical trials have been conducted in osteoarthritis, 14 of which yielded significant improvements in multiple disease parameters. Eight trials have been conducted in type 2 diabetes, all yielding significant improvement in clinical or laboratory outcomes. Three trials were in ulcerative colitis, two of which yielded significant improvement in at least one clinical outcome. Additionally, two clinical trials on rheumatoid arthritis, one clinical trial on lupus nephritis, and two clinical trials on multiple sclerosis resulted in inconclusive results. Longer duration, larger cohort size, and multiple dosage arm trials are warranted to establish the long term benefits of curcumin supplementation. Multiple mechanisms of action of curcumin on these diseases have been researched, including the modulation of the eicosanoid pathway towards a more anti-inflammatory pathway, and the modulation of serum lipid levels towards a favorable profile. Overall, curcumin supplementation emerges as an effective therapeutic agent with minimal-to-no side effects, which can be added in conjunction to current standard of care.
... It is worth mentioning that the decrease in glucose was only 18% and that of glycosylated hemoglobin was 11% compared to baseline within the group. The same group later found that the reduction in free fatty acid levels could be due to curcumin diminishes adipocyte-fatty acid binding protein (A-FABP) [162], an adipokine secreted from adipocytes [163] and other tissues that coordinate lipid-mediated processes [164]. ...
... Spranger et al. [175] identified increased levels of the inflammatory cytokine IL-6 as an independent predictor of incident type 2 diabetes in a European population. In this regard, a recent metaanalysis concluded that curcumin supplementation could be useful to lower circulating IL-6 levels; in the specific case of diabetes, two randomized, placebo-controlled studies in individuals with type 2 diabetes, found that curcumin lowers circulating IL-6 and TNF-a [162,176]. ...
Article
Full-text available
Turmeric or Curcuma longa is a natural product, whose medicinal properties have been extensively studied and a wide variety of therapeutic effects on several diseases such as neurodegenerative, hepatic and renal damage, cancer, and diabetes have been mainly attributed to its curcuminoid content. In the last decades, diabetes mellitus has become an alarming worldwide health issue, because of the increasing number of people suffering from the disease, as well as the devastating consequences for them. In this paper, we review the current basic and clinical evidence about the potential of curcumin/curcuminoids for the treatment of diabetes mellitus, mainly by its hypoglycemic, antioxidant, and anti-inflammatory properties. The activity of curcumin (or curcuminoids) as a hypoglycemic agent or just as an adjuvant to improve the metabolic profile and to ameliorate the associated complications of diabetes mellitus, such as diabetic nephropathy and cardiopathy is discussed. The interactions between curcumin and conventional antidiabetic drugs might be explored for the therapeutic management of diabetes mellitus.
... Administration of curcuminoids (300 mg/day) for 3 months to overweight T2DM individuals resulted in significantly reduced serum adipocyte-fatty acid binding protein (A-FABP) levels, suggesting reduced lipolysis in adipose tissue [83]. Pro-inflammatory cytokines TNF-α and IL-6 serum levels were reduced, while SOD activity was increased in T2DM individuals treated with curcuminoids. ...
... Pro-inflammatory cytokines TNF-α and IL-6 serum levels were reduced, while SOD activity was increased in T2DM individuals treated with curcuminoids. Correlational data analysis indicated that serum A-FABP levels were positively correlated to serum glucose, FFAs and c-reactive protein (CRP) levels with curcuminoid supplementation [83]. These data suggest that curcuminoid's reduction of serum A-FABP levels is associated with reduced T2DM metabolic parameters. ...
Article
Full-text available
Type 2 diabetes mellitus (T2DM) is a growing metabolic disease characterized by insulin resistance and hyperglycemia. Current preventative and treatment approaches to insulin resistance and T2DM lack in efficacy, resulting in the need for new approaches to prevent and treat the disease. In recent years, epidemiological studies have suggested that diets rich in fruits and vegetables have beneficial health effects, including protection against insulin resistance and T2DM. Curcumin, a polyphenol found in turmeric, and curcuminoids have been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, neuroprotective, immunomodulatory and antidiabetic properties. The current review (II of II) summarizes the existing in vivo studies examining the antidiabetic effects of curcumin.
... A meta-analysis of 8 randomised controlled trials (RCTs) [79,[100][101][102][103][104][105][106] in subjects with a variety of diseases showed that curcuminoids significantly lowered CRP levels (by a mean 2.2 mg/L) compared with a placebo [107]. In a meta-analysis of RCTs [108][109][110][111][112][113], curcumin significantly reduced TNF-α (weight mean difference −4.69 pg/mL; 95% CI: −7.10, −2.28; p < 0.001) [114]. In a meta-analysis of 9 RCTs [102,103,106,108,109,111,112,115,116] in subjects with different diseases, curcumin significantly lowered IL-6 by 0.6 pg/mL (P = 0.01) compared with control [117]. ...
... In a meta-analysis of RCTs [108][109][110][111][112][113], curcumin significantly reduced TNF-α (weight mean difference −4.69 pg/mL; 95% CI: −7.10, −2.28; p < 0.001) [114]. In a meta-analysis of 9 RCTs [102,103,106,108,109,111,112,115,116] in subjects with different diseases, curcumin significantly lowered IL-6 by 0.6 pg/mL (P = 0.01) compared with control [117]. Curcumin supplement (1 g/day, n = 59) for 8 weeks significantly decreased TNF-α, IL-6, transforming growth factor beta (TGF-β) and monocyte chemoattractant protein 1 (MCP-1) compared with placebo [112]. ...
Article
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Current research indicates curcumin [diferuloylmethane; a polyphenolic compound isolated from the rhizomes of the dietary spice turmeric (Curcuma longa)] exerts a beneficial effect on health which may be partly attributable to its anti-oxidative and anti-inflammatory properties. The aim of this review is to examine potential mechanisms of the actions of curcumin in both animal and human studies. Curcumin modulates relevant molecular target pathways to improve glucose and lipid metabolism, suppress inflammation, stimulate antioxidant enzymes, facilitate insulin signalling and reduce gut permeability. Curcumin also inhibits Aβ and tau accumulation in animal models and enhances mitochondria and synaptic function. In conclusion, in high-dose animal studies and in vitro, curcumin exerts a potential beneficial effect on cardiometabolic disease. However, human studies are relatively unconvincing. More intervention studies should be conducted with the new curcumin formulation with improved oral bioavailability.
... In another study by Ghorbani et al., curcumin was said to regulate blood sugar levels through reduced glucose production in the liver and increased insulin secretion, which leads to a reduction of insulin resistance [229]. It has also been shown by Na et al. that turmeric has anti-diabetic and anti-hyperglycaemic effects [230]. With all the positive health effects of turmeric that have been reported in literature, it would be interesting to see whether these effects could be related to the BAs by studying postprandial BA response (paper V). ...
