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Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats
Abstract
Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.
... In a rat model, dietary curcumin enhanced the apoptotic index in azoxymethaneinduced colonic tumors [207][208][209][210]. Azoxymethane treatment in rats induces the formation of aberrant crypt foci, but their number was significantly reduced with resveratrol (200 µg/kg per day for 100 d), together with the decreased level of Bax and upregulation of p21 in the crypts [211]. ...
... Curcumin decreased the incidence of colon adenocarcinomas, and reduced tumor size and expression of mucosal and tumor PGE 2 by over 38%. Furthermore, a gavage administration of curcumin (200 or 600 mg kg −1 ) decreased diethylnitrosamine-induced hepatic hyperplasia and inflammation, and prevented an increase in the expression of oncogenic proteins p21(ras) and p53 in the rat liver [210]. The reduced expression of cell-cycling proteins PCNA, cyclin E, and cdc2 was also observed, together with the suppression of DEN-induced NF-κB activation [210,267]. ...
... Furthermore, a gavage administration of curcumin (200 or 600 mg kg −1 ) decreased diethylnitrosamine-induced hepatic hyperplasia and inflammation, and prevented an increase in the expression of oncogenic proteins p21(ras) and p53 in the rat liver [210]. The reduced expression of cell-cycling proteins PCNA, cyclin E, and cdc2 was also observed, together with the suppression of DEN-induced NF-κB activation [210,267]. ...
In recent years, interest in natural products such as alternative sources of pharmaceuticals for numerous chronic diseases, including tumors, has been renewed. Propolis, a natural product collected by honeybees, and polyphenolic/flavonoid propolis-related components modulate all steps of the cancer progression process. Anticancer activity of propolis and its compounds relies on various mechanisms: cell-cycle arrest and attenuation of cancer cells proliferation, reduction in the number of cancer stem cells, induction of apoptosis, modulation of oncogene signaling pathways, inhibition of matrix metalloproteinases, prevention of metastasis, anti-angiogenesis, anti-inflammatory effects accompanied by the modulation of the tumor microenvironment (by modifying macrophage activation and polarization), epigenetic regulation, antiviral and bactericidal activities, modulation of gut microbiota, and attenuation of chemotherapy-induced deleterious side effects. Ingredients from propolis also ”sensitize“ cancer cells to chemotherapeutic agents, likely by blocking the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In this review, we summarize the current knowledge related to the the effects of flavonoids and other polyphenolic compounds from propolis on tumor growth and metastasizing ability, and discuss possible molecular and cellular mechanisms involved in the modulation of inflammatory pathways and cellular processes that affect survival, proliferation, invasion, angiogenesis, and metastasis of the tumor.
... Another investigation of the same research team, in a rat HCC model shown curcumin's capability to effectively suppress DENinduced hepatic inflammation and hyperplasia. According to the results of the immunoblotting experiments, curcumin inhibits DENmediated upregulation of oncogenic p53, p21(ras) proteins, PCNA, factor NF-κB, cyclin E, and p34(CDC2), yet it does not suppress c-Fos and c-Jun [142,143]. The effects of tetrahydro-curcumin and curcumin on tumor angiogenesis in HCC mouse models were also examined Yoysungnoen et al. ...
... Additionally, it has been shown that the levels of galetin-3 and IL-6 have diminished and MDA and NO have increased [159]. Fig. 4 shows the potential applicability in HCC of curcumin [141][142][143][144][145][160][161][162][163][164][165][166][167][168], resveratrol [169][170][171][172][173][174][175][176][177][178], silibinin [46,[146][147][148][149][150][151][152], tanshinone IIA [153][154][155][156][179][180][181][182][183][184], piperine [157], S-alyl cysteine [158], and andrographolide [159] due to their mechanisms of action evaluated in numerous assessments. ...
Hepatic disorders are considered major health problems, due to their high incidence, increased risk of chronicling or death and the costs involved in therapies. A large number of patients with chronic liver diseases use herbal medicines and dietary supplements in parallel with allopathic treatment.The current review provides a thorough analysis of the studies conducted on the most important species of medicinal plants used in this disease, bioactive compounds and on the activity of herbal medicines in the evolution of chronic liver diseases. However, a negative aspect is that there is frequently a lack of comprehensive data on the progression of the illness and the living standards of patients who are affected when evaluating the effects of these phytocomponents on the evolution of chronic liver disease, the patients' health, and their quality of life. It is essential to take this impairment into account when evaluating the long-term effects of herbal treatments on the health of individuals who suffer from liver illness. Bioactive phytocomponents may be a suitable source for the development of novel medications due to the correlation between traditional uses and medical advances. Additional high-quality preclinical examinations utilizing cutting-edge approaches are needed to assess safety and effectiveness and to detect, categorize, and standardize the active substances and their formulations for the most suitable therapeutic management of liver illnesses.
... Selection dose of sulfanilamide was attributed to previous literature [19,20]. Meanwhile, CUR dose was also referred to studies based on antioxidant effect [21]. The first group was served as control and injected by 1 mL isotonic saline containing i.p., second group rats were injected with a single dose of sulfanilamide. ...
... To inhibit renal injury that caused by sulfanilamide there are several drugs have been utilized like vitamin E, melatonin and so on [21]. Increasing of creatinine and plasma urea levels in these rats that administrated by sulfanilamide have been inhibited by treating this rats with curcumin, which decreases ischemia-reperfusion prompted an escalation in serum creatinine levels [28]. ...
... These plant derivatives include curcumin, a low 171 molecular weight polyphenol derived from the root of Curcuma longa has been extensively studied to 172 have hepatoprotective properties. In both mouse and rat models, curcumin was shown to inhibit 173 DEN-induced expression of oncogenic HRAS, focal dysplasia and hepatocarcinogenesis [42][43][44]. ...
... These plant derivatives include curcumin, a low molecular weight polyphenol derived from the root of Curcuma longa has been extensively studied to have hepatoprotective properties. In both mouse and rat models, curcumin was shown to inhibit DEN-induced expression of oncogenic HRAS, focal dysplasia and hepatocarcinogenesis [42][43][44]. Another phytochemical, resveratrol, abundant in peanuts and grapes, could interfere with DEN-induced hepatocarcinogenesis by activating apoptotic pathways in male Wistar rats [45]. ...
Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context.
... For instance, in a rat model of experimental hepatectomy, even 7 days of the administration of 100 mg/kg Cur increases the proliferative index by more than 20-fold, as estimated in terms of proliferating cell nuclear antigen expression [58]. On the contrary, in experiments involving diethylnitrosamine-induced liver inflammation, as an example, the expression of PCNA diminishes after Cur was administered to rats [59]. ...
Opisthorchiosis is a parasitic liver disease found in mammals that is widespread throughout the world and causes systemic inflammation. Praziquantel remains the drug of choice for the treatment of opisthorchiosis, despite its many adverse effects. An anthelmintic effect is attributed to the main curcuminoid of Curcuma longa L. roots—curcumin (Cur)—along with many other therapeutic properties. To overcome the poor solubility of curcumin in water, a micellar complex of curcumin with the disodium salt of glycyrrhizic acid (Cur:Na2GA, molar ratio 1:1) was prepared via solid-phase mechanical processing. In vitro experiments revealed a noticeable immobilizing effect of curcumin and of Cur:Na2GA on mature and juvenile Opisthorchis felineus individuals. In vivo experiments showed that curcumin (50 mg/kg) had an anthelmintic effect after 30 days of administration to O. felineus-infected hamsters, but the effect was weaker than that of a single administration of praziquantel (400 mg/kg). Cur:Na2GA (50 mg/kg, 30 days), which contains less free curcumin, did not exert this action. The complex, just as free curcumin or better, activated the expression of bile acid synthesis genes (Cyp7A1, Fxr, and Rxra), which was suppressed by O. felineus infection and by praziquantel. Curcumin reduced the rate of inflammatory infiltration, whereas Cur:Na2GA reduced periductal fibrosis. Immunohistochemically, a decrease in liver inflammation markers was found, which is determined by calculating the numbers of tumor-necrosis-factor-positive cells during the curcumin treatment and of kynurenine-3-monooxygenase-positive cells during the Cur:Na2GA treatment. A biochemical blood test revealed a normalizing effect of Cur:Na2GA (comparable to that of curcumin) on lipid metabolism. We believe that the further development and investigation of therapeutics based on curcuminoids in relation Opisthorchis felineus and other trematode infections will be useful for clinical practice and veterinary medicine.
... In the models of DEN-induced hepatocarcinogenesis, curcumin was shown to improve liver function by mediating oxidative stress in the liver, and ameliorating metabolic disorders through targeting glycometabolism and amino acid metabolism via affecting metabolic enzyme expressions, such as glucose transporter 1 (GLUT1), pyruvate kinase M (PKM), and FAS (Qiu et al. 2017). Besides, curcumin was also reported to inhibit DEN-induced liver inflammation and hyperplasia by attenuating p53-mediated cell cycle signaling and nuclear transcription of NF-κB in the prevention of HCC (Chuang et al. 2000). In Hep3B hepatoma-bearing mice, curcumin repressed tumor growth and blocked erythropoietin, and VEGF in tumors by inactivating HIF-1 through degrading ARNT via oxidation and ubiquitination (Choi et al. 2006). ...
Natural products have provided abundant sources of lead compounds for new drug discovery and development over the past centuries. Curcumin is a lipophilic polyphenol isolated from turmeric, a plant used in traditional Asian medicine for centuries. Despite the low oral bioavailability, curcumin exhibits profound medicinal value in various diseases, especially liver and gut diseases, bringing an interest in the paradox of its low bioavailability but high bioactivity. Several latest studies suggest that curcumin's health benefits may rely on its positive gastrointestinal effects rather than its poor bioavailability solely. Microbial antigens, metabolites, and bile acids regulate metabolism and immune responses in the intestine and liver, suggesting the possibility that the liver-gut axis bidirectional crosstalk controls gastrointestinal health and diseases. Accordingly, these pieces of evidence have evoked great interest in the curcumin-mediated crosstalk among liver-gut system diseases. The present study discussed the beneficial effects of curcumin against common liver and gut diseases and explored the underlying molecular targets, as well as collected evidence from human clinical studies. Moreover, this study summarized the roles of curcumin in complex metabolic interactions in liver and intestine diseases supporting the application of curcumin in the liver-gut system as a potential therapeutic option, which opens an avenue for clinical use in the future.
... Curcumin and turmeric extract-reduced GGT+ foci in AFB1-treated male Wistar rats (134), protected against DENA-induced hyperplasia in male Wistar rats (135), suppressed the DENA-induced hepatocellular carcinoma in male C3H/HeN mice (136), attenuated DENA-induced GGT+ foci and hepatocellular carcinoma in female Wistar rats (137), prevented the DENA-initiated and 2-AAFpromoted development of altered GGT+ /GST+ hepatic foci in male Wistar rats (138), significantly blocked the DENA-initiated and PB-promoted nodule incidence in male Wistar rats (139), suppressed the DHPN-induced liver adenoma formation in male BALB/c mice (140) 10. ...
Progression of chronic liver disease to hepatocellular carcinoma is not uncommon in India. Approximately 22,000 new cases of primary liver cancer are reported annually in the country. HCC is very complex and unique when compared with other cancer types. Treatment such as surgical resection, ablation, and chemo-embolization is useful only to selected patients. Over all very low (4%) survival rate of HCC underlines the limitations in treatment options and marks it as cause of major health burden. At present, liver transplantation remains the only curative option for the patients of cirrhosis and end stage liver diseases. The etiology and pathology of HCC is not clearly defined in detail in the Indian system of medicines. But tumors are discussed under the names various ASU terminology to designate basic common neoplasms, which can appear in any tissue or organ of the body. Both allopathic and ASU systems generally refer to neoplasms as the uncoordinated abnormal cell growth found within particular organs or body tissues. The Indian systems of medicine are the oldest traditional medicinal systems offering treatments for chronic liver diseases and cirrhosis for centuries. A large number of single and compound drug formulations are documented to have benefit over chronic liver conditions as hepatic tonic. The therapeutic benefits offered by various ASU formulations in treatment of chronic liver diseases have however not much explored in treatment of HCC. Experiments on animals and cell cultures have shown that some potential plants can alleviate and prevent pathological changes in the liver. The present paper is an attempt to list the plants with hepatoprotective and related beneficial effects which are used in Indian system of medicines. An attempt has been made to provide details on validation of certain potential plant drugs for anticancer and anti-metastatic properties against hepatocellular carcinoma.
