Curcumin relieves depressive-like behaviors via inhibition of the NLRP3 inflammasome and kynurenine pathway in rats suffering from chronic unpredictable mild stress.

Increasing evidence suggests that inflammation is related to the pathophysiology of depression. Curcumin (CUR), which is a natural component extracted from the rhizome of Curcuma longa, seems to be efficacious in depression treatment. Hence, the present study aims to explore whether the anti-depressive effect of curcumin is connected to its anti-inflammatory features. Twenty-one SD rats were randomly divided into three groups, namely, control, CUMS (chronic unpredictable mild stress), and CUMS + CUR. After stress exposure for four weeks, the CUMS group showed depressive-like behaviors, and the curcumin treatment successfully corrected the depressive-like behaviors in stressed rats. Additionally, the curcumin could effectively decrease mRNA expression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and suppress NF-κB activation. Curcumin also inhibited the stressed-induced P2X7R/NLRP3 inflammasome axis activation, along with the reduced transformation of pro-IL-1ß to mature IL-1ß. The stress-induced activation of indolamine-2, 3-dioxygenase (IDO) and an increased kynurenine/tryptophan ratio were also ameliorated by curcumin supplementation. In conclusion, the study revealed that curcumin relieves a depressive-like state through the inhibition of the NLRP3 inflammasome and kynurenine pathway.

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer.

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

Effect of Cinnamon and Turmeric Aqueous Extracts on Serum Interleukin-17F Level of High Fructose-Fed Rats.

BACKGROUND: Studies have indicated that extraweight and obesity induce chronic inflammation, which can lead to other diseases such as cancers. OBJECTIVE: To evaluate the effects of two weight-lowering and anti-inflammatory agents including cinnamon, and turmeric, on serum levels of interleukin-17 (IL-17) as a pro-inflammatory cytokine. METHODS: In this study, 64 rats were designated in eight groups. The control group received normal diet. The other groups were fed with normal diet plus high cinnamon (3 mg/ml), high turmeric (3 mg/ml), high-fructose solution (30%), fructose solution with low (0.15 mg/ml) and high doses (3 mg/ml) of cinnamon and turmeric three times per week. The serum level of IL-17F was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: High fructose consumption led to an increase in the weight and serum level of IL-17. While, feeding with cinnamon and turmeric caused to decline weight but, surprisingly increased IL-17F levels. CONCLUSION: Although, some studies have showed that cinnamon and turmeric supplementation decreased IL-17F under the standard diet, in the presence of high fructose diet and extraweight their effects were reversed and caused an increase in serum level of IL-17F.

Diarylheptanoid from rhizomes of Curcuma kwangsiensis (DCK) inhibited imiquimod-induced dendritic cells activation and Th1/Th17 differentiation.

BACKGROUND AND OBJECT: Dendritic cells (DCs) are critical for initiating the activation and differentiation of T cells in inflammatory diseases including psoriasis. Curcuma kwangsiensis S.G. Lee & C.F. Liang is a herb for treating psoriasis and we previously found Diarylheptanoid from rhizomes of Curcuma kwangsiensis (DCK) inhibited keratinocytes proliferation. However, it is unknown whether DCK influences DC functions. Thus we aimed to explore whether DCK affect the major immunological functions of DCs. MATERIALS AND METHODS: Primary DCs derived from mouse bone marrow cells and spleen were used for examining their general immunological functions, and OVA-specific T cells from OT-II mice were used for examining the DC-mediated T-helper (Th) 1 and Th17 cells differentiation and effect. RESULTS: We demonstrated DCK suppressed DC uptake of FITC-labeled ovalbumin (OVA) and DC maturation characterized by decreased MHCII, CD80 and CD86 following imiquimod (IMQ) stimulation. DCK also reduced DC expression of the lymphoid-homing chemokine receptor CCR7, and DC migration towards CCL21, the ligand for CCR7. Importantly, DCK significantly reduced the production of proinflammatory cytokines including IL-12, IL-6 and IL-1ß by IMQ-stimulated DCs. Moreover, in the coculture of OVA323-339 peptide-pulsed DCs and OVA-specific T cells from OT-II mice, DCK significantly inhibited T cell proliferation and the differentiation of Th1 and Th17 cells. Furthermore, DCK treatment greatly reduced phosphorylation of p65-associated cell signaling pathway in IMQ-stimulated DCs. CONCLUSION: These data together demonstrate a potential role of DCK in suppressing the biological function of DCs, and provide a possible mechanism for understanding the effects of herb Curcuma kwangsiensis in treating psoriasis.