Thesis
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Bile acids (BA) are formed from cholesterol in the liver and, apart from being part of fat digestion, they also act as signalling molecules in several health-related physiological processes. BA composition is regulated by gut microbiota as well as dietary fibre (DF) and fat in the diet. This thesis describes how different types of DF and fat levels, can alter BA composition in the caecum/faeces and blood. One methodology for analysing BAs in caecum was developed, while another methodology was set up to analyse BAs in blood/serum samples. In the first study, the method developed for BA analysis in caecum materials was based on hollow-fibre liquid-phase microextraction followed by gas chromatography with flame ionization detector. The method was applied by analysing the caecum content of rats fed three diets containing fermentable DF: pectin, guar gum and a mixture of the two, and a fibre-free control diet. All diets containing DF increased the total amounts of BAs related to beneficial health effects and reduced the amounts of those connected to diseases and cancers. Furthermore, an in vivo study of rats given guar gum of three different viscosities and pectin with two different degrees of methoxylation in low-fat (LF) and high-fat (HF) settings was performed. Guar gum with medium viscosity showed the best BA profile, containing higher amounts of BAs connected to health, and lower amounts of BAs associated with disease. There was a strong correlation between the gut microbiota, BAs and caecal short-chain fatty acids (SCFAs). BAs with beneficial health properties and SCFAs, with the exception of valeric acid, correlated positively with Bifidobacterium and RF32 and they were higher in groups fed fibre. The amounts of BAs connected to diseases were positively correlated with Firmicutes and were higher in groups fed the fibre-free control diet. The pectins behaved similarly and their effects on BA compositions were less pronounced. In study III, two barley varieties with different levels of DF and β-glucan in LF and HF settings were evaluated. In the LF groups, the higher content of β-glucan showed higher amounts of the health-promoting BAs, while in the HF setting the group with medium β-glucan content and highest amounts of arabinoxylan showed an increase in these BAs. The arabinoxylan seemed to be more effective at reducing the levels of BAs connected with negative effects (than the β-glucan), both in LF and HF settings. The BAs with beneficial health effects were associated with Bifidobacterium and Lactobacillus and their abundance was higher in LF diets. In study IV, free and conjugated BAs in serum samples from hearts of mice were determined using simple protein precipitation followed by ultra-high-performance liquid chromatography–mass spectrometry. Different lingonberry samples, consisting of soluble, insoluble or whole lingonberry fractions in a HF diet or cellulose in LF and HF diets, were investigated. The whole lingonberries showed a healthier BA profile and a greater abundance of Bifidobacterium and Prevotella. In study V, postprandial serum concentrations of BAs in healthy subjects after consumption of a turmeric-based beverage prior to medium-fat and HF breakfasts were registered. Turmeric could modify the BA profile towards a healthier composition, with higher levels of free and conjugated forms of cholic and ursodeoxycholic acids as well as free and taurine-conjugated forms of chenodeoxycholic acid but lower levels of conjugated forms of deoxycholic acid. In conclusion, using the new set of methodologies, the BA composition in rat caecum and in mice and human serum could be studied after the intake of different diets. The type and functional properties of prebiotic chosen, and the amount of fat can affect the BA profile and gut microbiota composition. A HF diet increased the total amounts of BAs in blood and caecum, as usually assumed. Less well-known is that fermentable DF can also shape the BA profile. The results of this work may be the basis for development of prebiotic food products for the promotion of improved BA metabolism and overall health.
... Curcumin showed liver protection in acute and chronic liver injury [31]. Gu et al. [44] demonstrated that curcumin supplementation decreased the production of ALT, proinflammatory cytokines such as TNF-a and IFN-c, and CRP, IL-6 levels [45,46] and, as a result, reduced hepatocyte apoptosis. ...
Article
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Aims Evidence indicates that curcumin seems to improve outcomes in non-alcoholic fatty liver disease (NAFLD). A meta-analysis was performed to evaluate the effects of curcumin inNAFLD. Methods We searched PubMed, EMBASE, and the Cochrane Library from inception through March 2018 to identify randomized controlled trials (RCTs) evaluating the role of curcumin inNAFLD. The mean difference (MD) and 95% confidence interval (CI) were calculated. Results Four RCTs with a total of 229 NAFLD patients were included. Curcumin was more likely to lower LDL-C, triglycerides, FBS, HOMA-IR, weight and AST levels compared with placebo, and the difference was statistically significant [MD = − 27.02, 95% CI (− 52.30, − 1.74); MD = − 33.20, 95% CI (− 42.30, − 24.09); MD = − 5.63, 95% CI (− 10.36, − 0.90); MD = − 0.53, 95% CI (− 1.00, − 0.05); MD = − 2.27, 95% CI (− 3.11, − 1.44); MD = − 7.43, 95% CI (− 11.31, − 3.54), respectively]. However, the beneficial effect of curcumin did not achieve statistical significance in lowering total cholesterol, HDL-C, HbA1c, ALT or insulin levels [MD = − 30.47,95% CI (− 60.89. − 0.06); MD = − 0.98, 95% CI (− 2.88, 0.92); MD = − 0.41, 95% CI (− 1.41, 0.59); MD = − 6.02, 95% CI (− 15.61, 3.57); MD = − 0.92, 95% CI (− 2.33, 0.49)]. Conclusions Curcumin is effective in lowering LDL-C, triglycerides, FBS, HOMA-IR, weight, and AST levels in NAFLD patients, and it is well tolerated. Further RCTs are required to confirm our findings.
... Curcuminoids (CE) (diferuloylmethane) such as curcumin or derivatives of curcumin like desmethoxycurcumin and bisdemethoxycurcumin are considered as bioactive compounds present in Curcuma longa Linn. CE has shown to possess significant anti-inflammatory, antioxidant, anti-carcinogenic, anti-coagulant, anti-infective and anti-diabetic effects [13][14][15][16]. ...
... In this trial, curcumin was administered at a dose of 300 mg/day and various biochemical and inflammatory parameters were analysed. In conclusion, it was found that curcumin decreases serum adipocyte-fatty acid binding protein (which in turn decreases serum glucose and free fatty acid), Creactive protein (CRP), tumour necrosis factor-α, and interleukin-6 levels and improved the condition of patients [62]. Curcumin acts synergistically with other established T2DM drugs like glyburide. ...
Chapter
Use of natural products as therapeutics, has been in practice even before the advent of modern medicine. Traditional medicinal systems like Ayurveda, Siddha and Unani which prescribe medicines based on natural products have been in practice for centuries, authenticating the medicinal efficacy of these drugs. However, with the advent of modern medicine, the focus shifted from medicines based on formulations to mostly single component drugs. Also, norms were established to standardize methodologies for clinical trials that will establish safety and efficacy of the drugs before human use. These stringent norms meant that most of the traditional medicines could not be used in the current medicinal system of treatment as drugs. Nevertheless, researchers have repeatedly mined these traditional natural sources and other similar materials for compounds with potential therapeutic value. Such research has yielded compounds like acetylsalicylic acid (aspirin), morphine, quinine and even Nobel prize winning natural products like artemisinin (anti-malarial agent) and avermectin (antibiotic). In fact, more than half of the drugs approved by FDA have either direct or indirect inspiration from natural products. Apart from these, several interesting natural products are also under various stages of clinical trials varying from inflammation, infection to dietary supplements. The present chapter reviews some of these attractive natural products namely curcumin, camptothecin, astaxanthin, and biochanin that are currently under various stages of clinical trials for their application as therapeutics in various diseases. The chapter also deals with challenges such as lead optimization, formulations and delivery systems that should be addressed by researchers to move the natural product from the realm of nutraceuticals to the area of clinical medicine.
... In T2DM patients supplemented with curcuminoids, the plasma A-FABP level positively correlated with blood glucose, FFAs, and CRP levels, implying that a decrease in the plasma A-FABP level may be associated with the improvement of metabolic and inflammatory indices in diabetic subjects. Furthermore, curcuminoids increased plasma SOD activity and decreased insulin resistance index (HOMA-IR) in T2DM subjects [43,44]. More recently, the efficacy of nano-CUR (as nano-micelle 80 mg/day for 3 months) on glucose and lipid parameters has been demonstrated in T2DM subjects, as evidenced by the decreased levels of HbA 1c , glucose, and low-density lipoprotein cholesterol (LDL-C) and reduced body mass index (BMI) [45]. ...
Article
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The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa , has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.
