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1.
Therap Adv Gastroenterol ; 11: 1756283X17741864, 2018.
Article in English | MEDLINE | ID: mdl-29383023

ABSTRACT

BACKGROUND: Curcumin, green tea polyphenols and selenium possess anti-inflammatory and anti-oxidant properties. Individually they have demonstrated some efficacy in animal models and human subjects with inflammatory bowel disease (IBD). To evaluate the efficacy and safety of Coltect [Curcumin (500 mg), green tea (250 mg) and selenium (100 µg)] in vivo and in patients with ulcerative colitis (UC). METHODS: Each component was compared to placebo in a DSS mice colitis model. The efficacy was validated in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) rat colitis model. Twenty patients with mild-to-moderate UC received two Coltect tablets twice daily for 8 weeks. Enrollees underwent sigmoidoscopy at study entrance and closure, and physical and laboratory evaluation at baseline, 4 and 8 weeks. RESULTS: Coltect showed a synergistic therapeutic effect in the DSS and TNBS models. Disease activity was significantly higher in the placebo versus the treated group (p < 0.05). Selenium was the more active component. The contribution of green tea was minor. In the TNBS model, the Wallace scores for macroscopic lesions were 4.8 ± 1.5 (treatment) and 8.2 ± 0.5 (placebo) (p = 0.01). In humans, Coltect was well tolerated and effective. Fourteen subjects (70%) improved: nine (45%) went into complete remission, four (20%) experienced marked improvement and one (5%) experienced moderate improvement at the end of the trial. Clinical activity index decreased significantly at 4 and 8 weeks (p < 0.001). Two patients had no change in their symptoms, and one withdrew after 4 weeks. Flare-up in four subjects caused three to withdraw from the study after less than 4 weeks. Endoscopic improvement was observed in 11 (69%) patients, and four patients (25%) achieved complete remission. CONCLUSIONS: Coltect may serve as a first-line or add-on therapy in patients with mild-to-moderate UC.

2.
Isr Med Assoc J ; 16(4): 233-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24834760

ABSTRACT

BACKGROUND: Atherosclerosis is a complex vascular inflammatory disease. In the last decade it was suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular inhibition of cyclooxygenase (COX)-2 are associated with an increase in cardiovascular morbidity and mortality. Aspirin is known to reduce the incidence and mortality from ischemic heart disease and is a mainstay in the prevention of vascular complications of atherosclerosis. OBJECTIVES: To examine the effect of meloxicam, a selective COX-2 inhibitor, or low dose aspirin on the development of experimental atherosclerosis in apoE knockout (KO) compared to wild-type (WT) mice. We aimed to test the hypothesis that meloxicam, a potential vasculitis inducer, would exacerbate atherosclerotic lesions while aspirin, which is known to reduce the incidence of thrombosis occlusive events, would increase protection in this model. METHODS: We randomly divided 36 male apoE KO and 36 WT mice, 8 weeks old. Mice were treated for 10 weeks with 0.1 mg/ml aspirin, or 0.05 mg/ml meloxicam, dissolved in their drinking water. Control groups received regular drinking water. At sacrifice, the hearts were removed for histochemical staining and plaque size and composition were examined. RESULTS: Aspirin-treated animals displayed a decreased atherosclerotic lesion area compared to the untreated control mice, while meloxicam had a null effect on the extent of atherosclerosis in Apo E KO mice. CONCLUSIONS: These results suggest that low dose aspirin reduces early atherosclerosis, while inhibition of COX-2 by meloxicam is not associated with an increase in atherosclerotic plaque size in this mouse model.


Subject(s)
Apolipoproteins E/genetics , Aspirin/pharmacology , Atherosclerosis/prevention & control , Cyclooxygenase 2 Inhibitors/pharmacology , Thiazines/pharmacology , Thiazoles/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Meloxicam , Mice , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic/pathology , Plaque, Atherosclerotic/prevention & control
3.
Eur J Intern Med ; 24(3): 245-9, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23312963

