63 публикувани проучвания за BCM-95 в резюме - 1ва част

Published Studies on BCM-95® Curcumin
With Study Results Summary

1.    Effect of citrus polyphenol-and curcumin-supplemented diet on inflammatory state in obese cats. Among obesity-associated disorders, low-grade inflammation has been described. The putative therapeutic properties of citrus and curcumin polyphenols could be associated with their anti-inflammatory properties. Two diets supplemented either with hesperidin (0•05 %) and naringin (0•1 %) from citrus extract or with highly bioavailable curcumin from Curcuma longa extract (0•09 %) were fed to eight obese cats for two 8-week periods (cross-over study design) while maintaining animals in an obese state. Plasma acute-phase protein (APP; a1-acid glycoprotein (AGP), serum amyloid A and haptoglobin) levels were assessed before and at the end of each test period. TNF-a, IL-1b, IL-2, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-b, interferon (IFN)-g mRNA levels were determined in peripheral blood mononuclear cells (PBMC) by real-time PCR. Compared with pre-study values, supplementation with citrus polyphenols resulted in lower plasma AGP and haptoglobin concentrations, while that with curcumin resulted in lower plasma AGP concentration. There were no differences between the supplementations. TNF-a, IL-1b, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-b, mRNA levels remained unaffected by either dietary supplementation. In contrast, IFN-g and IL-2 mRNA levels were lower at the end of the citrus and the curcumin supplementation, respectively. There were no differences between the supplementations. The present study results show a slight effect of citrus and curcumin supplementation on inflammatory markers expressed by PBMC, and a decreased concentration of APP, which are mainly expressed by the liver. This would confirm that hesperidin and naringin or highly bioavailable curcumin extract have beneficial effects, targeted in the liver and could improve the obesity-related inflammatory state. [Leray V, Freuchet B, Le Bloc'h J, Jeusette I, Torre C, Nguyen P. Effect of citrus polyphenol-and curcumin-supplemented diet on inflammatory state in obese cats. British Journal of Nutrition. 2011 Oct;106(S1):S198-201.]

2.    A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Curcumin is known to possess potent anti-inflammatory and antiarthritic properties. This pilot clinical study evaluated the safety and effectiveness of curcumin alone, and in combination with diclofenac sodium in patients with active rheumatoid arthritis (RA). Forty-five patients diagnosed with RA were randomized into three groups with patients receiving curcumin (500 mg) and diclofenac sodium (50 mg) alone or their combination. The primary endpoints were reduction in Disease Activity Score (DAS) 28. The secondary endpoints included American College of Rheumatology (ACR) criteria for reduction in tenderness and swelling of joint scores. Patients in all three treatment groups showed statistically significant changes in their DAS scores. Interestingly, the curcumin group showed the highest percentage of improvement in overall DAS and ACR scores (ACR 20, 50 and 70) and these scores were significantly better than the patients in the diclofenac sodium group. More importantly, curcumin treatment was found to be safe and did not relate with any adverse events. Our study provides the first evidence for the safety and superiority of curcumin treatment in patients with active RA, and highlights the need for future large-scale trials to validate these findings in patients with RA and other arthritic conditions. [Chandran B, Goel A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients with active rheumatoid arthritis. Phytotherapy research. 2012 Nov;26(11):1719-25.]

3.    Synergistic and additive effects of modified citrus pectin with two polybotanical compounds, in the suppression of invasive behavior of human breast and prostate cancer cells. The objective of this study was to evaluate the combined effect of a known galectin-3 inhibitor, PectaSol-C modified citrus pectin (MCP), and 2 novel integrative polybotanical compounds for breast and prostate health, BreastDefend (BD) and ProstaCaid (PC), on invasive behavior in human breast and prostate cancer cells in vitro, respectively. The effect of MCP and BD and of MCP and PC on invasiveness was assessed by cell adhesion, cell migration, and cell invasion assays. Secretion of urokinase plasminogen activator (uPA) was determined by Western blot analysis. Although low concentrations of MCP (0.25-1.0 mg/mL) do not suppress cell adhesion of breast or prostate cancer cells, the combination of MCP with BD or PC synergistically inhibits adhesion of these cells. Dose-dependent inhibition of breast and prostate cancer cell migration by MCP (0.25-1.0 mg/mL) is synergistically enhanced by BD (20 µg/mL) and PC (10 µg/mL), respectively. BD or PC did not further inhibit the invasion of breast and prostate cancer cells by MCP; however, the combination of MCP with BD or PC suppressed secretion of uPA from breast and prostate cancer cells, respectively. The combination of MCP with BD and of MCP with PC synergistically inhibits the metastatic phenotypes of human breast and prostate cancer cells, respectively. Further studies confirming these observations in animal models of breast and prostate cancer metastasis are warranted. [Jiang J, Eliaz I, Sliva D. Synergistic and additive effects of modified citrus pectin with two polybotanical compounds, in the suppression of invasive behavior of human breast and prostate cancer cells. Integrative cancer therapies. 2013 Mar;12(2):145-52.]

4.    A pilot clinical trial of radio protective effects of curcumin supplementation in patients with prostate cancer. Patients with prostate cancer who accede to radiation therapy usually experience several side effects and these toxicities are sometimes dose limiting. Some previous in vitro and in vivo studies have proposed a radioprotective role for curcumin, the yellow pigment of turmeric. The purpose of this investigation was to assess the radioprotective effects of curcumin supplementation in patients with prostate cancer. Forty prostate cancer patients undergoing external beam radiotherapy (EBRT) were randomly assigned to curcumin group, taking 3 g/d curcumin (6 × 500 mg capsules of BCM95 n=20), or placebo group (n=20). Quality of life was assessed by the Persian version of the European Organization for Research and Treatment of Cancer prostate cancer-specifc quality of life questionnaire (QLQ-PR25). Analysis of covariance was used to compare radiotherapy related symptoms between groups following the intervention, adjusted for baseline symptoms. No differences in urinary symptoms, bowel symptoms, treatment related symptoms and sexual activity were observed between the curcumin and placebo groups before the intervention. The change in urinary symptoms across the 20-week period differed signifcantly between groups (p=0.011) and patients in the curcumin group experienced much milder urinary symptoms compared with the placebo group. No group differences were observed in any other domain of the QLQ-PR25. Curcumin can confer radioprotective effect in patients with prostate cancer who undergo radiation therapy through reducing the severity of radiotherapy related urinary symptoms. However supplementation with 3 g/day curcumin could not reduce the severity of bowel symptoms or other treatment related symptoms. [Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Ehtejab G. A pilot clinical trial of radioprotective effects of curcumin supplementation in patients with prostate cancer. J Cancer Sci Ther. 2013;5(10):320-4.]

