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1.
Cancer research illustrated that combinatorial studies can provide significant improvement in safety and effectiveness over the monotherapy regimens. A combination of two drugs may restrain precancerous colon polyps, opening a new possible opportunity for chemoprevention of colon cancer. In this context, chemopreventive efficacy of a combination regimen of C-phycocyanin, a biliprotein present in Spirulina platensis, a cyanobacterium, which is a selective cycloxygenase-2 (COX-2) inhibitor and piroxicam, a traditional non-steroidal anti-inflammatory drug was considered in 1,2 dimethylhyadrazine (DMH)-induced colon carcinogenesis in rats. Western blotting, immunohistochemistry, DNA fragmentation, fluorescent staining, PGE(2) enzyme immunoassay, and carrageenan-induced paw edema test were performed along with morphological and histological analysis. DMH treatment showed a rich presence of preneoplastic lesions such as multiple plaque lesions, aberrant crypt foci, and well-characterized dysplasia. These features were reduced with piroxicam and C-phycocyanin administration. The number of apoptotic cells was featured prominently in all the groups compared with DMH. DMH treatment revealed intact high molecular weight genomic DNA with no signs of laddering/DNA fragmentation while it was noticeable significantly in control and DMH + piroxicam + C-phycocyanin. DMH group showed highest COX-2 expression and PGE(2) level in comparison with other groups. Doses of piroxicam and C-phycocyanin used in the present study were established at an anti-inflammatory range. A combination regimen of piroxicam and C-phycocyanin, rather than individually has the much greater potential for reduction of DMH-induced colon cancer development and COX-2 being the prime possible target in such chemoprevention.  相似文献   

2.
We have evaluated the interaction of radiation and 1,2-dimethylhydrazine (DMH) with respect to colon carcinogenesis in the Fischer 344 rat and have demonstrated the utility of this model for future more detailed mechanistic studies. In initial experiments, single doses of abdomen-only radiation (9 Gy) or DMH (150 mg/kg) were employed alone or in combination. Radiation was administered 3.5 days prior to the DMH. At 8 months post-treatment, the incidence of DMH-induced colon tumors was doubled by prior radiation exposure. When the protocol was repeated employing a DMH dose of 135 mg/kg with a 6-month observation period, the incidence of tumors induced by DMH alone was reduced, but the combination of radiation plus DMH still resulted in an augmentation of tumor incidence. When the protocol of radiation plus DMH was repeated three times at monthly intervals, a 15-fold increase in tumor incidence (from 5 to 74%) was observed at 6 months post-treatment. This finding demonstrates an apparent synergy between the radiation and the chemical carcinogen. Throughout these studies, the appearance of carcinomas was associated with preexisting colonic lymphoid nodules. The reproducibility of tumor induction as well as range of tumor incidence generated by variations in this system may be adequately sensitive to examine the combination of much lower doses of radiation and/or chemical carcinogen. The relationship between existing lymphoid aggregates which alter local epithelial cell kinetics and which are associated with fenestrations in the basement membrane, and the development of colon cancer in congruent sites may assist in defining dose-response curves for combined agents as well as providing a system for evaluating the mechanisms underlying their interactions.  相似文献   

3.
Concentrations of carnitine, acetyl carnitine, propionyl carnitine, and long chain acyl carnitines have been measured in hepatic tissue of normal and vitamin B-12 deficient rats using radiolabelled butyrobetaine to label carnitine pools. Increased levels of propionyl carnitine were seen in the livers of vitamin B-12 deprived animals when compared to those from normal animals. Methylmalonyl carnitine was not detected in the B-12 deprived animals. Free carnitine levels were no different in the livers from the B-12 deprived animals than from the normal control animals.  相似文献   