... Moreover, the anti-proliferative effects of curcumin were accompanied by pronounced apoptosis and attenuation of telomerase activity in Huh7 liver cancer cells [36]. Chuang et al. [37] found that curcumin treatment 0.2% reduced carcinoma cells in male mice by reducing p21 protein, thereby protecting against genome destabilization that occurs before entering the cancer state. The study of curcumin absorption in the human body found that curcuminoid extract from turmeric rhizome is absorbed to a greater extent in the human body than pure curcumin [38]. ...
Turmeric (Curcuma longa L.) powder is widely used as a spice and seasoning in Asian countries. This study investigated the effect of turmeric extracts on the anticancer activity of Huh7 and HCT 116 cells. The curcumin bioactive compounds were extracted using various methods such as microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and traditional extraction (TDE). The yield of dried extracts from MAE was found to be the highest at 17.89%, followed by UAE and TDE, with 11.34% and 5.54%, respectively. Antioxidant activities such as TPC, DPPH and FRAP from MAE were higher than those of UAE and TDE. The total curcuminoid contents from the novel extractions were higher than those from traditional extraction methods. For instance, curcuminoid contents from MAE, UAE and TDE were 326.79, 241.17 and 215.83 mg/g, respectively. Due to having the highest bioactive compounds and extraction yield, turmeric extract from MAE was used to investigate the potential anticancer properties. The extract showed significant cytotoxic potential against the human liver (Huh7) and human colon (HCT116) cell lines, in concentrations ranging from 31.25 to 1000.00 µg/mL. Turmeric extracts using MAE have potential anticancer effects on Huh7 and HCT116 cells. This study serves as scientific data for the chemotherapeutic properties of turmeric extracts and their use as functional ingredients.
... A study carried out in Wistar rats showed that CCM prevents the formation of hyperplastic liver nodules [73]. Microcapsules containing curcumin exhibited high, dosedependent cytotoxicity on HCT-116 colorectal carcinoma cell culture [74]. ...
Curcumin (CCM) is one of the most frequently explored plant compounds with various biological actions such as antibacterial, antiviral, antifungal, antineoplastic, and antioxidant/anti-inflammatory properties. The laboratory data and clinical trials have demonstrated that the bioavailability and bioactivity of curcumin are influenced by the feature of the curcumin molecular complex types. Curcumin has a high capacity to form molecular complexes with proteins (such as whey proteins, bovine serum albumin, β-lactoglobulin), carbohydrates, lipids, and natural compounds (e.g., resveratrol, piperine, quercetin). These complexes increase the bioactivity and bioavailability of curcumin. The current review provides these derivatization strategies for curcumin in terms of biological and physico-chemical aspects with a strong focus on different type of proteins, characterization methods, and thermodynamic features of protein–curcumin complexes, and with the aim of evaluating the best performances. The current literature review offers, taking into consideration various biological effects of the CCM, a whole approach for CCM-biomolecules interactions such as CCM-proteins, CCM-nanomaterials, and CCM-natural compounds regarding molecular strategies to improve the bioactivity as well as the bioavailability of curcumin in biological systems.
... Some literature data demonstrated that DEN may be a potent lung carcinogen in strains with a higher incidence of lung tumors than other cancers [19,20]. We selected a dose of 150 mg/kg DEN based on previous studies, which demonstrated that the application of DEN at this dose remarkably re ects the pathological and biochemical ndings in lung cancer in humans [17,21]. In parallel with the previous literature, we determined that DEN administration signi cantly increased histopathological scores and in ammation in the present study. ...
Background: This study was designed to assess the possible beneficial effects of sorafenib (SOR) in diethylnitrosamine (DEN) induced lung carcinogenesis in male rats and also to examine its probable mechanisms of action.
Methods and results: A total of 30 adult male rats were divided into three groups as (1) control, (2) DEN, and (3) DEN+SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum samples were analyzed to determine SOX2 levels. Levels of TNF-α and IL-1β were measured in lung tissue supernatants. Lung sections were evaluated histopathologically. Also, COX-2 and JNK were analyzed by immunohistochemistry and immunofluorescence methods respectively. SOR reduced the level of SOX2 that maintenance of cancer stemness and tumorigenicity, and TNF-α and IL-1β levels. Furthermore, SOR reduced lung histopathological structure and suppressed COX-2 and JNK expression
Conclusions: These results suggest that SOR reduces inflammation in the tumor microenvironment and decreases the level of SOX2 which has an important role in maintaining cancer stem cell properties.
... Evidence in the literature is indicative of the fact that much of the positive clinical results of curcumin administration are currently restricted to patients with colorectal cancer as sufficient curcumin concentrations are available in the colonic mucosa, unlike the limited bioavailability observed in other tissues (Adiwidjaja et al. 2017). In an animal model of N-nitrosodimethylamine (hepatocarcinogen)-induced experimental carcinogenesis, curcumin treatment was found to exhibit 81% reduction in the multiplicity and a 62% reduction in the incidence of hepatocarcinoma compared with the non-treated group (Chuang et al. 2000). In its activity against prostate cancer, curcumin has been observed to impede NICD (active product of Notch-1 receptor) binding to DNA, that induces apoptosis of prostate cancer cells . ...
Discouraging statistics of cancer disease has projected an increase in the global cancer burden from 19.3 to 28.4 million incidences annually within the next two decades. Currently, there has been a revival of interest in nutraceuticals with evidence of pharmacological properties against human diseases including cancer. Diet is an integral part of lifestyle, and it has been proposed that an estimated one-third of human cancers can be prevented through appropriate lifestyle modification including dietary habits; hence, it is considered significant to explore the pharmacological benefits of these agents, which are easily accessible and have higher safety index. Accordingly, an impressive embodiment of evidence supports the concept that the dietary factors are critical modulators to prevent, retard, block, or reverse carcinogenesis. Such an action reflects the ability of these molecules to interfere with multitude of pathways to subdue and neutralize several oncogenic factors and thereby keep a restraint on neoplastic transformations. This review provides a series of experimental evidence based on the current literature to highlight the translational potential of nutraceuticals for the prevention of the disease through consumption of enriched diets and its efficacious management by means of novel interventions. Specifically, this review provides the current understanding of the chemopreventive pharmacology of nutraceuticals such as cucurbitacins, morin, fisetin, curcumin, luteolin and garcinol toward their potential as anticancer agents.
... Possible mechanisms for the anti-HCC effect of curcumin include reducing the expression of proliferating cell nuclear antigen, cyclin E and p34 [118], inhibiting hypoxia-inducible growth factor-1α hepatic expression [119,120], protecting hepatocytes against oxidative stress through NF-E2-related factor 2 mediated induction of heme oxygenase-1 and modulating AKT, TGF-β, and caspase-3 expression [121][122][123][124]. Curcumin protects the liver against oxidative damages through increasing the expression of hemeoxygenase 1 via activation of NF-E2-related factor 2 signaling [125,126]. Oral nanocapsulated curcumin in diethylnitrosamine-induced HCC showed protection and restored redox homeostasis in liver cells by inducing cancer cell apoptosis [127]. ...
Food contaminants are one of the most important and concerning issues worldwide. Protecting the public from the harm of contaminated foods has become a daunting task. On the other hand, the elimination of these contaminants from food seems impossible. Therefore, one of the best solutions is to recommend inexpensive and publicly available food additives like many spices used in food as flavoring and coloring. Curcuma longa or turmeric is one of the well-known spice, which confers many medicinal properties. Curcumin is the main active ingredient in turmeric, which has many health benefits. Recent research has revealed that turmeric/curcumin has protective effects against toxicants, mostly natural and chemical toxins. In this review article, we reviewed studies related to the protective effects of turmeric and its active ingredient against food contaminants.
... • Group III: rats received, ASCR (250 mg/kg/day, orally) [11]. • Group IV: rats received CRCM (200 mg/kg/day, orally) [12]. • Group V: rats received a combination of ASCR and CRCM. ...
Lead acetate (lead ac.) is a widespread ecological toxicant that can cause marked neurotoxicity and decline in brain functions. This study aimed to evaluate the possible neuroprotective role of L-ascorbic (ASCR) and curcumin (CRCM) alone or together against lead ac.-induced neurotoxicity. Rats were injected with lead ac. then treated orally with ASCR and CRCM alone or in combination for seven days. Lead ac. caused elevation in brain tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), caspase-3, and malondialdehyde (MDA) levels, while superoxide dismutase (SOD), reduced glutathione (GSH) as well as the expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) and Beclin1 were down-regulated. Expressions of C/EBP homologous protein (CHOP) and mammalian Target of rapamycin kinase (mTOR) were upregulated in brain tissues matched with the control group. Histopathological examination supported the previously mentioned parameters, the administration of the antioxidants in question modulated all the altered previous parameters. The combination regimen achieved the superlative results in the antagonizing lead ac.-induced neurotoxicity via its antioxidant and anti-apoptotic activities.
... The choice of the doses of curcumin, rosemary and propolis were based on the results of the previous studies, where the antioxidant effects of these agents were confirmed. Curcumin was given orally at a dose of 200 mg/kg b. wt by gavage [28,29]. Rosemary was given at a dose of 220 mg/kg b. wt orally by gavage [30,31] and the propolis was given at a dose of 100 mg/kg b. wt orally by gavage [24]. ...
The kidney is a common target for toxic xenobiotics due to its capacity to extract and concentrate toxic substances by highly specialized cells and also, due to its large blood flow. Objective: The present work aimed to evaluate the effectiveness of different natural materials (curcumin, rosemary and propolis) against the histological and also biochemical alterations of gentamicin induced nephrotoxicity in guinea pigs. Materials and methods: 48 guinea pigs were used for this study and divided into 8 groups. The first 4 groups were control groups, the 5th group was the experimental and administered gentamicin at a dose of 100 mg/kg body wt for 10 days, and in the 6th , 7th , and 8th groups, gentamicin was co-administered with curcumin, rosemary, and propolis at the doses of 200 mg, 220 mg, and 100 mg/kg body wt respectively. The animals were sacrificed and the kidneys were dissected and specimens were obtained. The specimens were processed for light microscopic examinations. Blood samples were obtained for assessment of urea, creatinine and uric acid levels. Results: In gentamicin treated animals, there were structural changes. The proximal convoluted tubules showed degenerated epithelial lining with disruption of their brush borders and presence of epithelial debris inside their lumens. The renal corpuscle appeared with degeneration of the glomerulus and disrupted Bowman's capsule. The afferent arteriole showed thickening in its wall and degeneration of endothelial lining with extensive perivascular infiltration of inflammatory cells. Massive interstitial hemorrhage was seen. Also, the serum urea, creatinine, and uric acid were elevated. Co-administration of curcumin, rosemary, and propolis significantly improved the structural changes in the kidney and the blood urea, creatinine and uric acid were significantly declined. Conclusion: It can be concluded that, the gentamicin has adverse effects on the kidney. Different natural materials as curcumin, rosemary, and propolis were able to protect the kidney against these effects. So, the patients should be advised to take one of these materials while they are treated by gentamicin.
... Curcuma longa is another plant that has shown numerous theurapeutic properties which include antibilharzial [43], antidiabetics and antioxidant activities [44,45]. Curcumin gotten from powdered rhizomes of plant Curcuma longa Linn is ubiquitously used as a colouring agent in foods, cosmetics and drugs [46], as an antitumor agent [47]. It has also been shown to forestall gullblader sickness [48,49]. ...