... Curcumin, is a pleiotropic medicinal herb, that has many therapeutic effects, due to its capacity to interact in different signaling pathways ( Mock, Jordan, & Selvam, 2015;Zhou, Beevers, & Huang, 2011) ( Figure 1). Curcumin has anti-inflammatory and antimicrobial properties, and has been assessed in the treatment of diabetes, metabolic syndrome, rheumatoid arthritis, Alzheimer disease, and cancer (e.g., prostate, pancreatic, colorectal, ovarian, and breast cancer) ( Baum et al., 2008;Chandran & Goel, 2012;Epelbaum, Schaffer, Vizel, Badmaev, & Bar-Sela, 2010;Gou et al., 2015;Irving et al., 2015;Mahammedi et al., 2016;Na et al., 2014;Shafiee et al., 2017;Steigerwalt et al., 2012;Suskind et al., 2013;Yang et al., 2014). Furthermore, curcumin has antioxidant activity ( Calabrese et al., 2008;Pari, Tewas, & Eckel, 2008;Toda, Miyase, Arichi, Tanizawa, & Takino, 1985). ...
Article
Breast cancer is among the most important causes of cancer related death in women. There is a need for novel agents for targeting key signaling pathways to either improve the efficacy of the current therapy, or reduce toxicity. There is some evidence that curcumin may have antitumor activity in breast cancer. Several clinical trials have investigated its activity in patients with breast cancer, including a recent trial in breast cancer patients receiving radiotherapy, in whom it was shown that curcumin reduced the severity of radiation dermatitis, although it is associated with low bioavailability. Several approaches have been developed to increase its absorption rate (e.g., nano crystals, liposomes, polymers and micelles) and co-delivery of curcumin with adjuvants as well as different conjugation to enhance its bioavailability. In particular, micro-emulsions is an option for transdermal curcumin delivery, which has been reported to increase its absorption. Lipid-based nano-micelles is another approach to enhance curcumin absorption via gastrointestinal tract, while polymer-based nano-formulations (e.g., poly D, L-lactic-co-glycolic [PLGA]) allows the release of curcumin at a sustained level. This review summarizes the current data of the therapeutic potential of novel formulations of curcumin with particular emphasis on recent preclinical and clinical studies in the treatment of breast cancer. This article is protected by copyright. All rights reserved.
... It has also been reported that oral administration of curcumin in a mouse model of IgE/Ag-mediated passive systemic anaphylaxis significantly attenuates serum Leukotriene C4 (LTC 4 ), prostaglandin D2 (PGD 2 ), and histamine levels that are crucial mediators in the development of inflammation and allergic diseases such as asthma (Na et al., 2014). It is well known that Ca 2+ is essential for arachidonic acid release from phospholipids and degranulation in IgE/Ag-induced mast cells. ...
Article
Curcumin is a dietary polyphenol from turmeric with numerous pharmacological activities. Novel animal and human studies indicate that curcumin can affect different immune cells, such as various T lymphocyte subsets, macrophages, dendritic cells, B lymphocytes and natural killer cells, which results in decreasing severity of various diseases with immunological etiology. The present review provides a comprehensive overview of the effects of curcumin on different immune cells and immune system-related diseases. This article is protected by copyright. All rights reserved.
... To our knowledge, this study is the first clinical report on the impact of curcuminoid-piperine supplementation on oxidative indices of subjects with T2DM. There has been only one previous study in which 3-month supplementation with curcuminoids (300 mg/day) increased SOD activities but had no effect on glutathione peroxidase and MDA levels in diabetic individuals (Na et al. 2014); the latter effects may be due to the lower administered dose compared with this study. ...
Article
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Background Oxidative stress has a key role in the pathogenesis of type II diabetes mellitus (T2DM) and its vascular complications. Antioxidant therapy has been suggested as a potential approach to blunt T2DM development and progression. The aim of this study was to assess the effects of supplementation with curcuminoids, which are natural polyphenolics from turmeric, on oxidative indices in diabetic individuals. Methods In this randomized double-blind placebo-controlled trial, 118 subjects with T2DM were randomized to curcuminoids (1000 mg/day co-administered with piperine 10 mg/day) or matching placebo for a period of 8 weeks. Serum total antioxidant capacity, superoxide dismutase (SOD) activities and malondialdehyde (MDA) concentrations were measured at baseline and after the supplementation period. ResultsCurcuminoids supplementation caused a significant elevation in serum total antioxidant capacity (TAC) (p < 0.001) and SOD activities (p < 0.001), while serum MDA levels were significantly reduced compared with the placebo group (p < 0.001). These results remained statistically significant after adjustment for potential confounders (baseline differences in body mass index and fasting serum insulin). Conclusion The present results support an antioxidant effect of curcuminoids supplementation in patients with T2DM, and call for future studies to assess the impact of these antioxidant effects on the occurrence of diabetic complications and cardiovascular endpoints.
... The change in serum A-FABP level was connected with the change in levels of glucose, FFAs, and CRP. It was suggested that A-FABP regulates the metabolism of fatty acids and modulates oxidative stress and inflammation via the anti-diabetic effect of curcumin [122]. Other studies assume that the antidiabetic effect of curcumin is probably due to the observed decrease in serum FFAs. ...
Article
Background Obesity in the 21st century society became an important health problem, alarming both the scientists and medicine doctors around the world. That is why, the search for new drug candidates capable to reduce the body weight is of high concern. Objective This contribution tends to collect current findings on the biochemistry of obesity and on the application of plants and in particular turmeric tuber – a commonly used spice - as an anti-obesity agent. Methods Following an introduction on the biochemical characteristics of obesity, the description of Curcuma secondary metabolites, their pharmacological applications and a study on the plants’ regulatory properties in obesity was summarized. Particular attention was paid to curcumin – the major metabolite present in the extracts of Curcuma spp., which is known to exhibit a variety of pharmacological actions. Also, the characteristics of some semisynthetic analogues of this ferulic acid derivative, characterized by a higher polarity and better bioavailability will be discussed. Results Numerous scientific papers treat on the influence of turmeric on weight loss. Additionally, some of them describe its anti-inflammatory properties. Conclusions This important spice tends to fight the 21st century plague, which is an excessive weight gain, related to the development of metabolic syndrome, to the occurrence of cardiovascular problems and diabetes, and, in consequence, leading to a significant shortening of life span. As herein proven, the extracts of turmeric play an important role in the regulation of inflammatory reactions which are evoked in the overweight patients, helping them reduce the excess body weight.
... The same group also reported that the intake of curcumin could reduce atherogenic risks and amend the metabolic profiles of high-risk populations (Chuengsamarn et al., 2014). Similarly, in overweight/obese type 2 diabetic patients, curcuminoids lower blood glucose levels (Na et al., 2014). Furthermore, Meriva was shown to be effective in the management of diabetic microangiopathy and retinopathy Steigerwalt et al., 2012). ...
Article
Curcumin, a yellow pigment in the Indian spice Turmeric (Curcuma longa), which is chemically known as diferuloylmethane, was first isolated exactly two centuries ago in 1815 by two German Scientists, Vogel and Pelletier. However, according to the pubmed database, the first study on its biological activity as an antibacterial agent was published in 1949 in Nature and the first clinical trial was reported in The Lancet in 1937. Although the current database indicates almost 9000 publications on curcumin, until 1990 there were less than 100 papers published on this nutraceutical. At the molecular level, this multitargeted agent has been shown to exhibit anti-inflammatory activity through the suppression of numerous cell signalling pathways including NF-κB, STAT3, Nrf2, ROS and COX-2. Numerous studies have indicated that curcumin is a highly potent antimicrobial agent and has been shown to be active against various chronic diseases including various types of cancers, diabetes, obesity, cardiovascular, pulmonary, neurological and autoimmune diseases. Furthermore, this compound has also been shown to be synergistic with other nutraceuticals such as resveratrol, piperine, catechins, quercetin and genistein. To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans. However, more clinical trials in different populations are necessary to prove its potential against different chronic diseases in humans. This review's primary focus is on lessons learnt about curcumin from clinical trials. Linked articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
... Likewise, a study on obese patients with T2D showed the effect of curcumin supplementation in reducing serum concentration of high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 significantly (Aggarwal & Harikumar, 2009). Also, studies on mice suggest that curcumin can prevent vascular complications of diabetes through its effects on Txnip, intercellular adhesion molecule-1, and nitric oxide synthase (NOS) 2 enzyme expression (Na et al., 2014). ...
