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Curcumin Exerts Antidifferentiation Effect through AMPK alpha-PPAR-gamma in 3T3-L1 Adipocytes and Antiproliferatory Effect through AMPK alpha-COX-2 in Cancer Cells

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Curcumin Exerts Antidifferentiation Effect through AMPK alpha-PPAR-gamma in 3T3-L1 Adipocytes and Antiproliferatory Effect through AMPK alpha-COX-2 in Cancer Cells

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Abstract

Curcumin has been reported to have the potential to prevent obesity as well as cancers. The downstream targets regulated by AMP-activated protein kinase (AMPK) for inhibiting adipocyte differentiation or cancer cell proliferation of curcumin were investigated. The activation of AMPK by curcumin was crucial for the inhibition of differentiation or growth in both adipocytes and cancer cells. Stimulation of AMPK by curcumin resulted in the down-regulation of PPAR (peroxisome proliferator-activated receptor)-gamma in 3T3-L1 adipocytes and the decrease in COX-2 in MCF-7 cells. Application of a synthetic AMPK activator also supported the evidence that AMPK acts as an upstream signal of PPAR-gamma in 3T3-L1 adipocytes. In cancer cells, AMPK was found to act as a regulator of ERK1/2, p38, and COX-2. Regulation of AMPK and its downstream targets such as PPAR-gamma, Mapkinases, and COX-2 by curcumin appears to be important in controlling adipocytes and cancerous cells.

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... Curcumin was reported to inhibit the adipocyte differentiation of MSCs or mouse 3T3-L1 cells (a preadipocyte cell line) [27]. The adipogenic differentiation of cells is commonly characterized by the accumulation of lipid vesicles in the cytoplasm, as well as the expression of adipogenic marker genes such as peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein-α(C/EBPα), fatty acid-binding protein (FABP)-4, and Kruppel-like factor 15 (KLF15). ...
... The adipogenic differentiation of cells is commonly characterized by the accumulation of lipid vesicles in the cytoplasm, as well as the expression of adipogenic marker genes such as peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein-α(C/EBPα), fatty acid-binding protein (FABP)-4, and Kruppel-like factor 15 (KLF15). The role of KLF family members on adipogenic differentiation is diverse, in which KLF4 and KLF5 promote adipogenesis, whereas KLF2 and KLF3 suppress it [27]. Curcumin treatment was found to decrease the intracellular lipid droplet as observed by oil red O staining and the reduced expression of adipogenic markers via the mechanisms described below (Figure 1). ...
... PPARγ and C/EPBα expression synergistically stimulate adipogenesis, and FABP-4 regulates lipid storage and metabolism. Therefore, inhibiting the expression of these transcription factors prevents adipogenic differentiation [27,29]. ...
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Curcumin has been placed at the forefront of the researcher’s attention due to its pleiotropic pharmacological effects and health benefits. A considerable volume of articles has pointed out curcumin’s effects on the fate of stem cell differentiation. In this review, a descriptive mechanism of how curcumin affects the outcome of the differentiation of mesenchymal stem cells (MSCs) into the mesodermal lineage—i.e., adipocyte, osteocyte, and chondrocyte differentiation—is compiled from the literature. The sections include the mechanism of inhibition or induction of MSCs differentiation to each lineage, their governing molecular mechanisms, and their signal transduction pathways. The effect of different curcumin doses and its structural modifications on the MSCs differentiation is also discussed.
... Treatment of 3T3-L1 adipocytes with curcumin (10-50 µM) for 8 days resulted in reduced adipocyte differentiation [46]. Curcumin treatment significantly increased AMPKα activation/phosphorylation, similar to levels of synthetic AMPK activator, AICAR, while PPAR-γ transcriptional activity was inhibited (Table 1) [46]. ...
... Treatment of 3T3-L1 adipocytes with curcumin (10-50 µM) for 8 days resulted in reduced adipocyte differentiation [46]. Curcumin treatment significantly increased AMPKα activation/phosphorylation, similar to levels of synthetic AMPK activator, AICAR, while PPAR-γ transcriptional activity was inhibited (Table 1) [46]. ...
... In addition, gluconeogenesis was reduced, while glucokinase activity and glucose-6-phosphate levels were increased with curcumin treatment. [40,41,[43][44][45][46]57,67,73,97,98,101,102]. AKT: protein kinase B; PIP3: phosphatidylinositol-3,4,5-triphosphate; PIP2: phosphatidylinositol 4,5-bisphosphate; ERK: extracellular signal-regulated kinase; PI3K: phosphoinositide 3-kinase; IRS1: insulin receptor substrate 1; TNF-α: tumor necrosis factor-α; AMPK: AMP-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ACC: acetyl-CoA carboxylase; PGC-1: peroxisome proliferator-activated receptor gamma co-activator 1; FFAs: free fatty acids. ...
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Type 2 diabetes mellitus (T2DM) is a growing metabolic disease characterized by insulin resistance and hyperglycemia. Current preventative and treatment strategies for T2DM and insulin resistance lack in efficacy resulting in the need for new approaches to prevent and manage/treat the disease better. 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 (I of II) summarizes the existing in vitro studies examining the antidiabetic effects of curcumin, while a second (II of II) review summarizes evidence from existing in vivo animal studies and clinical trials focusing on curcumin’s antidiabetic properties.
... Supplementation with curcumin significantly reduces the high-fat diet-induced increase in body weight gain and adiposity in mice [13,14]. A similar inhibition of differentiation of 3T3-L1 adipocytes was reported by Lee et al. [15], who also found that curcumin can induce apoptosis of MCF-7 breast cancer cells; however, the apoptotic effect of curcumin on preadipocytes was not investigated. In addition, although curcumin is known to have an anti-obesity effect [10][11][12][13][14][15], little is known about the underlying mechanisms of inhibition of adipogenesis. ...
... A similar inhibition of differentiation of 3T3-L1 adipocytes was reported by Lee et al. [15], who also found that curcumin can induce apoptosis of MCF-7 breast cancer cells; however, the apoptotic effect of curcumin on preadipocytes was not investigated. In addition, although curcumin is known to have an anti-obesity effect [10][11][12][13][14][15], little is known about the underlying mechanisms of inhibition of adipogenesis. ...
... The other regulatory pathway of adipogenesis is the Wnt signaling pathway, which maintains preadipocytes in an undifferentiated state by inhibiting expression of the adipogenic transcription factors C/EBPα and PPARγ [32,33]. In 3T3-L1 adipocytes, curcumin is reported to activate phosphorylation of AMP-activated protein kinase (AMPK), thus downregulating the PPARγ expression, and to inhibit adipogenesis [15]. It also inhibits adipogenesis in 3T3-L1 adipocytes by restoring nuclear translocation of the Wnt signaling component β-catenin to a similar level compared to that in undifferentiated preadipocytes [34]. ...
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Patients with metabolic syndrome are at an increased risk of developing type 2 diabetes and cardiovascular diseases. The principal risk factor for development of metabolic syndrome is obesity, defined as a state of pathological hyperplasia or/and hypertrophy of adipose tissue. The number of mature adipocytes is determined by adipocyte differentiation from preadipocytes. The purpose of the present study is to investigate the effects of curcumin on adipogenesis and the underlying mechanism. To examine cell toxicity of curcumin, 3T3-L1 preadipocytes were treated with 0–50 µM curcumin for 24, 48, or 72 h, then cell viability was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The effect of curcumin on the cell cycle was determined by flow cytometry. Curcumin-induced cell apoptosis was determined by the TUNEL assay and curcumin-induced caspase activation was measured by immunoblotting. The effect of curcumin on adipocyte differentiation was determined by measuring mitotic clonal expansion (MCE), expression of adipogenic transcription factors, and lipid accumulation. Results showed the viability of preadipocytes was significantly decreased by treatment with 30 µM curcumin, a concentration that caused apoptosis in preadipocytes, as assessed by the TUNEL assay, and caused activation of caspases 8, 9, and 3. A non-cytotoxic dose of curcumin (15 µM) inhibited MCE, downregulated the expression of PPARγ and C/EBPα, prevented differentiation medium-induced β-catenin downregulation, and decreased the lipid accumulation in 3T3-L1 adipocytes. In conclusion, our data show that curcumin can induce preadipocyte apoptosis and inhibit adipocyte differentiation, leading to suppression of adipogenesis.