4.
Colorectal cancer is one of the leading causes of tumour‐related deaths. In the present study, the chemopreventive effect of green tea on 1,2‐dimethylhydrazine (DMH)‐induced colon carcinogenesis was studied in male Wistar rats. The DMH group received subcutaneous injections of DMH (30 mg kg?1 body weight) once a week for 30 weeks, the normal group received the vehicle of DMH, and the DMH + green tea group received DMH simultaneously with 1% green tea as their sole source of drinking fluid throughout the experimental period. In the DMH group treated with green tea, significant reductions in gene overexpressions of colonic nuclear factor κB (NF‐κB), tumour necrosis factor α, inducible nitric oxide synthase and cyclooxygenase 2, and NF‐κB immunostaining indicates the anti‐inflammatory effect of green tea in attenuating colon cancer. Moreover, the anti‐angiogenic and anti‐invasiveness effects of green tea were revealed as reductions of both vascular endothelial growth factor and matrix metalloproteinase‐7 mRNA expression levels. These effects were confirmed by the significant reduction of serum tumour necrosis factor α, C‐reactive protein levels, inhibition of tumour incidence, and nearly normal survival rate and colonic architecture. It can be concluded that green tea exerts a potent chemopreventive effect on colon carcinogenesis possibly due to the inhibition of NF‐κB. Copyright © 2012 John Wiley & Sons, Ltd.  相似文献   

5.
The method used here to assess the contribution of liver to plasma acylcarnitine is based on the idea that in rat, shortly after administration of [3H]butyrobetaine the [3H]carnitine appearing in the plasma derives from the liver and so does the acyl moiety of [acyl-3H] carnitine. In the perchloric acid extracts of plasma and liver, the ester fraction of total carnitine was determined by enzymatic analysis and that of [3H]carnitines was determined by high performance liquid chromatography. The ester fraction of total carnitine in the plasma of fed rats was 32.6% while that of [3H]carnitines was 67.9%, 1 h following injection of [3H]butyrobetaine. For 48 h starved rats the equivalent values were 54.2 and 84.0%, respectively. 24 h after the administration of [3H]butyrobetaine, the ester content became the same in the total and [3H]carnitines. That the newly synthesized carnitine was more acylated (67.9 versus 32.6%, fed) indicates that liver exports acyl groups with carnitine as carrier. The observation that the ester fraction in the newly synthesized plasma carnitine increased with fasting (84.0 versus 67.9%) indicates that the surplus plasma acylcarnitine in fasting ketosis derives from the liver. Perfused livers, however, released carnitine with the same ester content (60-61%) whether they were from fed or fasted animals. Probably, the increased plasma [acylcarnitine] in fasting develops not by an increased ester output from the liver but by an altered handling in extrahepatic tissues.  相似文献   

6.
Studies of [3H]ryanodine binding, 45Ca2+ efflux, and single channel recordings in planar bilayers indicated that the fatty acid metabolite palmitoyl carnitine produced a direct stimulation of the Ca2+ release channel (ryanodine receptor) of rabbit and pig skeletal muscle junctional sarcoplasmic reticulum. At a concentration of 50 microM, palmitoyl carnitine (a) stimulated [3H]ryanodine binding 1.6-fold in a competitive manner at all pCa in the range 6 to 3; (b) released approximately 65% (30 nmol) of passively loaded 45Ca2+/mg protein; and (c) increased 7-fold the open probability of Ca2+ release channels incorporated into planar bilayers. Neither carnitine nor palmitic acid could reproduce the effect of palmitoyl carnitine on [3H]ryanodine binding, 45Ca2+ release, or channel open probability. 45Ca2+ release was induced by several long-chain acyl carnitines (C14, C16, C18) and acyl coenzyme A derivatives (C12, C14, C16), but not by the short-chain derivative C8 or by free saturated fatty acids of chain length C8 to C18, at room temperature or 36 degrees C. This newly identified interaction of esterified fatty acids and ryanodine receptors may represent a pathway by which metabolism of skeletal muscle could influence intracellular Ca2+ and may be responsible for the pathophysiology of disorders of beta-oxidation such as carnitine palmitoyl transferase II deficiency.  相似文献   