Introduction: Medicinal plants have been the most productive source of leads for the development of drugs from ancient times. Current research in drug discovery involves a multifaceted approach combining botanical, biological, and molecular techniques. Medicinal plant based drug discovery continues to provide novel and important leads against several diseases. Methods: Relevant articles relating to the concept were identified using a combination of manual library search as well as journal publication on the subject and critically reviewed. Results: Drug discovery from medicinal plants continues to provide an important source of new drug leads however; numerous challenges are encountered including the procurement of plant materials and implementation of appropriate high-throughput screening bioassays. Medicinal plants have great prospect in the ultimate search for the cure against the dreaded coronavirus. Conclusion: It is hoped that the more efficient and effective application of medicinal plants would improve the drug discovery process against the dreaded coronavirus.
... Another study suggested that upregulation of both p53 and p21 in U266 cells exposed to curcumin is involved in cell cycle arrest [178]. Furthermore, curcumin decreased the expression of p53 and p21 in Wistar rats [179]. Resveratrol metabolites can promote a moderate cellular senescence induction in breast cancer cells, which involves inhibiting cell growth by G 2 /M phase arrest through the p53/p21Cip1/WAF1 pathway [180]. ...
Cancer arises through a complex interplay between genetic, behavioral, metabolic, and environmental factors that combined trigger cellular changes that over time promote malignancy. In terms of cancer prevention, behavioral interventions such as diet can promote genetic programs that may facilitate tumor suppression; and one of the key tumor suppressors responsible for initiating such programs is p53. The p53 protein is activated by various cellular events such as DNA damage, hypoxia, heat shock, and overexpression of oncogenes. Due to its role in cell fate decisions after DNA damage, regulatory pathways controlled by p53 help to maintain genome stability and thus “guard the genome” against mutations that cause cancer. Dietary intake of flavonoids, a C15 group of polyphenols, is known to inhibit cancer progression and assist DNA repair through p53-mediated mechanisms in human cells via their antioxidant activities. For example, quercetin arrests human cervical cancer cell growth by blocking the G2/M phase cell cycle and inducing mitochondrial apoptosis through a p53-dependent mechanism. Other polyphenols such as resveratrol upregulate p53 expression in several cancer cell lines by promoting p53 stability, which in colon cancer cells results in the activation of p53-mediated apoptosis. Finally, among vitamins, folic acid seems to play an important role in the chemoprevention of gastric carcinogenesis by enhancing gastric epithelial apoptosis in patients with premalignant lesions by significantly increased expression of p53. In this review, we discuss the role of these and other dietary antioxidants in p53-mediated cell signaling in relation to cancer chemoprevention and tumor suppression in normal and cancer cells.
... Rats were randomly divided into five groups (six rats for each) and were subjected to treatment as follows: (a) control naive group is the vehicle-treated group, (b) AD group received a single daily dose of AD 200 mg/kg dissolved in normal saline orally at 9 a.m. for 28 successive days to induce CRF [12], (c) CUR group was treated with a single daily dose of CUR 200 mg/kg dissolved in olive oil orally at 12 p.m. concomitant with AD 200 mg/kg/day dissolved in normal saline at 9 a.m. orally for 28 successive days [13], (d) sildenafil group was treated with a single daily dose of sildenafil 0.5 mg/kg dissolved in normal saline orally at 3 p.m. concomitant with AD 200 mg/kg/day dissolved in normal saline orally at 9 a.m. for 28 successive days [14], and (e) the combination group was treated with a combination of CUR (200 mg/kg/day) orally at 12 p.m. and sildenafil (0.5 mg/kg/day) orally at 3 p.m. concomitant with AD 200 mg/kg/day orally at 9 a.m. for 28 successive days. Initial and final body weight was measured for each rat. ...
... All groups received the treatment for seven consecutive days. The groups were shown as the following: Group 1 served as the control group, in which rats orally received only physiological saline and 1% carboxymethyl cellulose (CMC); Group 2: animals were received Lead diAC (100 mg kg -1 day -1 /Intra Peritoneal) (Mokhtari & Zanboori, 2011) and oral 1% CMC; Group 3: rats were received Lead diAC along with 200 mg/kg VIT-C dissolved in 1% CMC (Karabulut-Bulan et al., 2008); Group 4: rats were received Lead diAC along with TMRC dissolved in 1% CMC (200 mg kg -1 day -1 ) (Chuang et al., 2000); finally, Group 5: rats were treated with Lead diAC along with VIT-C (200 mg kg -1 day -1 ) and TMRC (200 mg kg -1 day -1 ). Both the antioxidants in question were taken by oral route. ...
Occupational and ecological contacts to lead persist as a universal concern. Lead alters most of the physiological processes via enhancing oxidative stress. Thus, this study was purposed to assess the influence of turmeric (TMRC) and/or vitamin C (VIT‐C) on Lead diacetate (Lead diAC)‐induced testicular atrophy with an emphasis on oxidative stress, inflammation, BAX/STAR and GRP‐78/17β‐HSD signalling. Rats were injected with Lead diAC and then treated with TMRC and/or VIT‐C orally for 1 week. Lead diAC decreased serum testosterone and testicular glutathione levels. It also decreased superoxide dismutase activity. On the contrary, levels of malondialdehyde, tumour necrosis factor‐α, IL‐1β and caspase‐3 were increased. mRNA levels and protein expressions of GRP‐78 and BAX were upregulated, while the expression of both steroidogenic acute regulatory protein and 17β‐HSD were downregulated. DNA fragmentation was increased as well. These changes were further confirmed by histopathological findings. Supplementation with TMRC and/or VIT‐C ameliorated all of the above parameters. In Conclusion: TMRC or VIT‐C specially in combination group prevents Lead diAC testicular damage via reduction of oxidative injury as well as inflammation, downregulation of GRP‐78/BAX and upregulation of 17β‐HSD and STAR expression as well as improvement in the histological architecture of the testis.
... The spicy Black cumin Nigella sativa has some potential as an anticancer agent [21,22]. Curcuma longa (Turmeric) is quite well-known as an anti-cancer herb [23][24][25]. Cinnamomum zeylenicum (Cinnamon bark) is able to induce apoptosis in cancer cell-lines [26,27]. Bacopa monnieri (Water hyssop) is possessing some cytotoxic effects [28,29]. ...
UNANI MEDICINE AND CANCER
Christer Sundqvist. Prepublished article, 2020
Petrafoundation, Helsinki, Finland https://www.petrafoundation.com/en/foundation
Unani medicine is an alternative medical system originating in ancient Greece almost 2500 years back. It is now practiced primarily in India. Herbal remedies, dietary practices and alternative therapies characterize Unani medicine. Let us study what it can offer for a cancer patient.
... One group of mice received a diet containing 0.2% curcumin, from 4 days prior to DENA injection until the end of the study. At the age of 42 weeks, the curcumin group exhibited an 81% reduction in the multiplicity and a 62% reduction in the incidence of hepatocarcinoma compared with the non-treated group 45 . In a phase II clinical study conducted in patients with advanced pancreatic cancer, curcumin was administered orally at the dose of 8 g/day for 8 weeks. ...
Cancer is one of the fastest growing diseases, with an estimated worldwide incidence of 10 million new cases per year. Mortality is high, with >7 million deaths per year. In the last two decades, great advances have been made in cancer therapy; however, the success rates still remain unsatisfactory. Current conventional anticancer therapies are associated with adverse effects, drug resistance, and cancer recurrence. In Unani system of medicine, Cancer is known as Sartān, an Arabic word which means "crab". In the classical Unani literature, Sartān (Cancer) has been mentioned with great description, causes, origin, expansion, metastasis and all of clinical presentations. Renowned physicians like Buqrat, Jalinoos, Razi, Ibn Sina, Tabri and Jurjani gave the details of Sartān and its management. Through this paper, an attempt has been made to highlight the strength of Unani medicine in Sartān.
... We have found that curcumin protected RPTEC/TERT1 cells against KBrO 3 induced deciliation. Another study showed that curcumin exerted an anti-proliferative effect via inhibition of cell cycle regulators of hepatic cells when they were exposed to diethylnitrosamine, a genotoxic carcinogen [73]. Blackmore et al. found that curcumin targeted colorectal cancer cells by arresting the G2/M Fig. (4). ...
Identification of the Multifaceted Chemopreventive Activity of Curcumin Against the Carcinogenic Potential of the Food Additive, KBrO3
... Animals were randomly divided into five groups. Group I (control): Rats were given corn oil orally for one week, Group II (Pb-acetate): Rats received Pb-acetate (100 mg/kg/ day i.p.) [10] for 7 days, Group III (l-ascb): Rats received l-ascb (250 mg/kg/day, orally) [11], Group IV (CRMN): Rats received CRMN in corn oil (200 mg/kg/day, orally) [12], Group V (l-ascb and CRMN): Rats received co-treatment of both CRMN& l-ascb. All treated groups were given concurrently with Pb-acetate for 7 days by oral route. ...
Background
Lead is a dangerous systemic toxicant and can provoke life-threatening renal injury. The plan of this study was to evaluate the potential impact of curcumin (CRMN) and l-ascorbic acid (l-ascb) alone or together to counteract lead acetate (Pb-acetate)-induced renal damage in rats and to find out the underlying mechanisms of action of these nutraceuticals.Methods
Pb-acetate (100 mg/kg/day, i.p.) was injected in male rats along with l-ascb (250 mg/kg/day) and/or CRMN (200 mg/kg/day) orally for 7 days.ResultsPb-acetate administration increased serum urea, creatinine and uric acid. Renal tissue showed a marked depletion in reduced glutathione level and superoxide dismutase activity and elevation in nitric oxide and malondialdehyde levels. Serum C-reactive protein and IL-1β levels were elevated. Up-regulation of the expression of kidney injury molecule, vascular adhesion molecule-1 and Cystatin C were noticed after Pb-acetate administration. DNA fragmentation was also increased in renal tissues. Histopathological examination revealed a destructed partial layer of Bowman’s capsule, proximal and distal convoluted tubules. Treatment with the aforementioned antioxidants ameliorated most of the altered measured biomarker levels.Conclusion
Interestingly, the combination of l-ascb and CRMN showed the superlative protective effect against Pb-acetate-induced nephrotoxicity.
... Received CUR (200 mg/ kg body weight [bw] /day) dissolved in corn oil and administered to animals orally by gastric gavage for 21 days [10] . ...
... It also inhibits c-Fos, c-Jun, and AP-1 activity (Pendurthi et al., 1997) a number of enzyme activities and kinases, i.e., protein kinase C, phosphorylase kinase, EGF receptor (EGF-R), erbB2, and ornithine decarboxylase (Korutla and Kumar, 1994). Cucurmin also affects a number of cell cycle protein's expression on the cells; these proteins are ras, p34 cdc2 , thymidine kinase, PCNA, cyclin E, p21 and Ki67 (Chuang et al., 2000). Additionally it also change the expression of proteins which are apoptosis related like p53, Bcl-2, and Bax (Anto, 2002;Choudhuri et al., 2002). ...
... 13 Groups IV (CM): rats were administered CuSO 4 and CM (80 mg/kg). 14 Group V (NCM): CuSO 4 and NCM: rats were administered CuSO 4 and NCM (80 mg/kg). All treatments were given orally simultaneously with CuSO 4 for 7 days. ...
Background
The consequences of excess copper in human tissue are the alterations in the oxidative stress markers and peroxidative damage of membrane lipids. Unselective copper binding may be the clue to damaging impact to protein construction and hence modifying their biological functions. The aim of this study is to match the hepatoprotective efficacy of curcumin (CM) or nanocurcumin (NCM) with that of desferrioxamine (DSF; standard heavy metal chelator) against toxic doses of copper sulphate (CuSO4).
Method
All treatments were given simultaneously with CuSO4 for 7 days.
Result
CuSO4 administration elevated serum alanine transaminase, and hepatic nitric oxide (NO), lipid peroxide, and caspase-3 as well as protein expression of cytochrome P4502E1, and nuclear factor-κB (NF-κB) and Bax gene expressions. On the other hand, hepatic levels of reduced glutathione, superoxide dismutase, and interleukin-10 were decreased, whereas DNA degradation was increased as well compared with the control group. The administration of the aforementioned antioxidants ameliorated all the previous altered measured parameters. Interestingly, NCM achieved the most pronounced hepatoprotective effect nearly equivalent to that of DSF.