... Some studies demonstrate that 10-25 μM of curcumin efficiently inhibited the differentiation of mouse adipocytes. In concentrations of 10-50 μM, curcumin is able to activate AMP-activated protein kinase (AMPK) (18) and it can also inhibit the activation of MAPK pathway, c-Jun N-terminal kinases (JNK), p38MAPK, and extracellular signal-regulated kinases (ERK) in adipocytes (19). Thus, it stimulates proliferation (20) but suppresses lipid accumulation and adipogenesis (21). ...
... PPARγ is restricted largely to adipose tissue and, to a much lesser extent, to immune cells. It is an activator of adipogenesis, as it induces fatty acid synthesis and storage, and thus it is likely inhibited by AMPK (18,183,184). Also, PPARγ represses the expression of inflammatory genes as iNOS suppresses transcription factors AP-1 and NF-κB, modulates MAPK activity, and influences glucose uptake (185). Hence, PPARγ is a suitable target for medical intervention, and PPARγ-activating pioglitazone is a well-known antidiabetic drug for treatment of T2DM (186). ...
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Background: Type 2 diabetes is a growing public health problem and is associated with increased morbidity and mortality. The worldwide prevalence of type 2 diabetes is rising. Polyphenols, such as flavonoids, phenolic acid, and stilbens, are a large and heterogeneous group of phytochemicals in plant-based foods. In this review, we aimed at assessing the studies on polyphenols and diabetes management. Methods: A literature search in the PubMed, EMBASE, Scopus, and ISI Web of Science databases was conducted to identify relevant studies published from 1986 to Jan 2017. Results: Several animal models and a limited number of human studies have revealed that polyphenols decrease hyperglycemia and improve acute insulin secretion and insulin sensitivity. The possible mechanisms include decrease in glucose absorption in the intestine, inhibition of carbohydrates digestion, stimulation of insulin secretion, modulation of glucose release from the liver, activation of insulin receptors and glucose uptake in insulin-sensitive tissues, modulation of intracellular signaling pathways, and gene expression. Conclusion: Growing evidence indicates that various dietary polyphenols may influence blood glucose at different levels and may also help control and prevent diabetes complication. However, we still need more clinical trials to determine the effects of polyphenols- rich foods, their effective dose, and mechanisms of their effects in managing diabetes.
... Thus, commercial curcumin provides better therapeutic potential to treat Alzheimer's disease compared to isolated curcumin (Ahmed and Gilani, 2014). Several studies evidence the curcumin's antioxidant (Basnet and Škalko-Basnet, 2011;Pizzo et al., 2010), anti-inflammatory (Aggarwal and Harikumar, 2009;Vishvakarma, 2014), antimicrobial (Aziz et al., 2012;Wang et al., 2009), anti-diabetic (Aziz et al., 2012 and antitumor (Ji et al., 2012;Lee et al., 2009;Milac et al., 2008;Naksuriya et al., 2014;Vishvakarma, 2014) activities. ...
... Notably, compound 100 was shown more potent to 99 in the liver cells at the same concentration [202]. (101) is reported to be crucial part of its mechanism for regulating PPAR-γ, MAPK, and COX-2 expression in adipocytes and cancerous cells differentiation [203]. Moreover, 101 induced PGC-1α expression is correlated to the activation of AMPK for AMPK/PGC-1α axis that increased superoxide dimutase-2 (SOD2) transcription [204]. ...
Article
This review covers recent discoveries of phytoconstituents, herbal extracts and some semi-synthetic compounds for treating metabolic syndrome with AMPK activation as one of their mechanisms of action. Recent researches have demonstrated AMPK activation to ameliorate multiple components of metabolic syndrome by regulating a balance between ana-bolic and catabolic cellular reactions. The review attempts to delineate the AMPK activation by natural agents from the perspective of its functional consequences on enzymes, transcription factors and signaling molecules and also on other potential factors contributing in the amelioration of metabolic syndrome.
... 37 A high dose of curcumin also reduces obesity by the inhibition of adipocyte differentiation through suppression of the transcription factor peroxisome proliferator-activated receptor-c. 38 Our results showed that the FBS was decreased significantly in the Cur group at the end of the study. Also, curcumin supplementation with aerobic training for 8 weeks reduced serum insulin level significantly and improved the QUICKI index. ...
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Background: This study aimed to investigate the effects of curcumin supplementation alone and in combination with aerobic training on body composition, glycemic variables, serum levels of C-reactive protein (CRP) and lipid profiles in overweight women. Methods: In this randomized, double-blind, placebo-controlled trial, 40 healthy sedentary overweight females (aged 30-45 years with body mass [BMI] of 25-30 kg/m2) were sampled and randomly assigned to four groups of ten subjects each: curcumin supplementation (Cur), placebo (Pla), Cur+aerobic training (Tra)" and Pla+Tra. Curcumin or placebo capsules (500 mg/day) were administered for 8 weeks. Results: At the end of the intervention, the within-group analysis showed significant reductions in weight, BMI and fasting blood sugar in the Cur group and decreased waist circumference, waist-to-hip ratio, homeostatic model assessment for insulin resistance and serum insulin as well as low-density lipoprotein to high-density lipoprotein ratio (LDL/HDL) and total cholesterol to high-density lipoprotein ratio (TC/HDL) ratios and increased serum HDL cholesterol in the Cur+Tra group. Moreover, the between-groups analysis indicated increased HDL cholesterol in the Cur and Cur+Tra groups compared to the Pla group. The estimated marginal means of serum CRP were significantly higher in Pla+Tra group than in the Cur and Cur+Tra groups. Conclusion: These findings suggest that the combination of curcumin supplementation with aerobic training more effectively improves glycemic and lipidemic statuses than curcumin supplementation or aerobic training alone.
... Higher levels of cortisol in adipocytes induces central obesity (Kumari et al., 2010). In addition, curcumin reduces weight and BMI through the inhibition of adipocyte differentiation in the early stages via suppression of transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and by increasing monophosphateactivated protein kinase and consequently lipolysis (Lee et al., 2009). Curcumin may increase adiponectin expression in adipocyte through increased PPAR-γ expression (Dong et al., 2007). ...
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Background and objective: The current systematic review and meta-analysis of randomized controlled trials (RCTs) was carried out to assess the influence of curcumin intake on weight among patients with metabolic syndrome and related disorders.Methods: We searched the following databases up until January 2018: MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. The relevant data were extracted and evaluated for quality of the studies in accordance with the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI).Results: Eighteen articles (21 studies) that comprised a total of 1,604 individuals were finally included in the meta-analysis. Curcumin intake significantly reduced body mass index (BMI) (SMD −0.37; 95% CI, −0.61, −0.13; P < 0.01), weight (SMD −0.23; 95% CI, −0.39, −0.06; P < 0.01), waist-circumference (WC) (SMD −0.25; 95% CI, −0.44, −0.05; P = 0.01), leptin levels (SMD −0.97; 95% CI, −1.18, −0.75; P < 0.001) and increased adiponectin levels (SMD 1.05; 95% CI, 0.23, 1.87; P = 0.01). We found no significant effect of curcumin intake on hip ratio (HR) (SMD −0.17; 95% CI, −0.42, 0.08; P = 0.18).Conclusions: Overall, we have found that curcumin intake among patients with metabolic syndrome and related disorders was correlated with a significant reduction in BMI, weight, WC, and leptin, and a significant increase in adiponectin levels, but did not affect HR.
... Curcumin (Cur) is one of the most widely used spices for the treatment of many inflammatory wounds and other diseases [5]. Cur, which is obtained from the rhizomes of Curcuma longa, has most of the pharmaceutical properties such as antioxidant [6], anti-inflammatory [7], hypoglycemic effect [8], antitumor [9], anti-HIV [10], induces apoptosis of damaged hepatocytes [11] and wound healing activities [12]. ...