Article
Diabetes mellitus is one of the most common and important metabolic diseases in human. Curcumin, which is a natural polyphenol found in turmeric, can be used in treatment of diabetes complications for its antidiabetic, anti‐inflammatory, and antioxidant properties. In this double‐blind randomized clinical trial, 44 patients with Type 2 diabetes randomly assigned to curcumin or placebo group. Patients consumed either 1,500‐mg curcumin or placebo daily for 10 weeks. Anthropometric measurements were measured at baseline and at the end of the study. Serum concentrations of triglyceride (TG), total cholesterol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, high‐sensitivity C‐reactive protein, and adiponectin were determined after 12‐hr fasting at the beginning and end of study. The mean serum level of TG decreased in curcumin group compared with baseline (109 ± 36 vs. 124 ± 36; p < 0.05). At the end of study, the mean concentration of high‐sensitivity C‐reactive protein decreased in the curcumin group compared to the control (2.9 ± 2.9 vs. 3.4 ± 4.2; p < 0.05). The mean serum concentration of adiponectin increased (64 ± 3 vs. 63 ± 4; p < 0.05) in the treatment group compared with the placebo at the end of the study. The results of the current study indicate that curcumin consumption may reduce diabetes complications through decreasing TG level as well as indicators of inflammation.
... Moreover, in a study of participants affected by obesity, with type II diabetes, reported that curcumin supplementation resulted in significant a reduction of high sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 [22]. Further, studies on rodent models suggest that curcumin may conceivably protect against vascular complications of diabetes, and other metabolic disorders, via its effects on Thioredoxin-interacting protein, intercellular adhesion molecule-1, and nitric oxide synthase 2 enzyme expression [23]. ...
Article
Objective: Our objective was to perform a systematic review and meta-analysis on randomized controlled trials (RCTs) assessing the effect of curcumin on serum adiponectin concentration. Methods: We searched PubMed/Medline, Scopus, ISI Web of Science, Cochrane Library, and Google scholar databases up to April 2019. RCTs conducted among human adults studied the effects of curcumin on serum adiponectin concentrations as an outcome variable was included. The weighted mean differences (WMD) and standard deviations (SD) of change in serum adiponectin levels were calculated. The random effects model was used for deriving a summary of mean estimates with their corresponding SDs. Results: Out of 313 records, 6 trials that enrolled 652 subjects were included. The pooled results showed that curcumin supplementation significantly increased adiponectin concentrations in comparison with placebo (WMD: 0.82 Hedges' g; 95% confidence interval (CI): 0.33 to 1.30, P˂0.001). Greater effects on adiponectin were observed in trials lasting ≤10 weeks (WMD: 1.05 Hedges' g; 95% CI: 0.64 to 1.45, P˂0.001). Conclusion: Curcumin significantly improves adiponectin concentrations. However, due to some limitations in this study, further studies are needed to reach a definitive conclusion about the effect of curcumin on the levels of adiponectin.
... Further, CUR significantly decreases necrotic cells, IL-6, and CRP levels, reducing liver inflammation by the induction of insulin sensitivity in rats [59]. In T2D patients, CUR decreased adipocyte-fatty acid-binding protein, IL-6, CRP, and TNF-α levels in 100 participants, improving metabolic parameters [75]. Furthermore, diabetic nephropathy showed improvement with CUR treatments by suppressing TGF-β, IL-8, and TNFα expression in T2D patients [76]. ...
Article
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Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical–drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product–drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.
... 174 Supplementation with curcuminoids (300 mg/day) for 3 months increased SOD activities but did not affect GSH and MDA levels in 50 diabetic patients. 186 Curcuminoids supplementation (1 g/day) with piperine (10 mg/day) in subjects with MetS for 8-weeks significantly enhanced serum SOD activities and reduced MDA concentrations. 187 CUR (10,20,50,70, and 100 μM) for 24 and 48 h in fibroblasts obtained from patients with graves orbitopathy, decreased inflammatory cytokines (IL-6, IL-8, MCP-1, and ICAM-1) at both mRNA and protein levels. ...
Article
Curcuma longa (C. longa) or turmeric is a plant with a long history of use in traditional medicine, especially for treating inflammatory conditions C. longa and its main constituent, curcumin (CUR), showed various pharmacological effects such as antioxidant and anti-microbial properties. The updated knowledge of anti-inflammatory, antioxidant, and immunomodulatory effects of C. longa and CUR is provided in this review article. Pharmacological effects of C. longa, and CUR, including anti-inflammatory, antioxidant, and immunomodulatory properties, were searched using various databases and appropriate keywords until September 2020. Various studies showed anti-inflammatory effects of C. longa and CUR, including decreased white blood cell, neutrophil, and eosinophil numbers, and its protective effects on serum levels of inflammatory mediators such as phospholipase A2 and total protein in different inflammatory disorders. The antioxidant effects of C. longa and CUR were also reported in several studies. The plant extracts and CUR decreased malondialdehyde and nitric oxide levels but increased thiol, superoxide dismutase, and catalase levels in oxidative stress conditions. Treatment with C. longa and CUR also improved immunoglobulin E (Ig)E, pro-inflammatory cytokine interleukin 4 (IL)-4, transforming growth factor-beta, IL-17, interferon-gamma levels, and type 1/type 2 helper cells (Th1)/(Th2) ratio in conditions with disturbance in the immune system. Therefore C. longa and CUR showed anti-inflammatory, antioxidant, and immunomodulatory effects, indicating a potential therapeutic effect of the plant and its constituent, CUR, for treating of inflammatory, oxidative, and immune dysregulation disorders.
... Moreover, a new formula of curcumin also protected the eyes by preventing diabetic retinopathy [101]. Oral curcumin (300 mg per day) showed a partial hypoglycemic effect in T2DM individuals by decreasing levels of adipocyte-fatty acid binding protein in serum [102]. And curcumin supplementation is beneficial to enhance insulin sensitivity in T2DM [103]. ...
Article
Background: The pathobiology of diabetes and associated complications has been widely researched in various countries, but effective prevention and treatment methods are still insufficient. Diabetes is a metabolic disorder of carbohydrates, fats, and proteins caused by an absence of insulin or insulin resistance, which mediates an increase of oxidative stress, release of inflammatory factors, and macro- or micro-circulation dysfunctions, ultimately developing into diverse complications. Summary: In the last decade through pathogenesis research, epigenetics has been found to affect metabolic diseases. Particularly, DNA methylation, histone acetylation, and miRNAs promote or inhibit diabetes and complications by regulating the expression of related factors. Curcumin has a wide range of beneficial pharmacological activities, including anti-inflammatory, anti-oxidation, anticancer, anti-diabetes, anti-rheumatism, and increased immunity. Key Messages: In this review, we discuss the effects of curcumin and analogs on diabetes and associated complications through epigenetics, and we summarize the preclinical and clinical researches for curcumin and its analogs in terms of management of diabetes and associated complications, which may provide an insight into the development of targeted therapy of endocrine diseases.
... Here, the use of curcuminoids at 150 mg per twice a day for 8 or 12 weeks could improve the oxidative and inflammatory status by significantly decreasing the levels of adipocyte-fatty acid binding protein, MDA, TNF-α, IL-6, and CRP, increasing serum concentrations of SOD in patients with T2D. 113,114 Jiménez-Osorio et al., 115 also confirmed that curcumin at 107 mg day −1 in each meal for 8 weeks could limit lipid peroxidation and enhanced the antioxidant capacity in people with T2D. RCTs by Panahi and colleagues, 116,117 as well as Adibian et al., 68 assessed the beneficial effects of curcuminoids at doses of either 500, 1000 and 1500 mg day −1 alone or co-supplemented with piperine at 5 or 10 mg day −1 for 12 weeks in patients with T2D. ...
