Assessing chromite ore processing residue (COPR) waste dump site using electrical resistivity tomography (ERT): a case study from Umaran, Kanpur, India.

Leaching of chromium ions causes a serious threat to groundwater around chromite ore processing residue (COPR) dump sites in many countries. As a result, detailed subsurface characterization of the affected region is crucial for assessing the associated risks as well as initiating remedial measures. Though the conventional approaches (e.g., drilling and water sampling) provide important information but are expensive and unable to decipher detailed subsurface scenario. Thus, in the present study, electrical resistivity tomography (ERT) (a cost-effective and faster approach) method has been employed to assess the effect of unplanned COPR waste dump beside agricultural land at Umaran, Kanpur, India, in conjunction with the available geochemical information. Inverted 2-D ERT sections depicted resistivity variation in the subsurface, and its correlation with previous geochemical results reveals the resistivity boundary between contaminated and clean zones as ~ 15 Ω·m. The study also depicts that the contamination plume is slowly migrating towards NE direction below the agriculture land but rate of migration is faster along southern direction. Therefore, the agriculture land and corresponding groundwater at ~ 50 m away from the dump site in NE direction are not affected by COPR leachate. Vertically, the COPR leachate has affected mostly up to ~ 20 m depth in the region inside the dump boundary; however, at some places, it is migrating further downward. Thus, the study demonstrates the efficacy of ERT method in characterizing COPR dump site and provides crucial information in managing safe agriculture practices over the region as well as for initiating scientific remedial measures.

Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis.

Breast cancer is the second leading cause of cancer-related death in women in the United States and discovery and development of safe chemopreventive drugs is urgently needed. The fruit pomegranate (Punica granatum) is gaining importance because of its various health benefits. This study was initiated to investigate chemopreventive potential of a pomegranate emulsion (PE) against 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis. The animals were orally administered with PE (0.2-5.0 g/kg), starting 2 wk before and 16 wk following DMBA treatment. PE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden, and reversed histopathological changes. PE dose-dependently suppressed cell proliferation and induced apoptosis in mammary tumors. Immunohistochemical studies showed that PE increased intratumor Bax, decreased Bcl2 and manifested a proapoptotic shift in Bax/Bcl2 ratio. In addition, our gene expression study showed PE-mediated upregulation of Bad, caspase-3, caspase-7, caspase-9, poly (ADP ribose) polymerase and cytochrome c in mammary tumors. Thus, PE exerts chemoprevention of mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis mediated through upregulation of Bax and downregulation of Bcl2 in concert with caspase cascades. Pomegranate bioactive phytoconstituents could be developed as a chemopreventive drug to reduce the risk of breast cancer.

Trianthema portulacastrum Linn. displays anti-inflammatory responses during chemically induced rat mammary tumorigenesis through simultaneous and differential regulation of NF-κB and Nrf2 signaling pathways.

Trianthema portulacastrum, a medicinal and dietary plant, has gained substantial importance due to its various pharmacological properties, including anti-inflammatory and anticarcinogenic activities. We have recently reported that a characterized T. portulacastrum extract (TPE) affords a considerable chemoprevention of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis though the underlying mechanisms are not completely understood. The objective of this study was to investigate anti-inflammatory mechanisms of TPE during DMBA mammary carcinogenesis in rats by monitoring cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-kappaB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). Mammary tumors were harvested from our previous study in which TPE (50-200 mg/kg) was found to inhibit mammary tumorigenesis in a dose-response manner. The expressions of intratumor COX-2, HSP90, NF-κB, inhibitory kappaB-alpha (IκBα) and Nrf2 were determined by immunohistochemistry. TPE downregulated the expression of COX-2 and HSP90, blocked the degradation of IκBα, hampered the translocation of NF-κB from cytosol to nucleus and upregulated the expression and nuclear translocation of Nrf2 during DMBA mammary carcinogenesis. These results in conjunction with our previous findings suggest that TPE prevents DMBA-induced breast neoplasia by anti-inflammatory mechanisms mediated through simultaneous and differential modulation of two interconnected molecular circuits, namely NF-κB and Nrf2 signaling pathways.