7.
Effects of carnitines on rat sertoli cell protein metabolism.   总被引:3,自引:0,他引:3  
The influence of carnitine on male reproductive function is well established. However, the molecular mechanism by which carnitines control male fertility have not yet been clearly identified. In the present study, we studied the role of carnitines at testis level by examining their effects on protein metabolism in cultured rat Sertoli cells. Our results demonstrate that L-carnitine and, in particular, L-acetylcarnitine administration affects overall protein synthesis, inducing a dose-dependent decrease in amino acid incorporation and consequently an increase of the intracellular amino-acid pool useful to speed up Sertoli cell energy metabolism. We also observed significant effect on the expression of specific proteins involved in the regulation of glucose uptake and Insulin-like Growth Factor (IGF) biological activity. Actually, an increased expression of the mRNA coding for the membrane Glucose Transporter-1 (GLUT-1) and a decreased expression of mRNA coding for the negative modulator insulin-like growth factor-binding protein-4 (IGFBP-4) were induced by in vitro treatment with L-carnitine and L- acetylcarnitine separately and in combination; in fact, the effects observed were far more pronounced following concomitant treatment with both compounds. Taken together, these data indicate that the influence of carnitines on male fertility could be partly mediated by an activity at Sertoli cell level.  相似文献   

8.
Alteration of appropriate cell‐cycle progression and of closely related apoptotic process is a basic feature of tumour cells, and development of new tumour‐targeted agents focus on apoptosis, either during cell‐cycle arrest or following premature cell‐cycle checkpoint exit. Increasingly, epidemiological and experimental studies suggest that curcumin protects against cancer, not only because of its well‐known antioxidant properties, but also because it modulates intracellular signalling, which is related to cell proliferation and apoptosis. Cisplatin and oxaliplatin are first‐line drugs in treatment of many types of epithelial cancer and their combination with other cytostatics are under investigation to limit their side effects and resistance to them. Objectives: The aim of this study was to evaluate effects of a combined treatment using curcumin with cisplatin or with oxaliplatin, in a human ovarian cancer cell line (2008) and in its cisplatin‐resistant variant (C13). Results: Curcumin per se caused concentration‐dependent (0.1–100 µm ) and time‐persistent (24–72 h) reduction in cell proliferation, as well as altered cell cycle parameters and induced apoptosis, in both cell lines. When carcinoma cells were simultaneously exposed to curcumin and to cisplatin or oxaliplatin (at concentrations lower than IC50) cell viability was reduced more than with single‐drug treatment. Moreover, dose and time related effects of curcumin, when combined with platinum drugs, were linked to consistent reduction in cell cycling and increased apoptosis, in comparison with single‐drug treatment. These effects were significant both in wild type and in cisplatin‐resistant cells, indicating that curcumin was also able to increase sensitivity of resistant ovarian cancer cells to cisplatin. Conclusions: The data suggests that curcumin is an interesting natural compound capable of limiting cell proliferation and possibly increasing clinical impact of platinum drugs, in ovarian cancer patients.  相似文献   

9.
Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.  相似文献   

10.
Systemic toxicity due to chemotherapy contributes to poor prognosis in patients receiving chemotherapy. The present study, therefore, explores the role of Ellagic acid, a phytochemical, in modulating cisplatin (CP) toxicity in dimethylhydrazine-induced colorectal cancer. Colons excised from DMH administered animals showed abnormal crypts and bulges over the mucosal surface. SEM revealed significant alterations and dysplastic lesions in DMH administered mice. Animals receiving combined treatment showed improvement in colonic epithelium with lesser irregularities. DMH and CP administration disturbed the membrane dynamics and integrity as observed with the fluorescent probes DPH and pyrene. However, EA co-supplementation with CP proved to be beneficial in normalizing the altered membrane. Ellagic acid co-supplementation along with CP; therefore, showed great promise and helped restore the membrane alterations in the colon caused due to CP-induced toxicity and DMH insult. These observations could pave way towards developing a combination therapy targeting colon carcinogenesis in future.  相似文献   

