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Background: Warburg effect is characterized by the upregulation of HIF-1 and c-Myc regulated LDH-A, even aerobically owing to hypoxic environment and alterations in oncogenes or tumor suppressor genes in cancer. Reduced antioxidant defence system in transformed cells favors higher ROS production, which plays a significant role in carcinogenesis and acts as an important regulator of NF-κB. In addition, various proinflammatory cytokines play active roles in maintenance and progression of cancer. Objective: In continuation with our previous studies illustrating the long-term effect of curcumin using a liver tissue, present study was aimed to elucidate the anti-cancer effect of curcumin due to its long-term effect in the regulation of glycolytic metabolism, NF-κB activation, expression of proinflammatory cytokines in Dalton’s lymphoma ascites cells in vivo. Method: Spectrophotometric assays, RT-PCR and EMSA were performed to address the problems. Results: Results revealed that curcumin-induced activation of antioxidant enzymes, Nrf2 and downstream signaling gene NQO1. Reduction of oxidative stress, down-regulation of NADPH: Oxidase, decline in ROS and H2O2 levels were also observed. Activation of NF-κB, expression of COX2, HIF-1α and cMyc, as well as expression and activity of LDH-A were significantly reduced by curcumin. Besides, expression of proinflammatory cytokines was significantly down-regulated via reducing binding of nuclear protein with AP-1, NF-IL6, ETS and NF-κB binding elements of IL-1α, IL-1β, TNF-α and IL-6 promoters, respectively. Conclusion: Curcumin downregulates glycolytic metabolism via modulation of stress-activated genes and reduces oxidative stress by enhancing antioxidant defence system, which inhibits activation of NF-κB signaling and expression of proinflammatory cytokines in Dalton’s lymphoma ascites cells in vivo.

Impact of reactive oxygen species (ROS) in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. Studies have indicated the usefulness of ROS scavengers and exogenous antioxidants as anti-nociceptive agents in animal models of neuropathic and inflammatory hyperalgesia. In present study, we suggest the anti-hyperalgesic potential of the dietary antioxidant quercetin on chronic inflammatory hyperalgesia induced by Complete Freund’s Adjuvant (CFA). Three doses of quercetin (25, 50 and 75 mg/kg body weight) for consecutive 7 days were used for the study. Thermal hyperalgesia was assessed by paw withdrawal latency (PWL) test and inflammation was checked in terms of changes in paw edema. The insight of molecular signaling during chronic hyperalgesia was analyzed by TNF-α–TNFR1–ERK1/2 pathway in relation to change in ROS level in DRG and spinal cord. CFA-induced hyperalgesia was confirmed by decreased PWL and increased c-Fos activity in dorsal horn of spinal cord, determined by immunohistochemical analysis. It was characterized with elevated level of ROS and TNF-α estimated by ELISA. The activation of ERK1/2 and NF-κB in DRG and spinal cord and over-expression of TNFR1 in DRG were analyzed by Western blotting. Up-regulation of Iba1 and GFAP indicates glial activation in spinal cord. Expression of GFAP and its co-localization with NF-κB were examined by immunofluorescence. All the molecular modulators of hyperalgesia were brought towards normal after quercetin treatment showing its anti-hyperalgesic activity, indicating that repeated quercetin treatment is able to alleviate chronic inflammatory hyperalgesia by attenuating TNF-α-TNFR1–ERK1/2 signaling pathway via modulation of ROS and by suppression of central sensitization via inhibition of spinal glial activation.

To develop new anti-inflammatory and DNA cleavage agent with improved pharmaceutical profile, five quilinium salt based compounds have been synthesized and x-ray characterization of these quinolinium salts have been reported here. These quinolinium salts have potential to show the better anti-inflammatory activity as well as DNA cleavage activity. The anti-inflammatory activities of quinolinium salts 1–5 have been evaluated by complete Freund's adjuvant (CFA) induced rat paw edema method. The DNA cleavage activities of quinolinium salts 1–5 were analyzed by using plasmid pBR322. The crystal structure of quinolium salt 1, 2 and 3 have shown the intermolecular non-covalent interactions such as cation···π, π···π, C H···π, C H···X (X = I and Br) and C H⋯N interactions.

Pain is an unpleasant sensation triggered by noxious stimulation. It is one of the most prevalent conditions, limiting productivity and diminishing quality of life. Non steroidal anti inflammatory drugs (NSAIDs) are widely used as pain relievers in present day practice as pain is mostly initiated due to inflammation. However, due to potentially serious side effects, long term use of these antihyperalgesic drugs raises concern. Therefore there is a demand to search novel medicines with least side effects. Herbal products have been used for centuries to reduce pain and inflammation, and phytochemicals are known to cause fewer side effects. However, identification of active phytochemicals of herbal medicines and clear understanding of the molecular mechanism of their action is needed for clinical acceptance. In this review, we have briefly discussed the cellular and molecular changes during hyperalgesia via inflammatory mediators and neuro-modulatory action involved therein. The review includes 54 recently reported phytochemicals with antihyperalgesic action, as per the literature available with PubMed, Google Scholar and Scopus. Compounds of high interest as potential antihyperalgesic agents are: curcumin, resveratrol, capsaicin, quercetin, eugenol, naringenin and epigallocatechin gallate (EGCG). Current knowledge about molecular targets of pain and their regulation by these phytochemicals is elaborated and the scope of further research is discussed.

Concomitant generation of reactive oxygen species during tissue inflammation has been recognised as a major factor for the development and the maintenance of hyperalgesia, out of which H2O2 is the ...

Impact of ROS in development of hyperalgesia has recently motivated scientists to focus on ROS as novel target of anti-hyperalgesic interventions. However, role of ROS in molecular signaling of hyperalgesia is still poorly understood. The present study is aimed to analyze the effect of dietary antioxidant resveratrol on antioxidant defense system, ROS level and TNFR1–ERK signaling pathway during early and late phase of inflammatory hyperalgesia. Hyperalgesia was assessed by paw withdrawal latency test in complete Freund’s adjuvant-induced hyperalgesic rats. Activities of antioxidant enzymes were measured by in-gel assays, ROS level was measured by DCFH2DA, and expression of pERK, ERK and TNFR1 was estimated by Western blotting. Anti-hyperalgesic effect of resveratrol was observed by paw withdrawal latency test. ROS level was increased in paw skin as well as spinal cord during early phase which was further increased in paw skin, but remained constant in spinal cord up to late phase. Resveratrol differentially regulated the activities of SOD, catalase and GPx in paw skin as well as spinal cord of hyperalgesic rats in both phases. Activities were normalized back showing anti-hyperalgesic effect of resveratrol. Upregulated ERK signaling was modulated by resveratrol, whereas TNFR1 level remained unchanged. Overall results suggest that resveratrol alleviates inflammatory hyperalgesia by downregulation of ERK activation, modulation of ROS and differential regulation of antioxidant enzymes during early and late phases.