Antiarthritic Effect of Polar Extract of Curcuma longa on Monosodium Iodoacetate Induced Osteoarthritis in Rats.

BACKGROUND: Curcuma longa Linn, "the golden spice" is a common spice used in Southern Asia and Middle East countries. It has a history of ethnopharmacological use for its various activities like anti-septic, anti-inflammatory, anti-oxidant, anti-microbial, anti-cancer and so on. OBJECTIVE: To investigate the effects of polar extract of C. longa (PCL) against monosodium iodoacetate (MIA) induced osteoarthritis in rat and to compare with curcuminoids, which are contemporarily believed to be the only active phytochemicals of C. longa for relieving pain in osteoarthritis. METHOD: Osteoarthritis in rats was induced by intra-articular injection of monosodium iodoacetate (MIA) in right knee. PCL or curcuminoids or tramadol was administered orally as single dose on the 5th day post MIA injection to rats. Weight bearing capacity and percentage inhibition of nociception of PCL treated groups were determined and compared with curcuminoids and tramadol (reference drug). In addition, gene expression levels of type II collagen and matrix metalloproteinases (MMP) in joint cartilage was measured by Reverse transcription polymerase chain reaction. RESULTS: PCL significantly decreased the difference in weight distribution between left and right limb in a dose dependent manner. Anti-arthritic activity of PCL is evident from significant up regulation of type II collagen gene (COL2A1) and down regulation of MMP-3 and MMP-7. CONCLUSION: Polar extract of C. longa showed beneficial effects on joints by exhibiting antiosteoarthritic effects via maintaining equilibrium between anabolic and catabolic factors of joint cartilage.

Curcumin-albumin conjugates as an effective anti-cancer agent with immunomodulatory properties.

Curcumin (diferuloylmethane) is an active ingredient in turmeric (Curcuma longa) with anti-inflammatory, antioxidant, chemopreventive, chemosensitization, and radiosensitization properties. Conjugation of curcumin (Curc) to albumin (Alb) has been found to increase the aqueous solubility of the drug. The current study aimed to prove the safe use of the Curc-Alb conjugate in animals and to demonstrate that it retains drug action both in vitro and in vivo. Dalton's lymphoma ascites (DLA) cell viability was inhibited by the Curc-Alb conjugate in a dose dependent manner in vitro, as evidenced by the MTT assay. Administration of up to 11.4 mg of conjugated curcumin per kg body weight to healthy animals was non-toxic both in terms of lethality and weight loss. Histological analysis of vital organs (kidney, liver and spleen) also did not show toxic effects. Favorable immuno-modulatory activity was observed after continuous administration of sub-acute doses of the conjugate which caused increase in total leukocyte count, platelet count, and viable cell count in bone marrow, and enhanced proliferation of lymphocyte in vitro upon culture. In vivo studies in the DLA tumor model in mice demonstrated that conjugated drug induces tumor reduction and prevention. Significant tumor reduction was observed when the Curc-Alb conjugate was administered intraperitoneally in DLA-induced mice after 1 day (prevention therapy) and 7 days (reduction therapy) of tumor induction. There was significant reduction in both tumor volume and tumor cell numbers in the treated animals as well as a marked increase in their mean survival time and percent increase in life span. The effect was greater when the conjugate was administered soon after inducing the tumor as compared to when treatment was started after allowing tumor to grow for 7 days. Thus, the results of the present study suggest that curcumin albumin conjugate has immunomodulatory and tumor growth inhibition properties. The study postulates the drug form has the potential to be used as an anticancer agent in affected human subjects.