Conclusion
It was concluded that NCM is considered a promising candidate against CuSO4 toxicity, and cytochrome P450, NF-κB, and Bax are involved in its toxicity and treatment.
... Polyphenol compounds have the ability to inhibit the proliferation of different types of cancer such as prostate, bladder, lung, gastrointestinal, breast, and ovarian cancers [154]. For instance, quercetin, resveratrol, green tea polyphenols [185], epigallocatechin-3-gallate [186], and curcumin [187] have demonstrated efficacy as anticancer compounds. Several studies reported that polyphenols are able to prevent cancer initiation (cyto-protective), progression, recurrence, and metastasis to distant organs (cytotoxic) as per different epidemiological, in vitro, and in vivo studie [188][189][190]. ...
This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines’ synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes’ expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.
... All in all, studies by different scientists have shown that curcumin inhibits skin (Conney et al. 1991;Lu et al. 1994;Limtrakul et al. 1997;Huang et al. 1997b), forestomach Piper et al. 1998), liver Chuang et al. 2000), and mammary carcinogensis (Singletary et al. 1996;Chan et al. 1998;Inano et al. 1999); B-and T-cell leukemia Kuo et al. 1996;Abe et al. 1999;Han et al. 1999;Piwocka et al. 1999); epidermoid carcinoma (Korutla and Kumar 1994); breast carcinoma Mehta et al. 1997;Simon et al. 1998;Ramachandran and You 1999); multiple myeloma ; and cervical, pancreatic, prostrate, and gastric cancers . ...
Medicinal plants possess chemical constituents and produce secondary metabolites having countless benefits regarding various ailments. The extract of these plants can act as anti-inflammatory, antioxidative, anti-allergic, anti-cancerous, analgesic, and antidiabetic. Due to these medicinal properties, these plants have been used since centuries for the cure and prevention of different kind of diseases. Derivatives from the medicinal plants and their extracts are effective in small amounts, economical, and safe to use, with negligible side effects. Moreover, medicinal plants are easily accessible and have better compatibility. Review of the literature proves that countless medicinal plants have been exploited for their antitumor as well as anticancer potential. This chapter intends to focus on these plants showing medicinal effects against cancer and tumor. The chapter digs into the detail methodologies through which daily usage plants can be explored for medicinal purposes, the preparation of extracts, and the physiological responses of body towards these extracts.
... Curcumin, a small molecular polyphenol compound, isolated from the turmeric longa rhizome, has received attention as a potential treatment for renal fibrosis. It is a relatively safe and inexpensive compound that contributes to kidney health (Trujillo et al., 2013), and is regarded as a natural potent antioxidant with other pharmacological properties, such as antitumor, anti-inflammation and anti-fibrosis (Chuang et al., 2000). Curcumin treatment could interfere several targets of TGF-β/ Smad signaling pathway in UUO rats, inhibit the occurrence of EMT in renal tubular epithelial cells and attenuate the TIF (Trujillo et al., 2013). ...
... We have found that curcumin protected RPTEC/TERT1 cells against KBrO 3 induced deciliation. Another study showed that curcumin exerted an anti-proliferative effect via inhibition of cell cycle regulators of hepatic cells when they were exposed to diethylnitrosamine, a genotoxic carcinogen [73]. Blackmore et al. found that curcumin targeted colorectal cancer cells by arresting the G2/M Fig. (4). ...
Background: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models Objectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity. Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8-OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. Results: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while upregulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. Conclusion: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.
... Monoclonal antibody, anti-angiogenesis Constipation, headache, abdominal pain, weakness, nose bleed, low blood count, high blood pressure [113] vis-à-vis activation of tumor suppressor protein p53 in the curcumin-treated HepG2 cells [27]. In a rat model of diethylnitrosamineinduced HCC, dietary supplementation of curcumin was found to be very effective in suppressing the induced liver inflammation, hyperplasia and hepatocarcinogenesis [126]. With low doses of curcuminoids of 10µM concentration, the anti-tumor inhibitory role of curcuminoids has been reported [127]. ...
Background:
Liver cancer is the fifth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Among the liver cancers, hepatocellular carcinoma has been reported to be responsible for 85-90% of primary liver cancer and it is the second most common cause of cancer mortality with 700,000 deaths documented annually. The major risk factors of HCC include chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) virus, chronic liver diseases, alcoholism as well as dietary carcinogens, such as aflatoxins. Highest incidence rates are estimated to occur in Asia and Africa.
Objective:
The effectiveness of current man-made agents in treating chronic liver disease is not satisfactory and they have uninvited side effects. Herbal medicines are extensively used all over the world; however, there is still a vast gap in their acceptance by the scientific community. Plants are rich in secondary metabolites and phytochemicals obtained from both, dietary and non-dietary sources. Natural plant products are potent therapeutic as well as chemopreventive agents for numerous chronic diseases like cardiovascular, metabolic, neurodegenerative and neoplastic diseases.
Results:
Dietary phytochemicals such as curcumin, resveratrol, quercetin, silibinin, N-trans-feruloyl octopamine, lycopene, emodin, caffeine, urolithin A and Phloretin have been found to be useful for the treatment of HCC and other diseases. According to recent reports 60% of the anticancer medication in current use has been obtained from natural sources.
Conclusion:
Thus, derivatives from plants have played an essential role in cancer prevention due to their pleiotropic abilities to scavenge free radicals, inhibit cell growth and induce apoptosis.
... Previous studies have shown that Curcumin, can reverse the hypermethylation state of crucial genes in cervical, breast and prostatic cancers (Jha et al., 2010;Shu et al., 2011;Kumar et al., 2017). Importantly, Curcumin has been shown to possess anti-HCC properties in vitro and in animal studies as revealed by Chuang et al. (2000) and Mann et al. (2009). However, its exact mechanism of action in the control of HCC is still not well-elucidated. ...
Worldwide, hepatocellular carcinoma (HCC) is the major subtype of primary liver cancers. HCC is typically diagnosed late in its course. With respect to cancer, the genomic actions of vitamin D are mediated through binding to the Vitamin D Receptor (VDR), which allows it to modulate the expression of genes in a cell-and tissue-specific manner. Epigenetics is a rapidly evolving field of genetic study applicable to HCC. Changes in DNA methylation patterns are thought to be early events in hepatocarcinogenesis. Curcumin has great potential as an epigenetic agent. Accordingly, the current study has been designed to study the methylation status of VDR gene promoter for the first time in HCC aiming to find its clinical significance and potential screening role in chronic Liver Disease (CLD). Additionally, we aimed to investigate, the effect of Curcumin on HCC cell line, aiming to discover new therapeutic targets through epigenetics. This study was conducted on 45 formalin-fixed, paraffin-embedded liver tissue blocks including 15 HCC samples (group A), 15 CLD samples (group B) and 15 apparently normal tissue taken from around benign lesions (group C). Methylation Specific Restriction Digestion and qPCR were done on all samples after DNA extraction. The percentage of VDR gene promoter methylation was significantly higher in the HCC group compared to both CLD and control groups (p ˂ 0.01). VDR promoter methylation by (MS-qPCR) was decreased and the relative expression of VDR by (qRT-PCR) was markedly increased in a dose-dependent fashion in cells grown in Curcumin-adequate medium. In conclusion, this study may open a new gate for the use of VDR promoter methylation as a potential biomarker in HCC.
... We have found that curcumin protected RPTEC/TERT1 cells against KBrO 3 induced deciliation. Another study showed that curcumin exerted an anti-proliferative effect via inhibition of cell cycle regulators of hepatic cells when they were exposed to diethylnitrosamine, a genotoxic carcinogen [73]. Blackmore et al. found that curcumin targeted colorectal cancer cells by arresting the G2/M Fig. (4). ...
Background:
Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models Objectives: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity Method: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8-OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3.
Results:
Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while up-regulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin.
Conclusion:
Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.
... phaeocaulis. The administration of 200mg/Kg curcumin suppressed diethyl nitrosamine-induced liver inflammation and hyperplasia in rats [83]. Such effects are due to the inhibition of lipoxygenase enzyme [84]. ...
Cancer is a major cause of death both in developed and developing countries. Among the various types of cancers, primary liver cancer represents about 4% of all cancers worldwide. Hepatocellular carcinoma (HCC) is a histological type of liver cancer; the fact being that the aspects related to the development of hepatocellular carcinoma and its metastasis are not yet known, and here animal models play an important role in diagnosis, prognosis, and treatment strategies of the disease. Animal models also provide an opportunity to explore new treatment strategies. N-nitroso compounds mainly N-diethylnitrosamine (DEN) is a hepatic carcinogen, which is well known to cause liver necrosis. The current review is based on research and review of works on animal models treated with DEN-induced hepatocarcinogenesis. Despite ongoing debate, animal models could provide valuable information about biotransformation of toxicants and how they worsen the damaging effects on DNA and cell proteins that result in the development of cancer. Today, the emergence of various therapies that target the immune system and the tumor microenvironment emphasizes the importance of the host, conditions of chronic inflammation, and fibrosis. Thus, the use of animal models for anti-HCC drug screening will find our best ability to successfully discover new drugs to combat HCC.
Gastrointestinal (GI) cancers are one of the most common human malignancies and a leading cause of morbidity and mortality worldwide. One of the most prominent hallmarks of cancer and a basic trait of almost all GI malignancies is genomic/epigenomics alterations. DNA methylation is highlighted as a fundamental mechanism underlying the inactivation of several tumor-suppressor gene signaling pathways. Thus, sites of DNA methylation can be triggered for cancer therapy. Available therapeutic procedures for GI cancer show unsatisfactory efficacy, and some treatments are associated with severe side effects, including ulceration or bleeding. Therefore, it is essential to find alternative treatments. There is growing evidence indicating that some chemopreventive phytochemicals can combat cancer. One of the most systematically investigated nutraceuticals for its advantages in managing different diseases is curcumin (CUR). CUR is well known for its potent anticancer characteristics by targeting epigenetic mechanisms, with DNA methylation at the forefront. Prior investigations have indicated that CUR treatment can benefit GI cancers by controlling several signaling pathways related to oxidative stress and epigenomics pathways. The present literature displays recent evidence regarding DNA methylation alterations by CUR and its potential role in GI cancer prevention and treatment.
Cisplatin is an effective antineoplastic drug which is used to treat many types of cancer. The most common known side effect of this drug is infertility. Curcumin, also called turmeric, has antioxidant and antitumor activities. This study was designed to investigate the effects of curcumin on the changes in spermatogenetic cells caused by cisplatin, which is used as a chemotherapeutic drug especially in testicular cancers. For this purpose, randomly selected 36 Spraque Dawley rats were seperated to 4 groups that of control, cisplatin, curcumin and curcumin+cisplatin and each group was seperated to 3 subgroups, each of them have 3 rats, so total 12 subgroups were obtained. The testicular tissues obtained from rats were evaluated histochemically, immunohistochemically and ultrastructually. In the results of this study, it is observed that the rate of apoptosis increased significantly in the experimental groups given curcumin together with cisplatin injection, and the transition-1 protein which is involved in DNA packaging in the elongated spermatids belonging to stages of XII, XIII an XIV, immunopositivity is increased statistically in the cisplatin-administered experimental groups compared to control groups. Both light and electron microscopic findings showed that intense degeneration, vacuolization, germ cell loss and spermatogenetic arrest occurred especially in the group given curcumin together with cisplatin. The results of our study showed that cisplatin can cause problems in infertility through DNA packaging and dragging cells to apoptosis and necrosis. Physicians who use cisplatin for cancer treatment are advised not to use curcumin together with cisplatin because it exacerbates the side effects of the cancer drug.
Excessive and uncontrolled oxidative stress can damage biomacromolecules, such as lipids, proteins, carbohydrates, and DNA, by free radical and oxidant overproduction. In this review, we critically discuss the main properties of free radicals, their implications in oxidative stress, and specific pathological conditions. In clinical medicine, oxidative stress can play a role in several chronic noncommunicable diseases, such as diabetes mellitus, cardiovascular, inflammatory, neurodegenerative diseases, and tumours. Antioxidant supplements can theoretically prevent or stop the progression of diseases, but a careful literature analysis finds that more evidence is needed to dissect the ultimate beneficial effect of antioxidants versus reactive oxygen species in several diseases.