Role of NADPH oxidase1 in the development of inflammatory pain has been demonstrated by gene knockout studies. Nevertheless, pharmacological inhibition of NOX1 is a requisite approach for therapeutic utility. Recently, we have reported the anti-nociceptive effect of newly identified NOX1 specific inhibitor ML171 (2-acetylphenothiazine). Inhibition of NOX1 resulted in attenuation of nociceptive sensitization during acute inflammatory pain via inhibition of ROS generation and its downstream ERK1/2 activation. However, glial activation accompanying inflammation is closely related to the initiation and maintenance of pain. Peripheral nociceptive inputs activate the primary afferents via release of various chemical mediators which are potentially capable of mediating signals from neuron to glia in DRG and subsequently in spinal cord dorsal horn. The subsequent interactions between neuron and glia contribute to pain hypersensitivity. Thus, the present study was focused to investigate the effect of ML171 on ERK1/2 signaling, glial activation, and crosstalk between neuron and glia in a mouse model of formalin induced acute nociception. Thus, the present study was focused to investigate the effect of ML171 on ERK1/2 signaling, glial activation, and crosstalk between neuron and glia in DRG and dorsal horn of the spinal cord of lumbar region (L3-L5) in a mouse model of formalin induced acute nociception. Intraperitoneal administration of ML171 decreased nociceptive behavioral responses, i.e. the flinch and lick counts, in formalin induced nociceptive mice. Immunofluorescence and Western blot analysis demonstrated decreased levels of nociceptive mediators like p-ERK1/2, p-NFκB p65, Iba1 and GFAP in DRG as well as in spinal cord dorsal horn; supporting anti-nociceptive potential of ML171. Further, co-localization studies showed the neuron-glia crosstalk in tissue dependent manner. ERK1/2 was found to be activated in glia and NFκB in neurons in DRG; whereas in case of spinal cord ERK1/2 was activated in neurons and NFκB in astrocytes. Decrease in nociceptive behavioral response and activation of nociceptive mediators after intraperitoneal administration of ML171 strongly advocate anti-nociceptive potential of ML171. This is the first report demonstrating modulation of ERK1/2-NFκB signaling pathway, glial activation and regulation of neuron-glia crosstalk by NADPH oxidase1 inhibition towards its anti-nociceptive action.

The spread of metastatic cancer cell is the main cause of death worldwide. Cellular and molecular basis of the action of phytochemicals in the modulation of metastatic cancer highlights the importance of fruits and vegetables. Quercetin is a natural bioflavonoid present in fruits, vegetables, seeds, berries, and tea. The cancer-preventive activity of quercetin is well documented due to its anti-inflammatory, anti-proliferative and anti-angiogenic activities. However, poor water solubility and delivery, chemical instability, short half-life, and low-bioavailability of quercetin limit its clinical application in cancer chemoprevention. A better understanding of the molecular mechanism of controlled and regulated drug delivery is essential for the development of novel and effective therapies. To overcome the limitations of accessibility by quercetin, it can be delivered as nanoconjugated quercetin. Nanoconjugated quercetin has attracted much attention due to its controlled drug release, long retention in tumor, enhanced anticancer potential, and promising clinical application. The pharmacological effect of quercetin conjugated nanoparticles typically depends on drug carriers used such as liposomes, silver nanoparticles, silica nanoparticles, PLGA (Poly lactic-co-glycolic acid), PLA (poly(D,L-lactic acid)) nanoparticles, polymeric micelles, chitosan nanoparticles, etc.:In this review, we described various delivery systems of nanoconjugated quercetin like liposomes, silver nanoparticles, PLGA (Poly lactic-co-glycolic acid), and polymeric micelles including DOX conjugated micelles, metal conjugated micelles, nucleic acid conjugated micelles, and antibody-conjugated micelles on in vitro and in vivo tumor models; as well as validated their potential as promising onco-therapeutic agents in light of recent updates.

New planar trans-copper(II) β-dithioester complexes, [Cu(L)2] (L = methyl-3-hydroxy-(3-pyridyl)-2-propenedithioate (L1 in 1), methyl-3-hydroxy-(2-naphthyl)-2-propenedithioate (L2 in 2), methyl-3-hydroxy-3-(p-methoxyphenyl)-2-propenedithioate (L3 in 3), methyl-3-hydroxy-3-(p-fluorophenyl)-2-propenedithioate (L4 in 4), and methyl-3-hydroxy-3-(p-bromophenyl)-2-propenedithioate (L5 in 5)), have been synthesized and characterized by elemental (C, H, N and S) analysis, ESI-MS, IR, and UV-vis spectra. The structures of HL3 and its corresponding complex 3 have been determined by X-ray crystallography. Electrochemical behavior of all complexes has been studied by cyclic voltammetry. All five planar complexes show efficient DNA-binding and DNA (PBR322)-cleavage in a concentration-dependent manner (1 > 3 > 5 > 2 > 4). Cleavage efficiency is enhanced in the presence of H2O2 as well as ascorbic acid. However, the order of increased efficiency of Cu(II) chelates differs in the presence of H2O2 as 4 > 1 > 2 > 3 > 5. Among these complexes, the pyridyl- and methoxy-functionalized 1 and 3 have shown higher self-activating capability in DNA-cleavage. All complexes show significant variation in IC50 on MCF-7 cell line. Additionally, treatment with the complexes gradually increases apoptotic cell death in dose-dependent manner in RAW 264.7 cell line. These findings highlight potential cancer protective nature of these complexes.

Aberrant activation of PI3K-AKT signaling in many pathological conditions including cancer has attracted much of interest for drug targeting. Various isoforms are known from three classes of PI3K. Targeting selective isoform is advantageous to overcome the global deleterious effects of drug. PI-103 is a specific inhibitor of p110α of class I PI3K. The present study is aimed to analyze anti-carcinogenic activity of PI-103 in Dalton's lymphoma ascite (DLA) cells. Result shows regression in cell proliferation and increased apoptosis in terms of increased Annexin V binding, nuclear fragmentation and active caspase 3 level. It is correlated with attenuation of PI3K-AKT signaling by PI-103 via downregulation of the level of p110α, phospho-p85α, phospho- AKT, and PKCα in DLA cells as well as in H2O2 induced DLA cells. Additionally, ROS accumulation is declined in H2O2 induced DLA cells. Overall result suggests that PI-103 attenuates PI3K-AKT signaling via induction of apoptosis in murine T-cell lymphoma.

Sensitization of nociceptive neurons by inflammatory mediators leads to hypersensitivity for normal painful stimuli which is termed hyperalgesia. Oxidative stress is an essential factor in pathological pain; therefore, antioxidants qualify as potential anti-hyperalgesic agents. The present study examines the efficacy of the natural antioxidant resveratrol in complete Freund's adjuvant (CFA) induced hyperalgesic rats. Thermal hyperalgesia was measured at different time points by paw withdrawal latency test and confirmed by c-Fos expression in spinal dorsal horn. The impact of resveratrol treatment on inflammatory mediators at peripheral (paw skin) and central (spinal cord) sites was determined during early (6 h) as well as late phase (48 h) of hyperalgesia. Intraplanter injection of CFA increased the level of cytokines IL-1β, TNF-α and IL-6 as well as inflammatory enzymes COX-2 and iNOS in paw skin in both phases. In case of spinal cord, the level of COX-2 was found to be elevated in both phases, whereas iNOS could not be detected. The cytokines were found to be elevated only in late phase in spinal cord. Administration of resveratrol (20 mg/kg) shifted the level of all inflammatory mediators towards normal, except cytokines in paw skin. The present study suggests that the anti-nociceptive effect of resveratrol is implicated at both peripheral and central sites in a tissue specific manner. Copyright © 2016 John Wiley & Sons, Ltd.