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Polimerik elektroeğirme lifler, yara iyileşme uygulamaları için iyi tasarımlı iskeleler sunmaktadır. Burada, kurkumin (Cur) içeren biyobazlı poliüretan (PU) karışım liflerin üretimi rapor edilmektedir. Yalnızca polimer konsantrasyonu değil, aynı zamanda kurkumin konsantrasyonu, fiberlerin morfolojisi, çapı ve temas açısı değerlerini etkilemiştir. Morfolojik araştırmalar, PU liflerinin çapının ve hidrofilikliğinin kurkumin ilavesi üzerine arttığını ortaya koymuştur. Proses parametrelerinin (uygulanan voltaj, akış hızı ve uçtan toplayıcıya mesafe) PU ve PU/Cur liflerinin ortalama çap ve hidrofilikliği üzerindeki etkileri incelenmiştir. Homojen ve boncuksuz PU/Cur lif elde etmek için optimum koşullar 12.5 kV, 1 mL/s ve 17 cm olarak belirlenmiştir. Bu çalışma, elektroeğirme işleminin, biyoaktif madde yüklü lifli iskeleleri elde etmenin basit bir yolunu sağlamasının yanı sıra, PU/Cur karışım liflerinin imalatında yara iyileşmesi uygulamaları için işlem değişkenlerinin etkisinin daha iyi anlaşılmasına katkıda bulunduğunu göstermektedir.
... Notably, compound 100 is shown more potent to compond 99 on treatment against the liver cells at the same concentration [202]. (101) is reported to be crucial part of its mechanism for regulating PPAR-γ, MAPK, and COX-2 expression in adipocytes and cancerous cells differentiation [203]. Moreover, 101 induced PGC-1α expression is correlated to the activation of AMPK for AMPK/PGC-1α axis that increased superoxide dimutase-2 (SOD2) transcription [204]. ...
... Inhibition of C/EBP was observed in the THY treatment group. AMPK inhibits the expression of factors such as SREBP-1c, and cholesterol and fatty acid synthesis, through the oxidation of glucose and fatty acids [19,20]. The fact that THY also increased AMPK phosphoric acidification in our results can be seen as THY inhibiting lipid accumulation through increased AMPK phosphorylation. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is a disease associated with metabolic syndromes such as diabetes and obesity, regardless of alcohol consumption, and refers to the accumulation of triacylglycerols in the liver. Thymol (THY) is a vegetable essential oil that is naturally contained in the Zingiberaceae and Lamiaceae families. THY was isolated from Curcuma longa L. The rhizomes of Curcuma longa L. were dried, sliced and extracted with 50% ethanol and then isolated through repeated column chromatography. This study was conducted to investigate the inhibitory effect of THY, even in non-alcoholic fatty liver disease, in relation to the inhibiting hyperlipidemia effect of THY, which was demonstrated in previous studies. Hepatocytes were treated with oleate (OA) containing THY to observe lipid accumulation by Oil Red O staining (ORO). We also tested the effect of THY on triacylglycerols (TG) and total cholesterol (TC) in HepG2 cells. Western blot and real-time RT-PCR using sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), CCAAT-enhancer-binding protein (C/EBP), proliferator-activated receptor γ (PPARγ), and adenosine monophosphate (AMP)-activated protein kinase (AMPK) expressions were carried out. Consequently, inhibition of lipogenesis by THY (100 μM or 200 μM) in NAFLD treated with OA in HepG2 cells was confirmed. The results of TG and TC experiments confirmed a decrease in the degree of fat accumulation in the liver. Furthermore, inhibition of the SREBP-1c, FAS, ACC, C/EBP and PPARγ expressions that mediated fat accumulation and increased AMPK phosphorylation was observed. Taken together, THY is proposed as a potential natural constituent for the treatment of NAFLD.
... The chemical name of curcumin is 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione [5]. Curcumin is now being widely promoted as a therapeutic owing to its antioxidant [6], antimicrobial [7], antitumor [8] and anti-inflammatory Mishra [22] demonstrated the effectiveness of curcumin silver nanoparticle against both Gram-positive and Gram-negative bacteria and Loo et al. [23] reported enhanced antibiofilm activity. These nanoparticles also exhibit efficient inhibition against respiratory syncytial virus infection with no host cell toxicity [24] and could be utilized for nucleic acid sensing [25] and collagen stabilization [26]. ...
Article
Curcumin, together with its analogs, namely, demethoxycurcumin and bisdemethoxycurcumin, are phenolic pigments extracted from turmeric. These curcuminoids are considered to be a potent antioxidants possessing a multitude of properties including anti-inflammatory, antitumor, anti-HIV and antimicrobial properties. One of the serious drawbacks of these curcuminoids as therapeutic agent is their fast degradation at physiological pH leading to poor bioavailability in the biological milieu. With a view to address this stability issue we synthesized curcuminoid-silver nanoparticle (CUR-AgNP) complexes, utilizing curcuminoids as reducing agents. The stability of individual curcuminoids in the CUR control and in the CUR-AgNP complex was compared after incubation in phosphate buffer of pH 7.4. Interestingly the initial degradation of curcuminoids at 4 h was only 9.6% in the CUR-AgNP complex when compared to 49.6% degradation observed in the CUR control. Among the three curcumin analogs, bisdemethoxycurcumin showed better pH stability compared to curcumin and demethoxycurcumin whereas all the three curcuminoids exhibited the same degradation pattern in the case of the CUR-AgNP complex. In vitro studies with the CUR-AgNP complex showed excellent antibacterial property against P. aeruginosa. CUR-AgNP complex also exhibited good cytotoxic effect on MDA-MB231 cells. The storage stability of CUR-AgNP complex, kept as a suspension at room temperature (~ 28oC), was tested by measuring its hydrodynamic size and zeta potential. It was found that after 340 days of storage the particle size (Z-average) and zeta potential were 65.5 ± 1.1 nm and -22.9 ± 0.2 mV, respectively, indicating that the nanoparticle suspension was stable The results obtained in the present study are promising and could be extended to improve the therapeutic efficacy of curcuminoids in the biological pH conditions.
... Even though curcumin has direct implications on several anti-obesity studies, its underlying mechanism for restricting adipogenesis is very limited [119]. Previous studies on 3T3-L1 adipocytes have indicated that activation of phosphorylation of AMPK (AMP-activated protein kinase), down-regulation of PPARγ expression, repairing nuclear translocation of β-catenin (of Wnt pathway), and modulation of the MCE (Mitotic clonal expansion) process have led to the inhibition of adipogenesis [120][121][122]. ...
Article
Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.
... Even though curcumin has direct implications on several anti-obesity studies, its underlying mechanism for restricting adipogenesis is very limited [119]. Previous studies on 3T3-L1 adipocytes have indicated that activation of phosphorylation of AMPK (AMP-activated protein kinase), down-regulation of PPARγ expression, repairing nuclear translocation of β-catenin (of Wnt pathway), and modulation of the MCE (Mitotic clonal expansion) process have led to the inhibition of adipogenesis [120][121][122]. ...
Article
Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.
... AMPK activation in cancer cells is known to modulate downstream mTOR pathway leading to tumor growth inhibition. Curcumin activates AMPK in breast cancer cells including triple negative breast cancer cells and regulates ERK, p38, and COX-2 [144]. AMPK stimulation in response to curcumin also leads to activation of autophagy pathway and Akt degradation aiding in inhibition of proliferation and migration of breast cancer cells [145]. ...
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Each cell in our body is designed with a self-destructive trigger, and if damaged, can happily sacrifice itself for the sake of the body. This process of self-destruction to safeguard the adjacent normal cells is known as programmed cell death or apoptosis. Cancer cells outsmart normal cells and evade apoptosis and it is one of the major hallmarks of cancer. The cardinal quest for anti-cancer drug discovery (bioactive or synthetic compounds) is to be able to re-induce the so called “programmed cell death” in cancer cells. The importance of bioactive compounds as the linchpin of cancer therapeutics is well known as many effective chemotherapeutic drugs such as vincristine, vinblastine, doxorubicin, etoposide and paclitaxel have natural product origins. The present review discusses various bioactive compounds with known anticancer potential, underlying mechanisms by which they induce cell death and their preclinical/clinical development. Most bioactive compounds can concurrently target multiple signaling pathways that are important for cancer cell survival while sparing normal cells hence they can potentially be the silver bullets for targeting cancer growth and metastatic progression.