Amelioration of some immunological disorders caused by the faeces of the dominant true house dust mites in El-Minia Governorate, Egypt.

BACKGROUND: House dust mites (HDMs) faeces are the main factor involved in respiratory disorder. The true HDMs, Dermatophagoides pteronyssinus and D. farinae, detected in the samples collected from the house dust are the most important causes of allergic disorders such as asthma. OBJECTIVE: The aim of this investigation was to study the curcuma and karkade amelioration of the allergenic immunological disorder, especially some cytokines, IgE and ROS, caused by the faeces of the dominant true HDM, D. pteronyssinus and D. farinae in valley and desert houses in EL-Minia Governorate, respectively. METHODS: HDM cultures, faeces isolation, plant extraction and ELISA techniques were used. Male albino rats were classified into control, inhaled, and treated groups. RESULTS: The present immunological study on the dominant allergenic true HDMs, D. pteronyssinus and D. farinae, revealed that significantly higher serum levels of TNF-α, IL-1ß, IL-4, IL-13 and IgE were found in rats treated with both D. pteronyssinus and D. farinae faeces than the other groups. In addition, statistical analysis of ROS data showed significant difference between the curcuma- and karkade-treated groups and either the control or the faeces-treated groups (P<0.05). CONCLUSIONS: Some immunological disturbances caused by repeated exposure to the faeces of two dominant allergenic true HDM species (D. pteronyssinus and D. farinae) in the valley and desert houses could be ameliorated by curcuma and karkade.

Curcumin attenuated acute Propionibacterium acnes-induced liver injury through inhibition of HMGB1 expression in mice.

Curcumin is a phenolic product isolated from the rhizome of Curcuma longa and has protective effects on inflammatory diseases. Here we investigated the protective effect of curcumin in acute Propionibacterium acnes (P. acnes)-induced inflammatory liver injury. C57BL/6 mice were primed with P. acnes followed by LPS challenge to induce fulminant hepatitis. Curcumin or vehicle control was administered perorally by gavage once daily starting 2days before P. acnes priming. We found that curcumin significantly improved mouse mortality. Then, to investigate the underlying mechanisms of curcumin in this acute inflammatory liver injury model, we primed C57BL/6 mice with P. acnes only. We found that curcumin treatment attenuated P. acnes-induced liver injury as evidenced by decreased production of ALT. In addition, curcumin treatment reduced the production of proinflammatory cytokines such as TNF-α and IFN-γ, accompanied by reduced hepatocyte apoptosis. Furthermore, curcumin treatment significantly reduced HMGB1 cytoplasmic translocation and expression by down-regulating acetylation of lysine. Taken together, our results suggest that curcumin protects mice from P. acnes-induced liver injury through reduction of HMGB1 cytoplasmic translocation and expression.

Intranasal curcumin attenuates airway remodeling in murine model of chronic asthma.

Curcumin, phytochemical present in turmeric, rhizome of Curcuma longa, a known anti-inflammatory molecule with variety of pharmacological activities is found effective in murine model of chronic asthma characterized by structural alterations and airway remodeling. Here, we have investigated the effects of intranasal curcumin in chronic asthma where animals were exposed to allergen for longer time. In the present study Balb/c mice were sensitized by an intraperitoneal injection of ovalbumin (OVA) and subsequently challenged with 2% OVA in aerosol twice a week for five consecutive weeks. Intranasal curcumin (5mg/kg) was administered from days 21 to 55, an hour before every nebulization and inflammatory cells recruitment, levels of IgE, EPO, IL-4 and IL-5 were found suppressed in bronchoalveolar lavage fluid (BALF). Intranasal curcumin administration prevented accumulation of inflammatory cells to the airways, structural alterations and remodeling associated with chronic asthma like peribronchial and airway smooth muscle thickening, sloughing off of the epithelial lining and mucus secretion in ovalbumin induced murine model of chronic asthma.