5.    Clinical evaluation of a formulation containing Curcuma longa and Boswellia serrata extracts in the management of knee osteoarthritis. A formulation containing Curcuma longa and Boswellia serrata extracts (CB formulation) was evaluated for safety and effcacy in osteoarthritic patients and directly compared with the selective COX-2 inhibitor, celecoxib. In total, 54 subjects were screened, 30 subjects were enrolled and 28 completed the study. The treatment was well tolerated and did not produce any adverse effect in patients, as judged by the vital signs, hemogram, liver and renal function tests. The CB formulation at 500 mg administered twice a day, was more successful than administering celecoxib 100 mg twice a day for symptom scoring and clinical examination. The formulation was found to be safe and no dose-related toxicity was found. [Kizhakkedath R. Clinical evaluation of a formulation containing Curcuma longa and Boswellia serrata extracts in the management of knee osteoarthritis. Molecular medicine reports. 2013 Nov 1;8(5):1542-8.]

6.    Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Curcumin, an active ingredient of Curcuma longa Linn (Zingiberaceae), has shown potential antidepressant-like activity in animal studies. The objectives of this trial were to compare the efficacy and safety of curcumin with fluoxetine in patients with major depressive disorder (MDD). Herein, 60 patients diagnosed with MDD were randomized in a 1:1:1 ratio for six weeks observer-masked treatment with fluoxetine (20 mg) and curcumin (1000 mg) individually or their combination. The primary efficacy variable was response rates according to Hamilton Depression Rating Scale, 17-item version (HAM-D17). The secondary efficacy variable was the mean change in HAM-D17 score after six weeks. We observed that curcumin was well tolerated by all the patients. The proportion of responders as measured by the HAM-D17 scale was higher in the combination group (77.8%) than in the fluoxetine (64.7%) and the curcumin (62.5%) groups; however, these data were not statistically significant (P = 0.58). Interestingly, the mean change in HAM-D17 score at the end of six weeks was comparable in all three groups (P = 0.77). This study provides first clinical evidence that curcumin may be used as an effective and safe modality for treatment in patients with MDD without concurrent suicidal ideation or other psychotic disorders. [Sanmukhani J, Satodia V, Trivedi J, Patel T, Tiwari D, Panchal B, Goel A, Tripathi CB. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytotherapy research. 2014 Apr;28(4):579-85.]

7.    Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. Curcumin, the principal curcuminoid derived from the spice turmeric, influences several biological mechanisms associated with major depression, namely those associated with monoaminergic activity, immune-inflammatory and oxidative and nitrosative stress pathways, hypothalamus-pituitaryadrenal (HPA) axis activity and neuroprogression. It was hypothesised that curcumin would be effective for the treatment of depressive symptoms in individuals with major depressive disorder. In a randomised, double-blind, placebo-controlled study, 56 individuals with major depressive disorder were treated with curcumin (500 mg twice daily) or placebo for 8 weeks. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI). From baseline to week 4, both curcumin and placebo were associated with improvements in IDS-SR30 total score and most secondary outcome measures. From weeks 4 to 8, curcumin was significantly more effective than placebo in improving several mood-related symptoms, demonstrated by a significant group x time interaction for IDS-SR30 total score (F1, 53=4.22, p=.045) and IDS-SR30 mood score (F1, 53=6.51, p=.014), and a non-significant trend for STAI trait score (F1, 48=2.86, p=.097). Greater efficacy from curcumin treatment was identified in a subgroup of individuals with atypical depression. Partial support is provided for the antidepressant effects of curcumin in people with major depressive disorder, evidenced by benefits occurring 4 to 8 weeks after treatment. Investigations with larger sample sizes, over extended treatment periods, and with varying curcumin dosages are required. [Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD. Curcumin for the treatment of major depression: a randomised, double-blind, placebo controlled study. Journal of affective disorders. 2014 Oct 1;167:368-75.]

8.    Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT. Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (b1-integrin, ICAM-1), transforming growth factor-b signaling molecules (TGF-b3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-kB, MMP-13), TGF-b3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to
mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment.  Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-b and EMT.  Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis. [Buhrmann C, Kraehe P, Lueders C, Shayan P, Goel A, Shakibaei M. Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT. PLoS One. 2014 Sep 19;9(9):e107514.]

9.    Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5- Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC subpopulation. [Shakibaei M, Buhrmann C, Kraehe P, Shayan P, Lueders C, Goel A. Curcumin chemosensitizes 5-fluorouracil resistant MMR-deficient human colon cancer cells in high density cultures. PLoS One. 2014 Jan 3;9(1):e85397.]

10.    Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer. To overcome the limitations of animal-based experiments, 3D culture models mimicking the tumor microenvironment in vivo are gaining attention. Herein, we investigated an alginate-based 3D scaffold for screening of 5-fluorouracil (5-FU) or/and curcumin on malignancy of colorectal cancer cells (CRC). The potentiation effects of curcumin on 5-FU against proliferation and metastasis of HCT116 cell and its corresponding isogenic 5-FU-chemoresistant cells (HCT116R) were examined in a 3D-alginate tumor model. CRC cells encapsulated in alginate were able to proliferate in 3D-colonospheres in a vivo-like phenotype and invaded from alginate. During cultivation of cells in alginate, we could isolate 3 stages of cells, (1) alginate proliferating (2) invasive and (3) adherent cells. Tumor-promoting factors (CXCR4, MMP-9, NF-κB) were significantly increased in the proliferating and invasive compared to the adherent cells, however HCT116R cells overexpressed factors in comparison to the parental HCT116, suggesting an increase in malignancy behavior. In alginate, curcumin potentiated 5-FU-induced decreased capacity for proliferation, invasion and increased more sensitivity to 5-FU of HCT116R compared to the HCT116 cells. IC50 for HCT116 to 5-FU was 8nM, but co-treatment with 5 μM curcumin significantly reduced 5-FU concentrations in HCT116 and HCT116R cells (0.8nM, 0.1nM, respectively) and these effects were accompanied by down-regulation of NF-κB activation and NF-κB-regulated gene products. Our results demonstrate that the alginate provides an excellent tumor microenvironment and indicate that curcumin potentiates and chemosensitizes HCT116R cells to 5-FU-based chemotherapy that may be useful for the treatment of CRC and to overcome drug resistance. [Shakibaei M, Kraehe P, Popper B, Shayan P, Goel A, Buhrmann C. Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancer. BMC cancer. 2015 Dec;15(1):250.]