... In 3T3-L1 adipocytes, activated AMPK, an upstream regulator of PPAR-γ, was discovered to be an inhibitor of adipocyte development. Sincse AMPK is involved in maintaining cellular energy balance and adipocyte death, curcumin-induced AMPK-mediated suppression of adipocyte proliferation has clinical implications in the treatment of obesity [98]. ...
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Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin’s anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin’s biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.
... In accordance with these data, we also found that CUR partly restored CLO-induced disturbance of lipid metabolism via modulating AMPK-SREBP pathway. CUR-induced activation of AMPK was also reported in cancer cells and primary white adipocytes (Lee et al., 2009;Lone et al., 2015;Tong et al., 2016). By using molecular modeling, we further demonstrated that CUR shares common binding features with the selective AMPK allosteric ligand, PF-249 (Cokorinos et al., 2017), both of which can form hydrogen bonds with the residue Arg83 and Asn111 and form π-π stacking interactions with the residue Hie109 at the allosteric regulatory site of AMPK (PDB: 5T5T). ...
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Clozapine (CLO) remains an ultimate option for patients with treatment resistant schizophrenia. However, the atypical antipsychotic is often associated with serious metabolic side effects, such as dyslipidemia. Hepatic sterol regulatory element-binding proteins (SREBPs) are central in the allosteric control of a variety of lipid biosynthetic pathways. There is emerging evidence that CLO can activate SREBP pathway and enhance downstream lipogenesis, whereas curcumin (CUR), a major active compound of Curcuma longa, contains hypolipidemic properties. Therefore, in the present study, we examined the protective effects of CUR against CLO-induced lipid disturbance and analyzed the expression of key components in hepatic lipid metabolism. Our data showed that 4-week treatment of CLO (15 mg/kg/day) markedly elevated serum lipid levels and resulted in hepatic lipid accumulation, whereas co-treatment of CUR (80 mg/kg/day) alleviated the CLO-induced dyslipidemia. We further demonstrated that CUR appears to be a novel AMP-activated protein kinase (AMPK) agonist, which enhanced AMPK phosphorylation and mitigated CLO-induced SREBP overexpression. Additionally, CUR also modulated the downstream SREBP-targeted genes involved in fatty acid synthesis and cholesterol metabolism, including fatty acid synthase (FAS) and HMG-CoA reductase (HMGCR). In summary, our study suggests that the suppressed AMPK activity and thereby enhanced SREBP-dependent lipid synthesis could be associated with the antipsychotic-stimulated dyslipidemia, whereas CUR may maintain lipid homeostasis by directly binding to AMPK, indicating that adjunctive use of CUR could be a promising preventive strategy for the drug-induced lipogenesis.
... Furthermore, curcumin inhibits adipocyte differentiation in the early stage and reduces adipocyte numbers and adipose tissue fat content. Scientists have proposed that curcumin reduces fat mass by decreasing microvessel density in the adipose tissue, especially the subcutaneous adipose tissue; enhancing monophosphate-activated protein kinase and lipolysis; and decreasing lipogenesis [9,37,38].Results of in the in vitro studies have indicated that curcumin can reduce adipogenesis by suppressing two transcription factors, namely, cytosine-cytosine-adenosine adenosine-thymidine and peroxisome proliferator-activated receptor g [39]. ...
Article
Objective: Curcumin is an active constituent of turmeric. Recently, scientists have suggested that curcumin can be used in weight reduction. We performed a systematic review based on randomized controlled trials to assess the effects of curcumin supplementation on anthropometric variables. Methods: We searched databases including PubMed, Embase, Web of Science, Scopus, and Google Scholar up to August 2017. Randomized clinical trials assessing the effects of curcumin on anthropometric parameters in human adults were included. Result: Eight randomized clinical trials were allowed to be included in the systematic review. Five articles used the regular form of curcumin with short follow-up duration and did not indicate any significant effect on anthropometric measures, while three articles with significant results used either the more bioavailable form of curcumin or a longer intervention duration. Conclusion: Randomized clinical trials related to curcumin effect on weight are limited but their result indicated useful effect of curcumin on weight. It seems that the bioavailable form of curcumin can reduce obesity and overweight. Further articles with longer duration of intervention and different forms of curcumin supplementation are necessary before any recommendation is made for clinical use of these interventions.
... However, DCC (10 µM) treatment was only able to decrease the ERK1/2 phosphorylation-it was not able to result in any significant change in p38 and JNK phosphorylation. The antagonistic relationship between AMPK and ERK1/2 might be the reason behind the DCC-mediated downregulation of ERK phosphorylation as the reports indicated that some anti-adipogenic phytochemicals act via AMPK-induced MAPK suppression [16,17]. ...
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... The activation of AMPK, a suggested target for diabesity, is known to suppress the adipogenesis of 3T3-L1 cells by downregulating PPARγ and CCAAT/enhancer-binding protein α (C/EBPα) [16,17]. Since AMPK is activated after the knockdown of PTPN6, PTPN6 was also evaluated as a target for obesity using siRNA. ...
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... Various obesity-related drugs have been developed to treat obesity, but these drugs can cause serious side effects [2,3]. Therefore, there is a need to develop anti-obesity materials using natural products with fewer or no side effects that can potentially be useful for treating obesity [4,5]. Adipocytes play an essential role in maintaining energy homeostasis and lipid metabolism. ...
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... Curcumin, isolated from Curcuma longa promotes adiponectin secretion [74]. It triggers AMPK and is involved in the inhibition of p38MAPK, which suppresses glucogenesis in liver [75][76][77]. Capsaicin obtained from Capsicum frutescens ( Fig. 1), acts by activating AMPK and PPARα, which in turn improves insulin sensitivity and increases the fatty acid oxidation in mitochondria [35,78]. Secondly, adiponectin promotes PPAR-a expression, which leads to increased fatty acid oxidation via upregulating acetyl CoA oxidase and uncoupling proteins (UCPs) (Fig. 2) [71]. ...
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... Curcumin has been reported to activate AMP-activated protein kinase (AMPK) to inhibit adipocyte differentiation. Stimulation of AMPK down-regulated PPAR-γ in 3T3-L1 adipocytes to prevent insulin resistance and obesity (87). Di Piero et al. reported that curcumin has a beneficial effect on weight management in 44 overweight subjects by improving weight loss, reducing body fat, increasing waistline reduction, improving hip circumference reduction, and enhancing reduction of BMI (p < 0.01 for all comparisons) without significant statistical effect on phosphatidylserine (88). ...
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Scope: The induction of brown-like adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity and metabolic disorders via the ability of these cells to release excess energy as heat in association with uncoupling protein 1. Some experimental trials suggest that curcumin (a yellow pigment from turmeric) has a suppressive effect on the accumulation of body fat. However, there is little evidence to show that curcumin induces the formation of brown-like adipocytes and the molecular mechanisms involved remain elusive. In addition, in most experimental trials, high doses of curcumin are administered. Methods and results: Highly dispersible and bioavailable curcumin (HC, i.e., 4.5 mg native curcumin/kg) but not the same dose of native curcumin induces the formation of brown-like adipocytes in mouse inguinal WAT. Moreover, the formation of brown-like adipocytes induced by HC in inguinal WAT may be mediated by the production of local norepinephrine from accumulated alternatively activated macrophages. Conclusion: These novel findings suggested that curcumin increased energy expenditure by inducing the formation of brown-like adipocytes via a unique molecular mechanism. Importantly, they showed that HC has significant bioactive effects in vivo at lower doses of curcumin. This article is protected by copyright. All rights reserved.