Mechanism of Breast Cancer Preventive Action of Pomegranate: Disruption of Estrogen Receptor and Wnt/ß-Catenin Signaling Pathways.

A pomegranate emulsion (PE), containing various bioactive phytochemicals, has recently been found to exert substantial chemopreventive effect against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumorigenesis in rats via antiproliferative and proapoptotic actions. Nevertheless, the underlying mechanisms of action are not completely understood. The present study was designed to investigate the effects of PE treatment on intratumor expression of estrogen receptor (ER)-α, ER-ß,ß-catenin and cyclin D1 during DMBA rat mammary carcinogenesis. Mammary tumor sections were harvested from a chemopreventive study in which PE (0.2, 1.0 and 5.0 g/kg) exhibited inhibition of mammary tumorigenesis in a dose-response manner. The expressions of ER-α, ER-ß, ß-catenin and cyclin D1 were analyzed by immunohistochemical techniques. PE downregulated the expression of intratumor ER-α and ER-ß and lowered ER-α:ER-ß ratio. PE also decreased the expression, cytoplasmic accumulation, and nuclear translocation of ß-catenin, an essential transcriptional cofactor for Wnt signaling. Moreover, PE suppressed the expression of cell growth regulatory protein cyclin D1, which is a downstream target for both ER and Wnt signaling. Our current results in conjunction with our previous findings indicate that concurrent disruption of ER and Wnt/ß-catenin signaling pathways possibly contributes to antiproliferative and proapoptotic effects involved in PE-mediated chemoprevention of DMBA-inflicted rat mammary tumorigenesis.

Suppression of inflammatory cascade is implicated in methyl amooranin-mediated inhibition of experimental mammary carcinogenesis.

Breast cancer represents the second leading cause of cancer-related deaths among women worldwide and preventive therapy could reverse or delay the devastating impact of this disease. Methyl-amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me), a novel synthetic oleanane triterpenoid, reduced the incidence and burden of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats through antiproliferative and proapoptotic effects. Since chronic inflammation plays an important role in the pathogenesis of breast cancer and several synthetic oleanane compounds are known potent anti-inflammatory agents, we aim to investigate anti-inflammatory mechanisms of AMR-Me by monitoring various proinflammatory and stress markers, such as cyclooxygenase-2 (COX-2) and heat shock protein 90 (HSP90), and nuclear factor-κB (NF-κB) signaling during DMBA mammary tumorigenesis in rats. Mammary tumors were harvested from a chemopreventive study in which AMR-Me (0.8-1.6 mg/kg) was found to inhibit mammary carcinogenesis in a dose-response manner. The expressions of COX-2, HSP90, NF-κB, and inhibitory κB-α (IκB-α) were determined by immunohistochemistry and reverse transcription-polymerase chain reaction. AMR-Me downregulated the expression of intratumor COX-2 and HSP90, suppressed the degradation of IκB-α, and reduced the translocation of NF-κB from cytosol to nucleus. Our present study provides the first in vivo evidence that NF-κB-evoked inflammatory cascade is a major target of AMR-Me in breast cancer. Our current results together with our previous findings suggest that disruption of NF-κB signaling contributes to anti-inflammatory, antiproliferative, and apoptosis-inducing mechanisms involved in AMR-Me-mediated chemoprevention of rat mammary carcinogenesis. These encouraging mechanistic results coupled with a safety profile should facilitate the clinical development of AMR-Me as breast cancer chemopreventive drug.

Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives.