11.    Novel evidence for curcumin and boswellic acid–induced chemoprevention through regulation of miR-34a and miR-27a in colorectal cancer. Colorectal cancer is one of the most common causes of cancer-associated mortality worldwide, but it is truly a prevent able disease. Both curcumin and boswellic acids are well established dietary botanicals with potent anti-tumorigenic properties that have been shown to modulate multiple oncogenic pathways. Recent data suggest that the chemopreventive effects of these botanicals may, in part, be mediated through regulation of key cancer-related microRNAs (miRNA) and their downstream gene targets. Here, we investigated the antitumorigenic effects of curcumin and 3 acetyl-11-keto-b-boswellic acid (AKBA) on modulation of specific cancer-related miRNAs in colorectal cancer cells and validated their protective effects in vivo using a xenograft mouse model. Both curcumin and AKBA inhibited cellular proliferation, induced apoptosis and cell cycle arrest in colorectal cancer cell lines, and these effects were significantly enhanced with combined treatment. Gene-expression arrays revealed that curcumin and AKBA regulated distinct cancer signaling pathways, including key cell-cycle regulatory genes. Combined bioinformatics and in silico analysis identified apoptosis, proliferation, and cell-cycle regulatory signaling pathways as key modulators of curcumin and AKBA-induced anticancer effects. It was discovered that curcumin and AKBA induced upregulation of tumor-suppressive miR-34a and down regulation of miR-27a in colorectal cancer cells. Furthermore, we demonstrated in a mouse xenograft model that both curcumin and AKBA treatments suppressed tumor growth, which corresponded with alterations in the expression of miR-34a and miR-27a, consistent with our in vitro findings. Herein, we provide novel mechanistic evidence for the chemo preventive effects of curcumin and AKBA through regulation of specific miRNAs in colorectal cancer. [Toden S, Okugawa Y, Buhrmann C, Nattamai D, Anguiano E, Baldwin N, Shakibaei M, Boland CR, Goel A. Novel evidence for curcumin and boswellic acid–induced chemoprevention through regulation of miR-34a and miR-27a in colorectal cancer. Cancer Prevention Research. 2015 May 1;8(5):431-43.]

12.    Curcumin and major depression: a randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change. A recent randomised, double-blind, placebo controlled study conducted by the research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500 mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p<0.05), and substance P (p<0.001); while placebo supplementation was associated with reductions in aldosterone (p<0.05) and cortisol (p<0.05). Higher baseline plasma endothelin-1 (rs= 0.587; p<0.01) and leptin (rs= 0.470; p<0.05) in curcumin-treated individuals was associated with greater reductions in IDS-SR30 score after 8 weeks of treatment. Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action. Plasma concentrations of leptin and endothelin-1 seem to have particular relevance to treatment outcome. Further investigations using larger samples sizes are required to elucidate these findings, as the multiple statistical comparisons completed in this study increased the risk of type I errors. [Lopresti AL, Maes M, Meddens MJ, Maker GL, Arnoldussen E, Drummond PD. Curcumin and major depression: a randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change. European Neuropsychopharmacology. 2015 Jan 1;25(1):38-50.]

13.    Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial–mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identifed and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC. [Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland CR, Goel A. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015 Feb 4;36(3):355-67.]

14.    BCM-95 and (2-hydroxypropyl)-β-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts. Saposin (Sap) C deficiency is a rare variant form of Gaucher disease caused by impaired Sap C expression or accelerated degradation, and associated with accumulation of glucosylceramide and other lipids in the endo/lysosomal compartment. No effective therapies are currently available for the treatment of Sap C deficiency. We previously reported that a reduced amount and enzymatic activity of cathepsin (Cath) B and Cath D, and defective autophagy occur in Sap C-deficient fibroblasts. Here, we explored the use of two compounds, BCM-95, a curcumin derivative, and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), to improve lysosomal function of Sap C-deficient fibroblasts. Immunofluorescence and biochemical studies documented that each compound promotes an increase of the expression levels and activities of Cath B and Cath D, and efficient clearance of cholesterol (Chol) and ceramide (Cer) in lysosomes. We provide evidence that BCM-95 and HP-β-CD enhance lysosomal function promoting autophagic clearance capacity and lysosome reformation. Our findings suggest a novel pharmacological approach to Sap C deficiency directed to treat major secondary pathological aspects in this disorder. [Tatti M, Motta M, Scarpa S, Di Bartolomeo S, Cianfanelli V, Tartaglia M, Salvioli R. BCM-95 and (2-hydroxypropyl)-β-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts. Human molecular genetics. 2015 Apr 29;24(15):4198-211.]

15.    Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study. Curcumin is the active ingredient of commonly used spice Curcuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain. [Sanmukhani J, Anovadiya A, Tripathi CB. Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study. Acta Pol Pharm. 2011 Sep 1;68(5):769-5.]

16.    The use of an anti-inflammatory supplement in patients with chronic kidney disease. Chronic kidney disease (CKD) is characterized by a continuous reduction in kidney function, increased inflammation, and reduced antioxidant capacity. The objective of this study was to assess the effects of a herbal supplement on systemic inflammation and antioxidant status in non-dialysis CKD patients. Sixteen patients with CKD (56.0±16.0 yrs, 171.4±11.9 cm, 99.3 ±20.2 kg) were randomly chosen to receive a herbal supplement composed of Curcuma longa and Boswellia serrata, or placebo. Plasma levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glutathione peroxidase (GPx), and serum C-reactive protein (CRP) were measured at baseline and 8 weeks. Baseline data demonstrated elevated inflammation and low antioxidant levels. A significant time effect (p=0.03) and time x compliance interaction effect (p=0.04) were observed for IL-6. No significant differences were observed for any other variables. This study demonstrates that mild and moderate CKD is associated with chronic inflammation and low antioxidant activity. Systemic inflammation and impaired antioxidant status may be greater in CKD populations with multiple comorbidities. Curcumin and Boswellia serrata are safe and tolerable and helped to improve the levels of an inflammatory cytokine. [Moreillon JJ, Bowden RG, Deike E, Griggs J, Wilson R, Shelmadine B, Cooke M, Beaujean A. The use of an anti-inflammatory supplement in patients with chronic kidney disease. Journal of Complementary and Integrative Medicine. 2013 Jul 1;10(1):143-52.]