Blue fluorescent hexagonal boron nitride quantum dots (h-BNQDs) of ∼10 nm size as an effective enhancer for DNA cleavage activity of anticancer drug doxorubicin (DOX) were synthesized using simple one-step hydrothermal disintegration of exfoliated hexagonal boron nitride at very low temperature ∼ 120 °C. Boron nitride quantum dots (BNQDs) at a concentration of 25 μg/ml enhanced DNA cleavage activity of DOX up to 70% as checked by converting supercoiled fragment into nicked circular PBR322 DNA. The interaction of BNQDs with DOX is proportional to the concentration of BNQDs, with binding constant Kb ∼0.07338 μg/ml. In addition, ab initio theoretical results indicate that DOX is absorbed on BNQDs at the N-terminated edge with binding energy −1.075 eV and prevented the normal replication mechanisms in DNA. BNQDs have been shown to kill the breast cancer cell MCF-7 extensively as compared with the normal human keratinocyte cell HaCaT. The cytotoxicity of BNQDs may be correlated with reduced reactive oxygen species level and increased apoptosis in MCF-7 cells, which may be liable to enhance the anticancerous activity of DOX. The results provide a base to develop BNQD-DOX as a more effective anticancer drug., Highlights • Blue fluorescent hexagonal boron nitride quantum dots (h-BNQDs) were developed at low temperature ∼ 120 °C. • h-BNQDs as an effective enhancer for DNA cleavage activity of the anticancer drug doxorubicin (DOX). • Enhanced DNA cleavage activity of DOX checked by converting supercoiled fragment into nicked circular PBR322 DNA. • BNQDs were shown to kill the breast cancer cell MCF-7 extensively as compared with the normal human keratinocyte cell HaCaT. • The reduced reactive oxygen species level and increased apoptosis in MCF-7 cells may liable to enhance the anticancerous activity of DOX.

Continuous accumulation of ROS maintains oxidative stress in tumor microenvironment and is implicated in hyperactivation of signaling pathways that promote cell proliferation, survival, and metabolic adaptations to cancer. Antioxidants are supposed to interfere with tumor microenvironment. Plant-derived flavonoids and curcuminoids are considered as promising therapeutic molecules due to least side effects. Anticarcinogenic activity of various herbal antioxidants is widely reported. However, supports from preclinical studies and clinical trials are insufficient. Critical insight in signaling pathways leading to cancer progression and regulation of specific targets by herbal antioxidants in preclinical studies is a prerequisite to overcome the lacuna in its successful translation into therapeutical medicine. Most of the studies are limited to in vitro tests, revealing the action at cellular level. However, the natural antioxidants need validation at the level of cancer regression and better survival of laboratory animals. This review will focus on various signaling pathways leading to cancer progression and their interception by herbal antioxidants with a greater emphasis on the antioxidants being most widely validated in vitro and in animal models. These drugs are at the preliminary stage of testing as supplementary or alternative drugs in patients. The review will provide insight to overcome the failures in clinical practice and scope for development of novel anticancer drugs.

Flavonoids have been chronicles of the history of a long way journey in the cure of physiological or pathophysiological conditions in various diseases including cancer. Our previous findings suggest the extensive mechanism of quercetin (QUE) mediated regression of cell survival, cell proliferation, oxidative stress, inflammation, and angiogenesis via modulating PI3K and PKC signaling in lymphoma as well as hepatocellular carcinoma. PI3K-PKC pathway is a key monitor of mammalian cells regulated by its different isoenzymes, which may exert similar or opposite cellular effects by differential coupling of signaling pathways. Put forward the invention of selective inhibitors against various isoenzymes is beneficial to reduce the burden of inclusive deleterious effects of drug for normal physiological process. Therefore, we hypothesized the improved anticancer efficacy of QUE in combination with isoenzyme inhibitors—rottlerin (ROT-PKCδ inhibitor), G0 6983 (PKCα inhibitor), and PI-103 (p110α-class I PI3K inhibitor) in MCF-7 and RAW 264.7 cells. QUE significantly improves the cytotoxicity of ROT + G0 6983 ranged 30–55% and PI-103 ranged 24–63% after 24–48 h against MCF-7 cells. Additionally in the presence of QUE, the improved cytotoxicity of ROT + G0 6983 is observed to range 69–75% and PI-103 ranged 45–88% after 24–48 h in RAW 264.7 cells. This increment in cell deaths are positively correlated with enhanced morphological alteration observed in MCF-7 cells. Further, QUE significantly increases the attenuation of PKCα level approximately by 50% in combination with PI-103. Overall results of the current study suggested that QUE improves the synergistic anticancer efficacy in combination with PI-103, ROT, and G0 6983 in MCF-7 and RAW 264.7 cells.

Protein kinase C (PKC) is a key regulator of cell growth and differentiation in mammalian cells and hyperactivation of PKC is believed to play an important role in tumor progression. PKC is downstream to signaling protein of phosphatidylinositol 3-Kinase (PI3K), a known up-regulator of cell proliferation and survival. Accumulation of reactive oxygen species (ROS) triggers oxidative stress in the tumor microenvironment, leading to the hyperactivation of various oxidative stress-stimulated signaling molecules. Quercetin (QUE) is a naturally occurring dietary flavonoid having antioxidant properties. QUE is reported to show antitumor activity both in vitro and in vivo; however, the molecular mechanism is yet to be thoroughly explored. HepG2 cells display cellular functions similar to the normal hepatocytes with high degree of morphological and functional differentiation, therefore HepG2 cell line is chosen as the suitable model for drug targeting. Present study is aimed to establish the signaling pathway involved in the anticarcinogenic action of QUE in HepG2 cell line. HepG2 cells were treated with different doses of QUE. Protein level and gene expression were analysed by Western blotting and RT-PCR, respectively. PKC activity was measured by non-radioactive-tagged phosphorylation. Results showed downregulation of expression of PI3K, PKC, COX-2 and ROS caused by QUE. Additionally, QUE enhanced the expression of p53 and BAX in HepG2 cells. Overall, results of the current study suggested that QUE elicited anticarcinogenic action by upregulation of p53 and BAX in HepG2 cells via downregulation of ROS, PKC, PI3K and COX-2, confirming our earlier report on the animal model.

Various oncogenes are associated with deregulation in cell proliferation, apoptosis, and cell survival, which ultimately cause cancerous growth. Phosphatidylinositol 3-kinase (PI3K) mediated signaling plays a key role in malignant transformation. Cell proliferation and cell survival of tumor cell are induced by hyper activation of PI3K, AKT1, glycolytic enzyme LDH-A, and inactivation of tumor suppressor gene p53. Dietary flavonoids such as quercetin are considered a powerful modulator of different cellular signaling pathways. The present study is focused on the role of quercetin on regulation of PI3K/AKT pathways in Dalton's lymphoma mice. Effect of quercetin was analyzed in ascite cells in terms of cell viability, glycolytic metabolism as well as expression, and level of PI3K (regulatory and catalytic subunit), AKT1, and p53 using standard methods. Results reflect hyperactivation of PI3K signaling in ascite cells of Dalton's lymphoma mice, leading to activation of AKT1 and inactivation of p53. Quercetin modulates the pathway toward suppression of lymphoma. Glycolytic metabolism was also downregulated by quercetin. Its tumor suppressor activity was confirmed by morphological parameters and longevity of mice. The findings suggest that quercetin may contribute to lymphoma prevention by downregulating PI3K-AKT1-p53 pathway as well as by glycolytic metabolism.