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Obesity is a multifactorial chronic disease or syndrome caused by an imbalance in energy expenditure and intake. Obesity and its associated complications make it has the fifth leading cause for global mortality. The benefits of the current anti-obesity treatment regimen have been masked by high cost and numerous adverse effects. Therefore, many researchers focus on plant-derived/natural products or altered dietary pattern for the management of obesity and its related complications (co-morbidities). Several epidemiological studies also confirmed that the consumption of functional foods/nutraceuticals could considerably lower the risk of various chronic diseases like obesity, diabetic mellitus, and cancer but the underpinning mechanism is still unclear. This comprehensive review brief on the prevalence of obesity, complications related obesity, current treatment regimen and the importance of functional foods and nutraceuticals (molecular mechanism) for the management of body weight and alleviates its co-morbid conditions. This is the first comprehensive review revealing the in-depth anti-obesity mechanism of various popular functional foods and nutraceuticals with special reference to randomized clinical trials (RCTs). Overall, this contribution would signify the importance and beneficial role of functional foods/nutraceuticals on weight management (anti-obesity) to convey the current treatment status related to clinical trials which would help in the development of novel functional foods/nutraceuticals for combatting obesity and its co-morbidities.
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Scientists proposed that curcumin could be used for treatment of non-alcoholic fatty liver disease (NAFLD). In this article, we aimed to identify the effect of curcumin on NAFLD improvement. Fifty patients with NAFLD, were divided into two groups in this randomized, double-blind, and controlled clinical trial. Patients in the curcumin group received 250 mg/day of phytosomal curcumin, while those in the control group received 250 mg/day of placebo for duration of eight weeks. Anthropometric measurements and fasting blood samples were taken once at the baseline and once at the end of the study. Analysis was performed on 45 patients (curcumin group n = 22, placebo group n = 22). According to between groups analysis, curcumin significantly reduced the carboxymethyl lisine (CML) (148 ± 108 ng/mL vs 197 ± 101 ng/mL, P = 0.04), 8-hydroxy-2' -deoxyguanosine (8-OHdG) (46.9 ± 31.1 ng/mL vs 52.1 ± 43.1 ng/mL P = 0.03), liver enzymes (P < 0.001), weight (P < 0.001), waist circumference (P < 0.001), body fat percent (P < 0.01), and body mass index (BMI) (P < 0.01) in comparison with placebo. However, curcumin supplementation compared to placebo did not reduce soluble receptors for advanced glycation end products (sRAGE), hip circumference, waist/hip, and fat free mass by the end of the study. Our study indicated that phytosamal curcumin might be able to reduce the NAFLD progress by reducing the anthropometric measures, AGEs, and DNA damage. However, we need more studies with longer intervention duration, and larger sample size.
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Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.
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Background The enhancement of oxidative stress in non-alcoholic fatty liver disease (NAFLD) patients may cause mutation in DNA by deamination of cytosine to 5-hydroxyuracil or uracil. This study aimed to discover the effects of curcumin on NAFLD progress, DNA damage caused by oxidative stress, and promoter methylation of mismatch repair enzymes. Material and methods in this study, 54 NAFLD patients were randomly devided into two groups, according to a double blind parallel design either phytosomal curcumin (250 mg/day) or placebo for 8 weeks. Fasting blood samples and anthropometric measures were taken twice, once at the baseline and once at the end of the study. Promoter methylation and 8-hydroxy-2' -deoxyguanosine (8-OHdG) concentration as DNA damage mediator were measured by restriction enzymes and enzyme-linked immunosorbent assay, respectively. Result Analysis was performed on 44 patients. According to our between groups analysis, curcumin significantly reduced the methylation in MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) promoter regions. The within-group comparison revealed that anthropometric variables significantly decreased. However, the result of the between groups comparison indicated no significant changes in the anthropometric variables except for BMI. Liver enzymes and 8-OHdG did not significantly change at the end of the study, neither in curcumin group nor in placebo group. Conclusion Curcumin might be able to reduce the risk of mismatch base pair in DNA among the NAFLD patients. However, it did not change the DNA damage mediator and liver enzymes. For confirming these results, more studies with longer duration, more numbers of examined genes, higher dose of curcumin, and larger sample size are required.
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Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.
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In recent years, the application of nanostructures in biomedical and pharmaceutical fields has increased. The special designs and compositions make nanocomposites very useful alternatives to conventional materials. Curcumin is a promising anti-cancer agent that has a positive and significant effect on chemotherapeutic achievements. The anticancer properties of curcumin have been widely investigated in different forms such as nanoparticles and nanocomposite structures. Chitosan-based nanocomposites, magnetic nanoparticles, polymer nanocomposites and blends, and montmorillonite- and alginate-based nanocomposites have been used in loading curcumin for various purposes. The anticancer preparations of curcumin nanoparticles and drug release systems employing curcumin-loaded nanoparticles, electrospun nanofibers, and hydrogel nanocomposites have been investigated. This review provides a summary of the applications of nanostructures containing curcumin, especially in controlled drug release systems. The curcumin nanoparticles and nanocomposites are suitable candidates for anticancer applications. On the nano-scale, curcumin has better aqueous solubility and, if used in a nanocomposite, there is a good ability for manipulating the drug delivery system properties.
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Obesity is recognized as a severe threat to overall human health and is associated with type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular diseases. Abnormal expansion of white adipose tissue involves increasing the existing adipocytes' cell size or increasing the number through the differentiation of new adipocytes. Adipogenesis is a process of proliferation and differentiation of adipocyte precursor cells in mature adipocytes. As a key process in determining the number of adipocytes, it is a possible therapeutic approach for obesity. Therefore, it is necessary to identify the molecular mechanisms involved in adipogenesis that could serve as suitable therapeutic targets. Reducing bodyweight is regarded as a major health benefit. Limited efficacy and possible side effects and drug interactions of available anti-obesity treatment highlight a constant need for finding novel efficient and safe anti-obesity ingredients. Numerous studies have recently investigated the inhibitory effects of natural products on adipocyte differentiation and lipid accumulation. Possible anti-obesity effects of natural products include the induction of apoptosis, cell-cycle arrest or delayed progression, and interference with transcription factor cascade or intracellular signaling pathways during the early phase of adipogenesis.
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Lambertianic acid (LA) is a diterpene bioactive compound mainly purified from different species of Pinus. It is an optical isomer of another natural compound daniellic acid and was firstly purified from Pinus lambertiana. LA can be synthesized in laboratory from podocarpic acid. It has been reported to have potential health benefits in attenuating obesity, allergies and different cancers including breast, liver, lung and prostate cancer. It exhibits anticancer properties through inhibiting cancer cell proliferation and survival, and inducing apoptosis, targeting major signalling components including AKT, AMPK, NFkB, COX-2, STAT3, etc. Most of the studies with LA were done using in vitro models, thus warranting future investigations with animal models to evaluate its pharmacological effects such as antidiabetic, anti-inflammatory and neuroprotective effects as well as to explore the underlying molecular mechanisms and toxicological profile. This review describes the chemistry, source, purification and therapeutic potentials of LA and it can therefore be a suitable guideline for any future study with LA.
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It is possible to reveal the potential of water-insoluble drugs by increasing their solubility in water with some nanotechnology techniques. Nanosuspension technology can solve this problem by increasing the water solubility and as well as bioavailability of these drugs. The present work is pointed at the evaluation of nanosuspension of curcumin, a poorly water-soluble drug. The Curcumin nanoparticules (CNs) were prepared with ultrasonnication method using dichloromethane as solvent and water as antisolvent and characterized via spectroscopic methods (UV–vis and FT-IR) and Scanning Electron Microscopy (SEM). Curcumin nanoparticules Biofilms (CNs-BF) supported gelatin-collagen scaffold were prepared. Curcumin nanoparticles were obtained by nanosuspension technique. And then, to overcome the limited effects of curcumin such as solubility and bioavailability, nanoparticle films were prepared by incorporating it into the structure of biocompatible collagen-gelatin scaffolds. Curcumin is limited by some factors that limit its clinical applicability, such as low oral bioavailability, poor water solubility and rapid degradation. However, they can be applied clinically when they are included in the structure of biocompatible gelatin-collagen scaffolds.