17.    Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Development of resistance to chemotherapeutic drugs is a major challenge in the care of patients with pancreatic ductal adenocarcinoma (PDAC). Acquired resistance to chemotherapeutic agents in PDAC has been linked to a subset of cancer cells termed “cancer stem cells” (CSCs). Therefore, an improved understanding of the molecular events underlying the development of pancreatic CSCs is required to identify new therapeutic targets to overcome chemoresistance. Accumulating evidence indicates that curcumin, a phenolic compound extracted from turmeric, can overcome de-novo chemoresistance and re-sensitize tumors to various chemotherapeutic agents. However, the underlying mechanisms for curcumin-mediated chemosensitization remain unclear. The Enhancer of Zeste Homolog-2 (EZH2) subunit of Polycomb Repressive Complex 2 (PRC2) was recently identified as a key player regulating drug resistance. EZH2 mediates interaction with several long non-coding RNAs (lncRNAs) to modulate epithelial-mesenchymal transition and cancer stemness, phenomena commonly associated with drug resistance. Here, we report the re-sensitization of chemoresistant PDAC cells by curcumin through the inhibition of the PRC2-PVT1-c-Myc axis. Using gemcitabine-resistant PDAC cell lines, we found that curcumin sensitized chemoresistant cancer cells by inhibiting the expression of the PRC2 subunit EZH2 and its related lncRNA PVT1. Curcumin was also found to prevent the formation of spheroids, a hallmark of cancer stem cells, and to down-regulate several selfrenewal driving genes. In addition, we confirmed our in vitro findings in a xenograft mouse model where curcumin inhibited gemcitabine-resistant tumor growth. Overall, this study indicates clinical relevance for combining curcumin with chemotherapy to overcome chemoresistance in PDAC. [Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 2017 Jul 17;38(10):1036-46.]

18.    A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin. Curcumin, the bioactive component of turmeric, Curcuma longa has an exceptionally wide spectrum of activities including antioxidant, anti-inflammatory and anti-cancer properties, and is currently under different phases of clinical trials for various types of soft tissue cancers. However, although in vitro and animal studies have shown anticancer activities of curcumin for virtually all types of human cancers, its poor bioavailability in the human body has severely limited its application to these diseases. Methods to increase its oral bioavailability are a subject of intense current research. Reconstituting curcumin with the non-curcuminoid components of turmeric has been found to increase the bioavailability substantially. In the present clinical study to determine the bioavailability of curcuminoids, a patented formulation, BCM-95®CG was tested on human volunteer group. Normal curcumin was used in the control group. Curcumin content in blood was estimated at periodical intervals. After a washout period of two weeks the control group and drug group were crossed over BCM-95®CG and curcumin, respectively. It was also compared with a combination of curcumin-lecithin-piperine which was earlier shown to provide enhanced bioavailability. The results of the study indicate that the relative bioavailability of BCM-95®CG (BiocurcumaxTM) was about 6.93-fold compared to normal curcumin and about 6.3-fold compared to curcumin-lecithin-piperine formula. BCM-95®CG thus, has potential for widespread application for various chronic diseases. [Antony B, Merina B, Iyer VS, Judy N, Lennertz K, Joyal S. A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin. Indian journal of pharmaceutical sciences. 2008 Jul;70(4):445.]

19.    Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. 34 participants were randomized to either 1 gram BCM-95® curcumin, 4 grams BCM-95 curcumin, or placebo. All participants were over age 50, and had a diagnosis of probable or possible Alzheimer’s disease based on the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer Disease and Related Disorders Association diagnostic criteria. Some measures were serum markers of amyloid beta, plasma isoprostanes (a measure of oxidative stress) and antioxidant status. Both 1 gram and 4 grams reduced oxidative stress and improved antioxidant status. There were more adverse effects in the placebo group than in either 1 g or 4 g BCM-95 group. There was a noted increase in serum amyloid beta in both 1 g and 4 g groups, but not placebo. The authors noted this “possibly reflected an ability of curcumin to disaggregate amyloid beta deposits in the brain, releasing the amyloid beta for circulation and disposal.”. [Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. Journal of clinical psychopharmacology. 2008 Feb 1;28(1):110-3]

20.    Curcumin effects on blood lipid profile in a 6-month human study. Pharmacological research. Studies in animals and a short-term human study have suggested that curcumin, a polyphenolic compound concentrated in the curry spice turmeric, decreases serum cholesterol concentration. However, no controlled human trials have examined the effect of curcumin on cholesterol. This study investigated the effects of consuming curcumin on the serum lipid profile in men and women. Elderly subjects (n = 36) consumed 4 g/d curcumin, 1 g/d curcumin, or placebo in a 6-month, randomized, double-blind trial. Plasma curcumin and its metabolites were measured at 1 month, and the serum lipid profile was measured at baseline, 1 month, and 6 months. The plasma curcumin concentration reached a mean of 490 nmol/L. The curcumin concentration was greater after capsule than powder administration. Consumption of either dose of curcumin did not significantly affect triacylglycerols, or total, LDL, and HDL cholesterol over 1 month or 6 months. However, the concentrations of plasma curcumin and serum cholesterol were positively and significantly correlated. Curcumin consumption does not appear to have a significant effect on the serum lipid profile, unless the absorbed concentration of curcumin is considered, in which case curcumin may modestly increase cholesterol.
[Baum L, Cheung SK, Mok VC, Lam LC, Leung VP, Hui E, Ng CC, Chow M, HoPC, Lam S, Woo J. Curcumin effects on blood lipid profile in a 6-month human study. Pharmacological research. 2007 Dec 1;56(6):509-14.]

