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BACKGROUND Rapamycin is hormetic in nature-it demonstrates contrasting effects at high and low doses. It is toxic at moderate/high doses, while it can restrain aging and extend lifespan at low doses. However, it is not fully understood how rapamycin governs cellular aging. On the other hand, aging is putatively correlated to mitochondrial dysregulation. Although previous studies have suggested that hormetic (low) doses of rapamycin can cause partial/incomplete inhibition of mTOR, the actual modus operandi of how such partial mTOR inhibition might modulate the mTOR-mitochondria cross-talk remained to be deciphered in the context of cellular aging. The present study was designed to understand the hormetic effects of rapamycin on cellular factors that govern aging-associated changes in mitochondrial facets, such as functional and metabolic homeostases, sustenance of membrane potential, biogenesis, mitophagy, and oxidative injury to mitochondrial macromolecules. METHODS AND RESULTS WRL-68 cells treated (24 h) with variable doses of rapamycin were studied for estimating their viability, apoptosis, senescence, mitochondrial density and Δψm. Expression levels of key functional proteins were estimated by immunofluorescence/immunoblots. Oxidative damage to mtDNA/mtRNA/proteins was measured in mitochondrial lysates. We demonstrated that hormetic doses (0.1 and 1 nM) of rapamycin can alleviate aging-associated mitochondrial dyshomeostasis in WRL-68 cells, such as oxidative injury to mitochondrial nucleic acids and proteins, as well as disequilibrium of mitochondrial density, membrane potential, biogenesis, mitophagy and overall metabolism. CONCLUSIONS We established that low doses of rapamycin can hormetically amend the mTOR-mitochondria cross-talk, and can consequently promote anti-aging outcome in cells.

In the recent years, the reported cases of mitochondrial disorders have reached a colossal number. These disorders spawn a sundry of pathological conditions, which lead to pernicious symptoms and even fatality. Due to the unpredictable etiologies, mitochondrial diseases are putatively referred to as “mystondria” (mysterious diseases of mitochondria). Although present-day research has greatly improved our understanding of mitochondrial disorders, effective therapeutic interventions are still at the precursory stage. The conundrum becomes further complicated because these pathologies might occur due to either mitochondrial DNA (mtDNA) mutations or due to mutations in the nuclear DNA (nDNA), or both. While correcting nDNA mutations by using gene therapy (replacement of defective genes by delivering wild-type (WT) ones into the host cell, or silencing a dominant mutant allele that is pathogenic) has emerged as a promising strategy to address some mitochondrial diseases, the complications in correcting the defects of mtDNA in order to renovate mitochondrial functions have remained a steep challenge. In this review, we focus specifically on the selective gene therapy strategies that have demonstrated prospects in targeting the pathological mutations in the mitochondrial genome, thereby treating mitochondrial ailments.

In this study, we assessed the potential of aqueous extract (CSEaq) of Cuminum cyminum L. (cumin) seeds in protecting WRL-68 cells from hexavalent chromium [Cr(VI)]-induced oxidative injury. Cells exposed to Cr(VI) (10 μM CrO3) for 24 h demonstrated a twofold increase in ROS, which, in turn, led to extensive oxidative stress, consequently causing colossal decline in cell viability (by 58.82 ± 9.79%) and proliferation (as was evident from a reduced expression of Ki-67, a proliferation marker). Immunofluorescence studies showed that Cr(VI) diminished the expressions of mTOR and survivin in WRL-68 cells. It also led to a substantial elevation of BECN1 expression, which suggested autophagy. Overall, our results indicated that 24 h exposure of WRL-68 cells to Cr(VI) caused oxidative stress-induced autophagic cell death. CSEaq was found to protect WRL-68 cells from the same fate by refurbishing their viability and proliferation in a dose-dependent manner. The extract reduced ROS in these cells, which consequently decreased the degree of autophagic cell death by restoring expressions of mTOR, survivin and BECN1 to their respective normal levels. Biochemical assays revealed that CSEaq is rich in phenolic constituents. Total phenolic content of CSEaq demonstrated positive correlations with (i) its antioxidant potential, (ii) its alleviation of cellular oxidative stress and (iii) its cytoprotective efficacy in Cr(VI)-treated WRL-68 cells. We also identified the major phenolic constituents of CSEaq. Our study suggested that polyphenols in CSEaq might be responsible for protecting WRL-68 cells from Cr(VI)-governed oxidative assault that would have otherwise led to survivin/mTOR-mediated autophagic death.