11.
Galectin-3 (Gal-3) is a multifunctional protein that plays different roles in cancer biology. To better understand the role of Gal-3 and its ligands during colon carcinogenesis, we studied its expression in tumors induced in rats treated with 1,2-dimethylhydrazine (DMH) and in human tissues. Normal colon from untreated rats showed no staining using two specific monoclonal antibodies. In contrast, morphologically normal colon from DMH-treated rats and dysplastic aberrant crypt foci were strongly stained, indicating that increased Gal-3 expression is an early event during the neoplastic transformation in colon cells. Gal-3 was weakly expressed in adenocarcinomas. Overall, the Gal-3 expression pattern observed in the DMH rat model closely resembles that displayed by human colon stained with the same antibodies. We also found that Gal-3 phosphorylation diminishes in serines while increasing in tyrosines during rat colon carcinogenesis. Finally, we showed that Gal-3–ligands expression is strikingly similar in rat and human malignant colon and in non-malignant tissues. In conclusion, the DMH-induced rat colon cancer model displays expression patterns of Gal-3 and its ligands very similar to those observed in human samples. This animal model should contribute to clarifying the role of Gal-3 in colon carcinogenesis and also to finding effective preventive cancer agents based on Gal-3 targeting. (J Histochem Cytochem 58:553–565, 2010)  相似文献   

12.
The adenosine 3',5'-cyclic monophosphate (cAMP)-dependent and cAMP-independent kinase activities were measured in the 1,2-dimethylhydrazine (DMH) induced rat colon cancer and in untreated colon. Previous studies had shown that intestinal tumors induced by chronic exposure to DMH contained 2-fold less intracellular cAMP. The present findings indicate that reduction in cAMP-dependent protein kinase activities also occur in colon cancer cells. Similar hydrogen ion dependence (pH 6-7) and approximate association constants (Ka approximately 0.1 microM) were observed for the enzymes existing in both normal and tumor tissues, while the cAMP-dependent tumor protein kinase was found to phosphorylate phosvitin and casein to a greater degree. These recent findings are consistent with the concept that the concentrations of cAMP and activities of its associated enzyme system are inversely related to the cell proliferation state.  相似文献   

13.
Autophagy is an evolutionarily conserved cell survival pathway that enables cells to recoup ATP and other critical biosynthetic molecules during nutrient deprivation or exposure to hypoxia, which are hallmarks of the tumour microenvironment. Autophagy has been implicated as a potential mechanism of resistance to anticancer agents as it can promote cell survival in the face of stress induced by chemotherapeutic agents by breaking down cellular components to generate alternative sources of energy. Disruption of autophagy with chloroquine (CQ) induces the accumulation of ubiquitin‐conjugated proteins in a manner similar to the proteasome inhibitor bortezomib (BZ). However, CQ‐induced protein accumulation occurs at a slower rate and is localized to lysosomes in contrast to BZ, which stimulates rapid buildup of ubiquitinated proteins and aggresome formation in the cytosol. The histone deacetylase (HDAC) inhibitor vorinostat (VOR) blocked BZ‐induced aggresome formation, but promoted CQ‐mediated ubiquitinated protein accumulation. Disruption of autophagy with CQ strongly enhanced VOR‐mediated apoptosis in colon cancer cells. Accordingly, knockdown of the essential autophagy gene Atg7 also sensitized cells to VOR‐induced apoptosis. Knockdown of HDAC6 greatly enhanced BZ‐induced apoptosis, but only marginally sensitized cells to CQ. Subsequent studies determined that the CQ/VOR combination promoted a large increase in superoxide generation that was required for ubiquitinated protein accumulation and cell death. Finally, treatment with the CQ/VOR combination significantly reduced tumour burden and induced apoptosis in a colon cancer xenograft model. Collectively, our results establish that inhibition of autophagy with CQ induces ubiquitinated protein accumulation and VOR potentiates CQ‐mediated aggregate formation, superoxide generation and apoptosis.  相似文献   