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The cancer therapy using cyclophosphamide (CP) has been associated with adverse effects on the testicular function that raises concerns about the future fertility potential among cancer survivors. Curcumin, a polyphenol, has shown to possess a plethora of biological functions including tissue protective effects. In the present study, we investigated the protective effects of curcumin nanocrystals (NC) in mitigation of CP-induced testicular toxicity. Healthy adult (8–10 week) and prepubertal (2 week) male Swiss albino mice were injected with a single dose of CP (200 mg/kg) intraperitoneally (i.p). NC (4 mg/kg, i.p.) was administered every alternate day, for 35 days in adult mice while, a single dose of NC was injected intraperitoneally to prepubertal mice 1 h prior to CP. Administration of multiple doses of NC ameliorated CP-induced testicular toxicity in adult mice, which was evident from the improved sperm functional competence, sperm chromatin condensation, seminiferous tubule architecture and decreased apoptosis in testicular cells. Further, administration of NC 1 h prior to CP in prepubertal mice modulated the expression of genes pertaining to proliferation, pluripotency, DNA damage and DNA repair in spermatogonial cells at 24 h after the treatment. Overall, these results suggest that NC could be a promising chemoprotective agent, which can have potential application in male fertility preservation.
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Tuberculosis (TB), the deadliest infectious-disease caused by Mycobacterium tuberculosis (M.tb) created a global-threat to the entire human race since the past few-millennia. The initiation of the antibiotic-era limited the TB infection; however, generation of antibiotic-resistance bacteria causes re-emergence of this infection and makes an alarm to TB-pandemic. Moreover, BCG is the only used vaccine still its inception and its efficacy varies from 0 to 80%. Therefore, the creation of new drugs has become the focus of scientists to combat this deadly-disease. Ethnomedicine was the only therapy at pre-antibiotic-era which in modern-days re-attracted scientists as phytochemical based drug development as it has a huge opportunity. Curcumin is one of the most highlighted phytochemicals found in turmeric of Curcuma plant. From ancient literature, turmeric was found very effective in varieties of infectious and metabolic diseases and in light of modern science, its compound curcumin shows that efficacy. However, due to its less bioavailability initially, scientists were hesitant to use it as a drug molecule but after the emergence of nanotechnology and development of nano-forms of curcumin resolve the bioavailability issue of curcumin and it emerges as a novel drug molecule. Nano-formulation improves its aqueous solubility as well as the guided tissue delivery which will increase the bioavailability of a molecule for a better-transport of drugs and will help in the improvement of TB treatment. In this chapter, we will concentrate on the formulation of different nanocurcumin-particle and its implication in tuberculosis treatment. In brief, we will seek about comprehensive-mechanisms of action of nanocurcumin on therapy and vaccine-development of tuberculosis.
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Background Curcumin is an antioxidant agent that improves glycemia in animal models of diabetes. Clinically curcumin use is limited due to poor solubility, weak absorption, and low bioavailability; therefore, this study to investigate the effects of curcumin’s analog, difluorinated curcumin (CDF), on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and insulin tolerance test (ITT), in streptozotocin (STZ)-induced diabetic rats was undertaken. Methods STZ-induced diabetes rats were randomly assigned to six groups (7 rats per group). They were treated daily by oral gavage with curcumin (200 and 100 mg/kg/day), CDF (200 and 100 mg/kg/day), and metformin (200 mg/kg/day) as a positive control group, for 4 weeks. Two diabetic control (DC) and normal control (NC) groups (non-diabetic rats) received normal saline and citrate buffer, respectively. FBG was measured at the beginning and end of the treatment (Day 0 and week 4) and OGTT and ITT were performed to determine glucose tolerance and insulin sensitivity. Results Cur100, CDF 100, and CDF200 significantly decreased FBG levels after 4 weeks oral administration by −34% (−150 mg/dL ± 70, p = 0.02), −36% (123 mg/dL ±67, p < 0.04), and − 40% (−189 mg/dL ± 91, p = 0.03), respectively. Glucose sensitivity by OGTT showed a significant improvement in glucose tolerance ability in all treated groups compared with DC group. ITT demonstrated that insulin response improved significantly in Cur100 and CDF 200 groups. Conclusion Overall, CDF improved glucose tolerance and insulin sensitivity, while reducing FBG compared to curcumin, suggesting that curcumin analogs may have therapeutic utility in diabetes.
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Obesity is a global health problem needing urgent research. Synthetic anti-obesity drugs show side effects and variable effectiveness. Thus, there is a tendency to use natural compounds for the management of obesity. There is a considerable body of knowledge, supported by rigorous experimental data, that natural polyphenols, including curcumin, can be an effective and safer alternative for managing obesity. Curcumin is a is an important compound present in Curcuma longa L. rhizome. It is a lipophilic molecule that rapidly permeates cell membrane. Curcumin has been used as a pharmacological traditional medicinal agent in Ayurvedic medicine for ∼6000 years. This plant metabolite doubtless effectiveness has been reported through increasingly detailed in vitro, in vivo and clinical trials. Regarding its biological effects, multiple health-promoting, disease-preventing and even treatment attributes have been remarkably highlighted. This review documents the status of research on anti-obesity mechanisms and evaluates the effectiveness of curcumin for management of obesity. It summarizes different mechanisms of anti-obesity action, associated with the enzymes, energy expenditure, adipocyte differentiation, lipid metabolism, gut microbiota and anti-inflammatory potential of curcumin. However, there is still a need for systematic and targeted clinical studies before curcumin can be used as the mainstream therapy for managing obesity.
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Background and aims Curcuminoids and vitamin D have been shown to improve blood pressure and body weight in diabetic animals; however, consistent findings in type 2 diabetes mellitus (T2DM) patients are limited. This study was performed to evaluate the effects of curcuminoids and vitamin D, simultaneously or singly on anthropometric measurements and blood pressure in T2DM patients with insufficient vitamin D level. Methods In this randomized, placebo-controlled clinical trial, eighty T2DM patients were randomly assigned into 4 groups receiving (1) 500 mg/day curcuminoids; (2) 50,000 IU/week vitamin D3; (3) 50,000 IU/week vitamin D3 plus 500 mg/d curcuminoids; or (4) placebos for 12 weeks. Blood pressure and anthropometric measurements were evaluated before and after intervention. Results Intergroup comparisons showed that Vitamin D (main effect) significantly reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP) (P = 0/000). Curcuminoids (main effect) significantly reduced DBP (P = 0/001). Interaction effects showed that curcuminoids significantly prevented the effect of vitamin D on the reduction of SBP (P = 0.006). Whereas, vitamin D and curcuminoids had a synergistic effect on DBP reduction (P = 0.006). The comparison of changes in anthropometric measurements between the four groups showed no significant differences in the raw and adjusted models. In-group comparisons showed that SBP, DBP, waist to hip circumference (WHR), body fat mass (BFM), percent body fat (PBF) and visceral fat area (VFA) values were significantly reduced in all groups except the placebo group compared to baseline values. Only in the CR-D group, there was a significant reduction in body weight (P = 0/047). Conclusions Curcuminoids and vitamin D may have beneficial effects on blood pressure and anthropometric measurements in T2DM patients. Clinical registration http://www.IRCT.ir:IRCT2017041213678N22.
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This paper examines the in vitro transepithelial transport of antihypertensive peptides derived from egg proteins using Caco-2 cell monolayers. Ovokinin (FRADHPFL) was absorbed intact through the Caco-2 cell epithelium, although it was also susceptible to the action of brush-border aminopeptidases that yielded shorter fragments prior to their transport. The tripeptide YPI was resistant to cellular peptidases and transported through the monolayer, what suggests that the reduction in systemic blood pressure caused by this peptide may be mediated by effects at tissue level. Its pathway for transepithelial absorption was examined using inhibitors of the different mechanisms for oligopeptide transport in the intestinal tract. The main route involved in the transepithelial flux of YPI is probably the peptide H(+)-coupled transporter PepT1. These results highlight the potential of antihypertensive peptides to be used in the formulation of functional foods.