Sepsis is a grievous health concern with limited understanding of its precise etiology. Although studies on sepsis have implicated the Warburg effect (mitigation of mitochondrial oxidative phosphorylation, as evident from aerobic glycolysis), we propose that an evolutionary perspective might further unravel its etiology. The endosymbiotic theory suggests that evolution of a eukaryotic cell is a consequence of the fruitful association between an archaea (Asgard) and an alphaproteobacterium (Rickettsia). We hypothesize that, during pathological conditions like sepsis, such endosymbiotic homeostasis between the two systems is perturbed. We underscore the fact (supported by in silico homology analyses) that during sepsis, the Asgard component of a cell is promoted to trigger aerobic glycolysis as well as the innate immune response (spearheaded by the TLR pathway), while suppressing the Rickettsia counterpart, thereby promoting the Warburg effect. It might be this discord between the two endosymbiotic partners (Asgard and Rickettsia-derived cellular components) that promotes sepsis.

In this study, we assessed the potential of aqueous extract (CSE(aq)) of Cuminum cyminum L. (cumin) seeds in protecting WRL-68 cells from hexavalent chromium [Cr(VI)]-induced oxidative injury. Cells exposed to Cr(VI) (10 μM CrO(3)) for 24 h demonstrated a twofold increase in ROS, which, in turn, led to extensive oxidative stress, consequently causing colossal decline in cell viability (by 58.82 ± 9.79%) and proliferation (as was evident from a reduced expression of Ki-67, a proliferation marker). Immunofluorescence studies showed that Cr(VI) diminished the expressions of mTOR and survivin in WRL-68 cells. It also led to a substantial elevation of BECN1 expression, which suggested autophagy. Overall, our results indicated that 24 h exposure of WRL-68 cells to Cr(VI) caused oxidative stress-induced autophagic cell death. CSE(aq) was found to protect WRL-68 cells from the same fate by refurbishing their viability and proliferation in a dose-dependent manner. The extract reduced ROS in these cells, which consequently decreased the degree of autophagic cell death by restoring expressions of mTOR, survivin and BECN1 to their respective normal levels. Biochemical assays revealed that CSE(aq) is rich in phenolic constituents. Total phenolic content of CSE(aq) demonstrated positive correlations with (i) its antioxidant potential, (ii) its alleviation of cellular oxidative stress and (iii) its cytoprotective efficacy in Cr(VI)-treated WRL-68 cells. We also identified the major phenolic constituents of CSE(aq). Our study suggested that polyphenols in CSE(aq) might be responsible for protecting WRL-68 cells from Cr(VI)-governed oxidative assault that would have otherwise led to survivin/mTOR-mediated autophagic death.

Cancer is a grievous concern to human health, owing to a massive heterogeneity in its cause and impact. Dysregulation (numerical, positional and/or structural) of centrosomes is one of the notable factors among those that promote onset and progression of cancers. In a normal dividing cell, a pair of centrosomes forms two poles, thereby governing the formation of a bipolar spindle assembly. A large number of cancer cells, however, harbor supernumerary centrosomes, which mimic the bipolar arrangement in normal cells by centrosome clustering (CC) into two opposite poles, thus developing a pseudo-bipolar spindle assembly. Manipulation of centrosome homeostasis is the paramount pre-requisite for the evasive strategy of CC in cancers. Out of the varied factors that uphold centrosome integrity, microtubule motors (MiMos) play a critical role. Categorized as dyneins and kinesins, MiMos are involved in cohesion of centrosomes, and also facilitate the maintenance of the numerical, positional and structural integrity of centrosomes. Herein, we elucidate the decisive mechanisms undertaken by MiMos to mediate centrosome homeostasis, and how dysregulation of the same might lead to CC in cancer cells. Understanding the impact of MiMos on CC might open up avenues toward a credible therapeutic target against diverse cancers.

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the 'route and reach' of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.

Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-MB-231). On 24 h treatment, the nID caused decline in the viability of MDA-MB-231 and MDA-MB-468 cells, but did not significantly (P 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-MB-231 and MDA-MB-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21