Concomitant generation of reactive oxygen species during tissue inflammation has been recognised as a major factor for the development and the maintenance of hyperalgesia, out of which H

Interleukin-1 (IL-1α and IL-1β) is a prototypic, potent, multifunctional proinflammatory cytokine affecting almost all cell types. Expression of IL-1 is up regulated in different tumor phenotypes and is implicated as an important factor in tumor progression via expression of metastatic, angiogenic genes and growth factors. Therefore, down regulation of expression of IL-1 may be able to inhibit cancer progression. Mechanism of transcriptional regulation of mouse IL-1α is not yet reported. AP-1 binding site at -12 to -6 on human IL-1α promotor is highly conserved in rat IL-1α gene and regulates its expression. Based on in silico analysis, regions -12 to -6bp is found to be conserved in human and mouse IL-1α gene promotor and therefore selected to study activation of IL-1α. Further, the regions -12 to -6bp in mouse IL-1α gene promotor corresponding to AP-1 binding element show 3'→5' orientation, necessary for AP-1 binding. The present work is focused on long term effect of curcumin on expression of IL-1α and IL-1β in liver of lymphoma bearing mice. Transcriptional regulation of IL-1α and IL-1β was analyzed by AP-1 and NF-IL-6 respectively. Elevated expression and protein level of IL-1α and IL-1β were found in lymphoma bearing mice compared to normal, which were significantly down regulated by curcumin treatment. Similarly, curcumin treatment down regulated activation of IL-1α and IL-1β via AP-1 and NF-IL-6 respectively. The findings conclude that curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 respectively in lymphoma bearing mice.

Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are typical multifunctional proinflammatory cytokines involved actively in the regulation of immunity, hematopoiesis, inflammation and carcinogenesis. Coordinated regulation of these cytokines could be required for effective regulation of early phase inflammation and cancer progression. The present work was aimed to analyze the anti-carcinogenic action of curcumin on the expression of TNF-α and IL-6 even after withdrawal of treatment. Up-regulated expressions of TNF-α and IL-6 in terms of mRNA and protein levels in lymphoma bearing mice were significantly down-regulated by curcumin as compared to normal. Electrophoretic mobility shift assay (EMSA) results revealed that curcumin reduced binding of nuclear protein with ETS and NF-κB binding elements of TNF-α and IL-6 promoters, respectively. The anti-carcinogenic effect of curcumin against lymphoma progression has been reported previously. In continuation, the present study suggests that the long-term effect of curcumin may contribute to attenuate cancer progression via the down-regulation of TNF-α and IL-6 modulated by E26 transformation-specific protein (ETS) and nuclear factor-κB (NF-κB), respectively.

Reactive oxygen species (ROS) have a key role in different etiologies of pain. At sub-cellular level, mitochondria and plasma membranes have been identified as endogenous sources of ROS required for pain generation. NADPH oxidase (NOX) is the main contributor of membrane associated ROS generation. Out of 7 isozymes, NOX1, NOX2 and NOX4 are reported to be associated with nociceptive sensitization. Therefore, it has been hypothesized that specific inhibition of the NOX isozymes could be putative strategy for treatment of pain. However, unavailability of specific inhibitors was the biggest obstacle to test this hypothesis. Here, we investigated anti-nociceptive potential of a newly identified specific NOX1 inhibitor ML171 in formalin induced inflammatory pain. ML171 administration decreased the paw lickings and flinching response in both phases of formalin test. Behavioral response was supported with decreased activation of c-Fos in spinal dorsal horn. The increased level of total NOX activity, ROS and pERK1/2 in dorsal root ganglion (DRG) and spinal dorsal horn of formalin induced nociception were reversed by ML171 administration. ML171 also inhibited the upregulated Tumor necrosis factor receptor 1 (TNFR1) expression in DRG, whereas did not show any effect in spinal dorsal horn which was unaltered after formalin insult. The study for the first time depicts anti-nociceptive potential of ML171 via regulation of ROS mediated ERK1/2 signaling by inhibition of NOX1 activity.

Antioxidant ellagic acid is a herbal polyphenolic compound shown to possess growth-inhibiting and apoptotic activities in cancer. Protein kinase C (PKC) plays an important role in cell proliferation, apoptosis, and differentiation. Apoptosis of tumor cells is induced by inactivation of glycolytic enzyme of anaerobic metabolism, lactate dehydrogenase (LDH)-A, and by activating apoptotic protein caspase-3 via PKCδ. The present study aims to analyze the role of ellagic acid on regulation of novel and atypical isozymes of PKC to modulate apoptosis and anaerobic metabolism to prevent lymphoma growth as its role on classical PKCs is reported earlier. Expression of novel and atypical isozymes of PKC, activity of PKCδ, expression and activity of caspase-3, and LDH-A have been analyzed. Expression is measured by RT-PCR, activities of PKCδ as level of its catalytic fragment, caspase-3 as level of its p17 fragment, and LDH-A by specific staining. Lymphoma bearing mice were treated with 3 different doses of ellagic acid. The treatment enhanced expression of all novel and atypical PKCs, activity and expression of caspase-3, and activity of PKCδ but decreased activity and expression of LDH-A. Our results suggest that ellagic acid induces apoptosis via novel and atypical PKCs in association with caspase-3 and induces cancer cell death by blocking the energy metabolism.

AKT signaling is important to maintaining normal physiology. Hyperactivation of AKT signaling is frequent in cancer, which maintains a high oxidative state in a tumor microenvironment that is needed for tumor adaptation. Therefore, antioxidants are proposed to exhibit anticancer properties by interfering with the tumor microenvironment. Quercetin is an ubiquitous bioactive antioxidant rich in vegetables and beverages. The present study aimed to analyze cancer preventive property of quercetin in ascite cells of Dalton's lymphoma-bearing mice. Protein level was determined by Western blotting. Nitric oxide (NO) level was estimated spectrophotometrically using Griess reagent. Results show downregulation in phosphorylation of AKT and PDK1 by quercetin, which was consistent with decreased phosphorylation of downstream survival factors such as BAD, GSK-3β, mTOR, and IkBα. Further, quercetin attenuated the levels of angiogenic factor VEGF-A and inflammatory enzymes COX-2 and iNOS as well as NO levels, whereas it increased the levels of phosphatase PTEN. Overall results suggest that quercetin modulates AKT signaling leading to attenuation of cell survival, inflammation, and angiogenesis in lymphoma-bearing mice.

New homoleptic zinc(II) complexes, [Zn(L)2], where L = methyl-3-hydroxy-(3-pyridyl)-2-propenedithioate L1 1, and methyl-3-hydroxy-(4-pyridyl)-2-propenedithioate L2 2, have been synthesized and characterized by elemental (C, H, and N) analysis, ESI-MS, and (IR, UV–vis, NMR) spectroscopy; the structure of 1 has been deduced by X-ray crystallography. The DNA binding and cleavage activity of the complexes have been studied. The cleavage potential of pBR322 DNA by 1 and 2 has been checked. Complex 1, which contains nitrogen of the pyridine group in the 3-position enhances DNA cleavage potential in the presence of ascorbic acid; however, the complex is protective against DNA cleavage in the presence of DMSO or H2O2. Also, 1 causes cytotoxicity against the MCF-7 breast cancer cell line. The efficient cytotoxic activity and DNA cleavage ability of 1 in the presence of ascorbic acid shows its potential anticancer properties and the need for further investigations of its potential as an anticancer drug.