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Activation of COX-2 and inhibition of PPARgamma have been observed in human and animal models of breast cancer. Both inhibition of COX-2 and activation of PPARgamma can inhibit proliferation of breast cancer cells in vitro. Here, we examine the effects of the COX-2 inhibitor celecoxib and the PPARgamma agonist N-(9-fluorenyl-methyloxycarbonyl)-l-leucine (F-L-Leu) on mouse breast tumor cells in vitro and in vivo. We created and characterized a mouse mammary adenocarcinoma cell (MMAC-1) line from C3 (1)-SV40 tumor antigen mice to study COX-2 and PPARgamma expression and response to celecoxib and F-L-Leu in vitro. To study the in vivo effects, C3 (1)-SV40 tumor antigen mice were given either control diet or diets containing three different concentrations of celecoxib and F-L-Leu as well as a combination of both agents. Mice were then followed for tumor formation up to 1 year. MMAC-1 cells express both COX-2 and PPARgamma mRNA and exhibited cooperative growth inhibition with a combination of celecoxib and F-L-Leu. In mice, the median age of death due to mammary tumors was significantly delayed in celecoxib-treated animals at all three concentrations but was not significantly affected by F-L-Leu treatment alone. A combination of celecoxib and F-L-Leu was significantly more effective than celecoxib alone. Our findings suggest that a combination of a COX-2 inhibitor and PPARgamma agonist can delay breast cancer in a mouse model and suggest that these agents should be studied in the context of human populations with high breast cancer risk.
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Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. Through these pathways, PPARs can regulate cell proliferation, differentiation and survival, so controlling carcinogenesis in various tissues. But what are the links between each PPAR isotype and carcinogenesis and what is the relevance of these findings to human pathology and therapy?
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Since its identification as the receptor for antidiabetic thiazolidinedione drugs, peroxisome proliferator-activated receptor-gamma (PPARgamma) has been the focus of pharmaceutical drug discovery programs directed toward finding better drugs for the treatment of diabetes, as well as the object of basic research aimed at understanding its role in the regulation of metabolism. We now understand a great deal about the crucial role that PPARgamma plays in adipocyte differentiation and development, and are rapidly gaining knowledge about the role of the receptor in the regulation of metabolism. However, many crucial aspects of the molecular mechanism by which modulation of PPARgamma activity affects insulin resistance and glucose homeostasis are still not clearly understood. Here the authors review the current status of PPARgamma research, with an emphasis on its role in the causes and treatment of type 2 diabetes.
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The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPAR gamma receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPAR gamma ligands including BRL49653 (rosiglitazone), 15-deoxy-Delta 12,14-prostaglandin J(2), and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPAR gamma ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin's cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPAR gamma ligands induced the differentiation of myeloid leukemic cells. A combination of PPAR gamma ligands with a retinoid X receptor agonist (i.e., LG100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPAR gamma ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-induced apoptosis. These results suggest that PPAR gamma ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias.
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LKB1, mutated in Peutz-Jeghers and in sporadic lung tumours, phosphorylates a group of protein kinases named AMP-activated protein kinase (AMPK)-related kinases. Among them is included the AMPK, a sensor of cellular energy status. To investigate the relevance of LKB1 in lung carcinogenesis, we study several lung cancer cells with and without LKB1-inactivating mutations. We report that LKB1-mutant cells are deficient for AMPK activity and refractory to mTOR inhibition upon glucose depletion but not growth-factor deprivation. The requirement for wild-type LKB1 to properly activate AMPK is further demonstrated in genetically modified cancer cells. In addition, LKB1-deficient lung primary tumours had diminished AMPK activity, assessed by complete absence or low level of phosphorylation of its critical substrate, acetyl-CoA carboxylase. We also demonstrate that LKB1 wild-type cells are more resistant to cell death upon glucose withdrawal than their mutant counterparts. Finally, modulation of AMPK activity did not affect PI3K/AKT signalling, an advantage for the potential use of AMPK as a target for cancer therapy in LKB1 wild-type tumours. Thus, sustained abrogation of cell energetic checkpoint control, through alterations at key genes, appear to be an obligatory step in the development of some lung tumours.
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5'-AMP-activated protein kinase (AMPK) serves as an energy sensor and is at the center of control for a large number of metabolic reactions, thereby playing a crucial role in Type 2 diabetes and other human diseases. AMPK is present in the nucleus and cytoplasm; however, the mechanisms that regulate the intracellular localization of AMPK are poorly understood. We have now identified several factors that control the distribution of AMPK. Environmental stress regulates the intracellular localization of AMPK, and upon recovery from heat shock or oxidant exposure AMPK accumulates in the nuclei. We show that under normal growth conditions AMPK shuttles between the nucleus and the cytoplasm, a process that depends on the nuclear exporter Crm1. However, nucleocytoplasmic shuttling does not take place in high-density cell cultures, for which AMPK is confined to the cytoplasm. Furthermore, we demonstrate that signaling through the mitogen-activated protein kinase kinase (MEK)-->extracellular signal-regulated kinase 1/2 (ERK1/2) cascade plays a crucial role in controlling the proper localization of AMPK. As such, pharmacological inhibitors that interfere with this pathway alter AMPK distribution under nonstress conditions. Taken together, our studies identify novel links between the physiological state of the cell, the activation of MEK-->ERK1/2 signaling, and the nucleocytoplasmic distribution of AMPK. This sets the stage to develop new strategies to regulate the intracellular localization of AMPK and thereby the modification of targets that are relevant to human disease.
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Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.
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Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.
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The recent development of a novel class of insulin-sensitizing drugs, the thiazolidinediones (TZDs), represents a significant advance in antidiabetic therapy. One key mechanism by which these drugs exert their effects is by activation of the peroxisome proliferator activated receptor γ (PPAR-γ), a member of the nuclear receptor family. Evidence supporting this mechanism of action of the TZDs will be reviewed in this article. Recent data suggests that PPAR-γ agonists might also have therapeutic potential in the treatment of inflammatory diseases and certain cancers.
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Germline mutations in LKB1, TSC2, or PTEN tumor suppressor genes result in hamartomatous syndromes with shared tumor biological features. The recent observations of LKB1-mediated activation of AMP-activated protein kinase (AMPK) and AMPK inhibition of mTOR through TSC2 prompted us to examine the biochemical and biological relationship between LKB1 and mTOR regulation. Here, we report that LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR. These findings position aberrant mTOR activation at the nexus of these germline neoplastic conditions and suggest the use of mTOR inhibitors in the treatment of Peutz-Jeghers syndrome.
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The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. Whenever the cellular ATP:ADP ratio falls, owing to a stress that inhibits ATP production or increases ATP consumption, this is amplified by adenylate kinase into a much larger increase in the AMP:ATP ratio. AMP activates the system by binding to two tandem domains on the gamma subunits of AMPK, and this is antagonized by high concentrations of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumour suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1-->AMPK-->TSC2 pathway negatively regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.
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Epidemiologic studies in human populations and experimental studies in rodents provide evidence that green tea and its constituents can inhibit both the development and growth of tumors at a variety of tissue sites. In addition, EGCG, a major biologically active component of green tea, inhibits growth and induces apoptosis in a variety of cancer cell lines. The purpose of this paper is to review evidence that these effects are mediated, at least in part, through inhibition of the activity of specific receptor tyrosine kinases (RTKs) and related downstream pathways of signal transduction. We also review evidence indicating that the antitumor effects of the related polyphenolic phytochemicals resveratrol, genistein, curcumin, and capsaicin are exerted via similar mechanisms. Some of these agents (EGCG, genistein, and curcumin) appear to directly target specific RTKs, and all of these compounds cause inhibition of the activity of the transcription factors AP-1 and NF-kappaB, thus inhibiting cell proliferation and enhancing apoptosis. Critical areas of future investigation include: (1) identification of the direct molecular target(s) of EGCG and related polyphenolic compounds in cells; (2) the in vivo metabolism and bioavailability of these compounds; (3) the ancillary effects of these compounds on tumor-stromal interactions; (4) the development of synergistic combinations with other antitumor agents to enhance efficacy in cancer prevention and therapy, and also minimize potential toxicities.