21.    Bioavailability of BiocurcumaxTM (BCM-095TM) Curcuminoids are the yellow colouring matter, the most active molecules of turmeric (Curcuma longa) one of the familiar spice possessing numerous bioactive components. But it is suggested and proved that the total curcuminoids absorb by animal system limit to 50 – 60 per cent. BiocurcumaxTM (BCM-095TM) is a unique blend which enhances the bioavailability of curcumin. The study described here reveals the bioavailability of BiocurcumaxTM (BCM-095TM) in human volunteers. [Benny M, Antony B. Bioavailability of BiocurcumaxTM (BCM-095TM), Spice India  2006 (Sept);11-15]

22.    Enhancing the Absorption of Curcuminoids. Turmeric (Curcuma longa) one of the familiar spice has got number of medicinal properties such as anti-septic, anti-inflammatory, wound healing, anti-oxidant, anti-tumour etc. These properties of turmeric are attributed to the active principle, curcumin and essential oil present in the rhizome. But it is suggested and proved that only 50-60 percent of total curcumin is absorbed by animal system. Studies conducted on  albino rats and results described in this paper reveal that 96-97 percent absorption of curcuminoids by mixing curcumin and standardized essential oil of turmeric. [Antony B, Benny M, Rao SB. Enhancing the Absorption of Curcuminoids,  Spice India 2005(July); 23-26]

23.    Effect of a topical curcumin preparation (BIOCURCUMAX) on burn wound healing in rats. Curcumin, a naturally occurring o-methoxyphenol derivative, has been shown to possess several biological properties including antioxidant (free radical scavenging activity), induction of detoxification enzymes and provides protection against degenerative diseases. Topical applications of compounds with free radical scavenging properties in patients have shown to improve significantly wound healing and protect tissues from oxidative damage. To assess the effect of a topical curcumin preparation on healing of partial thickness burn wounds in rats. The rats are randomly divided into four groups, comprising of six rats in each group. Partial thickness burn wounds are created by pouring hot molten wax at 80ºC. Group I acts a control, Group 2 receives the standard silver sulphadiazine cream, Group 3 gets 20% curcumin cream, and Group 4 receives the combination of the dexamethasone and curcumin cream. Parameters observed are epithelialization period and wound contraction. The percentage of wound contraction was significantly increased in the topical curcumin preparation (20%) and silver sulfadiazine group compared to control group. The mean period of epithelization was significantly reduced in topical curcumin preparation (20%) group and silver sulfadiazine group as compared to the control. Topical curcumin preparation is effective in healing burn wound and the effect was comparable to that of standard drug i.e. silver sulfadiazine. [Durgaprasad S, Reetesh R, Hareesh K, Rajput R. Effect of a topical curcumin preparation (BIOCURCUMAX) on burn wound healing in rats. Journal of Pharmaceutical and Biomedical Sciences (JPBMS). 2011;8(08).]

24.    The effect of exercise and nutritional supplementation on proinflammatory cytokine expression in young racehorses during training. The inflammatory response to vigorous exercise ranges from the mild symptoms of delayed-onset muscle soreness to debilitating injuries affecting soft tissue, joint, and bone. Although there is a great deal of information available on the inflammatory response to exercise in human athletes, less information is available regarding the inflammatory response to exercise in young horses undergoing training for racing careers. Here, we assessed the cytokine response to exercise in a group of young Thoroughbred racehorses during their initial training. Because there is interest in nonpharmacologic approaches to control or ameliorate exercise-induced inflammation, we also examined the anti-inflammatory effect of a nutritional supplement fed to half of the horses undergoing training. Twenty-five Thoroughbred horses aged 2 years were followed through their initial race training. Peripheral blood samples were collected at various times during the exercise for the quantitation of lactic acid, oxidative stress, and inflammatory cytokine gene expression. There was an intensity-dependent effect of exercise on lactate, malondialdehyde, and proinflammatory cytokine gene expression. Although training itself was associated with an overall reduction in inflammatory markers, horses receiving the supplement exhibited further reductions in their indicators of inflammation. As such, this study provides novel evidence of nutritional supplementation reducing postexercise inflammation. [Horohov DW, Sinatra ST, Chopra RK, Jankowitz S, Betancourt A, Bloomer RJ. The effect of exercise and nutritional supplementation on proinflammatory cytokine expression in young racehorses during training. Journal of Equine Veterinary Science. 2012 Dec 1;32(12):805-15.]

25.    Evaluation of Antiepileptic and Memory Retention Activity of Curcumin Per SE and in Combination with Antiepileptic Drugs. Antiepileptic activity of curcumin and its combination with phenytoin and sodium valproate were studied in chronic model (14 days) of Maximal Electroshock Seizure (MES) and Pentylenetetrazole (PTZ) induced seizure respectively. Elevated plus maze test was used to study effect of drugs and/or seizures on memory retention in MES and PTZ groups. Curcumin in both doses did not show any significant effect (P = 0.33) on tonic extension, while curcumin 100 mg/kg significantly (P < 0.01) reduced clonic phase compared to vehicle control. Curcumin in 100 mg/kg dose significantly (P < 0.001) inhibited PTZ induced seizure. Addition of curcumin to sub therapeutic dose of sodium valproate showed synergistic effect. Curcumin did not show any effect on memory retention. Inhibition of PTZ induced seizure by curcumin could be due to effect on γ-amino butyric acid receptor (GABA) pathway and its antioxidant property. Curcumin can be effective in absence seizure alone and as add on with sodium valproate. [Anovadiya AP, Sanmukhani JJ, Vadgama VK, Tripathi CB. Evaluation of Antiepileptic and Memory Retention Activity of Curcumin Per SE and in Combination with Antiepileptic Drugs, Asian J Pharm Clin Res. 2014;6(2):145-148]