Tamoxifen (Tmx) embedded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-Tmx) is prepared to evaluate its better DNA cleavage potential, cytotoxicity using Dalton's lymphoma ascite (DLA) cells and MDA-MB231 breast cancer cells. PLGA-Tmx nanoparticles are prepared through emulsified nanoprecipitation technique with varying dimension of 17-30nm by changing the concentrations of polymer, emulsifier and drug. Nanoparticles dimension are measured through electron and atomic force microscopy. Interactions between tamoxifen and PLGA are verified through spectroscopic and calorimetric methods. PLGA-Tmx shows excellent DNA cleavage potential as compared to pure Tmx raising better bioavailability. In vitro cytotoxicity studies indicate that PLGA-Tmx reduces DLA cells viability up to ∼38% against ∼15% in pure Tmx. Hoechst stain is used to detect apoptotic DLA cells through fluorescence imaging of nuclear fragmentation and condensation exhibiting significant increase of apoptosis (70%) in PLGA-Tmx vis-a-vis pure drug (58%). Enhanced DNA cleavage potential, nuclear fragmentation and condensation in apoptotic cells confirm greater bioavailability of PLGA-Tmx as compared to pure Tmx in terms of receptor mediated endocytosis. Hence, the sustained release kinetics of PLGA-Tmx nanoparticles shows much better anticancer efficacy through enhanced DNA cleavage potential and nuclear fragmentation and, thereby, reveal a novel vehicle for the treatment of cancer.

Protein Kinase C (PKC) isozymes are key components involved in cell proliferation and their over activation leads to abnormal tumor growth. PKC follows signalling pathway by activation of downstream gene NF-kB and early transcription factor c-Myc. Over activation of NF-kB and c-Myc gene are also linked with unregulated proliferation of cancer cells. Therefore any agent which can inhibit the activation of Protein kinase C, NF-kB and c-Myc may be useful in reducing cancer progression. To investigate this hypothesis we have tested the effect of ellagic acid on these genes in Dalton's lymphoma bearing (DL). The role of ellagic acid was also tested in regulation of tumor suppressor gene Transforming growth factor-β1 (TGF-β1). DL mice were treated with three different doses (40, 60 and 80 mg/kg body weight) of ellagic acid. Ascites cells of mice were used for the experiments. Ellagic acid administration to DL mice decreased oxidative stress by reducing lipid peroxidation. Ellagic acid also down regulates the expression of classical isozymes of PKC i.e. PKCα, PKCβ, and PKCγ as well as activity of total PKC and NF-kB, indicating its antitumor action. The anticarcinogenic action of ellagic acid was also confirmed by up regulation of TGF-β1 and down regulation of c-Myc. Lymphoma prevention by ellagic acid is further supported by decrease in cell proliferation, cell viability, ascites fluid accumulation and increase in life span of DL mice. All these findings suggest that ellagic acid prevents the cancer progression by down regulation of PKC signaling pathway leading to cell proliferation.

Increased level of ROS causes oxidative stress and leads to various pathological conditions including cancer. Therefore antioxidants should contribute to cancer prevention by improving antioxidant defense system and thereby protecting the cell from oxidative damage. In the present study we have validated the hypothesis by evaluating the antioxidant action of α-tocopherol. The effect of α-tocopherol is analyzed on oxidative stress as well as its regulation on antioxidant defense system. Oxidative stress is measured in terms of reduced glutathione and protein carbonylation. To evaluate the role of α-tocopherol on antioxidant defense system, the activities and expressions of antioxidant enzymes like glutathione peroxidase, catalase and superoxide dismutase are analyzed by activity gel assay and by RT-PCR respectively. These enzyme activities and/or expressions are found to be improved by α-tocopherol in lymphoma bearing mice which brings down the oxidative stress as reflected by increased level of reduced glutathione as well as decreased protein carbonylation. The effect of α-tocopherol is further analyzed on general characteristics of lymphoma growth like body weight, longevity, accumulation of ascites fluid, angiogenesis in peritoneum, morphology of liver and abundance of lymphocytes. The antioxidant α-tocopherol is found to check lymphoma growth. The results suggest that α-tocopherol contributes to lymphoma prevention by improving antioxidant defence system of mice.

NF-κB (nuclear factor κB) plays a significant role in inflammation, immunity, cell proliferation, apoptosis and malignancy. ROS (reactive oxygen species) are among the most important regulating factors of NF-κB. Intracellular ROS are mainly regulated by an endogenous antioxidant defence system. Any disruption of redox balance leads to oxidative stress, which causes a number of pathological conditions including inflammation and malignancy. Increased metabolic activity in cancerous cells leads to oxidative stress, which is further enhanced due to depletion of the endogenous antioxidant defence system. However, the activation and signalling of NF-κB are reported to be inhibited by overexpression and induced activity of antioxidant enzymes. Therefore the present study focuses on the correlation between the endogenous antioxidant defence system, ROS and NF-κB activation during lymphoma growth in mice. The study highlights the anti-carcinogenic role of curcumin by modulation of NF-κB activation and oxidative stress via the endogenous antioxidant defence system. Oxidative stress was monitored by lipid peroxidation, protein carbonylation and antioxidant enzyme activity. NF-κB-mediated signalling was tested by DNA-binding activity. The results reflect that intracellular production of H2O2 in oxidative tumour micro-environment regulates NF-κB activation. Curcumin inhibits oxidative state in the liver of lymphoma-bearing mice by enhancing the transcription and activities of antioxidant enzymes, which in turn modulate activation of NF-κB, leading to a decrease in lymphoma growth. Morphological changes as well as cell proliferation and cell survival assays confirmed reduced lymphoma growth. Thus curcumin contributes to cancer prevention by disrupting the vicious cycle of constant ROS production, responsible for a high oxidative micro-environment for tumour growth.