Article
Oxidative stress and inflammation remain the major complications implicated in the development and progression of metabolic complications, including obesity, type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). In fact, due to their abundant antioxidant and anti-inflammatory properties, there is a general interest in understanding the therapeutic effects of some major food-derived bioactive compounds like curcumin against diverse metabolic diseases. Hence, a systematic search, through prominent online databases such as MEDLINE, Scopus, and Google Scholar was done focusing on randomized controlled trials (RCTs) reporting on the impact of curcumin supplementation in individuals with diverse metabolic complications, including obesity, T2D and NAFLD. Summarized findings suggest that curcumin supplementation can significantly reduce blood glucose and triglycerides levels, including markers of liver function like alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with T2D and NAFLD. Importantly, this effect was consistent with the reduction of predominant markers of oxidative stress and inflammation, such as the levels of malonaldehyde (MDA), tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP) and monocyte chemoattractant protein-1 (MCP-1) in these patients. Although RCTs suggest that curcumin is beneficial in ameliorating some metabolic complications, future research is still necessary to enhance its absorption and bioavailability profile, while also optimizing the most effective therapeutic doses.
... In addition, a reduction in serum levels of adipocytefatty acid binding protein was also observed with curcumin supplementation. 29 . The change in levels of adipocyte-fatty acid binding protein was correlated with the change in free fatty acids and fasting glucose levels. ...
Article
Herbs and spices are recommended to increase flavor and displace salt in the diet. Accumulating evidence suggests herbs and spices may improve risk factors for cardiometabolic diseases. In this narrative review, an overview of evidence from human clinical trials examining the effect of herbs and spices on risk factors for cardiometabolic diseases is provided. Human clinical trials examining supplemental doses of individual spices and herbs, or the active compounds, have yielded some evidence showing improvements to lipid and lipoprotein levels, glycemic control, blood pressure, adiposity, inflammation, and oxidative stress. However, cautious interpretation is warranted because of methodological limitations and substantial between-trial heterogeneity in the findings. Evidence from acute studies suggests intake of mixed herbs and spices as part of a high-saturated fat, high-carbohydrate meal reduces postprandial metabolic impairments, including lipemia, oxidative stress, and endothelial dysfunction. Limited studies have examined the postprandial metabolic effects of incorporating mixed herbs and spices into healthy meals, and, to our knowledge, no trials have assessed the effect of longer-term intake of mixed herbs and spices on risk factors for cardiometabolic diseases. To inform evidence-based guidelines for intake of herbs and spices for general health and cardiometabolic disease risk reduction, rigorously conducted randomized controlled trials are needed, particularly trials examining herb and spice doses that can be incorporated into healthy dietary patterns.
... Curcumin is a herbal drug consisting of pleiotropic activity [27] and utilized effectively against several diseases such as diabetics [28], arthritis [29], Alzheimer [30], and even cancer [31]. Curcumin is effective against different cancer such as colorectal [32], prostate [33], pancreatic [34], ovarian [35], and breast cancer [36]. ...
Article
We developed here the stimuli responsive curcumin loaded microgels based on Pluronic F-127. These microgels were prepared using coupling reaction between the amine modified Pluronic and EDTA. The microgel exhibited the affinity for hydrophobic drug, curcumin and showed pH as well as temperature-dependent release. Furthermore, the cytotoxicity study demonstrated dose-dependent inhibition of MDAMB-231 cell growth with the most effective IC 50 value (3.8 ±0.2μg ml −1 after 24 h). Based on these findings, the fabricated curcumin loaded microgels offered additional advantages over conventional drug therapies for treatment of cancer.
... In vivo studies have clearly shown that curcumin intake decreases inflammation and protects the liver by upregulating Nrf2 [225] . Several drug-development studies have indicated that the oral intake of curcumin reduces serum triglycerides, IL-1β, IL-4, and VEGF and increases lipoprotein lipases that are helpful in breaking down fat [226,227] . With respect to cancer, the well-known anti-inflammatory and anti-cancer properties, and the multimodal actions of this phytochemical, prompted a number of laboratories to investigate the utility of curcumin as an adjunct to chemotherapy [228] . ...
Article
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Androgen deprivation therapy (ADT) is the mainstay regimen in patients with androgen-dependent prostate cancer (PCa). However, the selection of androgen-independent cancer cells leads to castrate resistant prostate cancer (CRPC). The aggressive phenotype of CRPC cells underscores the need to elucidate mechanisms and therapeutic strategies to suppress CRPC outgrowth. Despite ADT, the activation of androgen receptor (AR) transcription factor continues via crosstalk with parallel signaling pathways. Understanding of how these signaling cascades are initiated and amplified post-ADT is lacking. Hormone deprivation can increase oxidative stress and the resultant reactive oxygen species (ROS) may activate both AR and non-AR signaling. Moreover, ROS-induced inflammatory cytokines may further amplify these redox signaling pathways to augment AR function. However, clinical trials using ROS quenching small molecule antioxidants have not suppressed CRPC progression, suggesting that more potent and persistent suppression of redox signaling in CRPC cells will be needed. The transcription factor Nrf2 increases the expression of numerous antioxidant enzymes and downregulates the function of inflammatory transcription factors, e.g., nuclear factor kappa B. We documented that Nrf2 overexpression can suppress AR-mediated transcription in CRPC cell lines. Furthermore, two Nrf2 activating agents, sulforaphane (a phytochemical) and bardoxolone-methyl (a drug in clinical trial) suppress AR levels and sensitize CRPC cells to anti-androgens. These observations implicate the benefits of potent Nrf2-activators to suppress the lethal signaling cascades that lead to CRPC outgrowth. This review article will address the redox signaling networks that augment AR signaling during PCa progression to CRPC, and the possible utility of Nrf2-activating agents as an adjunct to ADT.
... In type 2 diabetes clinical trials, curcumin has shown a capability to decrease blood glucose levels and to improve the function of beta cells, to increase HOMA-B levels and reduce C-peptide levels thus acting as an adjuvant for preventing diabetes onset (Chuengsamarn et al. 2012, Na et al. 2014. ...
Chapter
Chapter 17 - Epilepsy is a life-shortening brain disorder that currently affects ~ 1% of the worldwide population. Despite the availability of several antiepileptic drugs (AEDs), severe side effects such as cognitive and affective disorders, teratogenicity, hepatotoxicity, among others, have been reported after chronic administration. Also, some patients remain refractory to the available AEDs. Such is the case of metabolic epilepsy. Hence, there is a current need for the discovery of novel active principles with minimal or no adverse side effects. Nature is an exciting source of potential drug candidates for the treatment of pharmacoresistant epilepsy (PRE) due to the highly diverse and complex chemical structures of bioactive vegetal compounds. In this context, the authors analyzed the rhizome powder of Curcuma longa, commonly known as turmeric. Until the authors’ study, the anticonvulsant properties of turmeric were exclusively attributed to its curcuminoids. For the first time, the authors revealed the anticonvulsant properties of turmeric oil and its main bisabolene sesquiterpenoids, ar-turmerone, α-, β-turmerone, and α-atlantone. Thus, the present chapter discusses the botanical aspects of turmeric, the chemical composition, and phytopharmacological aspects of turmeric, curcumin, and turmeric oil as well as the authors’ results obtained from the anticonvulsant activity characterization of turmeric oil and ar-turmerone. The authors’ findings support further characterization of the anticonvulsant properties of these active compounds and demonstrate the usefulness of the zebrafish and mouse models for searching novel AEDs. Also, the potential therapeutic application of turmeric oil and ar-turmerone for the treatment of metabolic epilepsy is discussed.
... The same group also reported that the administration of curcumin could dwindle atherogenic risks and change the metabolic profiles of high-risk populations [275]. Correspondingly, in overweight or obese Type 2 DM patients, curcuminoids were reported to decrease blood glucose levels [276]. In addition, Meriva® was also found to be effective in the treatment of diabetic microangiopathy and retinopathy [277,278]. ...