This study aims to evaluate in vivo protective effects of eumelanin (EU) on diethylnitrosamine (DEN)-induced liver injury. Wistar albino male rats were divided into 6 groups (n=6), Control, DMSO, DEN, DEN+EU10, DEN+EU15, and DEN+EU20. Animals in the DEN group were injected i.p a single dose of 200 mg/kg DEN, DEN+EU10 group was given 10 mg/kg EU, DEN+EU15 group was given 15 mg/kg, DEN+EU20 group was given 20 mg/kg EU for a week. The results showed that there was no significant difference in vessel volume density between the groups. Inflammatory cell infiltration, hydropic degeneration, and necrotic cells were observed in the DEN group, and these histopathological changes were significantly reduced in all treatment groups. Although there was a low intensity of PAS-positive staining in the DEN groups, moderate staining was observed in the treatment groups. While Caspase-3, PCNA, TNF-α, and IL-6 expressions increased in the DEN group, their expressions decreased in the EU-treated groups. DEN increased AST, ALT, and MDA levels and decreased CAT levels. In particular, the EU10 dose significantly improved these parameters. The present study revealed that eumelanin has protective effects against DEN-induced liver injury.
Physiological roles of copper in metabolic homeostasis have been well established, however, whether and how copper is dysregulated in tumors and contributes to tumorigenesis are not recapitulated. Here, we comprehensively summarize the potential origins of copper accumulation in diseases especially in cancers by dysregulating copper transporter 1 (CTR1) or ATPase copper transporting alpha/beta (ATP7A/B) and further demonstrate the underlying mechanism of copper contributing to tumorigenesis. Specifically, in addition to modulating reactive oxygen species (ROS), angiogenesis, immune response, and metabolic homeostasis, copper recently has drawn more attention by directly binding to oncoproteins such as MEK, ULK, Memo, and PDK1 to activate distinct oncogenic signals and account for tumorigenesis. In the end, we disclose the emerging applications of copper in cancer diagnosis and highlight the promising strategies to target the copper-CTR1 axis for cancer therapies.
Liver is an important organ of human body involved in the regulation of several physiological processes including lipolysis, glycogenolysis, drug detoxification, emulsification of food, and urea formation. Liver diseases including cancer, reduce its functional rate and damage tissue completely. It is found that liver cancer (hepatocellular carcinoma) is a second leading disease causing death worldwide. Carcinoma develops in the hepatocytes of liver or due to migration of cancer cells from other tissue tumors at metastatic stage. These malignant hepatic cells are dangerous and grow faster. The uncontrollable large tumors in liver cause inflammation, cirrhosis, and finally failure of liver functions. Methods in curing cancer often show side effects besides deteriorating the health. Various types of treatments using different nature medicine are in use against hepatocellular carcinoma. Among all, plant-based anticancer pharmaceuticals hold great importance in treating or preventing lung cancer without or less side effects. The present review emphasizes the basics of liver cancer and available natural compounds from plants and their role in antihepatocellular carcinoma.
Background and objectives
N-(4-hydroxyphenyl) acetamide (NHPA) is the most commonly used analgesic and antipyretic agent worldwide; however, it remains the leading cause of drug-induced acute liver failure. This study explored the potential impact of curcumin (Curc) and/or α-lipoic acid (Lip acid) on liver damage induced by NHPA overdose.
Materials and Methods
Male Wistar rats were intoxicated with a single oral dose of NHPA (1000 mg/kg) and treated with Curc (200 mg/kg p. o.) and/or Lip acid (100 mg/kg i. p.). These treatments were given in 2 doses at 2 hours and 10 hours post-NHPA-administration. Animals were sacrificed 24 hours post-NHPA-administration.
Results
Treatment with Curc and/or Lip acid showed effective reduction of NHPA-induced liver injury, demonstrated by reducing serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, as well as hepatic nitric oxide and malondialdehyde. Curc and/or Lip acid treatments counteracted these changes. They also ameliorated NHPA-induced centrilobular hepatocellular necrosis, evidenced by histopathological examination. Moreover, Curc and Lip acid reduced the expression of alpha-smooth muscle actin and collagen III, upregulated by NHPA intoxication in response to oxidative stress and inflammation.
Discussion and Conclusion
Curc and Lip acid can be considered as promising natural therapies against liver injury, induced by NHPA, through their antioxidant and antifibrotic actions.
A lot of advancements have taken place in the wound dressing materials and in wound healing process. Alginate based wound dressings materials are more preferable due to their biocompatibility and non-toxic unique biological characteristics. There’s always a need to increase the efficacy of alginates by combining with other biopolymers like chitosan, collagen and cellulose etc. However, the recent trend towards the natural and herbal bio-compounds are more likely attracting to develop alginate based wound dressing materials with higher efficiency, antimicrobial and anti-inflammatory potency. Out of many natural compounds tested, curcumin has shown high potency and more effectively used for wound healing purpose. Due to curcumin’s bio-medical properties it has been used as a vital ingredient combined with alginate and other biopolymers to prepare wound dressing materials. Based on the available literatures, this review chapter on alginate-curcumin nanocomposite will help the reader to develop better wound healing materials with evolutionary therapeutic applications.
Epidemiological evidence indicates that a diet rich in fruits and vegetables lowers the risk of certain cancers. The cancer-lowering effect of fruits and vegetables is attributed, in part, to several compounds such as nondigestible polysaccharides, polyphenols present in these foods. Plant polyphenols are an integral part of the human and animal diet. The anticarcinogenic polyphenols act in various roles such as antioxidant, antiinflammatory, and the modulation of multiple pathways involved in tumor progression. Polyphenol classes such as flavonoids, phenolic acids, lignans, and stilbenes have anticarcinogenic properties. The polyphenols kill cancer cells and prevent metastasis by modulating DNA damage, cell cycle arrest, disruption of mitochondrial membrane, and nitric oxide production. This chapter describes the anticarcinogenic effects of polyphenols on cancer prevention and treatment.
DOI: 10.9734/bpi/ctmmr/v1
Purpose: The aim of our study was to assess the clinical effectiveness of topical adipose derived stem cell (ADSC) treatment in laser induced corneal wounds in mice by comparing epithelial repair, inflammation and histological analysis between treatment arms. Methods: Corneal lesions were performed on both eyes of 40 mice by laser induced photorefractive keratectomy. All eyes were treated with topical azythromycin bid for 3 days. Mice were divided in three treatment groups (n = 20), which included: Control, stem cells and basic serum; which received topical treatment 3 times daily for 5 consecutive days. Biomicroscope assessments and digital imaging were performed by two masked graders at 30, 54, 78, 100 and 172 h to analyze extent of fluorescein positive epithelial defect, corneal inflammation, etc. Immunohistochemical techniques were used in fixed eyes to assess corneal repair markers Ki67, α Smooth Muscle Actin (α-SMA) and E-Cadherin. Results: The fluorescein positive corneal lesion areas were significantly smaller in the stem cells group on days 1 (p < 0.05), 2 (p < 0.02) and 3. The stem cell treated group had slightly better and faster re-epithelization than the serum treated group in the initial phases. Comparative histological data showed signs of earlier and better corneal repair in epithelium and stromal layers in stem cell treated eyes, which showed more epithelial layers and enhanced wound healing performance of Ki67, E-Cadherin and α-SMA. Conclusions: Our study shows the potential clinical and histological advantages in the topical ADSC treatment for corneal lesions in mice.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death worldwide. Oxidative stress contributes significantly to HCC pathogenesis. In this study, we investigated the possible chemoprotective effect of the thiol group‐containing compound, tiopronin, against HCC induced chemically by diethylnitrosamine (DENA) in rats. In addition, we elucidated the possible underlying molecular mechanism. Adult male Wistar rats were divided into: Control group, DENA treated group and tiopronin + DENA treated group. Liver function tests (ALT, AST, ALP, albumin, total and direct bilirubin) as well as alpha fetoprotein (AFP) concentration were measured in the sera of samples. Oxidative stress biomarkers such as malondialdehyde, nitric oxide, catalase and glutathione peroxidase were measured in the liver tissue homogenates. Determination of the phosphorylated apoptosis signal‐regulating kinase 1 (phospho‐ASK1), phospho‐P38 and phospho‐P53 proteins by Western blotting, Caspase 3 by immunofluorescence in addition to histopathological examination of the liver tissues were performed. Our results showed that tiopronin prevented the DENA‐induced elevation of the liver function enzymes and AFP. It also preserved the activities of antioxidant enzymes as well as protected from the appearance of HCC histopathological features. Interestingly, tiopronin significantly decreased the expression level of phospho‐ASK1, phospho‐P38 and phospho‐P53, Caspase 3 in the liver tissues. These novel findings suggested that tiopronin is an antioxidant drug with a chemoprotective effect against DENA induced HCC through maintaining the normal activity of ASK1/ P38 MAPK/ P53 signaling pathway.
As our understanding of the science and functions of color in food has increased, the preferred colorants, forms of use, and legislation regulating their uses have also changed. Natural Colorants for Food and Nutraceutical Uses reflects the current tendency to use natural pigments. It details their science, technology, and applications as well as their nutraceutical properties. Starting with the basics, the book creates an understanding of physical colors, discusses color measurement, and analyzes why natural pigments are preferred today. The authors present an overview of global colorants, including safety, toxicity and regulatory aspects. Information about inorganic and synthetic colorants is included. The book then focuses on applications of natural colorants, with special attention given to characteristics, extraction and processing stability, and the use of biotechnology and molecular biology to increase colorant production. Finally, the book examines the nutraceutical properties of natural colorants and compares them to other well-known nutraceutical components. From the basics to highly specialized concepts and applications, Natural Colorants for Food and Nutraceutical Uses presents essential, practical information about pigments in the food industry. With its coverage of state-of-the-art technologies and future trends in the application of color to food, this book provides the most comprehensive, up-to-date survey of the field.
Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus which has attracted attention for its anti-inflammatory and anti-cancer activities. The aim of this study was to evaluate the anti-cancer effect of neferine against diethylnitrosamine (DEN)-induced lung carcinogenesis in Wistar rats and to explore the underlying molecular mechanism. DEN-induced oxidative stress is mediated by alterations in the levels of pulmonary reactive-oxygen species, lipid peroxidation, protein carbonyl content and antioxidant status. Thus, treatment with neferine restored cellular normalcy, highlighting the antioxidant potential of neferine in mitigating the oxidative stress-mediated damage produced during DEN-induced lung carcinogenesis. Histopathological analysis showed disorganized alveolar structure, thickened alveolar wall, infiltration of inflammatory cells in DEN-induced rats, the damage was significantly reduced upon neferine treatment. DEN-induced rats exhibited increased gene expression of NF-κB, COX-2, CYP2E1, VEGF, Bcl-2, PI3K/AKT/mTOR and significantly decreased the gene expression of p53, Bax, caspase-9 and caspase-3. Neferine treatment restored the DEN- induced alteration of these gene expression levels. Further, blotting analysis also revealed increased expression of NF-κB, COX-2, Bcl-2 and decreased expression of Bax, caspase-9 and caspase-3 proteins in DEN-induced rats. Neferine treatment restored the expression of these proteins in DEN- induced lung carcinogenesis.
The rising bacterial infection severely threatens human health and has already become a worldwide issue. Safe, green and efficient antibiotics are urgently needed. Curcumin is well known as a natural and green food additive, and has effective biological and pharmaceutical activity. To overcome its hydrophobic disadvantage, here, tannic acid and metal coordination were used to coat curcumin nanoparticles (NPs) for the antibacterial application. On the one hand, the coating method produced a high drug loading content. On the other hand, the involvement of metal ions enhanced the bacterial inhibition efficiency compared to curcumin and metal ions alone. Especially for S. aureus, the minimum inhibitory concentration of copper containing complex NPs was 7.5 times lower than that curcumin alone. Thus, our research provides a natural and green antibiotics system to effectively prevent bacterial infections, and has potential to be widely produced in industry due to the naturally derived raw materials.