An elevated level of reactive oxygen species (ROS) in a cancerous condition causes oxidative stress which in turn activates a number of genes, and therefore an interruption in the oxidative microenvironment should be able to inactivate these genes, contributing to cancer prevention. The present work was designed to evaluate the role of ellagic acid in the modulation of protein kinase Cα (PKCα) activity and expression and its correlation with the oncogene, c-Myc, and tumor suppressor gene, transforming growth factor-β (TGF-β1), in lymphoma bearing mice. We also evaluated its implication for cell viability. Our results show that ellagic acid leads to down-regulation of the expression and activity of PKCα via decreasing the oxidative stress, measured in terms of lipid peroxidation and protein carbonylation. It also reduces c-Myc expression and improves TGF-β1 expression besides decreasing cell viability in Dalton lymphoma bearing mice, which supports its anti-carcinogenic action.

tRNAs possess a high content of modified nucleosides, which display an incredible structural variety. These modified nucleosides are conserved in their sequence and have important roles in tRNA functions. Most often, hypermodified nucleosides are found in the wobble position of tRNAs, which play a direct role in maintaining translational efficiency and fidelity, codon recognition, etc. One of such hypermodified base is queuine, which is a base analogue of guanine, found in the first anticodon position of specific tRNAs (tyrosine, histidine, aspartate and asparagine tRNAs). These tRNAs of the ‘Q-family’ originally contain guanine in the first position of anticodon, which is post-transcriptionally modified with queuine by an irreversible insertion during maturation. Queuine is ubiquitously present throughout the living system from prokaryotes to eukaryotes, including plants. Prokaryotes can synthesize queuine de novo by a complex biosynthetic pathway, whereas eukaryotes are unable to synthesize either the precursor or queuine. They utilize salvage system and acquire queuine as a nutrient factor from their diet or from intestinal microflora. The tRNAs of the Q-family are completely modified in terminally differentiated somatic cells. However, hypomodification of Q-tRNA (queuosine-modified tRNA) is closely associated with cell proliferation and malignancy. The precise mechanisms of queuine- and Q-tRNA-mediated action are still a mystery. Direct or indirect evidence suggests that queuine or Q-tRNA participates in many cellular functions, such as inhibition of cell proliferation, control of aerobic and anaerobic metabolism, bacterial virulence, etc. The role of Q-tRNA modification in cellular machinery and the signalling pathways involved therein is the focus of this review.

Constant production of reactive oxygen species (ROS) during aerobic metabolism is balanced by antioxidant defense system of an organism. Although low level of ROS is important for various physiological functions, its accumulation has been implicated in the pathogenesis of age-related diseases such as cancer and coronary heart disease and neurodegenerative disorders such as Alzheimer's disease. It is generally assumed that frequent consumption of phytochemicals derived from vegetables, fruits, tea and herbs may contribute to shift the balance towards an adequate antioxidant status. The present study is aimed to investigate the effect of aqueous extract of medicinal plant Terminalia arjuna on antioxidant defense system in lymphoma bearing AKR mice. Antioxidant action of T. arjuna is monitored by the activities of catalase, superoxide dismutase and glutathione S transferase which constitute major antioxidant defense system by scavenging ROS. These enzyme activities are low in lymphoma bearing mice indicating impaired antioxidant defense system. Oral administration of different doses of aqueous extract of T. arjuna causes significant elevation in the activities of catalase, superoxide dismutase and glutathione S transferase. T. arjuna is found to down regulate anaerobic metabolism by inhibiting the activity of lactate dehydrogenase in lymphoma bearing mice, which was elevated in untreated cancerous mice. The results indicate the antioxidant action of aqueous extract of T. arjuna, which may play a role in the anti carcinogenic activity by reducing the oxidative stress along with inhibition of anaerobic metabolism.

Regulation of the balance between production of reactive oxygen species (ROS) by cellular processes and its removal by antioxidant defense system maintains normal physiological processes. Any condition leading to increased ROS results in oxidative stress which has been related with a number of diseases including cancer. Improvement in antioxidant defense system is required to overcome the damaging effects of oxidative stress. Therefore in the present study, effect of the aqueous extract of a medicinal plant Andrographis paniculata (AP) on antioxidant defense system in liver is investigated in lymphoma bearing AKR mice. Estimating catalase, superoxide dismutase and glutathione S transferase monitored the antioxidant action. Oral administration of the aqueous extract of A. paniculata in different doses causes a significant elevation of catalase, superoxide dismutase and glutathione S transferase activities. It reveals the antioxidant action of the aqueous extract of AP, which may play a role in the anticarcinogenic activity by reducing the oxidative stress. LDH activity is known to increase in various cancers due to hypoxic condition. Lactate dehydrogenase is used as tumor marker. We find a significant decrease in LDH activity on treatment with AP, which indicates a decrease in carcinogenic activity. A comparison with Doxorubicin (DOX), an anticancerous drug, indicates that the aqueous extract of AP is more effective than DOX with respect to its effect on catalase, superoxide dismutase, glutathione S transferase as well as on lactate dehydrogenase activities in liver of lymphoma bearing mice.

Protein phosphorylation or dephosphorylation is the most important regulatory switch of signal transduction contributing to control of cell proliferation. The reversibility of phosphorylation and dephosphorylation is due to the activities of kinases and phosphatase, which determine protein phosphorylation level of cell under different physiological and pathological conditions. Receptor tyrosine kinase (RTK) mediated cellular signaling is precisely coordinated and tightly controlled in normal cells which ensures regulated mitosis. Deregulation of RTK signaling resulting in aberrant activation in RTKs leads to malignant transformation. Queuine is one of the modified base of tRNA which participates in down regulation of tyrosine kinase activity. The guanine analogue queuine is a nutrient factor to eukaryotes and occurs as free base or modified nucleoside queuosine into the first anticodon position of specific tRNAs. The tRNAs are often queuine deficient in cancer and fast proliferating tissues. The present study is aimed to investigate queuine mediated inhibition in phosphorylation of tyrosine phosphorylated proteins in lymphoma bearing mouse. The result shows high level of cytosolic and membrane associated tyrosine phosphoprotein in DLAT cancerous mouse liver compared to normal. Queuine treatments down regulate the level of tyrosine phosphoproteins, which suggests that queuine is involved in regulation of mitotic signaling pathways.

Sensitization of nociceptive neurons by inflammatory mediators leads to hypersensitivity for normal painful stimuli which is termed hyperalgesia. Oxidative stress is an essential factor in pathological pain; therefore, antioxidants qualify as potential anti-hyperalgesic agents. The present study examines the efficacy of the natural antioxidant resveratrol in complete Freund's adjuvant (CFA) induced hyperalgesic rats. Thermal hyperalgesia was measured at different time points by paw withdrawal latency test and confirmed by c-Fos expression in spinal dorsal horn. The impact of resveratrol treatment on inflammatory mediators at peripheral (paw skin) and central (spinal cord) sites was determined during early (6 h) as well as late phase (48 h) of hyperalgesia. Intraplanter injection of CFA increased the level of cytokines IL-1β, TNF-α and IL-6 as well as inflammatory enzymes COX-2 and iNOS in paw skin in both phases. In case of spinal cord, the level of COX-2 was found to be elevated in both phases, whereas iNOS could not be detected. The cytokines were found to be elevated only in late phase in spinal cord. Administration of resveratrol (20 mg/kg) shifted the level of all inflammatory mediators towards normal, except cytokines in paw skin. The present study suggests that the anti-nociceptive effect of resveratrol is implicated at both peripheral and central sites in a tissue specific manner. Copyright © 2016 John WileySons, Ltd.