26.    Anti-inflammatory activity of BCM-95 (bio-enhanced formulation of turmeric with increased bioavailabilty) compared to Curcumin in Wistar rats. The study was conducted to evaluate anti-inflammatory activity of bioenhanced turmeric formulation (BCM-95) and compared to commercial Curcumin formulation (Curcuminoids 95%) in Carrageenan-induced acute inflammatory model. Thirty six Wistar rats were divided into six groups-Normal control (2 ml of vehicle), Standard control (Indomethacin 10 mg/kg), 2 doses of BCM 95 (10 and 20 mg/kg) and Curcuminoids 95% (10 and 20 mg/kg). Paw volume was measured using a digital plethysmometer. Vehicle or test drugs were given to rats 30 min before carrageenan administration. Baseline paw volume reading (V0) was noted just prior to administration of 0.1 ml of 1% carrageenan to right hind paw of the rat. Test paw volume readings (Vt) were measured at 30, 60, 120, 180, 240, 300 and 360 min, after carrageenan injection. Oedema expressed as increased paw volume (vt-v0) was noted and percentage inhibition of oedema was calculated for all treatment groups. Difference between groups were analyzed with ANOVA followed by Tukey test. All treatment groups demonstrated signifcant (p<0.05) anti-inflammatory activity (oedema suppression) compared to normal control. Anti-inflammatory activity of BCM 95 treated groups were comparable to standard control group except at certain time points, whereas the same activity at all-time points with Curcuminoid 95% treated groups were signifcantly less than standard control group. Percentage inhibition of paw oedema was maximum with standard control group followed by BCM 95 treated groups followed by Curcuminoid 95% treated groups. BCM 95 treated groups showed signifcant anti-inflammatory activity compared to Curcuminoid 95% treated groups. [Vinaykumar S, Rathnakar UP, Dinkar US, Priyanka K, Gaurav T, Kudgi SA, Nishith RS. Anti-inflammatory activity of BCM-95 (bio-enhanced formulation of turmeric with increased bioavailabilty) compared to Curcumin in Wistar rats. Pharmacognosy Journal. 2016;8(4).]

27.    Systematic and comprehensive investigation of the toxicity of curcuminoid essential oil complex: A bioavailable turmeric formulation. Curcumin, the active component present in Curcuma longa of the family Zingiberaceae, has a number of pharmacological effects, including potential anti inflammatory activity. One of the major limitations of curcumin/turmeric extract is its poor absorption through the gastrointestinal tract. Several approaches have been adopted to increase the bioavailability of curcumin, including loading curcumin into liposomes or nanoparticles, complexation with phospholipids, addition of essential oils and synthesizing structural analogues of curcumin. In the present study, the toxicity and safety of one such bioavailable turmeric formulation, curcuminoid-essential oil complex (CEC), the toxicity profle of which has not been reported, were examined using in vivo and in vitromodels, as per the guidelines of the Organisation for Economic Co-operation and Development. Investigations of acute toxicity study were performed in rats and mice, and the results revealed no signs and symptoms or toxicity or mortality in any of the animals at the maximum recommended dose level of 5,000 mg/kg body weight. The repeated administration of CEC for 90 days in Wistar rats at a dose of 1,000 mg/kg body weight did not induce any observable toxic effects, compared with corresponding control animals. Mutagenicity/genotoxicity investigations were also performed using a bacterial reverse mutation assay (Ames test), a mammalian bone marrow chromosome aberration test and a mammalian erythrocyte micronucleus test in mice. CEC was found to be non mutagenic in all three mutagenic investigations. Consequently, the present study indicated that CEC elicited no toxic effects in animals or  in vitro. Therefore, following investigations of acute toxicity, repeated dose toxicity and mutagenicity, CEC was deemed a safe, non toxic pharmacological formulation. [Aggarwal ML, Chacko KM, Kuruvilla BT. Systematic and comprehensive investigation of the toxicity of curcuminoid essential oil complex: A bioavailable turmeric formulation. Molecular medicine reports. 2016 Jan 1;13(1):592-604.]

28.     Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. Curcumin therapy in animals has produced positive cognitive and behavioural outcomes; results of human trials, however, have been inconsistent. In this study, we report the results of a 12-month, randomised, placebo-controlled, double-blind study that investigated the ability of a curcumin formulation to prevent cognitive decline in a population of community-dwelling older adults. Individuals (n 96) ingested either placebo or 1500 mg/d BiocurcumaxTM for 12 months. A battery of clinical and cognitive measures was administered at baseline and at the 6-month and 12-month follow-up assessments. A significant time × treatment group interaction was observed for the Montreal Cognitive Assessment (repeated-measures analysis; time × treatment; F = 3•85, P < 0•05). Subsequent analysis revealed that this association was driven by a decline in function of the placebo group at 6 months that was not observed in the curcumin treatment group. No differences were observed between the groups for all other clinical and cognitive measures. Our findings suggest that further longitudinal assessment is required to investigate changes in cognitive outcome measures, ideally in conjunction with biological markers of neurodegeneration. [Rainey-Smith SR, Brown BM, Sohrabi HR, Shah T, Goozee KG, Gupta VB, Martins RN. Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. British Journal of Nutrition. 2016 Jun;115(12):2106-13.]

29.    Effect of curcumin supplementation during radiotherapy on oxidative status of patients with prostate cancer: a double blinded, randomized, placebo-controlled study. Curcumin is an antioxidant agent with both radiosensitizing and radioprotective properties. The aim of the present study was to evaluate the effect of curcumin supplementation on oxidative status of patients with prostate cancer who undergo radiotherapy. Forty patients treated with radiotherapy for prostate cancer were randomized to the curcumin (CG, n D 20) or placebo group (PG, n D 20). They received curcumin (total 3 g/day) or placebo during external-beam radiation therapy of up to 74 Gy. Plasma total antioxidant capacity (TAC) and activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) were measured at baseline and 3 mo after radiotherapy completion. Analysis of covariance was used to compare the variables between groups following the intervention. Serum PSA levels and MRI/MRS images were investigated. In CG, TAC significantly increased (P < 0.001) and the activity of SOD decreased (P D 0.018) after radiotherapy compared with those at baseline. In CG, however, the activity of SOD had a significant reduction (P D 0.026) and TAC had a significant increase (P D 0.014) compared with those in PG. PSA levels were reduced to below 0.2 ng/ml in both groups, 3 mo after treatment, however, no significant differences were observed between the 2 groups regarding treatment utcomes. [Hejazi J, Rastmanesh R, Taleban FA, Molana SH, Hejazi E, Ehtejab G, Hara N. Effect of curcumin supplementation during radiotherapy on oxidative status of patients with prostate cancer: a double blinded, randomized, placebo-controlled study. Nutrition and cancer. 2016 Jan 2;68(1):77-85.]