Article
Introduction: Since ancient times, turmeric has been used in several folklore remedies against various ailments. The principle component of turmeric is curcumin and its efficacy has been advocated in in vitro, in vivo and clinical studies for different chronic diseases. However, some studies suggest that curcumin bioavailability is a major problem. Areas covered: This article discusses over 200 clinical studies with curcumin that have demonstrated pronounced protective role of this compound against cardiovascular diseases, inflammatory diseases, metabolic diseases, neurological diseases, skin diseases, liver diseases, various types of cancer, etc. The review also describes the combination of curcumin with many natural and synthetic compounds as well as various formulations of curcumin that have shown efficacy in multiple clinical studies. Expert opinion: The therapeutic potential of curcumin as demonstrated by clinical trials has overpowered the myth that poor bioavailability of curcumin poses a problem. Low curcumin bioavailabilty in certain studies has been addressed by using higher concentrations of curcumin within nontoxic limits. Moreover, curcumin in combination with other compounds or as formulations have shown enhanced bioavailability. Hence, bioavailability is not a problem in curcumin mediated treatment of chronic diseases. Therefore, this golden nutraceutical presents a safe, low-cost and effective treatment modality for different chronic diseases.
Chapter
In this chapter, the use of nutraceuticals for metabolic syndrome therapies is explored. Metabolic syndrome is characterized by having three or more out of six variables (risk factors), ranging from high triglycerides, to elevated waist circumference and high blood pressure. Metabolic syndrome is also characterized by elevated serum cholesterol (cholesterolemia), and is considered the consequence of a complex interaction of factors generally leading to increased insulin resistance and high blood glucose. Recently C-reactive protein has been considered as a risk factor also. Current pharmaceutical treatments are complex and have side effects, thus well-characterized nutraceuticals may offer effective alternatives. While lifestyle approaches, such as with the Mediterranean diet and exercise, may prove to be too complex for the single patient, better knowledge of selected nutraceuticals and more appropriate formulations leading to improved bioavailability, will likely increase the use of these agents. Nutraceuticals are already in use for the management of some patient groups. This chapter discusses various aspects of the above issues.
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Background relevance: A plethora of literature is available regarding the clinical trials for natural products however; no information is available for critical assessments of the quality of these clinical trials. Aim of study: This is a first time report to critically evaluate the efficacy, safety and large scale applications of up-to-date clinical trials for diabetes, based on the three scales of Jadad, Delphi, and Cochrane. Methodology: An in-depth and extensive literature review was performed using various databases, journals, and books. The keywords searched included, "clinical trials," "clinical trial in diabetes," "diabetes," "natural products in diabetes," "ethnopharmacological relevance of natural products in diabetes," etc. Results: Based on eligibility criteria, 16 plants with 74 clinical trials were found and evaluated. Major drawbacks observed were; "non-randomization and blindness of the studies," "non-blindness of patients/healthcare/outcome assessors," "lack of patient compliance and co-intervention reports," "missing information regarding drop-out/withdrawal procedures," and "inappropriate baseline characteristics." Principal component analysis and Pearson correlation revealed four components with %variability; PC1: 23.12, PC2: 15.83, PC3: 13.11, and PC4: 11.38 (P ≤ .000). According to descriptive statistics, "non-blinding of outcome assessors" was the major drawback (82%) whereas, "not mentioning the timing of outcome assessment" was observed lowest (6.8%). An in-house quality grading (scale 0-24) classified these clinical trials as; poor (67.6%), acceptable (19.9%), and good quality trials (13.5%). Conclusion: Proper measures in terms of more strict regulations with pharmacovigilance of plants are utmost needed in order to achieve quality compliance of clinical trials.
Article
Curcumin is derived from the roots of the plant Curcuma longa known as turmeric. Curcumin mediates glucose homeostasis through activation of glycosis, inhibition of hepatic gluconeogenesis and reducing lipid metabolism. As a nuclear factor kappa B inhibitor, curcumin helps to alleviate insulin resistance; activates peroxisome proliferator-activated receptor gamma and shows hypoglycemic effects and thus suppresses increases in blood glucose levels. There are studies showing that curcumin may have an effect on insulin secretion. By regulating the expression of the Ang II Type-1 receptor in the arteries, it can prevent the development of hypertension, an important component of the metabolic syndrome. The triglyceride-lowering effects of curcumin were confirmed in various experimental studies. In addition to the effects on the lipid metabolism, there is some evidence that curcumin can reduce body weight by increasing the basal metabolic rate and release of some cytokines. Curcumin was found to reduce hepatic fat accumulation and prevent steatosis by down-regulating lipogenic factors. In addition, it reduces the biomarkers of systemic inflammation, hepatocyte injury and oxidative stress, and improves insulin sensitivity and glycemic control. Curcumin reduces hepatic cholesterol and total cholesterol levels by inhibiting hepatic enzymes HMG-CoA reductase and acyl CoA cholesterol acyltransferase. In addition, it inhibits hepatic fatty acid synthase activity and increases beta oxidation of fatty acids. Curcumin is a promising agent in the treatment of metabolic syndrome by correcting the parameters caused by the metabolic syndrome and eliminating its negative effects.
Article
Aim: We aimed to explore the relation between the level of adipocyte fatty-acid binding protein (A-FABP) in the gestational period and related indices of glucolipid metabolism, and the possible mechanisms of occurrence and development of pre-eclampsia. Methods: Seventy-six pre-eclampsia patients were enrolled and divided into the mild pre-eclampsia (n = 42) and severe pre-eclampsia (n = 34) groups. Forty-eight healthy pregnant women were selected as a control group. The indices of all participants were examined, including serum A-FABP, fasting insulin (FINS), fasting blood glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), and homeostatic model assessment insulin resistance (HOMA-IR) index was calculated. After the delivery of the placenta, the level of A-FABP in the placenta was detected by immunochemistry. Then, the correlation between serum A-FABP and indices of glucolipid metabolism and placental A-FABP were analyzed. Results: Serum A-FABP, FINS, TG, TC, HOMA-IR, and placental A-FABP were significantly higher in pre-eclampsia patients and the level of HDL was obviously lower than in the control group. Serum A-FABP was positively correlated with FINS, TG, TC, and HOMA-IR, and placental A-FABP was negatively correlated with HDL in pre-eclampsia patients. In the control group, serum A-FABP was positively correlated only with TG, and uncorrelated with the other indices (P > 0.05). Conclusion: The level of A-FABP was correlated with insulin resistance and indices of glucolipid metabolism in pre-eclampsia patients. High-levels of A-FABP might increase insulin resistance by causing glucose and lipid metabolism disorders and ultimately inducing the occurrence and development of pre-eclampsia.
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The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.
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Nisha Amalaki (NA), an Indian herbal formulation consisting of two herbs, Curcuma longa and Emblica officinalis , has been commonly used to treat Type 2 diabetes mellitus (T2DM). However, the pharmacological mechanism of NA remains unknown. In this study, a network pharmacology-based approach was used to explore its underlying mechanism. NA phytochemicals were collected from PubChem, KNApSAcK, IMPPAT, and ChEBI databases, and their potential targets were investigated using similarity ensemble approach (Tanimoto coefficient ≥ 0.6). A protein-protein interaction network was constructed to study the interactions among the targets and clustered into separate modules using NetworkAnalyst 3.0. A significant module ( P ≤ .01) was identified, and DAVID web tool was utilized for the enrichment analysis. A total of 201 phytochemicals and 262 targets of NA were selected. Forty-five nodes of the significant module were identified as potential targets of NA. The enrichment analysis exhibited 27 biological processes and 78 pathways ( P ≤ .01). Out of 45, 18 nodes were associated with T2DM as probable targets of NA. The metabolite-target-pathway network revealed that anti-diabetic effect of NA is a synergy of multi-target and multi-pathway efforts via regulation of glucose, lipid metabolism, insulin resistance, β-cell survival and proliferation, inflammation, apoptosis, and cell cycle.