Le curcuma provient du rhizome séché et broyé d'une plante de la famille des Zingiberaceae. Cette plante herbacée, Curcuma longa, est cultivée en Inde et en Asie du Sud-est. L'Inde est le plus grand producteur et le plus grand consommateur de curcuma au monde.Par contre, en Occident, en dehors de ses usages médicinaux et tinctoriaux, son emploi n'a jamais été très répandu. Son emploi, en Asie, en Afrique et au Proche et Moyen-Orient, remonte à plus de 4000 ans. Dès cette époque, le curcuma est utilisé en tant qu'épice, mais aussi comme agent de coloration de plusieurs aliments, tel que le curry, de même que dans la production de cosmétiques, de teintures et de médicaments.La couleur jaune du curcuma provient d'un mélange de pigments phénoliques, les curcuminoïdes. La teneur en curcuminoïdes dans la poudre de curcuma est d'environ 5%. Ce mélange de composés phénoliques se compose de 70 à 75% de curcumine, de 15 à 20% de diméthoxycurcumine et de 3 à 5% de bisdiméthoxycurcumine. De ces trois curcuminoïdes, c'est la curcumine qui présente les propriétés pharmacologiques les plus intéressantes.Dans la médecine indienne traditionnelle, le curcuma est employé comme remède contre la toux, les désordres biliaires, l'anorexie, les plaies des diabétiques, les désordres hépatiques, les rhumatismes et les sinusites.Plus récemment, des études, effectuées in vitro et in vivo, ont montré que la curcumine possédait des activités biologiques intéressantes pour la santé humaine incluant un effet antioxydant, anti-inflammatoire et anti-cancer.Depuis ces dix dernières années, le nombre d'études sur le curcuma et surtout sur son constituant majeur, la curcumine, n'a cessé d'augmenter afin de comprendre ses mécanismes d'actions et dans l'espoir de traiter de nombreuses maladies. Des siècles d'utilisation ont montré son innocuité et les premières études cliniques n'ont rapporté aucun effet secondaire. Enfin, de fil en aiguille, les recherchessont passées des laboratoires à la clinique, et la curcumine devrait trouver une application en tant que nouveau médicament dans un futur proche pour contrôler des maladies variées, notamment les désordres inflammatoires, le cancer, et lespathologies causées par le stress oxydatif.
Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released
by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes,
and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch
model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with
that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines
in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting
that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released
by human T lymphotropic virus (HTLV)-1–infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx
production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest
because circulating Trx levels are elevated in inflammatory diseases and HIV infection.
Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level.
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Human epidemiological and laboratory animal model studies have suggested that nonsteroidal antiinflammatory drugs reduce the risk of development of colon cancer and that the inhibition of colon carcinogenesis is mediated through the alteration in cyclooxygenase metabolism of arachidonic acid. Curcumin, which is a naturally occurring compound, is present in turmeric, possesses both antiinflammatory and antioxidant properties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to investigate the chemopreventive action of dietary curcumin on azoxymethane-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phospholipase C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 weeks of age, all animals, except those in the vehicle (normal saline)-treated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. All groups were continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phospholipase C gamma 1, ex vivo prostaglandin (PG) E2, cyclooxygenase, and lipoxygenase activities. The results indicate that dietary administration of curcumin significantly inhibited incidence of colon adenocarcinomas (P < 0.004) and the multiplicity of invasive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus noninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also significantly suppressed the colon tumor volume by > 57% compared to the control diet. Animals fed the curcumin diet showed decreased activities of colonic mucosal and tumor phospholipase A2 (50%) and phospholipase C gamma 1 (40%) and levels of PGE2 (> 38%). The formation of prostaglandins such as PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2 through the cyclooxygenase system and production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the lipoxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control diet. Although the precise mechanism by which curcumin inhibits colon tumorigenesis remains to be elucidated, it is likely that the chemopreventive action, at least in part, may be related to the modulation of arachidonic acid metabolism.
The modifying effects of two natural products, curcumin and hesperidin, given during the initiation and postinitiation phases of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats and compared with that of beta-carotene. At 6 weeks of age, rats were divided into experimental and control groups and fed the diet containing beta-carotene, hesperidin, or curcumin at a dose of 0.5 g/kg diet (500 ppm). At 7 weeks of age, all animals except those treated with each test chemical alone and control groups were given 4-NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Seven days after the 4-NQO exposure, groups of animals fed the diets containing test chemicals were switched to the basal diet and continued on this diet until the end of the study. Starting 1 week after the stop of 4-NQO exposure, the groups given 4-NQO and a basal diet were switched to the diets containing beta-carotene, hesperidin, and curcumin and maintained on these diets for 22 weeks. The other groups consisted of rats given 500 ppm beta-carotene, hesperidin, or curcumin alone or untreated rats. All animals were necropsied at the termination of the experiment (week 32). The incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated by bromodeoxyuridine-labeling index and by morphometric analysis of silver-stained nucleolar organizer region proteins were compared among the groups. Feeding of curcumin and beta-carotene during the initiation and postinitiation phases and hesperidin at the initiation stage caused a significant reduction in the frequency of tongue carcinoma (41-91% reduction, P < 0.05) and the order of chemopreventive efficacy was curcumin > beta-carotene > hesperidin. The incidences of oral preneoplasia in rats fed the diets mixed with these compounds were also decreased (P < 0.05). There were no such lesions in rats treated with test compounds alone or those in an untreated control group. Dietary administration of these compounds significantly decreased the labeling index of bromodeoxyuridine and the number and area of silver-stained nucleolar organizer region proteins per cell nucleus that are proliferation biomarkers, of the tongue squamous epithelium (P < 0.05). In addition, polyamine levels in the oral mucosa were lowered in rats treated with 4-NQO and three test compounds when compared to those give 4-NQO alone (P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Curcumin and quercetin were evaluated in rats for their ability to modulate the carcinogenic activity of azoxymethane (AOM) in the colon and 7,12-dimethylbenz[a]anthracene (DMBA) in the mammary gland. In the AOM-induced colon cancer model, male Fischer 344 rats at 8 weeks of age started to receive either curcumin (8 and 16 g/kg) or quercetin (16.8 and 33.6 g/kg) in the diet and 1 week later, were administered AOM (30 mg/kg body wt.) by subcutaneous injection. The animals continued to receive the two agents in the diet until sacrificed 45 weeks later. Curcumin mediated a dose-dependent inhibition of the incidence and multiplicity of adenomas from 47% and 0.58 +/- 0.12 adenomas/rat in the AOM-treated control group to 19% and 0.22 +/- 0.08 and 0.06% and 0.08 +/- 0.06 adenomas/rat for the low and high dose groups, respectively. A low yield of adenocarcinomas (0.06 +/- 0.04 adenocarcinomas/rat) was induced by AOM which was not significantly altered by curcumin. Treatment with quercetin caused a dose-dependent increase in the yield of AOM-induced tumors in the colon from 0.06 +/- 0.04 adenocarcinoma/rat to 0.64 +/- 0.12 and 1.14 +/- 0.17 for the low and high dose groups, respectively. In the DMBA-induced mammary cancer model, curcumin or quercetin was administered at either 10 or 20 g/kg diet, beginning 7 days prior to DMBA and continually throughout the remainder of the experiment. Neither curcumin nor quercetin significantly altered the incidence of animals with tumors or the tumor multiplicity, while the high concentration of both agents significantly increased tumor latency. These results demonstrate different responses to these agents in the two models. While curcumin was highly effective as a chemopreventive agent in the colon model, it was only weakly effective in the mammary model. In contrast, quercetin which was also only weakly effective in the mammary model, caused a dose-dependent enhancement of tumors induced by AOM in the colon model.
Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl-3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 640 ppm of PHITC. At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis. In the current study, chronic administration of sulindac, curcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary PHITC blocked the process of apoptosis during colon carcinogenesis. The apoptotic index in PHITC diet was 7.0%. Taken together, our data show that chemopreventive properties of agents are correlated with the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.
Curcumin is a beta-diketone constituent of the spice turmeric that possesses anticarcinogenic properties in several animal models. The present studies were conducted in order to identify beta-diketones structurally-related to curcumin that would be effective dietary blocking agents toward the initiation stage of 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Of the beta-diketone compounds initially screened for their capacity to induce quinone-reductase (QR) activity in wild-type Hepa1c1c7 cells and a mutant subclone, curcumin (diferuloylmethane) and dibenzoylmethane were most effective. However, when added to semipurified diets fed to female rats, dibenzoylmethane (1%), but not curcumin (1%), was effective in inhibiting in vivo mammary DMBA-DNA adduct formation. This inhibitory effect on mammary adduct formation was associated with a significant increase in liver activities of glutathione S-transferase, QR and 7-ethoxyresorufin-O-deethylase activities. Female rats provided diets supplemented with dibenzoylmethane at 0.1, 0.5 and 1.0% for 14 days prior to dosing with DMBA exhibited a significant decrease in mammary tumor development, compared with controls. However, tumor development for animals fed diets containing 1.0% curcumin was not different from that of controls. Therefore, dibenzoylmethane, and possibly other structurally-related beta-diketones, warrant examination as breast cancer chemopreventative blocking agents.
Curcumin (diferuloylmethane), the major yellow pigment in turmeric, has been shown to inhibit benzo[a]pyrene (BaP)-induced forestomach cancer in mice through mechanism(s) not fully understood. It is well known that while cytochrome P4501A1 (CYP1A1) and epoxide hydrolase (EH) are important in the conversion of BaP to its activated form, (+)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BaPDE], the detoxification of (+)-anti-BaPDE is accomplished by glutathione (GSH) S-transferases (GST). Therefore, it seems reasonable to postulate that curcumin may exert anti-carcinogenic activity either by inhibiting activation of BaP or (and) by enhancing the detoxification of (+)-anti-BaPDE. Administration p.o. of 2% curcumin in the diet to female A/J mice for 14 days, which has been shown to cause a significant inhibition in BaP-induced forestomach tumorigenesis, resulted in a modest but statistically significant reduction in hepatic ethoxyresorufin O-deethylase (EROD) activity, a reaction preferentially catalyzed by CYP1A1. While EROD activity could not be detected in the forestomach of either control or treated mice, curcumin feeding caused a statistically significant increase (approximately 2.3-fold) in hepatic EH and GST activities. Hepatic and forestomach GSH levels, and forestomach EH and GST activities were not affected by curcumin treatment. Even though the levels of various hepatic GST isoenzymes were significantly increased upon curcumin feeding, maximum induction was noticed for the pi class isoenzyme (mGSTP1-1), which among murine hepatic GSTs is highly efficient in the detoxification of (+)-anti-BaPDE. In conclusion, the results of the present study suggest that curcumin may inhibit BaP-induced forestomach cancer in mice by affecting both activation as well as inactivation pathways of BaP metabolism in the liver.
Reactive free radical species are known to trigger biochemical events culminating in transcription factor activation and modulation of gene expression. The cytosolic signaling events triggered by free radicals that result in nuclear responses are largely unknown. Here we identify a signaling cascade triggered immediately upon redox activation of Ras. We examined two physiologically relevant models of redox signaling: 1) nitric oxide in human T cells, and 2) advanced glycation end product in rat pheochromocytoma cells. Reactive free radical species generated by nitric oxide donors and the interaction of advanced glycation end product with its receptor led to the recruitment of p85/p110 phosphatidylinositol 3'-kinase (PI3K) to the plasma membrane, where it associated directly with the effector domain of Ras and became activated. Only the p110beta and p110delta (but not p110alpha) catalytic subunits were recruited by redox-activated Ras. Activation of downstream targets of PI3K such as protein kinase B/Akt and mitogen-activated protein kinase was found to be PI3K dependent. Our study demonstrates that nitrosative and oxidative stressors trigger Ras-dependent and PI3K-regulated events in cells and define a biochemical pathway that is triggered by redox signaling.
Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme responsible for DNA strand breaks, has been recently suggested to be crucial for apoptosis induced by a number chemotherapeutic drugs. In this study, we demonstrated that the PARP activity could be evidently elevated with a peak at 6 h when HL-60 cells were treated with a new anticancer drug GL331. Coincident with the peak of PARP activity, an apparent DNA fragmentation and apoptotic morphology were observed in cells treated with GL331. The subsequent apoptotic DNA fragmentation induced by GL331 could be completely blocked by transfecting cells with anti-sense PARP retroviral vector or by treating cells with PARP inhibitor, 3-aminobenzamide (3-AB). This blocking effect thus suggests that activation of PARP was critically involved in GL331-induced apoptosis. The fact that Bcl-2 has been found to antagonize cell death induced by a wide variety of agents, accounts for why we examined whether if Bcl-2 could antagonize GL331 effects. Interestingly, ectopic overexpression of Bcl-2 in either HL-60 or U937 cells caused in resistance towards GL331-elicited DNA fragmentation and cytotoxic effect. Additionally, Bcl-2 also attenuated the poly(ADP-ribosyl)ation of PARP itself as well as Histone H1 at the early period of drug treatment. However, Bcl-2 did not influence the extent of DNA strand breaks induced by GL331 in either control or Bcl-2-overexpressing cells. In addition, analysis of basal PARP activity in control and several Bcl-2 overexpressing clones revealed that Bcl-2 down-regulated PARP activity under the condition without DNA damages. Above findings suggest that poly(ADP-ribosyl)ation of nuclear targets is important for apoptosis induced by DNA-reactive anticancer drugs.
The development of a malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes that have highly diverse functions. Some of these genes code for pathways of signal transduction that mediate the action of growth factors. The enzyme protein kinase C plays an important role in these events and in the process of tumor promotion. Therefore, we examined the effects of three inhibitors of protein kinase C, CGP 41251, RO 31-8220, and calphostin C, on human glioblastoma cells. These compounds inhibited growth and induced apoptosis; these activities were associated with a decrease in the level of CDC2 and cyclin B1/CDC2-associated kinase activity. This may explain why the treated cells accumulated in G2-M. In a separate series of studies, we examined abnormalities in cell cycle control genes in human cancer. We have found that cyclin D1 is frequently overexpressed in a variety of human cancers. Mechanistic studies indicate that cyclin D1 can play a critical role in carcinogenesis because: overexpression enhances cell transformation and tumorigenesis; introduction of an antisense cyclin D1 cDNA into either human esophageal or colon cancer cells reverts their malignant phenotype; and overexpression of cyclin D1 can enhance the amplification of other genes. The latter finding suggests that cyclin D1 can enhance genomic instability and, thereby, the process of tumor progression. Therefore, inhibitors of the function of cyclin D1 may be useful in both cancer chemoprevention and therapy. We obtained evidence for the existence of homeostatic feedback loops between cyclins D1 or E and the cell cycle inhibitory protein p27Kip1. On the basis of these and other findings, we hypothesize that, because of their disordered circuitry, cancer cells suffer from "gene addiction" and "gene hypersensitivity," disorders that might be exploited in both cancer prevention and therapy.
Helicobacter pylori, the main cause of chronic gastritis, is a class I gastric carcinogen. Chronic gastritis progresses to cancer through atrophy, metaplasia, and dysplasia. Precancerous phenotypic expression is generally associated with acquired genomic instability.
To evaluate the effect of H pylori infection and its eradication on gastric histology, cell proliferation, DNA status, and oncogene expression.
Morphometric and immunohistochemical techniques were used to examine gastric mucosal biopsy specimens from eight controls, 10 patients with H pylori negative chronic gastritis, 53 with H pylori positive chronic gastritis, and 11 with gastric cancer.
All patients with chronic gastritis were in a hyperproliferative state related to mucosal inflammation, regardless of H pylori infection. Atrophy was present in three of 10 patients with H pylori negative chronic gastritis and in 26 of 53 with H pylori positive chronic gastritis, associated in 18 with intestinal metaplasia. DNA content was abnormal in only 11 patients with atrophy and H pylori infection; eight of these also had c-Myc expression, associated in six cases with p53 expression. Fifty three patients with H pylori positive chronic gastritis were monitored for 12 months after antibiotic treatment: three dropped out; infection was eradicated in 45, in whom cell proliferation decreased in parallel with the reduction in gastritis activity; atrophy previously detected in 21/45 disappeared in five, regressed from moderate to mild in nine, and remained unchanged in seven; complete metaplasia disappeared in 4/14, and markers of genomic instability disappeared where previously present. In the five patients in whom H pylori persisted, atrophy, metaplasia, dysplasia, and markers of genomic instability remained unchanged.
Chronic H pylori infection seems to be responsible for genomic instability in a subset of cases of H pylori positive chronic atrophic gastritis; eradication of H pylori infection can reverse inflammation and the related atrophy, metaplasia, and genomic instability.
Human liver cancers have been associated mainly with chronic inflammations such as viral hepatitis B or C. This suggests that prolonged cell damage by chronic inflammation is critical in cancer development. Overproduction of nitric oxide (NO-) and its derivative (NO x , peroxynitrite) has been implicated as a cause of tissue damage by inflammation, thus contributing to tumor promotion. We have demonstrated the expression of the inducible isoform of nitric oxide synthase (iNOS) and 3-nitrotyrosine, a marker of peroxynitrite formation, by immunohistochemistry in preneoplastic and neoplastic rat liver tissues induced by continuous infusion of N-nitrosodiethylamine with mini-pumps. The preneoplastic lesions were characterized by proliferation of phenotypically altered hepatic foci (PAHF), dysplastic hepatocytes and oval cells. Histologically, the tumors were hepatocellular carcinomas (HCCs) of trabecular, (pseudo)glandular and solid types with or without cholangiocellular involvement, iNOS was located mainly in oval cells, capillary endothelial and muscular cells, epithelia of cholangiomas and glandular HCCs. 3-Nitrotyrosine was observed in the cytoplasms of PAHF and dysplastic hepatocytes in preneoplasias and in the cytoplasms of some living or apoptotic HCC cells, connective tissues, proteinaceous fluids, sinusoidal endothelia of tumorous hepatocytes and cholangiomas in tumors. From these observations, we suggest that: (i) chronic tissue damage by chemical carcinogens may act to induce iNOS and peroxynitrite formation; (ii) oval cells play a key role in development and/or growth of tumor tissues by producing NO- via iNOS, which may also cause tissue damage by peroxynitrite; (iii) iNOS can be considered as a phenotypic marker in cells of oval cell lineage and neovascularized capillaries in tumor tissues.
The tissues of the mouse were surveyed for glucose-6-phosphatase activity and the enzyme was found to be present only in the liver, kidney, small intestine, and rectum. The amount and distribution of the enzyme in the liver was not perceptibly altered in adrenalectomized animals or animals with alloxan diabetes. Some increase in activity was appreciated in animals starved for 72 and 96 hours. When sections were incubated in the presence of insulin or dextrose, no activation or inhibition was observed. Alloxan, on the other hand, did partially inhibit the enzyme. The action of fluoride, zinc, magnesium, and cyanide ions was also investigated. The possible role of the enzyme in the transport of glucose across cell membranes, involving phosphorylation and dephosphorylation, is discussed.
1The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5).2The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10−6–10−4m) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10−6 to 10−5m in A7r5 cells. However, the number of viable cells after 10−4m curcumin treatment was less than the basal value (2×105 cells).3To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10−6–10−4m) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation.4Following curcumin (10−6–10−4m) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10−4m also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation.5The apoptotic effect of 10−4m curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10−4m) induced cell shrinkage, chromatin condensation, and DNA fragmentation.6The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10−5 to 10−4m. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10−4m curcumin, but unaffected by lower concentrations (10−6–10−5m).7The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10−5–10−4m) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10−4m curcumin. However, the alteration of the p53 mRNA level by curcumin (10−5–10−4m) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting.8Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.British Journal of Pharmacology (1998) 124, 1029–1040; doi:10.1038/sj.bjp.0701914
Mutant p53 has been found in a wide variety of human malignancies including carcinomas of the lung, breast and colon. Because of the controversial mutational rate of the p53 gene in hepatocellular carcinoma, a large series of liver tumors from white patients with different risk factors was examined immunohistochemically for expression of the p53 mutant to assess its prevalence and the relationships between p53 overexpression and clinicopathological data. Nine of 58 specimens were found to have detectable evidence of p53 gene mutation by virtue of the immunohistochemical detection of mutant p53 protein. The p53 mutation was more frequent in patients with serological hepatitis B and C markers than in patients without these markers (p = 0.046). The prevalence of p53-positive tumors was also significantly higher in the group of tumors with invaded portal branches than in the group without (p = 0.02). Our results showed that p53-positive hepatocellular carcinoma is a rare finding in patients exposed to a low dietary aflatoxin intake and that p53 mutation seems to occur at a late stage of the tumoral process and could contribute to an aggressive tumoral phenotype.
The effects of topical administration of curcumin on the formation of benzo[a]pyrene (B[a]P)–DNA adducts and the tumorigenic activities of B[a]P and 7,12-dimethyl-benz[a]anthracene (DMBA) in epidermis were evaluated in female CD-1 mice. Topical application of 3 or 10 μmol curcumin 5 min prior
to the application of 20 nmol [3H]B[a]P inhibited the formation of [3H]B[a]P—DNA adducts in epidermis by 39 or 61% respectively. In a two-stage skin tumorigenesis model, topical application of 20
nmol B[a]P to the backs of mice once weekly for 10 weeks followed a week later by promotion with 15 nmol 12-O-tetradecanoylpborbol-13-acetate (TPA) twice weekly for 21 weeks resulted in the formation of 7.1 skin tumors per mouse, and
100% of the mice had tumors. In a parallel group of mice, in which the animals were treated with 3 or 10 μmol curcumin 5 min
prior to each application of B[a]P, the number of tumors per mouse was decreased by 58 or 62% respectively. The percentage of tumor-bearing mice was decreased
by 18–25%. In an additional study, topical application of 3 or 10 μmol curcumin 5 min prior to each application of 2 nmol
DMBA once weekly for 10 weeks followed a week later by promotion with 15 nmol TPA twice weekly for 15 weeks decreased the
number of tumors per mouse by 37 or 41% respectively.
During the last few years, there has been a growing evidence that hepatocytes are not merely 'passive' target cells for immunological attack by effector T-cells, but may play a more 'active' role in the initiation and perpetuation of the immune response. Immune modulators released by inflammatory cells at the site of inflammation, as well as the eliciting antigen itself, are able to modulate the phenotype of hepatocytes. This would result in abnormal cytokine production and/or cytokine/receptor expression, as well as active synthesis and display of surface immune 'activation' markers and adhesion molecules, which act as co-stimulatory signals for T-cell activation. These accessory functions involve multiple molecular pathways of cell-cell interactions, which in turn will enable hepatocytes to play a role as 'accessory' cells in both the afferent and efferent arms of the cell-mediated immune response.
In order to assess the association between antibodies to hepatitis C virus (anti-HCV) and hepatocellular carcinoma (HCC), as well as the interaction of anti-HCV with other HCC risk factors in Taiwan, a total of 127 pairs of newly diagnosed HCC patients and healthy community controls were studied. Case-control pairs were individually matched for age (+/- 3 years), sex, residence, and ethnicity. Serum samples from study subjects were examined for anti-HCV by enzyme immunoassays as well as hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) by radioimmunoassays using commercial kits. The habits of cigarette smoking, alcohol drinking, and peanut consumption were obtained through standardized interviews according to a structured questionnaire. Both the anti-HCV as well as the carrier status of HBsAg and HBeAg were significantly associated with HCC showing a multivariate-adjusted odds ratio of 24.8 for carriers of HBsAg alone, 33.5 for carriers of both HBsAg and HBeAg, and 23.7 for those who were positive for anti-HCV. The population-attributable risk percentage was estimated as 3% for anti-HCV alone, 69% for HBsAg carrier status alone, and 6% for both anti-HCV and HBsAg in Taiwan. There were also synergistic effects on HCC development for anti-HCV with HBsAg carrier status, cigarette smoking, and habitual alcohol drinking.