30.    A randomized double-blind placebo-controlled phase IIB trial of curcumin in oral leukoplakia. Oral leukoplakia is a potentially malignant lesion of the oral cavity, for which no effective treatment is available. We investigated the effectiveness of curcumin, a potent inhibitor of NF-kB/COX-2, molecules perturbed in oral carcinogenesis, to treat leukoplakia. Subjects with oral leukoplakia (n = 223) were randomized (1:1 ratio) to receive orally, either 3.6 g/day of curcumin (n = 111) or placebo (n  = 112), for 6 months. The primary endpoint was clinical response obtained by bi-dimensional measurement of leukoplakia size at recruitment and 6 months. Histologic response, combined clinical and histologic response, durability and effect of long-term therapy for an additional six months in partial responders, safety and compliance were the secondary endpoints. Clinical response was observed in 75 (67.5%) subjects [95% confidence interval (CI), 58.4–75.6] in the curcumin and 62 (55.3%; 95% CI, 46.1–64.2) in placebo arm (P = 0.03). This response was durable, with 16 of the 18 (88.9%; 95% CI, 67.2–96.9) subjects with complete response in curcumin and 7 of 8 subjects (87.5%) in placebo arm, demonstrating no relapse after 6 months follow up. Difference in histologic response between curcumin and placebo was not significant (HR, 0.88, 95% CI, 0.45–1.71; P = 0.71). Combined clinical and histologic response assessment indicated a significantly better response with curcumin (HR, 0.50; 95% CI, 0.27–0.92; P = 0.02). Continued therapy, in subjects with partial response at 6 months, did not yield additional benefit. The treatment did not raise any safety concerns. Treatment of oral leukoplakia with curcumin (3.6 g for six months), thus was well tolerated and demonstrated significant and durable clinical response for 6 months. [Kuriakose MA, Ramdas K, Dey B, Iyer S, Rajan G, Elango KK, Suresh A, Ravindran D, Kumar RR, Prathiba R, Ramachandran S. A randomized double-blind placebo-controlled phase iib trial of curcumin in oral leukoplakia. Cancer Prevention Research. 2016 Aug 1;9(8):683-91.]


31.    The efficacy and safety of a combination of glucosamine hydrochloride, chondroitin sulfate and bio-curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled study. Knee osteoarthritis (OA) conservative treatment aims to delay cartilage degeneration; chondroprotective agents are a valid approach in this sense. A commercially available dietary supplement, CartiJoint Forte, containing glucosamine hydrochloride (GH), chondroitin sulfate (CS) and Bio-Curcumin BCM-95®, was used in this trial.The aim of this study was to assess efficacy and safety of CartiJoint Forte combined with physical therapy in treating subjects with knee OA.A multicenter, prospective, randomized, double blind, placebo-controlled clinical trial.Outpatients referred to the Rehabilitation Departments of two University Hospitals.Fifty-three patients were randomly assigned to an experimental group (N=26) or a control group (N.=27). Experimental subjects received two tablets of CartiJoint Forte each day for 8 weeks, while those in the control group were provided with a placebo. Three subjects dropped out during the course of the study.The two groups both received 20 sessions of physical therapy during the course of the trial. Primary outcome was pain intensity, measured both at motion and at rest, using the Visual Analogue Scale (VAS). A secondary outcome was an assessment of knee function by Western Ontario and McMaster Universities Arthritis Index and Lequesne Index, knee ROM, and two inflammation markers (C-reactive protein and erythrocyte sedimentation rate). Each assessment was carried out at baseline (T0), at 8 weeks (T1) and at 12 weeks (T2).VAS at rest was found to be reduced between T0 and T1, as well as between T0 and T2 (F=13.712; P=0.0001), with no differences between groups (F=1.724; P=0.191). VAS at motion revealed a significant "group × time-check" interaction (F=2.491; P=0.032), with increasing effect of time on VAS reduction (F=17.748; P=0.0001). This was most pronounced in the experimental group at 8 weeks (F=3.437; P=0.045). The Lequesne Index showed reductions at T1 and T2 compared to T0 (F=9.535; P=0.0001), along with group effect, since the experimental group presented a lower score at T2 (F=7.091; P=0.009). No significant changes were found in the knee ROM and inflammation markers.CartiJoint Forte, added to physical therapy, may ameliorate pain and help to improve algofunctional score in knee OA patients.Treatment of knee OA with curcuminoids plus glycosaminoglycans, added to physical therapy, improves VAS at motion and Lequesne Index scores. [Sterzi S, Giordani L, Morrone M, Lena E, Magrone G, Scarpini C, Milighetti S, Pellicciari L, Bravi M, Panni I, Ljoka C. The efficacy and safety of a combination of glucosamine hydrochloride, chondroitin sulfate and bio-curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo-controlled study. European journal of physical and rehabilitation medicine. 2016 Jun;52(3):321-30.]

32.    Short Report of a Preliminary Open Study of Synofit-Containing Bio-Curcumin, Greenlipped Mussel and Blackcurrant Leaf Extract in Arthritis. The study was conducted to evaluate the potential benefit of Synofit—an association of Curcumin, Perna canaliculus greenmussels and blackcurrant leaf extracts. A real life open study was performed among 86 adult outpatients suffering from Fibromyalgia (n = 22), low back pain (n = 33) or knee osteoarthritis (n = 31) who accepted to take 3 tablets a day during 1 week then 2 capsules of Synofit during 2 months in addition to their conventional therapy (mainly analgesics and anti-inflammatory) and then to report their evaluation of this complementary treatment. Statistical analysis included paired t test and when possible Wilcoxon signed rank test. Accordingly, the intermediate analysis showed that already within 4 weeks of treatment, an improvement quoted as “light” was statistically reported in patients with low back pain and knee osteoarthritis but not among those with fibromyalgia on pain, physical condition, global assessment of a benefit, quality of life but not on joint stiffness (although joint stiffness considered for the whole group was statistically improved). The limited number of patients and time duration of the study and the absence of double blind controlled study do not allow concluding on the efficacy but these preliminary analyses obtained from an intermediate analysis are encouraging for further studies. [Qu J, Mélot C, Appelboom T. Short Report of a Preliminary Open Study of Synofit-Containing Bio-Curcumin, Greenlipped Mussel and Blackcurrant Leaf Extract in Arthritis. Open Journal of Rheumatology and Autoimmune Diseases. 2015 Oct 27;5(04):113.]