Background Protein kinase C regulates various cellular processes including cell proliferation, cell adhesion, apoptosis, angiogenesis, invasion, and metastasis. Activation of different PKC isozymes results in distinct cellular responses. Novel PKCs are mainly involved in apoptotic process. Atypical PKC subfamily plays a critical role in cell proliferation and apoptosis, cell differentiation and motility. However, Atypical PKCs show contradictory regulation in different tissues or cancer cells. The mechanism of diversified effects is not well explored. Antioxidant ellagic acid shows hepatoprotective, anti-carcinogenic and anti-mutagenic properties. Present study is focused to analyze the effect of ellagic acid on novel and atypical isozymes of PKC in regulation of PKC-mediated apoptosis in liver of lymphoma bearing mice. Implication of ellagic acid treatment to DL mice was analyzed on caspase-3 mediated apoptosis via PKCδ induced activation; and on maintenance of adequate supply of energy during cancer growth. Methods 15–20 weeks old adult DL mice were divided into four groups (n = 6). Group 2, 3, 4 were treated with different doses of ellagic acid (40 mg/kg, 60 mg/kg and 80 mg/kg bw). The mice were sacrificed after 19 days of treatment and liver was used for study. The effect of ellagic acid was determined on expression of novel and atypical PKC isozymes. Apoptotic potentiality of ellagic acid was checked on activities of caspase-3 and PKCδ in terms of their catalytic fragments. Aerobic glycolysis was monitored by LDH activity, especially activity of LDH A. Results Ellagic acid treatment caused up regulation of expression of almost all novel and atypical PKC isozymes. Activities of PKCδ and caspase-3 were enhanced by ellagic acid, however activities of total LDH and LDH-A were inhibited. Conclusion The results show that ellagic acid promotes apoptosis in lymphoma bearing mice via novel and atypical PKCs which involves PKCδ induced caspase-3 activation; and inhibition of glycolytic pathway.

Reactive oxygen species are signaling mediators of nociceptive pathways. Exogenous administrations of antioxidants show anti-hyperalgesic effect. However, very little is known about the role of endogenous antioxidant defense system in pain pathology. Curcumin is a dietary antioxidant which shows ameliorative effect on thermal hypersensitivity, however detailed study is lacking. Present study was aimed to analyze the changes in oxidative stress, modulation of antioxidant enzymes and pro-inflammatory cytokines in complete Freund’s adjuvant induced inflammatory hyperalgesia and the effect of curcumin on antioxidant defense system and pro-inflammatory cytokines. Anti-hyperalgesic activity of curcumin was evidenced after 6 h of treatment. Oxidative stress was evidenced in paw skin and spinal cord of hyperalgesic rats by high level of lipid peroxidation. A decrease in activity of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and an increase in level of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in paw skin was observed as compared to normal rats. However, activity of antioxidant enzymes was enhanced in spinal cord. The changes were brought towards normal level after curcumin treatment. The results suggest that modulation of antioxidant defense system is early event in initiation of inflammatory hyperalgesia which might lead to initiation of other signaling pathways mediated by lipid peroxide, TNF-α, IL-1β and IL-6. Decrease in oxidative stress and down regulation of these cytokines by curcumin is suggested to be involved in its anti-hyperalgesic effect.

Rate of protein synthesis in ovary is analyzed throughout the annual reproductive cycle of H. fossilis. It is highest during previtellogenic phase and lowest during post spawning phase. The variation pattern matches with aminoacylation capacity of tRNA. The aminoacylation capacity of tRNA is compared in the two phases under homologous and heterologous conditions. Both tRNA and aRS are obtained from the same phase under homologous conditions and from different phases under heterologous conditions. Aminoacylation capacity is also compared in ovary and liver under homologous and heterologous conditions. Both tRNA and aRS show higher activity in previtellogenic phase. However, tRNA contributes more for higher aminoacylation activity. Transfer RNA fractionates into similar isoacceptors during the two phases. This indicates that the primary structure of tRNA may not change during the reproductive cycle. Therefore, it is suggested that the difference in aminoacylation activity may be due to post-transcriptional modifications of tRNA leading to conformational changes. Gm modification and 2-O′ methylation of tRNA are reported earlier to vary during the reproductive cycle [2]. The results support the earlier suggestion of conformational changes in tRNA in ‘active’ and ‘inactive’ forms in previtellogenic and post spawning phases respectively. Aminoacylation capacity of tRNA shows organ specificity. It is high in ovary than in liver. Poor aminoacylation capacity is shown under heterologous conditions. This may be due to incompatible aRS related to specific amino acid pool in the tissue, or post transcriptional changes in tRNA, which may not allow cross acylation with full efficiency.

The present study is a comparison of tRNA conformation from ovary of Heteropneustes fossilis in its active phase of reproduction (when it is highly engaged in protein synthesis i.e. previtellogenic phase) with inactive phase (when tRNA is mainly stored in mature ovary i.e. spawning phase). Transfer RNA of active phase is shown to be compact, flexible and susceptible towards nuclease. Compact tRNA structure is evidenced by higher hyperchromicity and presence of relatively less Gm modifications thereby allowing adequate hydrogen bonding between D loop and T loop. Higher sensitivity of tRNA towards Mg++ reflects its higher flexibility towards internal environment. This structure of tRNA may be required for active protein synthesis. On the other hand tRNA of inactive phase is shown to be relaxed but resistant towards nuclease which may be favoured for storage in mature ova of a teleost as maternal carry over.

Antioxidants protect the cells from the damaging effects of reactive oxygen species (ROS). Production of ROS during cellular metabolism is balanced by their removal by antioxidants. Any condition leading to increased levels of ROS results in oxidative stress, which participates in multistage carcinogenesis by causing oxidative DNA damage, mutations in the proto-oncogenes and tumor suppressor genes. Antioxidant defense system is required to overcome the process of carcinogenesis generated by ROS. Antioxidant enzymes are major contributors to endogenous antioxidant defense system. Protein kinase C (PKC) is generally involved in cell proliferation and its over expression leads to abnormal tumor growth. Out of three classes of PKC, classical PKC is mainly involved in cell proliferation and tumor growth. Classical PKC initiates signaling pathway and leads to activation of a number of downstream protein via activation of NF-κB. Therefore any agent which can promotes the endogenous antioxidant defense system should be able to down regulate PKC and NF-κB activation and thus may be useful in reducing cancer progression. To investigate this hypothesis we have tested the effect of antioxidant ellagic acid on antioxidant enzymes and PKC signaling in Dalton’s lymphoma bearing (DL) mice. DL mice were treated with three different doses of ellagic acid. The treatment significantly increases the activity and expression of antioxidant enzymes and down regulates the expression of classical isozymes of PKC as well as the activation of NF-κB, indicating that ellagic acid improves antioxidant defense system and PKC signaling via NF-κB which may contribute to its cancer preventive role.

Total RNA as well as transfer RNA were quantified from mature ova apart from four different embryonic stages namely mid-cleavage, early gastrula, mid-gastrula and organogenesis of the freshwater teleost Heteropneustes fossilis. Total RNA as well as transfer RNA quantity follow a similar variation pattern, being maximum during mid-gastrulation. When analysed by total amino acid acceptance capacity, transfer RNA shows its maximum activity during mid-gastrulation. This coincides with the higher ratio of tRNA to total RNA at this stage. The relative aminoacylation capacity for Ser, Gly, Asn and Thr are found to be higher (9-34%) compared to that for other amino acids. Total tRNA, resolved into three peaks upon HPLC fractionation, shows a high cumulative peak area during mid-gastrulation and organogenesis. These results indicate a switch over of maternal to embryonic translation machinery during gastrulation.