Breast cancer is one of the most frequently diagnosed cancers and major cause of death in women in the world. Emerging evidence underscores the value of dietary and non-dietary phytochemicals, including triterpenoids, in the prevention and treatment of breast cancer. Oleanolic acid, an oleanane-type pentacyclic triterpenoid, is present in a large number of dietary and medicinal plants. Oleanolic acid and its derivatives exhibit several promising pharmacological activities, including antioxidant, anti-inflammatory, hepatoprotective, cardioprotective, antipruritic, spasmolytic, antiallergic, antimicrobial and antiviral effects. Numerous studies indicate that oleanolic acid and other oleanane triterpenoids modulate multiple intracellular signaling pathways and exert chemopreventive and antitumor activities in various in vitro and in vivo model systems. A series of novel synthetic oleanane triterpenoids have been prepared by chemical modifications of oleanolic acid and some of these compounds are considered to be the most potent anti-inflammatory and anticarcinogenic triterpenoids. Accumulating studies provide extensive evidence that synthetic oleanane derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate and skin cancer. This review critically examines the potential role of oleanolic acid, oleanane triterpenoids and related synthetic compounds in the chemoprevention and treatment of mammary neoplasia. Both in vitro and in vivo studies on these agents and related molecular mechanisms are presented. Several challenges and future directions of research to translate already available impressive preclinical knowledge to clinical practice of breast cancer prevention and therapy are also presented.

Chemopreventive effect of a novel oleanane triterpenoid in a chemically induced rodent model of breast cancer.

Breast cancer represents one of the most frequently diagnosed cancers and predominant causes of death in women worldwide. The value of preventive therapy to limit the devastating impact of breast cancer is well established. Various plant triterpenoids and their synthetic analogs have shown significant promise as potent chemopreventive agents in breast cancer. The current study was initiated to investigate mechanism-based chemopreventive potential of a novel synthetic oleanane triterpenoid (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis, an experimental rodent tumor model that closely resembles human mammary cancer. Rats were orally administered with AMR-Me (0.8, 1.2 and 1.6 mg/kg) three times per week for 18 weeks. Following two weeks of AMR-Me treatment, mammary carcinogenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks following DMBA exposure), AMR-Me exhibited a striking inhibition of DMBA-induced mammary tumor incidence, total tumor burden, average tumor weight and reversed histopathological alterations without toxicity. AMR-Me dose-dependently suppressed abnormal cell proliferation, induced apoptosis, up-regulated pro-apoptotic protein Bax and down-regulated antiapoptotic protein Bcl-2 in mammary tumors. AMR-Me upregulated the transcriptional levels of Bax, Bad, caspase-3, caspase-7 and poly(ADP-ribose) polymerase and down-regulated Bcl-2. These results clearly demonstrate for the first time that novel triterpenoid AMR-Me exerts chemopreventive efficacy in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through mitochondrial pro-apoptotic mechanisms. AMR-Me could be developed as a chemopreventive drug to reduce the risk of human breast cancer that remains a devastating disease.

Black currant phytoconstituents exert chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis by suppression of the inflammatory response.

Black currant fruits containing high amounts of anthocyanins are known to possess potent antioxidant and anti-inflammatory properties. We have previously reported that anthocyanin-rich black currant skin extract (BCSE) inhibits diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats although the underlying mechanisms are not fully understood. Our present study investigates the anti-inflammatory mechanisms of BCSE during DENA rat liver carcinogenesis. Dietary BCSE (100 or 500 mg/kg) treatment for 22 wk afforded a striking inhibition of DENA-induced hepatic gamma-glutamyl transpeptidase-positive preneoplastic foci in a dose-responsive fashion. There was a significant increase in hepatic expression of heat shock proteins (HSP70 and HSP90), cyclooxygenase-2, and nuclear factor-κB (NF-κB) in DENA-exposed rat livers. Dietary BCSE dose-dependently abrogated all these elevated inflammatory markers. The possible cardiotoxicity of BCSE was assessed by monitoring cardiac functions using transthoracic echocardiography. BCSE-mediated anti-inflammatory effects during rat liver carcinogenesis have been achieved without any cardiotoxicity. Our results provide convincing evidence, for the very first time, that suppression of the inflammatory cascade through modulation of the NF-κB signaling pathway could be implicated, at least in part, in the chemopreventive effects of black currant bioactive phytoconstituents against experimental hepatocarcinogenesis. These results coupled with an excellent safety profile of BCSE support the development of black currant phytochemicals for the chemoprevention of inflammation-driven hepatocellular cancer.