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The AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status, and recent data demonstrate that it also plays a critical role in systemic energy balance. AMPK integrates nutritional and hormonal signals in peripheral tissues and the hypothalamus. It mediates effects of adipokines (leptin, adiponectin, and possibly resistin) in regulating food intake, body weight, and glucose and lipid homeostasis. AMPK is regulated by upstream kinases of which the tumor suppressor, LKB1, is the first to be identified. Complex signaling networks suggest that AMPK may prevent insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. Through signaling, metabolic, and gene expression effects, AMPK enhances insulin sensitivity and fosters a metabolic milieu that may reduce the risk for obesity and type 2 diabetes.
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This study evaluated the anti-tumor efficacy of combining the RXR agonist, bexarotene, with the PPARgamma agonist, rosiglitazone, in colon cancer. Moser, a human colon cancer cell line, was treated with bexarotene and rosiglitazone alone or in combination and the effect on growth and differentiation were examined. The data demonstrated that the bexarotene/rosiglitazone combination produced greater efficacy in growth inhibition than either single agent. Furthermore, combination treatment acted cooperatively to decrease COX-2 expression and PGE2 synthesis while increasing expression of the differentiation marker, CEA. These findings were confirmed in vivo in a Moser xenograft tumor model. Collectively, our data suggest a potential role for utilizing a combination regimen of a RXR and PPARgamma agonist in the treatment of colon cancer.
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AMP-activated protein kinase (AMPK) is a metabolic master switch regulating glucose and lipid metabolism. Recently, AMPK has been implicated in the control of adipose tissue content. Yet, the nature of this action is controversial. We examined the effect on F442a adipocytes of the AMPK activator-AICAR. Activation of AMPK induced dose-dependent apoptotic cell death, inhibition of lipolysis, and downregulatation key adipogenic genes, such as peroxisome proliferator-activated receptor (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha). We have identified the alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha) as a target gene which is phosphorylated following AICAR treatment. Such phosphorylation is one of the best-characterized mechanisms for downregulating protein synthesis. 2-Aminopurine (2-AP), an inhibitor of eIF2alpha kinases, could overcome the apoptotic effect of AICAR, abolishing the reduction of PPARgamma and C/EBPalpha and the lipolytic properties of AMPK. Thus, AMPK may diminish adiposity via reduction of fat cell number through eIF2alpha-dependent translation shutdown.
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While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the molecular level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various molecular targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-kappaB, AP-1, STAT3, Akt, Bcl-2, Bcl-X(L), caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the molecular targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.
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AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
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Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.
Article
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
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Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
Article
AMP-activated protein kinase (AMPK) is an energy sensing/signaling protein that, when activated, increases ATP production by stimulating glucose uptake and fatty acid oxidation while at the same time inhibiting ATP = consuming processes such as protein synthesis. Chronic activation of AMPK inhibits expression of lipogenic enzymes in the liver and enhances expression of mitochondrial oxidative enzymes in skeletal muscle. Deficiency of muscle LKB1, the upstream kinase of AMPK, results in greater fluctuation in energy charge during muscle contraction and decreased capacity for exercise at higher work rates. Because AMPK enhances both glucose uptake and fatty acid oxidation in skeletal muscle, it has become a target for prevention and treatment of type 2 diabetes and obesity.
Article
The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.
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Metabolic disorders such as obesity are major obstacles in improving the average life span. Therefore, a therapeutic approach using natural compounds has been proposed as a novel strategy for preventing metabolic disorders. Ginsenoside Rh2 is one of the ginsenosides that exert anti-diabetes, anti-inflammatory, and anti-cancer effects. However, the anti-obesity effects of Ginsenoside Rh2 remain unclear. Here, we investigated the anti-obesity ability of ginsenoside Rh2 using cell culture systems. Ginsenoside Rh2 effectively inhibited adipocyte differentiation via PPAR-gamma inhibition. Next, to find specific target molecules based on this result, we used cell culture systems to examine whether AMPK activation was involved in the anti-obesity ability of ginsenoside Rh2 since several published papers have indicated that AMPK signaling is involved in the regulation of metabolic disorders. Ginsenoside Rh2 significantly activated AMPK in 3T3-L1 adipocytes. In addition, we also examined the effect of AMPK on lipolysis molecules such as CPT-1 and UCP-2 by using an AMPK inhibitor. Ginsenoside Rh2 effectively induced CPT-1 and UCP-2 and this induction was abolished by AMPK inhibitor treatment. Moreover, we observed that ROS is an important upstream signal for AMPK activation during ginsenoside Rh2 treatment. Taken together, these results indicate that ginsenoside Rh2 is the most effective candidate for preventing metabolic disorders such as obesity and that it acts via the AMPK signaling pathway. Thus, AMPK signaling might contribute toward improving human health.
Article
Metabolic syndrome is characterized by a cluster of metabolic disorders, such as reduced glucose tolerance, hyperinsulinemia, hypertension, visceral obesity and lipid disorders. The benefit of exercise in maintaining total metabolic control is well known and recent research indicates that AMP-activated protein kinase (AMPK) may play an important role in exercise-related effects. AMPK is considered as a master switch in regulating glucose and lipid metabolism. AMPK is an enzyme that works as a fuel gauge, being activated in conditions of high phosphate depletion. In the liver, activation of AMPK results in decreased production of plasma glucose, cholesterol, triglyceride and enhanced fatty acid oxidation. AMPK is also robustly activated by skeletal muscle contraction and myocardial ischemia, and is involved in the stimulation of glucose transport and fatty acid oxidation by these stimuli. In adipose tissue, activated AMPK inhibits deposition of fat, but enhances breakdown and burning of stored fat, resulting in reduction of body weight. The two leading diabetic drugs, namely metformin and rosiglitazone, and adipokines, such as adiponectin and leptin, show their metabolic effects partially through AMPK. These data suggest that AMPK may be a key player in the development of new treatments for obesity, Type 2 diabetes and the metabolic syndrome. In this review, the author provide insight into the role of AMPK as a probable target for treatment of metabolic syndrome.
Article
Curcumin is a natural polyphenol used in ancient Asian medicine. Since the first article referring to the use of curcumin to treat human disease was published in The Lancet in 1937, >2,600 research studies using curcumin or turmeric have been published in English language journals. The mechanisms implicated in the inhibition of tumorigenesis by curcumin are diverse and appear to involve a combination of antiinflammatory, antioxidant, immunomodulatory, proapoptotic, and antiangiogenic properties via pleiotropic effects on genes and cell-signaling pathways at multiple levels. The potentially adverse sequelae of curcumin's effects on proapoptotic genes, particularly p53, represent a cause for current debate. When curcumin is combined with some cytotoxic drugs or certain other diet-derived polyphenols, synergistic effects have been demonstrated. Although curcumin's low systemic bioavailability after oral dosing may limit access of sufficient concentrations for pharmacologic effects in tissues outside the gastrointestinal tract, chemical analogues and novel delivery methods are in preclinical development to overcome this barrier. This article provides an overview of the extensive published literature on the use of curcumin as a therapy for malignant and inflammatory diseases and its potential use in the treatment of degenerative neurologic diseases, cystic fibrosis, and cardiovascular diseases. Despite the breadth of the coverage, particular emphasis is placed on the prevention and treatment of human cancers.
Article
A growing body of research suggests that curcumin, the major active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. Preclinical data have shown that curcumin can both inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. In vitro studies have demonstrated that curcumin is an efficient inducer of apoptosis and some degree of selectivity for cancer cells has been observed. Clinical trials have revealed that curcumin is well tolerated and may produce antitumor effects in people with precancerous lesions or who are at a high risk for developing cancer. This seems to indicate that curcumin is a pharmacologically safe agent that may be used in cancer chemoprevention and therapy. Both in vitro and in vivo studies have shown, however, that curcumin may produce toxic and carcinogenic effects under specific conditions. Curcumin may also alter the effectiveness of radiotherapy and chemotherapy. This review article analyzes the in vitro and in vivo cancer-related activities of curcumin and discusses that they are linked to its known antioxidant and pro-oxidant properties. Several considerations that may help develop curcumin as an anticancer agent are also discussed.
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