Preventive action of curcumin in experimental acute pancreatitis in mouse.

BACKGROUND & OBJECTIVES: Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. The purpose of the present study was to investigate the preventive effects of curcumin against acute pancreatitis (AP) induced by caerulein in mouse and to elucidate possible mechanism of curcumin action. METHODS: Curcumin (50 mg/kg/day) was intraperitoneally injected to Kun Ming male mice for 6 days, followed by injection of caerulein to induce AP. GW9662 (0.3 mg/kg), a specific peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, was intravenously injected along with curcumin. Murine macrophage RAW264.7 cells were treated with 100 µmol/l curcumin for 2 h, and then stimulated with 0.1 µ g/ml lipopolysaccharide (LPS). Serum amylase and transaminase levels were measured at 10 h after AP. TNF-α level in mouse serum and cell culture medium were detected by ELISA. Expression of PPARγ and NF-κB were analyzed by RT-PCR and Western blot. RESULTS: Curcumin significantly decreased the pancreas injury and reversed the elevation of serum amylase, ALT and AST activities and TNF-α level in mice with AP. Curcumin treatment inhibited the elevation of NF-κB-p65 in the nucleus of mouse pancreas AP group and RAW264.7 cells, but significantly increased the expression of PPARγ. GW9662 could abolish the effects of curcumin on serum levels of amylase, ALT, AST, TNF-α, and NF-κB level. INTERPRETATION & CONCLUSIONS: Our results suggest that curcumin could attenuate pancreas tissue and other organ injury by inhibiting the release of inflammatory cytokine TNF-α. These effects may involve upregulation of PPARγ and subsequent downregulation of NF-κB.

Curcumin induces maturation-arrested dendritic cells that expand regulatory T cells in vitro and in vivo.

Dendritic cells (DC) and regulatory T cells (T(regs) ) are vital to the development of transplant tolerance. Curcumin is a novel biological agent extracted from Curcuma longa (turmeric), with anti-inflammatory and anti-oxidant activity mediated via nuclear factor (NF)-κB inhibition. We investigated the immunomodulatory effects of curcumin on human monocyte-derived and murine DC. Human monocyte-derived DC (hu-Mo-DC) were generated in the presence (CurcDC) or absence (matDC) of 25 µM curcumin, and matured using lipopolysaccharide (1 µg/ml). DC phenotype and allostimulatory capacity was assessed. CD11c(+) DC were isolated from C57BL/6 mice, pretreated with curcumin and injected into BALB/c mice, followed by evaluation of in vivo T cell populations and alloproliferative response. Curcumin induced DC differentiation towards maturation-arrest. CurcDC demonstrated minimal CD83 expression (<2%), down-regulation of CD80 and CD86 (50% and 30%, respectively) and reduction (10%) in both major histocompatibility complex (MHC) class II and CD40 expression compared to matDC. CurcDC also displayed decreased RelB and interleukin (IL)-12 mRNA and protein expression. Functionally, CurcDC allostimulatory capacity was decreased by up to 60% (P < 0·001) and intracellular interferon (IFN-γ) expression in the responding T cell population were reduced by 50% (P < 0·05). T cell hyporesponsiveness was due to generation of CD4(+) CD25(hi) CD127(lo) forkhead box P3 (FoxP3)(+) T(regs) that exerted suppressive functions on naïve syngeneic T cells, although the effect was not antigen-specific. In mice, in vivo infusion of allogeneic CurcDC promoted development of FoxP3(+) T(regs) and reduced subsequent alloproliferative capacity. Curcumin arrests maturation of DC and induces a tolerogenic phenotype that subsequently promotes functional FoxP3(+) T(regs) in vitro and in vivo.

Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni.