33.    Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. Several studies have supported the antidepressant effects of curcumin (from the spice turmeric) and saffron for people with major depressive disorder. However, these studies have been hampered by poor designs, small sample sizes, short treatment duration, and similar intervention dosages. Furthermore, the antidepressant effects of combined curcumin and saffron administration are unknown. Methods: In a randomised, double-blind, placebo-controlled study, 123 individuals with major depressive disorder were allocated to one of four treatment conditions, comprising placebo, low-dose curcumin extract (250 mg b.i.d.), high-dose curcumin extract (500 mg b.i.d.), or combined low-dose curcumin extract plus saffron (15 mg b.i.d.) for 12 weeks. The outcome measures were the Inventory of Depressive Symptomatology self-rated version (IDS-SR30) and Spielberger State-Trait Anxiety Inventory (STAI). The active drug treatments (combined) were associated with significantly greater improvements in depressive symptoms compared to placebo (p=.031), and superior improvements in STAI-state (p < .001) and STAI-trait scores (p=.001). Active drug treatments also had greater efficacy in people with atypical depression compared to the remainder of patients (response rates of 65% versus 35% respectively, p=.012). No differences were found between the differing doses of curcumin or the curcumin/saffron combination. Investigations with larger sample sizes are required to examine the efficacy of differing doses of curcumin and saffron/curcumin combination. Its effects in people with atypical depression also require examination in larger scale studies. Active drug treatments comprising differing doses of curcumin and combined curcumin/saffron were effective in reducing depressive and anxiolytic symptoms in people with major depressive disorder. [Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. Journal of affective disorders. 2017 Jan 1;207:188-96.]


34.    Effect of Infla-Kine supplementation on the gene expression of inflammatory markers in peripheral mononuclear cells and on C-reactive protein in blood.
Chronic infammation is a predisposing factor to numerous degenerative diseases including cancer, heart failure and Alzheimer’s disease. Infa-Kine is a natural supplement comprised of a proprietary blend of Lactobacillus fermentum extract, burdock seed (arctigenin), zinc, alpha lipoic acid, papaya enzyme and an enhanced absorption bio-curcumin complex (BCM-95®). Infa-Kine was administered twice daily to 24 health volunteers for 4 weeks. Quantitative RT-PCR was used to assess mRNA transcripts of IL-1b, IL8, IL-6, NF-κB, and TNF-α from peripheral blood mononuclear cells (PBMC). C reactive protein (CRP) was measured from serum. Additionally, quality of life questionnaires were employed to assess general feeling of well-being. Assessments were made before treatment and at conclusion of treatment (4 weeks). As compared to pre-treatment, after 4 weeks, a statistically signifcant reduction of IL8, IL-6, NF-κB, and TNF-α transcripts was observed in PBMC. Furthermore, reduction of IL-1b transcript and serum CRP was observed but did not reach statistical signifcance. Quality of life improvements were most prevalent in muscle and joint pains. Overall, our data demonstrate that twice daily administration of Infa-Kine for 4 weeks reduces infammatory markers and quality of life in healthy volunteers. [Mikirova NA, Kesari S, Ichim TE, Riordan NH. Effect of Infla-Kine supplementation on the gene expression of inflammatory markers in peripheral mononuclear cells and on C-reactive protein in blood. Journal of translational medicine. 2017 Dec;15(1):213.]

35.    Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice. Antipsychotics, such as risperidone, increase food intake and induce alteration in glucose and lipid metabolism concomitantly with overweight and body fat increase, these biological abnormalities belong to the metabolic syndrome definition (high visceral adiposity, hypertriglyceridemia, hyperglycemia, low HDL-cholesterol and high blood pressure). Curcumin is a major component of traditional turmeric (Curcuma longa) which has been reported to improve lipid and glucose metabolism and to decrease weight in obese mice. We questioned the potential capacity of curcumin, contained in Curcuma longa extract (Biocurcuma™), to attenuate the risperidone-induced metabolic dysfunction. Two groups of mice were treated once a week, for 22 weeks, with intraperitoneal injection of risperidone (Risperdal) at a dose 12.5 mpk. Two other groups received intraperitoneal injection of the vehicle of Risperdal following the same schedule. Mice of one risperidone-treated groups and of one of vehicle-treated groups were fed a diet with 0.05% Biocurcuma™ (curcumin), while mice of the two other groups received the standard diet. Curcumin limited the capacity of risperidone to reduce spontaneous motricity, but failed to impede risperidone-induced
increase in food intake. Curcumin did not reduce the capacity of risperidone to induce weight gain, but decreased visceral adiposity and decreased the risperidone-induced hepatomegaly, but not steatosis. Furthermore, curcumin repressed the capacity of risperidone to induce the hepatic over expression of enzymes involved in lipid metabolism (LXRα, FAS, ACC1, LPL, PPARγ, ACO, SREBP2) and decreased risperidoneinduced glucose intolerance and hypertriglyceridemia. Curcumin decreased risperidone-induced increases in serum markers of hepatotoxicity (ALAT, ASAT), as well as of one major hepatic pro-inflammatory transcription factor (NFκB: p105 mRNA and p65 protein). These findings support that nutritional doses of curcumin contained in Curcuma longa extract are able to partially counteract the risperidoneinduced metabolic dysfunction in mice, suggesting that curcumin ought to be tested to reduce the capacity of risperidone to induce the metabolic syndrome in human. [Auger F, Martin F, Pétrault O, Samaillie J, Hennebelle T, Trabelsi MS, Bailleul F, Staels B, Bordet R, Duriez P. Risperidone-induced metabolic dysfunction is attenuated by Curcuma longa extract administration in mice. Metabolic brain disease. 2018 Feb 1;33(1):63-77.]

36.    Curcumin and metformin‐mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents, curcumin and metformin are reportedto exhibit chemopreventive properties, in vitro as well as in patients with oral cancer. In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40-100-fold) and protein levels (P ≤ 0.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4 mm3; P = 0.04) and improved overall survival of the animals (P = 0.03). Assessment of the molecular status showed an overall downregulation of CSC markers in the treatment arms as compared to the untreated control. Further, in vitro assessment of the treatment on the primary cells generated from progressive stages of 4NQO-induced mice tissue showed a concordant and consistent downregulation of the CSC markers following combination treatment (P < 0.05). Thetreatment also inhibited the migratory and self-renewal properties of these cells; the effect of which was prominent in the cultures of early dysplastic tissue (P < 0.002). Collectively, our observations suggest that the combination of curcumin and metformin may improve chemopreventive efficacy against oral squamous cell carcinoma through a CSC-associated mechanism. [Siddappa G, Kulsum S, Ravindra DR, Kumar VV, Raju N, Raghavan N, Sudheendra HV, Sharma A, Sunny SP, Jacob T, Kuruvilla BT. Curcumin and metformin‐mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. Molecular carcinogenesis. 2017 Nov;56(11):2446-60.]