Under a Creative Commons license.-- et al., Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression., Drs. Feitelson and Arzumanyan were supported by NIH (AI076535) and by Temple University. Dr. Rob J. Kulathinal was supported by the National Science Foundation, and by the American Cancer Society. Dr. Marino was supported by grant from University Roma Tre (CLA 2013) and by the Italian Association for Cancer Research (no. IG15221). Dr. Georgakilas was supported by the EU Marie Curie Reintegration Grant (MC-CIG-303514), Greek National funds through the Operational Program ‘Educational and Lifelong Learning of the National Strategic Reference Framework (NSRF)- Research Funding Program: THALES (MIS 379346) and COST Action CM1201 ‘Biomimetic Radical Chemistry.’ Dr. Amedei was supported by the Italian Ministry of University and University of Italy. Dr. Amin was supported by the Terry Fox Foundation (TF-36), UAEU Program for Advanced Research (UPAR25183), Al-Jalila Foundation (AJF201454) and Zayed Center for Health Sciences (ZCHS2014). Dr. Sanchez-Garcia was supported by FEDER, by MICINN (SAF2012-32810), by NIH (R01 CA109335-04A1), by Junta de Castilla y León (BIO/SA06/13), by the ARIMMORA project (FP7-ENV-2011, EU 7th Framework Program) and by the EuroSyStem and the DECIDE Network (EU FP7). Dr. Sharma was funded by NIH grants (R01CA131294, CA155686), the Avon Foundation and a Breast Cancer Research Foundation grant (90047965). Dr. Saxena was supported by a grant from NIH (K01DK077137 and R03DK089130). Dr. Singh was supported by the Fast Track Scheme for Young Scientists, Department of Science and Technology, India (SR/FT/LS-063/2008). Dr. Honoki was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (no. 24590493). Dr. Ciriolo was supported by the Italian Association for Cancer Research (AIRC – grant #IG10636). Dr. Aquilano was supported by MIUR-PRIN (20125S38FA 002) and Ministero della Salute (GR-2011-02348047). Dr. Chen was funded from the Ovarian and Prostate Cancer Research Trust, UK. Dr. Mohammed is supported by the Purdue University Center for Cancer Research. W. Nicol Keith & Alan Bilsland were supported by the University of Glasgow, Beatson Oncology Centre Fund, and Cancer Research UK (http://www.cancerresearchuk.org) grant C301/A14762.

Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.

Chemotherapy is one of the most popular therapeutic strategies to treat cancer. However, cancer chemotherapeutics have often been associated with impairment of the immune system, which might consequently lead to an augmented risk of autoimmune disorders, such as rheumatoid arthritis. Though the accurate mechanistic facets of rheumatoid arthritis induction have not been interpreted yet, a conglomeration of genetic and environmental factors might promote its etiology. What makes the scenario more challenging is that patients with rheumatoid arthritis are at a significantly elevated risk of developing various types of cancer. It is intriguing to note that diverse cancer chemotherapy drugs are also commonly used to treat symptoms of rheumatoid arthritis. However, a colossal multitude of such cancer therapeutics has demonstrated highly varied results in rheumatoid arthritis patients, including both beneficial and adverse effects. Herein, we attempt to present a holistic account of the variegated modalities of this complex tripartite cross-talk between cancer, rheumatoid arthritis and chemotherapy drugs in order to decode the sinuous correlation between these two appalling pathological conditions.

Oryza sativa Linn. (rice) and Corchorus capsularis Linn. (jute) are the two major crops of the Bengal basin. Both rice and jute are generally grown in submerged flooded conditions, where arsenic bioavailability is high in soil. The consumers of the edible parts from both plants therefore face an inevitable source of exposure to arsenic, with consequent accumulation and toxicity. The objective of the study was to observe the in-vivo temporal variation of arsenic bioaccumulation in the different parts of O. sativa and C. capsularis. Rice plant specimens (Aman rice, Ratna variety) of different age groups (1, 2 and 3 months old) were analyzed in HG-AAS for absorbed arsenic content in different parts. The accumulation of arsenic remained significantly high in the initial phase of growth, but decreased with time. Amount of arsenic bioaccumulation followed the decreasing order: root > basal stem > median stem > apical stem > leaves > grains in all the three age groups of the rice plant samples. C. capsularis followed a trend of arsenic bioaccumulation similar to O. sativa. O. sativa had more accumulation potential than C. capsularis, but C. capsularis showed much higher efficiency of arsenic translocation in the above ground parts. This is the first ever report of time-dependent decrease in arsenic bioaccumulation in O. sativa and C. capsularis. The contamination level can reach the grain part in significant amount and can cause health hazards in more severely arsenic affected areas. Intensive investigation on a complete food chain is urgently needed in the arsenic contaminated zones for further risk assessments.

Degenerative conditions are associated with free radical-induced oxidative damages in the mitochondrial paraphernalia. Antimycin A (AMA) treatment of cells mimics such conditions in vitro by augmentation in ROS levels, thus causing injury to mitochondrial DNA (mtDNA), proteins and lipids, along with depolarization of mitochondrial membrane, activation of pro-apoptotic factors, resulting in apoptosis. This study investigates the potential of aqueous and methanolic extracts of Lawsonia inermis in prevention of such oxidative damage to the cell homeostasis. The extracts significantly mitigated membrane damages induced by peroxide, along with substantial decline in AMA-induced degeneration of mitochondrial proteins and lipids in hepatic carcinoma (Hep3B) cells. mtDNA analyzed for oxidative damage by assaying for 8-OHdG revealed considerable protective effect of both extracts against AMA-induced mtDNA damage. SQ-PCR of selected mtDNA genes confirmed that both extracts alleviated amplitudes of mtDNA injury. FACS analysis with JC-1 dye established that both extracts maintained homeostasis of mitochondrial membrane potential in AMA-treated cells. Extract treatments caused decline in AMA-induced discharge of cytochrome c and AIF into the cytoplasm along with consequent subjugation of apoptosis. All activities of the extracts reported in the present study significantly ( P