ABSTRACT

BACKGROUND: Cancer is a leading cause of mortality worldwide. Screening is a key strategy for reducing cancer morbidity and mortality. METHODS: We aimed to describe the experience of an integrated cancer prevention center in screening an asymptomatic population for the presence of neoplasia. One-thousand consecutive asymptomatic, apparently healthy adults, aged 20-80 years, were screened for early detection of 11 common cancers that account for 70-80% of cancer mortality. RESULTS: Malignant and benign lesions were found in 2.4% and 7.1% of the screenees, respectively. The most common malignant lesions were in the gastrointestinal tract and breast followed by gynecological and skin. The compliance rate for the different screening procedures was considerably higher than the actual screening rate in the general Israeli population - 78% compared to 60% for mammography (p<0.001) and 39% compared to 16% for colonoscopy (p<0.001). Advanced age, family history of cancer and certain lifestyle parameters were associated with increased risk. Moreover, polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a neoplastic lesion was extremely high (OR 2.3 [95% CI 0.94-5.9]). CONCLUSIONS: One stop shop screening for 11 common cancers in the setting of a multidisciplinary outpatient clinic is feasible and can detect cancer at an early stage.


Subject(s)
Asymptomatic Diseases/epidemiology , Early Detection of Cancer/methods , Mass Screening , Neoplasms , Academic Medical Centers/methods , Adult , Age Factors , Aged , CD24 Antigen/genetics , Early Detection of Cancer/statistics & numerical data , Female , Genes, APC , Humans , Israel/epidemiology , Life Style , Male , Mass Screening/methods , Mass Screening/statistics & numerical data , Neoplasms/classification , Neoplasms/diagnosis , Neoplasms/epidemiology , Neoplasms/genetics , Polymorphism, Genetic , Preventive Health Services/methods , Risk Factors
4.
Exp Cell Res ; 318(2): 160-8, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22020090

ABSTRACT

BACKGROUND: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. RESULTS: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our "gene therapy" approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce ~50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by ~35% tumor progression in vivo in already established tumors. CONCLUSIONS: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.


Subject(s)
Adenoviruses, Human , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Genes, ras , Genetic Therapy , Animals , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Cell Line, Tumor , Disease Progression , Genetic Vectors , Humans , Mice , Promoter Regions, Genetic , Proto-Oncogene Mas , Proto-Oncogene Proteins/genetics , Rats , Xenograft Model Antitumor Assays
5.
Therap Adv Gastroenterol ; 3(5): 281-9, 2010 Sep.
Article in English | MEDLINE | ID: mdl-21180609

ABSTRACT

OBJECTIVES: Coltect is a novel dietary supplement containing curcumin, green tea and selenomethionine. Previous reports have suggested that these agents can prevent colorectal cancer (CRC). The present study examined the chemopreventive effect of Coltect alone or combined with 5-aminosalicylic acid (5-ASA) using the 1,2-dimethylhydrazine (DMH) model in rats. METHODS: The effect of Coltect was examined on HT-29 CRC cells by growth inhibition assay. Apoptosis was determined by annexin V-FITC/PI staining. Male rats were injected with DMH in vivo and treated with Coltect 150 mg/kg, 5-ASA 50 mg/kg or their combination, by oral gavage. Aberrant crypt foci (ACF) were identified by methylene blue staining. RESULTS: HT-29 cells exhibited a dose-dependent response to Coltect. Part of the growth inhibition can be explained by the induction of mild-moderate apoptosis in cancer cells (28%) compared with the untreated cells (10%). In the in vivo model, the average number of ACF was divided into small (1-3 crypts) or large (≥4 crypts). The Coltect compound reduced the number of small and large ACF similarly to 5-ASA (40% reduction). This reduction was amplified by combining the two agents (70% reduction). CONCLUSION: Coltect inhibits the growth of colon cancer cells, induces apoptosis and inhibits ACF development. Furthermore, it augments the growth inhibitory effect of 5-ASA in vivo. This may be clinically important since this safe dietary supplement-drug combination can be administered as a chemopreventive regimen for the treatment of CRC.