Sequential and transient expression of c-fos, c-jun, c-myc, c-Ha-ras and c-Ki-ras proto-oncogene RNA transcripts with zonal heterogeneity was demonstrated in virtually all hepatocytes of adult rat liver by in situ hybridization with single-stranded, [35S]-labeled cRNA probes at various time points after intraperitoneal administration of a single dose of carbon tetrachloride (CCl4). After a brief interval, elevated RNA levels of these genes were also observed in nonparenchymal cells. A second phase of proto-oncogene expression was characterized by high RNA levels in only a fraction of parenchymal cells with preference of mediolobular areas. Distribution and number of these cells were comparable tl hepatocytes expressing the proliferation-associated nuclear antigen Ki-67 72 hours after toxic injury. Oncogene expression in the nonparenchymal compartment correlated with distinct morphologic changes preceding type I procollagen gene expression by desmin-positive perisinusoidal cells, accumulating together with numerous c-fms expressing cells in the areas of hepatocellular necrosis. We conclude that zonal hepatic destruction by carbon tetrachloride induces proto-oncogene expression with distinct temporal and spatial patterns initiated by the most severely damaged hepatocytes. Proto-oncogene products thus represent valuable markers of cellular activation preceding and accompanying various aspects of tissue repair reactions.
The data reviewed indicate that extracts of Curcuma longa exhibit anti-inflammatory activity after parenteral application in standard animal models used for testing anti-inflammatory activity. It turned out that curcumin and the volatile oil are at least in part responsible for this action. It appears that when given orally, curcumin is far less active than after i.p. administration. This may be due to poor absorption, as discussed. Data on histamine-induced ulcers are controversial, and studies on the secretory activity (HCl, pepsinogen) are still lacking. In vitro, curcumin exhibited antispasmodic activity. Since there was a protective effect of extracts of Curcuma longa on the liver and a stimulation of bile secretion in animals, Curcuma longa has been advocated for use in liver disorders. Evidence for an effect on liver disease in humans is not yet available.
From the facts that after oral application only traces of curcumin were found in the blood and that, on the other hand, most of the curcumin is excreted via the faeces it may be concluded that curcumin is absorbed poorly by the gastrointestinal tract and/or underlies pre-systemic transformation. Systemic effects therefore seem to be questionable after oral application except that they occur at very low concentrations of curcumin. This does not exclude a local action in the gastrointestinal tract.
We measured the levels of c-myc and c-ras expression before and after diethylnitrosamine (DENA) treatment in the liver of rats previously submitted to partial hepatectomy
(PH), in the presence or absence of indomethacin (IMC), given at a dose that reduced by 75% the incidence of preneoplastic
foci of altered hepatocytes scored 8 weeks after application of the carcinogen. The time-course evolution of c-myc response to PH was similar In IMC-treated and untreated rats (with a peak at 3–8 h at least as high in IMC-treated animals
as in the hepatectomized reference group), whereas the overall c-ras response was significantly reduced by the IMC treatment, resulting in much lower c-ras expression at 18–24 h post-hepatectomy. Treatment with DENA 24 h after PH did not significantly modify c-ras expression compared to partially hepatectomized controls. In contrast, DENA treatment resulted in a marked transient increase
in c-myc expression that was at least as pronounced, If not the same, in the IMC-treated animals. These results leave open the possibility
that increased c-myc expression under DENA influence might play a role in foci induction but exclude that this might be sufficient. They are consistent
with a role for c-ras expression in determining the susceptibility of hepatocytes towards the carcinogenic action of DENA.
The effects of topically applied curcumin, chlorogenic acid, caffeic acid, and ferulic acid on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors were evaluated in female CD-1 mice. Topical application of 0.5, 1, 3, or 10 mumol of curcumin inhibited by 31, 46, 84, or 98%, respectively, the induction of epidermal ornithine decarboxylase activity by 5 nmol of TPA. In an additional study, the topical application of 10 mumol of curcumin, chlorogenic acid, caffeic acid, or ferulic acid inhibited by 91, 25, 42, or 46%, respectively, the induction of ornithine decarboxylase activity by 5 nmol of TPA. The topical application of 10 mumol of curcumin together with 2 or 5 nmol of TPA inhibited the TPA-dependent stimulation of the incorporation of [3H]-thymidine into epidermal DNA by 49 or 29%, respectively, whereas lower doses of curcumin had little or no effect. Chlorogenic acid, caffeic acid, and ferulic acid were less effective than curcumin as inhibitors of the TPA-dependent stimulation of DNA synthesis. Topical application of 1, 3, or 10 mumol of curcumin together with 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene inhibited the number of TPA-induced tumors per mouse by 39, 77, or 98%, respectively. Similar treatment of mice with 10 mumol of chlorogenic acid, caffeic acid, or ferulic acid together with 5 nmol of TPA inhibited the number of TPA-induced tumors per mouse by 60, 28, or 35%, respectively, and higher doses of the phenolic acids caused a more pronounced inhibition of tumor promotion. The possibility that curcumin could inhibit the action of arachidonic acid was evaluated by studying the effect of curcumin on arachidonic acid-induced edema of mouse ears. The topical application of 3 or 10 mumol of curcumin 30 min before the application of 1 mumol of arachidonic acid inhibited arachidonic acid-induced edema by 33 or 80%, respectively.
Liposomal lipid peroxidation and peroxide induced DNA damage were investigated. Inhibition of lipid peroxidation was studied using 400 microM uric acid, beta-carotene, alpha-tocopherol, curcumin and butylated hydroxyanisole (BHA). Curcumin, the active principle of turmeric (Curcuma longa), was as effective an antioxidant as BHA. An aqueous extract of turmeric was also found to be an effective inhibitor. The inhibition obtained using this aqueous extract, incorporated into the liposome itself, was 70% at 300 ng/microliter. This indicates the presence of yet another antioxidant in turmeric besides the lipophilic curcumin. The aqueous antioxidant extended 80% protection to DNA against peroxidative injury at 100 ng/microliter. This component of turmeric is being characterised and investigated as an antioxidant/anticlastogen and as an antipromoter.
A prospective general population study of 22 707 Chinese men in Taiwan has shown that the incidence of primary hepatocellular carcinoma (PHC) among carriers of hepatitis B surface antigen (HBsAg) is much higher than among non-carriers (1158/100 000 vs 5/100 000 during 75 000 man-years of follow-up). The relative risk is 223. PHC and cirrhosis accounted for 54·3% of the 105 deaths among HBsAg carriers but accounted for only 1·5% of the 202 deaths among non-carriers. These findings support the hypothesis that hepatitis B virus has a primary role in the aetiology of PHC.
Infection by bacteria, parasites or viruses and tissue inflammation such as gastritis, hepatitis and colitis are recognized risk factors for human cancers at various sites. Nitric oxide (NO) and other oxygen radicals produced in infected and inflamed tissues could contribute to the process of carcinogenesis by different mechanisms, which are discussed on the basis of authors' studies on liver fluke infection and cholangiocarcinoma development. A similar mechanism could apply to other suspected and known cancer-causing agents including Helicobacter pylori infection (stomach cancer) or asbestos exposure (lung mesothelioma). Studies on the type of tissue and DNA damage produced by NO and by other reactive oxygen species are shedding new light on the molecular mechanisms by which chronic inflammatory processes may initiate or enhance carcinogenesis in humans.
Curcumin, the natural antioxidant from turmeric, an Indian spice, and its derivatives have significant abilities to protect plasmid pBR322 DNA against single-strand breaks induced by singlet oxygen (1O2), a reactive oxygen species with potential genotoxic/mutagenic properties. 1O2 was generated at 37 degrees C in an aqueous buffer system by the thermal dissociation of the endoperoxide of 3,3'-(1,4-naphthylene)dipropionate (NDPO2). Among the compounds tested, curcumin was the most effective inhibitor of DNA damage followed by desmethoxycurcumin, bisdesmethoxycurcumin and other derivatives. The observed antioxidant activity was both time- and concentration-dependent. The protective ability of curcumin was higher than that of the well-known biological antioxidants lipoate, alpha-tocopherol and beta-carotene. However, the highest protective ability with saturating concentrations of curcumin did not exceed 50%. The ability of curcumin and its derivatives to protect DNA against 1O2 seems to be related to their structures and may at least partly explain the therapeutic and other beneficial effects of these compounds including anticarcinogenic and antimutagenic properties.
L-Arginine-derived nitric oxide (NO) and its derivatives, such as peroxynitrite and nitrogen dioxide, play a role in inflammation and also possibly in the multistage process of carcinogenesis. We investigated the effect of various non-steroidal anti-inflammatory agents and related compounds on the induction of NO synthase (NOS) in RAW 264.7 macrophages activated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Low concentrations of curcumin, a potent anti-tumour agent having anti-inflammatory and anti-oxidant properties, inhibited NO production, as measured by the amount of nitrite released into the culture medium in 24 h (IC50 = 6 microM). NOS activity in soluble extracts of macrophages activated for 6-24 h in the presence of curcumin (10 microM) was significantly lower than that of macrophages activated without curcumin. Northern-blot and immunoblotting analyses demonstrated that significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in macrophages activated with curcumin, compared to those without curcumin. Inhibition of NOS induction was maximal when curcumin was added together with LPS and IFN-gamma and decreased progressively as the interval between curcumin and LPS/IFN-gamma was increased to 18 h.
Dichloroacetic (DCA) and trichloroacetic (TCA) acids, two major by-products formed during chlorine disinfection of drinking water, increase the incidence of tumors in B6C3F1 mice by 6- and 3-fold respectively. In order to understand better the mechanism by which these two compounds induce liver tumors, the incidence and spectrum of mutations in the K- and H-ras proto-oncogenes in these tumors were analyzed. DNA from spontaneous, DCA- and TCA-induced liver tumor from B6C3F1 male mice was evaluated for point mutations in exons 1, 2 and 3 of the two genes by single-stranded conformation polymorphism. Results demonstrated a similar incidence of mutations for exon 2 of H-ras in spontaneous carcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%), 1.0 g/l (48%) and TCA 4.5 g/l (45%). Only four showed mutations in the other exons of Hras or in K-ras. Sequence analysis of spontaneous tumor samples with second exon H-ras mutations revealed a change in codon 61 from CAA to AAA in 80% and CAA to CGA in 20% of tumors. In contrast, tumors with H-ras mutations from DCA-treated mice revealed a H-61 change from CAA to AAA in 21% at 3.5 g/l and 16% at 1.0 g/l. CAA to CGA was observed in 50% of tumors from mice given DCA 3.5 or 1.0 g/l, and CAA to CTA was present in 29% and 34% of the two dosage groups respectively. Interestingly, TCA showed the same mutational spectrum as the spontaneous liver tumors. The data indicates that induction of liver carcinoma by DCA and TCA involves activation of the H-ras proto-oncogene at a frequency similar to that observed in spontaneous tumors. However, the mechanism(s) for including hepatocellular carcinoma does not appear to be identical for DCA and TCA.
Livers of mangrove rivulus (Rivulus ocellatus marmoratus) were examined after an acutely necrogenic dose of diethyl-nitrosamine (DEN). Immunohistochemical detection of oncoproteins and bromodeoxyuridine (BrdU), enzyme histochemical detection of gamma-glutamyltranspeptidase, and histological stains were used in an attempt to separate changes in protooncogene expression related to hepatic regeneration from those changes that were putatively preneoplastic. Perivenous hepatocytes were rounded and shrunken within 3 days of the beginning of DEN exposure, and widespread necrosis and hepatocyte proliferation occurred by 21 days (the last day of DEN exposure). Twenty-four days after the end of DEN exposure, livers were primarily composed of nodules of regenerated hepatocytes. Epidermal growth factor receptor expression in hepatocytes increased in inflamed areas and then returned to control levels as inflammation subsided. Increased expression of Fos, Ras and Myc occurred prior to necrosis in a zonal and chronological progression consistent with regeneration of hepatocytes. Fos, Ras, Myc and p53 expression persisted in scattered cells and foci for 24 days after the end of DEN exposure, and this expression was at levels higher than during normal cell-cycle progression. The spatial pattern and persistence of cells expressing Fos, Ras, Myc and p53 at high levels may have represented preneoplastic changes.