Simultaneous disruption of estrogen receptor and Wnt/ß-catenin signaling is involved in methyl amooranin-mediated chemoprevention of mammary gland carcinogenesis in rats.

Methyl-amoorain (methyl-25-hydroxy-3-oxoo-lean-12-en-28-oate, AMR-Me), a novel synthetic oleanane triterpenoid, exerts a striking chemopreventive effect against 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumorigenesis through antiproliferative and proapoptotic actions. Nevertheless, the underlying mechanisms of action remain to be established. As estrogen receptor (ER) and canonical Wnt/b-catenin signaling are involved in the development and progression of breast cancer, the current study was designed to investigate the effects of AMR-Me treatment on the expressions of ER-a, ER-b, b-catenin and cyclin D1 in rat mammary tumors induced by DMBA. Mammary tumor samples were harvested from an 18-week chemopreventive study in which AMR-Me (0.8­1.6 mg/kg) was shown to inhibit mammary carcinogenesis in a dose­response manner. The expressions of ER-a, ER-b, b-catenin, and cyclin D1 were determined by immunohistochemistry and reverse transcription-polymerase chain reaction. AMR-Me downregulated the expression of intratumor ER-a and ER-b and lowered the ratio of ER-a to ER-b. AMR-Me also reduced the expression, cytoplasmic accumulation, and nuclear translocation of b-catenin, the essential transcriptional cofactor for Wnt signaling. Furthermore, AMR-Me modulated the expression of cell growth regulatory gene cyclin D1, which is a downstream target for both ER and Wnt signaling. AMR-Me at 1.6 mg/kg for 18 weeks did not exhibit any hepatotoxicity or renotoxicity. The results of the present study coupled with our previous findings indicate that simultaneous disruption of ER and Wnt/b-catenin signaling possibly contributes to antiproliferative and apoptosis-inducing effects implicated in AMR-Me-mediated chemoprevention of DMBA-induced breast tumorigenesis in rats. Our results also suggest a possible crosstalk between two key regulatory pathways, namely ER and Wnt/b-catenin signaling, involved in mammary carcinogenesis and the value of simultaneously targeting these pathways to achieve breast cancer chemoprevention.

Antitumor activities of extracts from selected desert plants against HepG2 human hepatocellular carcinoma cells.

CONTEXT: Phytochemicals are produced by desert plants to protect themselves against stressful environments. They have been shown to be useful in preventing and fighting adverse pathophysiological conditions and complex diseases, including cancer. Although many desert plants have been investigated for their antitumor properties, a large number of them still remain to be explored for possible therapeutic applications in oncologic diseases. OBJECTIVE: To screen the antitumor effects of selected desert plants, namely Achillea fragrantissima (Forssk.) Sch. Bip. (Compositae), Ochradenus baccatus Delile (Resedaceae), Origanum dayi Post (Lamiaceae), Phlomis platystegia Post (Lamiaceae) and Varthemia iphionoides Boiss (Compositae), against an in vitro tumor model utilizing HepG2 human hepatocellular carcinoma cells. MATERIALS AND METHODS: The aqueous extracts of aerial parts of the aforementioned plants were prepared and used for the in vitro experiments. The HepG2 cells were exposed to varying concentrations (0-4 mg/mL) of each plant extract for 24 or 48 h and the cytotoxicity was measured by the MTT assay. RESULTS: Following 24 h exposure, O. dayi extract exhibited a substantial antiproliferative effect in HepG2 cells (IC50 = 1.0 mg/mL) followed by O. baccatus (IC50 = 1.5 mg/mL). All plant extracts displayed cytotoxicity following 48 h exposure. Nevertheless, a substantial effect was observed with O. dayi (IC50 = 0.35 mg/mL) or O. baccatus (IC50 = 0.83 mg/mL). CONCLUSION: The aqueous extracts from aerial parts of O. dayi and O. baccatus possess antitumor effects against human liver cancer cells. These desert plants represent valuable resources for the development of potential anticancer agents.

Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways.

Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2-5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling.

Health-promoting and disease-preventive potential of Trianthema portulacastrum Linn. (Gadabani) -An Indian medicinal and dietary plant.

It is estimated that 80% of the world population depends on traditional medicine for primary healthcare need. Trianthema portulacastrum Linn. (family: Aizoaceae) is a small perennial weed found in the Americas, Africa, India, and other regions of the world. This plant is used extensively in Indian traditional medicines and is also consumed as a vegetable throughout Asia for its perceived health benefits. Phytochemical analysis of T. portulacastrum reveals the presence of alkaloids, flavonoids, terpenoids, saponins, and phenolic compounds. Emerging studies demonstrate that crude extracts as well as bioactive phytoconstituents of T. portulacastrum exhibit potent antioxidant, anti-infective, analgesic, and anti-inflammatory activities. A growing number of in vitro and in vivo studies demonstrate various biological and pharmacological activities, including prevention and amelioration of hepatotoxicity, nephrotoxicity, hyperglycemia, hyperlipidemia, infectious diseases and cancer. This review aims to present and analyze available literature to understand the full potential of T. portulacastrum in health promotion and disease prevention. Current limitations and future directions of research on this medicinal and dietary plant are also critically discussed.

Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats.

Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight and reversed intratumor histopathological alterations. TPE dose-dependently suppressed proliferating cell nuclear antigen and cyclin D1 expression, induced apoptosis, upregulated proapoptotic protein Bax, downregulated antiapoptotic protein Bcl-2 and diminished the expression of nuclear and cytosolic ß-catenin in mammary tumors. Our results clearly provide the first experimental evidence that TPE exerts chemopreventive effect in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through alteration of Bax/Bcl-2 ratio. Mechanistically, TPE is capable of diminishing activated canonical Wnt/ß-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during an early-stage breast cancer. These results may encourage further studies to explore full potential of T. portulacastrum phytoconstituents as breast cancer chemopreventive agents.

Pomegranate Bioactive Constituents Suppress Cell Proliferation and Induce Apoptosis in an Experimental Model of Hepatocellular Carcinoma: Role of Wnt/ ß -Catenin Signaling Pathway.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and chemoprevention represents a viable approach in lowering the mortality of this disease. Pomegranate fruit, an abundant source of anti-inflammatory phytochemicals, is gaining tremendous attention for its wide-spectrum health benefits. We previously reported that a characterized pomegranate emulsion (PE) prevents diethylnitrosamine (DENA)-induced rat hepatocarcinogenesis though inhibition of nuclear factor-kappaB (NF- κ B). Since NF- κ B concurrently induces Wnt/ ß -catenin signaling implicated in cell proliferation, cell survival, and apoptosis evasion, we examined antiproliferative, apoptosis-inducing and Wnt/ ß -catenin signaling-modulatory mechanisms of PE during DENA rat hepatocarcinogenesis. PE (1 or 10 g/kg) was administered 4 weeks before and 18 weeks following DENA exposure. There was a significant increase in hepatic proliferation (proliferating cell nuclear antigen) and alteration in cell cycle progression (cyclin D1) due to DENA treatment, and PE dose dependently reversed these effects. PE substantially induced apoptosis by upregulating proapoptotic protein Bax and downregulating antiapoptotic protein Bcl-2. PE dose dependently reduced hepatic ß -catenin and augmented glycogen synthase kinase-3 ß expression. Our study provides evidence that pomegranate phytochemicals exert chemoprevention of hepatic cancer through antiproliferative and proapoptotic mechanisms by modulating Wnt/ ß -catenin signaling. PE, thus, targets two interconnected molecular circuits (canonical NF- κ B and Wnt/ ß -catenin pathways) to exert chemoprevention of HCC.