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Ethnopharmacological evidence Curcumin (CUR) is the active ingredient of Traditional Chinese Medicine turmeric (Curcuma longa L.), which has been used for treatment of diabetes in Ayurveda and China. CUR exerts potent anti-insulin-resistant effects in various cell lines. However, previous studies indicated CUR was metabolized extensively in vivo and massively degraded in a medium alkaline buffer solution. The real active component of the anti-insulin-resistant activity of CUR in vitro is not clear. Aim of the study Our study identified the functional contribution of the metabolites of CUR and the related molecular mechanism in improving insulin sensitivity. Materials and methods HPLC and UPLC-QQQ-MS analyses were used to investigate the stability and metabolism of CUR in HepG2 cells. The effect of the metabolic products of CUR on insulin sensitivity was evaluated in high glucose (HG)-induced insulin-resistant HepG2 cells. A network pharmacology approach was used to examine the potential targets of the metabolites, and Western blotting was performed to verify changes in the targets. Results CUR was unstable in the cell culture medium, but the prototypes, metabolites and degradation products of CUR coexisted in the HepG2 cell culture experiment. The insulin sensitivity assay demonstrated that CUR and its metabolites enhanced insulin sensitivity in HG-induced insulin-resistant HepG2 cells, but the total degradation products of CUR may not play the major role. Similar to CUR, hexahydrocurcumin (HHC) and octahydrocurcumin (OHC) improved insulin sensitivity by strengthening the PI3K-AKT-GSK3B signal and suppressing the phosphorylation of ERK/JNK in HG-induced insulin-resistant HepG2 cells. Conclusions Metabolites of CUR played a critical role in counteracting insulin resistance in HG-induced HepG2 cells. CUR exerted anti-insulin resistance effect in HepG2 cells in a multi-component, multi-target, and multi-pathway manner.
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Aging is one of the key contributors to a broad spectrum of chronic diseases. Reactive oxygen species (ROS) increase oxidative stress in cells and thus induces inflammatory cascades. The antioxidant defense systems are declined during aging. Antioxidant controls the oxidative radical process by suppressing the formation of free radicals and interrupting the propagation and initiation of free radicals through several mechanisms. Considering the crucial roles of oxidative stress in age-related diseases, the manipulation of ROS levels would represent a useful option to delay age-related diseases and attenuate associated symptoms. Numerous compounds with antioxidant activity have demonstrated their potential to alleviate age-related diseases; however, mixed results are yielded. Therefore, this chapter discussed the potential of dietary antioxidants against age-related diseases. We also explored on how dietary choices dampen or exacerbate the inflammation and metabolic disorders. Collectively, this information may shed light on the discovery for potential intervention, and thus promoting healthy longevity.
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Background/objectives: First-degree relatives of patients with diabetes bear an increased risk of diabetes, overweight/obesity, and cardiovascular disease. Accumulating evidence indicates that circulating concentrations of adipokines are altered in individuals with a first-degree family history of diabetes (FHD), but the adipokine adipocyte fatty acid binding protein (A-FABP) has been rarely studied in this population. The present study explored the association between a first-degree FHD and serum A-FABP levels. Subjects/methods: A total of 1962 normoglycemic participants were divided into subgroups of men, premenopausal women, and postmenopausal women. Serum A-FABP levels were measured using a sandwich enzyme-linked immunoabsorbent assay. Abdominal fat distribution, including visceral fat area and subcutaneous fat area, was assessed by magnetic resonance imaging. Results: Totals of 792 men, 544 premenopausal women, and 626 postmenopausal women were enrolled. Serum A-FABP levels were much higher in subjects with a first-degree FHD than in those without a FHD in all subgroups (all P<0.05). Logistic regression analysis revealed an independent and positive relationship between a first-degree FHD and serum A-FABP levels in men (P=0.029), premenopausal women (P=0.036), and postmenopausal women (P=0.008). Multiple stepwise regression analysis showed that a first-degree FHD was an independent factor positively associated with serum A-FABP levels in men (standardized β=0.068, P=0.029), premenopausal women (standardized β=0.090, P=0.018), and postmenopausal women (standardized β=0.102, P=0.004). Conclusion: Serum A-FABP levels were increased significantly in normoglycemic individuals with a first-degree FHD. The contribution of the first-degree FHD to the elevated serum A-FABP levels was independent of total body fat content and abdominal fat distribution. Thus, use of serum A-FABP as a biomarker in the first-degree relatives of patients with diabetes may result in overestimation of the risk of obesity-induced metabolic disease and cardiovascular disease.International Journal of Obesity accepted article preview online, 18 August 2016. doi:10.1038/ijo.2016.147.
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Despite continuous advances in pharmacotherapy, atherosclerotic cardiovascular disease remains the world's leading killer. Atherosclerosis relates not only to an increased level of cholesterol, but involves the development of atherosclerotic plaques, which are formed as a result of processes including inflammation and oxidative stress. Therefore, in addition to the classical risk factors for ASCVD (such as type 2 diabetes, overweight, obesity, hypertension and metabolic syndrome), residual risk factors such as inflammation and oxidative stress should also be reduced. The most important intervention in ASCVD is prevention, which includes promoting a healthy diet based on products of natural origin. Curcumin, which is often present in the diet, has been demonstrate to confer several benefits to health. It has been shown in numerous clinical trials that curcumin exhibited anti-diabetic, lipid-lowering, antihypertensive, antioxidant and anti-inflammatory effects, as well as promoting weight loss. All this means that curcumin has a comprehensive impact on the most important risk factors of ASCVD and may be a beneficial support in the treatment of these diseases. Recently, it has also been shown that curcumin may have a beneficial effect on the course of SARS-CoV-2 infection and might be helpful in the prevention of long-COVID complications. The aim of this review is to summarize the current knowledge regarding the safety and efficacy of curcumin in the prevention and treatment of cardiometabolic diseases.
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Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E(2), prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
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The adipocyte/macrophage fatty acid-binding protein 4 (FABP4) has been described as a biomarker for adiposity and metabolic syndrome (MS). The aims of this study were to assess the relationship between FABP4 and inflammatory cytokines related to obesity, and to evaluate FABP4 mRNA expression in visceral and subcutaneous adipose tissue in non-diabetic morbidly obese women versus healthy lean women. We analyzed circulating levels of FABP4 in 81 Spanish women: 38 lean (body mass index (BMI)<25 kg/m(2)) and 43 morbidly obese (BMI>40 kg/m(2)). We took 30 follow-up blood samples at 6 and 12 months after bariatric surgery. We assessed FABP4 gene expression in samples of subcutaneous abdominal and visceral adipose tissue. Adipose tissue mRNA expression was determined by real-time RT-PCR. In morbidly obese women, plasma FABP4 levels were significantly higher than in non-obese patients. These levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin levels. Post-operative FABP4 levels decreased by a maximum of 30% after 12 months. We also found an inverse association between FABP4 and adiponectin levels, and positive correlations between FABP4 and circulating leptin, tumor necrosis factor (TNF) receptors, C-reactive protein (CRP) and interleukin 6 levels. Linear regression analysis revealed that FABP4 was more closely related to HOMA2-IR than adiponectin, CRP, TNF-RI, or leptin. Furthermore, high circulating FABP4 levels were associated with the presence of MS. FABP4 mRNA expression in visceral adipose tissue was related to its circulating levels in morbidly obese women. Our results indicate that serum FABP4 is associated with inflammatory factors related to obesity and MS in non-diabetic morbidly obese women.