6.
Expert Opin Investig Drugs ; 19 Suppl 1: S117-24, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20374023

ABSTRACT

OBJECTIVE: The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment. METHODS: HT-29 CRC cells were exposed to SFN (200 - 400 microM), curcumin (5 - 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle analysis were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group. RESULTS: Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 - 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF. CONCLUSIONS: Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Colorectal Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cell Cycle/drug effects , Cell Proliferation/drug effects , Curcumin/administration & dosage , Dose-Response Relationship, Drug , Drug Synergism , HT29 Cells , Humans , Male , Precancerous Conditions/drug therapy , Precancerous Conditions/pathology , Rats , Rats, Wistar , Sulindac/administration & dosage , Sulindac/analogs & derivatives
7.
Am J Reprod Immunol ; 62(6): 400-11, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19895375

ABSTRACT

PROBLEM: Potentiation of the maternal immune system was shown by us to affect the embryonic response to teratogenic insults. In order to understand better the mechanisms underlying that phenomenon, we explored the effect of maternal immunopotentiation by rat splenocytes on the early stages of the embryonic response to cyclophosphamide (CP). METHOD OF STUDY: Immunopotentiated CP-treated embryos were analysed for cell cycle changes by flow cytometry, while cell proliferation and apoptosis were assessed by 5'-bromo-2'-deoxyuridine (BrdU) incorporation and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) respectively. The expression of the p65 subunit of NF-kappaB, IkappaBalpha, Bax, bcl-2 and p53 was assessed by flow cytometry. RESULTS: Exposure to CP resulted in significant growth retardation and in the appearance of cellular damage, a reduction in cell proliferation and the appearance of apoptotic cells, which were all found to be delayed in immunopotentiated embryos. In parallel, CP-treated embryos demonstrated a reduction in the percentage of p65- or IkappaBalpha-positive cells, while the percentage of bcl-2- or p53-positive cells increased initially and decreased later. Those changes were normalized by maternal immunopotentiation when tested at 24 hrs after exposure to the teratogen. CONCLUSION: Our data implicate maternal immunopotentiation to protect the embryo against teratogenic insults, possibly through its effect on the expression of p65, bcl-2 or p53.


Subject(s)
Abnormalities, Drug-Induced/immunology , Cyclophosphamide/administration & dosage , Embryo, Mammalian/immunology , Fetal Growth Retardation/immunology , Animals , Apoptosis/drug effects , Apoptosis/immunology , Cell Cycle/drug effects , Cell Cycle/immunology , Cell Proliferation/drug effects , Cyclophosphamide/adverse effects , Embryo, Mammalian/drug effects , Embryo, Mammalian/metabolism , Embryo, Mammalian/pathology , Female , I-kappa B Proteins/biosynthesis , Immunization , Maternal-Fetal Exchange/immunology , Mice , Mice, Inbred ICR , Mutagens/adverse effects , Pregnancy , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Rats , Spleen/immunology , Spleen/pathology , Tumor Suppressor Protein p53/biosynthesis , eIF-2 Kinase/biosynthesis
8.
Reprod Toxicol ; 22(4): 774-82, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16952439

ABSTRACT

The mechanisms underlying the teratogen-induced apoptotic process leading to anomaly formation are not as yet understood. Therefore, we tried to evaluate possible changes in the expression of molecules regulating the apoptotic process induced in the embryo and placenta by exposure to cyclophosphamide (CP). Exposure to CP resulted in clear growth retardation that was accompanied by a time-dependent increase in cellular damage and an appearance of apoptotic cells in the embryonic brain and limbs as well as a decrease in cell proliferation. Western blot analysis demonstrated an increase in the level of Bax and a decrease in the expression of the p65 subunit of NF-kappaB and IkappaB alpha in the embryo and placenta. Immunohistochemical analysis localized cells expressing those molecules to the areas that exhibited CP-induced cellular damage, while in the placenta they were revealed mainly in the luminal and glandular epithelium. Our results suggest a possible involvement of Bax, p65 and IkappaB alpha in the response of the embryo and the placenta to teratogenic insults.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Cyclophosphamide/toxicity , Fetus/drug effects , Placenta/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cyclophosphamide/administration & dosage , Female , Fetus/metabolism , Flow Cytometry/methods , G1 Phase/drug effects , Gestational Age , I-kappa B Proteins/metabolism , Immunochemistry , In Situ Nick-End Labeling/methods , Injections, Intraperitoneal , Male , Mice , Mice, Inbred ICR , Mutagens/administration & dosage , Mutagens/toxicity , Placenta/metabolism , Pregnancy , Synaptotagmin I/metabolism , bcl-2-Associated X Protein/metabolism
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