Curcumin is a polyphenol derived from the dietary spice turmeric. It has been shown to regulate numerous transcription factors, cytokines, adhesion molecules, and enzymes that have been linked to inflammation. In addition to inhibiting the growth of a variety of pathogens, curcumin has been shown to have nematocidal activity. The present study was designed to evaluate the schistosomicidal activity of curcumin in vivo as well as immunomodulation of granulomatous inflammation and liver pathology in acute schistosomiasis mansoni. Mice were infected each with 80 Schistosoma (S.) mansoni cercariae and injected intraperitoneally with curcumin at a total dose of 400mg/kg body weight. Curcumin was effective in reducing worm and tissue-egg burdens, hepatic granuloma volume and liver collagen content by 44.4%, 30.9%, 79%, and 38.6%, respectively. Curcumin treatment restored hepatic enzymes activities to the normal levels and enhanced catalase activity in the liver tissue of infected mice. Moreover, hepato-spleenomegaly and eosinophilia induced by S. mansoni infection were largely improved with curcumin treatment. Infected mice treated with curcumin showed low serum level of both interleukin (IL)-12 and tumor necrosis factor alpha (TNF-alpha), but IL-10 level was not significantly altered. Specific IgG and IgG1 responses against both soluble worm antigen (SWAP) and soluble egg antigen (SEA) were augmented with curcumin treatment, but IgM and IgG2a responses were not significantly changed. In conclusion, curcumin treatment modulates cellular and humoral immune responses of infected mice and lead to a significant reduction of parasite burden and liver pathology in acute murine schistosomiasis mansoni.

Immunostimulating activity of crude polysaccharide extract isolated from Curcuma xanthorrhiza Roxb.

Curcuma xanthorrhiza Roxb., commonly known as Javanese turmeric, has been reported to possess a variety of biological activities, including anti-inflammatory effects, anticarcinogenic effects, wound healing effects, and serum cholesterol-lowering effects. CPE, crude polysaccharide extract isolated from the rhizome of C. xanthorrhiza using 0.1 N NaOH, consisted of arabinose (18.69%), galactose (14.0%), glucose (50.67%), mannose (12.97%), rhamnose (2.73%), and xylose (0.94%), with an average molecular weight of 33,000 Da. In the present study, we investigated the effect of CPE on nitric oxide (NO), hydrogen peroxide (H2O2), tumor necrosis factor-alpha (TNF-alpha), and prostaglandin E2 (PGE2) production in RAW 264.7 cells. The uptake of fluorescein-labeled Escherichia coli was measured to determine whether CPE stimulates the phagocytic activity of RAW 264.7 cells. CPE significantly increased the phagocytosis of macrophages and the release of NO, H2O2, TNF-alpha, and PGE2 in a dose-dependent manner, and showed a similar activity to lipopolysaccharide (LPS). To study the mechanisms of CPE, we examined induction of iNOS and COX-2. NO and PGE2 were produced as a result of stimulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) respectively. Both modulations of iNOS and COX-2 expression by CPE were evaluated by Western immunoblotting and RT-PCR. Since transcription of these enzymes is under the control of nuclear factor-kappa B (NF-kappaB), we assessed the phosphorylation of inhibitor kappaBalpha (IkappaBalpha) through Western immunoblotting. CPE clearly induced phosphorylation of IkappaBalpha, suggesting a role as an NF-kappaB activator. Taking all this together, we conclude that CPE isolated from Curcuma xanthorrhiza stimulates the immune functions of macrophages, which is mediated in part by specific activation of NF-kappaB.

"Spicing up" of the immune system by curcumin.

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. Traditionally known for its an antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB. Interestingly, however, curcumin at low doses can also enhance antibody responses. This suggests that curcumin's reported beneficial effects in arthritis, allergy, asthma, atherosclerosis, heart disease, Alzheimer's disease, diabetes, and cancer might be due in part to its ability to modulate the immune system. Together, these findings warrant further consideration of curcumin as a therapy for immune disorders.