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Previous in vitro studies have established that hormone sensitive lipase (HSL) and adipocyte fatty acid-binding protein (AFABP) form a physical complex that presumably positions the FABP to accept a product fatty acid generated during catalysis. To assess AFABP-HSL interaction within a cellular context, we have used lipocytes derived from 293 cells (C8PA cells) and examined physical association using fluorescence resonance energy transfer. Transfection of C8PA cells with cyan fluorescent protein (CFP)-HSL, yellow fluorescent protein (YFP)-adipocyte FABP, or YFP-liver FABP revealed that under basal conditions each protein was cytoplasmic. In the presence of 20 microm forskolin, CFP-HSL translocated to the triacylglycerol droplet, coincident with BODIPY-FA labeled depots. Fluorescence resonance energy transfer analysis demonstrated that CFP-HSL associated with YFP-adipocyte FABP in both basal and forskolin-treated cells. In contrast, little if any fluorescence resonance energy transfer could be detected between CFP-HSL and YFP-liver FABP. These results suggest that a pre-lipolysis complex containing at least AFABP and HSL exists and that the complex translocates to the surface of the lipid droplet.
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Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.
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Adipose tissue inflammation is a characteristic of obesity. However, the mechanisms that regulate this inflammatory response and link adipose inflammation to systemic metabolic consequences are not fully understood. In this study, we have taken advantage of the highly restricted coexpression of adipocyte/macrophage fatty acid-binding proteins (FABPs) aP2 (FABP4) and mal1 (FABP5) to examine the contribution of these lipid chaperones in macrophages and adipocytes to local and systemic inflammation and metabolic homeostasis in mice. Deletion of FABPs in adipocytes resulted in reduced expression of inflammatory cytokines in macrophages, whereas the same deletion in macrophages led to enhanced insulin signaling and glucose uptake in adipocytes. Using radiation chimerism through bone marrow transplantation, we generated mice with FABP deficiency in bone marrow and stroma-derived elements in vivo and studied the impact of each cellular target on local and systemic insulin action and glucose metabolism in dietary obesity. The results of these experiments indicated that neither macrophages nor adipocytes individually could account for the total impact of FABPs on systemic metabolism and suggest that interactions between these 2 cell types, particularly in adipose tissue, are critical for the inflammatory basis of metabolic deterioration.
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We previously found that curcuminoids decreased blood glucose and improved insulin resistance by reducing serum free fatty acids (FFAs) and increasing fatty acid oxidation in skeletal muscle of diabetic rats. This study was to investigate whether curcuminoids have beneficial effects on type 2 diabetic patients, and its possible mechanisms. Overweight/obese type 2 diabetic patients (BMI ≥ 24.0; fasting blood glucose ≥ 7.0 mmol/L or postprandial blood glucose ≥11.1 mmol/L) were randomly assigned to curcuminoids (300 mg/day) or placebo for 3 months. Bodyweight, glycosylated hemoglobin A1c (HbA1c,%), serum fasting glucose, FFAs, lipids, and lipoprotein lipase (LPL) were determined. A total of 100 patients (curcuminoids, n = 50; placebo, n = 50) completed the trial. Curcuminoids supplementation significantly decreased fasting blood glucose (p < 0.01), HbA1c (p = 0.031), and insulin resistance index (HOMA-IR) (p < 0.01) in type 2 diabetic patients. Curcuminoids also led to a significant decrease in serum total FFAs (p < 0.01), triglycerides (P = 0.018), an increase in LPL activity (p < 0.01). These findings suggest a glucose-lowering effect of curcuminoids in type 2 diabetes, which is partially due to decrease in serum FFAs, which may result from promoting fatty acid oxidation and utilization.
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Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2−/− animals failed to express in adipose tissue tumor necrosis factor-α (TNF-α), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-α.
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The adipocyte fatty acid-binding protein (FABP) aP2 is expressed by adipocytes and macrophages and modulates insulin resistance, glucose and lipid metabolism, and atherosclerosis. Insulin sensitivity is improved in obese but not in lean aP2-deficient mice. A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. Male and female apoE-/- mice null for both aP2 and mal1 (3KO) and apoE-/- controls were fed a low-fat chow diet for 16 or 56 weeks. Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE-/- controls when challenged with the Western diet for 1 year. Combined aP2 and mal1 deficiency improved glucose and lipid metabolism, reduced atherosclerosis, and improved survival in apoE-/- mice, making these proteins important therapeutic targets for the prevention of the cardiovascular consequences of the metabolic syndrome.
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The metabolic impact of the murine adipocyte fatty acid-binding protein (AFABP/aP2) on lipid metabolism was investigated in the AFABP/aP2(-/-) mouse and compared with wild-type C57BL/6J littermates. Mice were weaned on a high-fat diet (59% of energy from fat) and acclimated to meal feeding. Stable isotopes were administered, and indirect calorimetry was performed to quantitate fatty acid flux, dietary fatty acid utilization, and substrate oxidation. Consistent with previous in situ and in vitro studies, fasting serum nonesterified fatty acid (NEFA) release was significantly reduced in AFABP/aP2(-/-) (17.1 +/- 9.0 vs. 51.9 +/- 22.9 mg.kg(-1).min(-1)). AFABP/aP2(-/-) exhibited higher serum NEFA (1.4 +/- 0.6 vs. 0.8 +/- 0.4 mmol/l, AFABP/aP2(-/-) vs. C57BL/6J, respectively) and triacylglycerol (TAG; 0.23 +/- 0.09 vs. 0.13 +/- 0.10 mmol/l) and accumulated more TAG in liver tissue (2.9 +/- 2.3 vs. 1.1 +/- 0.8% wet wt) in the fasted state. For the liver-TAG pool, 16.4 +/- 7.3% of TAG-fatty acids were derived from serum NEFA in AFABP/aP2(-/-). In contrast, a significantly greater portion of C57BL/6J liver-TAG was derived from serum NEFA (42.3 +/- 25.5%) during tracer infusion. For adipose-TAG stores, only 0.29 +/- 0.04% was derived from serum NEFA in AFABP/aP2(-/-), and, in C57BL/6J, 1.85 +/- 0.97% of adipose-TAG was derived from NEFA. In addition, AFABP/aP2(-/-) preferentially oxidized glucose relative to fatty acids in the fed state. These data demonstrate that in vivo disruption of AFABP/aP2(-/-) leads to changes in the following two major metabolic processes: 1) decreased adipose NEFA efflux and 2) preferential utilization of glucose relative to fatty acids.
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Adipocyte fatty acid-binding protein (A-FABP) is traditionally thought to be a cytosolic fatty acid chaperone expressed in adipocytes. Mice with targeted disruption of the A-FABP gene exhibit a striking phenotype with strong protection from insulin resistance, hyperglycemia, and atherosclerosis. The clinical relevance of these findings remains to be confirmed. We used tandem mass spectrometry-based proteomic analysis to identify proteins secreted from adipocytes and present in human serum. We measured serum A-FABP concentrations in 229 persons (121 men and 108 women; age range, 33-72 years), including 100 lean [body mass index (BMI) <25 kg/m2] and 129 overweight/obese individuals (BMI >25 kg/m2) selected from a previous cross-sectional study. A-FABP was released from adipocytes and was abundantly present in human serum. Mean (SD) circulating concentrations of A-FABP were significantly higher in overweight/obese than in lean persons [32.3 (14.8) vs 20.0 (9.8) microg/L; P < 0.001]. Age- and sex-adjusted serum A-FABP concentrations correlated positively (P < 0.005) with waist circumference, blood pressure, dyslipidemia, fasting insulin, and the homeostasis model assessment insulin resistance index. Moreover, we observed a significant increase in A-FABP concentrations corresponding with increases in the number of components of the metabolic syndrome (P < 0.05). A-FABP is a circulating biomarker closely associated with obesity and components of the metabolic syndrome, and measurement of serum concentrations of A-FABP might be useful for clinical diagnosis of obesity-related metabolic and cardiovascular disorders.