Overproduction of reactive oxygen species (ROS) due to environmental challenge or metabolic imbalance leads to oxidative stress, causing overactivation of a number of oncogenes that promote cancer development. Therefore, antioxidants should be able to check cancer growth by modulating oncogene activity. The requirement of high energy during unlimited cell proliferation is fulfilled by the switching of cancerous cells to a fast glycolytic pathway bypassing the oxygen dependent respiratory pathway. Almost all cancers exhibit a high expression of lactate dehydrogenase A (LDH-A) to ensure a high energy supply. The present study focused on modulating redox-sensitive oncogenes such as protein kinase C (PKC) and c-Myc by treatment of lymphoma bearing mice with the antioxidant α-tocopherol, the most active component of vitamin E. Further, the impact of α-tocopherol on LDH activity was tested. The results showed down-regulation of expression of stress-activated genes PKC-α, c-Myc and LDH-A by α-tocopherol in cancerous mice. α-Tocopherol contributes to the check of cell proliferation by decreasing the activity of LDH-A.

Cancer development and progression are closely associated with inflammation. NF-κB (nuclear factor κB) provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of malignant cells to resist tumour surveillance mechanisms. NF-κB might also regulate tumour angiogenesis and invasiveness and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches. ROS (reactive oxygen species) initiate inflammation by up-regulation of pro-inflammatory cytokines and therefore antioxidants provide a major defence against inflammation. α-Tocopherol is a lipid-soluble antioxidant. In addition to decreasing lipid peroxidation, α-tocopherol may exert intracellular effects. Hence, the aim of this study was to test the effect of α-tocopherol supplementation in cancer prevention via suppression of NF-κB-mediated pro-inflammatory cytokines. α-Tocopherol treatment significantly down-regulates expression, synthesis as well as secretion of pro-inflammatory cytokine IL-6 (interleukin-6) in cancerous mice. It also suppresses NF-κB binding to IL-6 promoter in liver leading to decreased secretion of IL-6 in serum. The regulation of the signalling pathway by α-tocopherol is found apart from its antioxidant capacity to reduce lipid peroxidation. Thus, the present study provides evidence for the hypothesis that besides the powerful free radical scavenging effects, α-tocopherol has genomic effects in down-regulation of pro-inflammatory cytokine and cancer prevention via the NF-κB-dependent pathway.

Antioxidants are substances that fight against ROS (reactive oxygen species) and protect the cells from their damaging effects. Production of ROS during cellular metabolism is balanced by their removal by antioxidants. Any condition leading to increased levels of ROS results in oxidative stress, which promotes a large number of human diseases, including cancer. Therefore antioxidants may be regarded as potential anticarcinogens, as they may slow down or prevent development of cancer by reducing oxidative stress. Fruits and vegetables are rich source of antioxidants. Moreover, a number of phytochemicals present in medicinal plants are known to possess antioxidant activity. Therefore the aim of the present study was to investigate antioxidant activity of the aqueous extract of nuts of the medicinal plant Semecarpus anacardium in AKR mouse liver during the development of lymphoma. Antioxidant action was monitored by the activities of antioxidant enzymes catalase, superoxide dismutase and glutathione transferase. The effect of S. anacardium was also studied by observing the activity of LDH (lactate dehydrogenase), an enzyme of anaerobic metabolism. LDH activity serves as a tumour marker. The activities of antioxidant enzymes decreased gradually as lymphoma developed in mouse. However, LDH activity increased progressively. Administration of the aqueous extract of S. anacardium to lymphoma-transplanted mouse led to an increase in the activities of antioxidant enzymes, whereas LDH activity decreased significantly, indicating a decrease in carcinogenesis. The aqueous extract was found to be more effective than doxorubicin, a classical anticarcinogenic drug, with respect to its action on antioxidant enzymes and LDH in the liver of mice with developing lymphomas.

Cancer is characterized by uncontrolled cell growth, which results from unlimited proliferation and disturbs various cellular activities. Queuine is a highly modified base analogue of guanine found at first anti-codon position of specific tRNAs i.e. tRNA(Tyr), tRNA(His), tRNA(Asp) and tRNA(Asn). These tRNAs are known as Q-family of tRNA. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuosine modification of tRNAs may be essential for normal development, differentiation and cellular functions. Physiological role of queuine remains ill defined but direct or indirect evidences suggest that queuine or Q-tRNA participates in many cellular functions such as regulation of cell proliferation, control of glycolytic metabolism, alteration in expression of proto-oncogenes, modulation of signal transduction pathways but the mechanism is not well known. Increase in LDH-A expression regulated by c-myc is well documented in a variety of tumor cells. Overexpression of proto-oncogenes cause deregulated cellular responses which may lead to development of cancer. The cellular proto-oncogenes like c-myc and c-fos have important role in cell growth, proliferation and differentiation. The present study is aimed to investigate queuine mediated modulation in the activity of lactate dehydrogenase and expression of proto-oncogenes like c-myc and c-fos in T-cell lymphoma (DLAT) induced cancerous mouse. The results indicate that elevated lactate dehydrogenase activity is brought down by queuine treatments and the elevated levels of c-Myc and c-Fos in DLAT cancerous mouse are down-regulated, suggesting that queuine inhibits anaerobic metabolism and cell proliferation.

An increase in cell number is one of the most prominent characteristics of cancer cells. This may be caused by an increase in cell proliferation or decrease in cell death. Queuine is one of the modified base which is found at first anticodon position of specific tRNAs. It is ubiquitously present throughout the living system except mycoplasma and yeast. The tRNAs of Q-family are completely modified to Q-tRNAs in terminally differentiated somatic cells, however hypomodification of Q-tRNA is closely associated with cell proliferation and malignancy. Queuine participates at various cellular functions such as regulation of cell proliferation, cell signaling and alteration in the expression of growth associated proto-oncogenes. Like other proto-oncogenes bcl2 is known to involve in cell survival by inhibiting apoptosis. Queuine or Q-tRNA is suggested to inhibit cell proliferation but the mechanism of regulation of cell proliferation by queuine or Q-tRNA is not well understood. Therefore, in the present study regulation in cell proliferation by queuine in vivo and in vitro as well as the expression of cell death regulatory protein Bcl2 are investigated. For this DLAT cancerous mouse, U87 cell line and HepG2 cell line are treated with different concentrations of queuine and the effect of queuine on cell proliferation and apoptosis are studied. The results indicate that queuine down regulates cell proliferation and expression of Bcl2 protein, suggesting that queuine promotes cell death and participates in the regulation of cell proliferation.

Constant generation of ROS (reactive oxygen species) during normal cellular metabolism of an organism is generally balanced by a similar rate of consumption by antioxidants. Imbalance between ROS production and antioxidant defence results in an increased level of ROS, causing oxidative stress, which leads to promotion of malignancy. Queuine is a hyper-modified base analogue of guanine, found at the first anticodon position of the Q-family of tRNAs. These tRNAs are completely modified with respect to queuosine in terminally differentiated somatic cells; however, hypo-modification of Q-tRNAs is closely associated with cell proliferation. Q-tRNA modification is essential for normal development, differentiation and cellular function. Queuine is a nutrient factor for eukaryotes. It is found to promote the cellular antioxidant defence system and inhibit tumorigenesis. The activities of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase are found to be low in the DLAT (Dalton's lymphoma ascites transplanted) mouse liver compared with normal mouse liver. However, exogenous administration of queuine to the DLAT cancerous mouse improves the activities of antioxidant enzymes. These results suggest that queuine promotes the antioxidant defence system by increasing antioxidant enzyme activities and in turn inhibits oxidative stress and tumorigenesis.