14.
Gastric cancer (GC) is one of the prevalent human malignancies and the third most common cause of cancer‐related death worldwide. The doxorubicin hydrochloride is one of the important chemotherapeutic anticancer agents, with a limited therapeutic efficacy for treatment of GC. Therefore, taking advantage of synergistic effects by strategies like combination therapy seems appropriate and promising in treatment of GC. The aim of this study was to investigate a novel method to enhance the therapeutic efficacy of doxorubicin (as a chemotherapeutic agent) by co‐administration of curcumin (as a bioactive herbal compound) in GC treatment. In the present study, the effects of curcumin, doxorubicin, and their combinations (Dox‐Cur) were evaluated on the viability, morphological features, tumor spheroid formation, migration, invasion, and apoptosis of gastric adenocarcinoma cell line (AGS). Moreover, expression levels of BAX, BCL‐2, and CASP9 genes were assessed among AGS cells treated with curcumin, doxorubicin, and Dox‐Cur. The obtained results showed that all of curcumin, doxorubicin, and Dox‐Cur treatments significantly decreased the viability, tumor spheroid formation, migration, and invasion in the GC model cells. Furthermore, apoptosis rates in AGS cells were increased in a concentration‐ and time‐dependent manner in all of the treatment groups. Moreover, the anticancer activity of the Dox‐Cur combination was significantly more than curcumin and doxorubicin treatments alone. According to the results, Dox‐Cur combination therapy exerts more profound apoptotic and anticancer effects on the AGS cell line than curcumin or doxorubicin monotherapy.  相似文献   

15.
The parenteral administration of 1,2-dimethylhydrazine to rats caused the development of colonic neoplasms in about 90% of animals by 24--30 weeks of treatment. Usually there were multiple tumours with a mean of 2.7 per rat. The lesions have been classified histologically into adenomata (26% of all tumours) and carcinomata, the latter showing varying degrees of differentiation. No completely anaplastic tumours were seen, and there were none originating in connective tissue. The distributions of the different tumour types along the length of the colon varied. The more benign lesions were situated predominantly in the distal half of the colon, while the poorly differentiated adenocarcinomata were concentrated in the proximal third of the colon. There was good evidence to suggest that adenomata often progressed to frank malignancy in the distal colon. In the proximal part, however, it appeared that tumours frequently developed de novo as poorly differentiated carcinomata. Perhaps regional variations in the kinetic organisation of the normal colonic mucosa somehow influence the nature of the neoplastic change induced by DMH, thus accounting for the differences in tumor distribution. After 24 weeks of DMH treatment there was only a small increase in the mean number of tumours per rat.  相似文献   

16.
17.
The aim of the present study was to unravel the chemopreventive effect of luteolin on bacterial enzymes such as beta-glucuronidase and mucinase in a colon carcinogenesis model induced by 1, 2-dimethyl hydrazine (DMH). Twenty mg/kg body weight of DMH were administered subcutaneously once a week for the first 15 weeks and then discontinued. Luteolin (0.1, 0.2, or 0.3 mg/kg body weight/everyday (p.o.) was administered in a dose dependent manner at the initiation and also at the post-initiation stages of carcinogenesis to DMH treated rats. The animals were sacrificed at the end of 30 weeks. Colon cancer incidence and the activities of bacterial enzymes beta-glucuronidase (in the proximal colon, distal colon, intestines, liver and colon contents) and mucinase (colon and fecal contents) were significantly increased in DMH -treated rats compared to the control rats. On luteolin administration, colon cancer incidence, number of tumors per rat and the activities of beta-glucuronidase and mucinase, were significantly decreased both in the initiation and post-initiation stages of colon carcinogenesis dependent on the three different doses given. The increase in beta-glucuronidase activity may augment the hydrolysis of glucuronide conjugates, liberating toxins, while the increase in the mucinase activity may enhance the hydrolysis of the protective mucins in the colon. Thus our results demonstrate for the first time that luteolin, a dietary flavonoid, exerts chemopreventive and anticarcinogenic effects against DMH induced colon cancer.  相似文献   

18.
L-Propionyl carnitine has been shown to improve the heart's mechanical recovery and other metabolic parameters after ischemia-reperfusion. However, the mechanism of protection is unknown. The two dominating hypotheses are: (i) L-propionyl carnitine can serve as an energy source for heart muscle cells by being enzymatically converted to propionyl-CoA and subsequently utilized in the Krebs cycle (a metabolic hypothesis), and (ii) it can act as an antiradical agent, protecting myocardial cells from oxidative damage (a free radical hypothesis). To test the two possible pathways, we compared the protection afforded to the ischemia-reperfused hearts by L-propionyl carnitine and its optical isomer, D-propionyl carnitine. The latter cannot be enzymatically utilized as an energy source. The Langendorff perfusion technique was used and the hearts were subjected to 40 min of ischemia and 20 min of reperfusion. In analysis of ischemia-reperfused hearts, a strong correlation was found between the recovery of mechanical function and the presence of protein oxidation products (protein carbonyls). Both propionyl carnitines efficiently prevented protein oxidation but L-propionyl carnitine-perfused hearts had two times greater left ventricular developed pressure. The results indicate that both metabolic and antiradical pathway are involved in the protective mechanism of L-propionyl carnitine. To obtain a better insight of the antiradical mechanism of L-propionyl carnitine, we compared the ability of L- and D-propionyl carnitines, L-carnitine, and deferoxamine to interact with: (i) peroxyl radicals, (ii) oxygen radicals, and (iii) iron. We found that none of the carnitine derivatives were able to scavenge peroxyl radicals or superoxide radicals. L- and D-propionyl carnitine and deferoxamine (not L-carnitine) suppressed hydroxyl radical production in the Fenton system, probably by chelating the iron required for the generation of hydroxyl radicals. We suggest that L-propionyl carnitine protects the heart by a dual mechanism: it is an efficient fuel source and an antiradical agent.  相似文献   

19.
The effect of hyperammonemia on plasma and urinary levels of carnitine was studied in different groups of +/Y (normal) and spf/Y (chronically hyperammonemic) mice. Experimental models of acute and subacute hyperammonemia were prepared in +/Y and spf/Y mice by the use of ammonium acetate ip injections and arginine-free diets, respectively. In acute hyperammonemia, the plasma levels of both free and acylcarnitines increased significantly whereas acyl/free carnitine ratio was decreased, indicating a mobilization of carnitine from the storage sites. The subacute hyperammonemia model showed the same tendency in respect of plasma and urinary carnitines; however, the values in plasma were more significantly different. The effect of sodium benzoate on plasma carnitine levels, during both an acute and a prolonged treatment, consisted in a significant lowering of free carnitine and a significant increase in the acyl/free carnitine ratio, in both +/Y normal and spf/Y mouse models. The changes in the urinary profile, on benzoate treatments, were not significant. These results demonstrate the individual effects of hyperammonemia and benzoate therapy on carnitine metabolism, which may be helpful in understanding and ameliorating the therapeutic approach to hereditary hyperammonemias.  相似文献   

20.
Vibrational circular dichroism spectra (VCD) in the mid‐IR region and electronic circular dichroism (ECD) spectra for three carnitine derivatives in the form of hydrochloride salts were recorded in deuterated methanol solutions. Density Functional Theory calculations help one to understand the significance of the observed VCD bands. VCD and ECD spectra are informative about the absolute configuration of the molecule, but VCD data reveal also some conformational aspects in the N,N,N‐trimethyl moiety and inform us about intermolecular interactions gained from the carbonyl stretching region for the acyl substituted carnitines. Chirality 27:907–913, 2015. © 2015 Wiley Periodicals, Inc.  相似文献   

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