Arsenic (As) is a metalloid that causes severe water pollution due to its extravagant toxicity. Ceriodaphnia dubia, a freshwater crustacean, was selected as a model system to evaluate the degree of time and dosage dependent acute toxicity caused by pentavalent As [As(V)]. C. dubia were collected from a natural pond and treated with different concentrations of As(V) for 24 hours and 48 hours. For both 24 hours and 48 hours treatment periods, the mortality rates were increased significantly ( P< 0.05) with increase in As(V) concentrations. Simultaneously, it was also observed that As(V) - induced mortality in C. dubia also depended on the time of exposure to the metalloid. We propose this model as a low-cost technique towards rapid screening of water quality in relation to As contamination.

The two newer antiplatelet drugs, prasugrel and ticagrelor have both been incorporated in various national guidelines and are both under consideration for approval or have already been approved by various drug regulatory authorities. Mortality benefits with clopidogrel were comparable to newer anti-platelets, and prasugrel had great anti-ischemic potency than ticagrelor. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials' databases for randomized controlled trials conducted between 1990 and 2012 that assessed clinical outcomes with prasugrel or ticagrelor. The comparator was standard dosage of clopidogrel. Outcomes assessed were the risk of all causes mortality, TIMI non-CABG major bleeding, and a composite of stent thrombosis, recurrent ischemia and serious recurrent ischemia in the intervention groups versus the comparator groups. Event rates were compared using a forest plot of relative risk using a random effects model (Mantel-Haenszel); and Odd's ratio was calculated in the absence of significant heterogeneity. Prasugrel was indirectly compared with ticagrelor using network meta-analysis. Four studies (total N = 34,126) met the inclusion/exclusion criteria. Both drugs had improved mortality and greater risk of bleeding compared to clopidogrel; but outcomes were comparable for both (p = NS). However a composite of recurrent ischemic events, including rates of stent thrombosis (p = 0.045) was reduced to a modest degree with prasugrel compared with ticagrelor. This systematic review suggests greater clinical efficacy of both prasugrel and ticagrelor compared with clopidogrel and an indirect comparison indicates prasugrel may be more effective than ticagrelor for preventing stent thrombosis and recurrent ischemic events.

Objective To isolate metabolites from the methanolic extract of Oroxylum indicum (O. indicum) stem bark and test their bioactivities.

Picrorhizakurroa Royle ex Benth., a well-known traditional herb from the Scrophulariaceae family has a remarkable reputation among the indigenous medical practitioners. The antioxidant and anti-neoplastic activities of methanolic and aqueous extracts of P. kurroa rhizome were investigated in the present study. The total phenolic content was determined by a spectrophotometric method. The antioxidant efficacies of the extracts were studied employing radical scavenging assays (DPPH· and ·OH), ferric reducing antioxidant property (FRAP) and thiobarbituric acid (TBA) assay for testing inhibition of lipid peroxidation. Furthermore, the cytotoxicity of the extracts was tested by XTT assay in MDA-MB-435S (human breast carcinoma), Hep3B (human hepatocellular carcinoma) and PC-3 (human prostate cancer) cell lines. The ability of the extracts to induce apoptosis was also investigated. Both extracts exhibited promising antioxidant potentials. The extracts were also observed to be cytotoxic at the tested dosage and were able to target cells towards apoptosis. The study concludes that P. kurroa possess diverse therapeutic potentials which might be useful in development of drugs or their precursors.

This study was aimed at investigating the phenolic constituents of methanolic and aqueous extracts of Vitex negundo in context of antioxidant potential and inhibition of oxidative stress-induced cytotoxicity. Antioxidant efficacies of both extracts were estimated by their abilities to scavenge DPPH(*) and to reduce Fe(+3) to Fe(+2). Their protective potential against H(2)O(2)-driven oxidative damage to cells were evaluated by XTT assay in Hep3B (human hepatoma) cells. Total phenolic content of both extracts were estimated, and were tested for correlation with antioxidant potential and protection against oxidative cytotoxicity. Polyphenolic levels in both extracts showed significant (P

Prevention of various diseases using natural compounds has been of interest for many decades. Floral diversity has been widely investigated for possible protective and preventive properties, and various plant-based medicines have been introduced in the recent times. Antioxidant potential, cytotoxicity and DNA cleavage protective properties of methanolic and aqueous extracts of Acalypha fruticosa Forssk were evaluated in this study. The amount of total phenolics was determined by a spectrophotometric method. Ferric reducing antioxidant property (FRAP) assay, radical scavenging assays (DPPH() and ()OH) and thiobarbituric acid (TBA) assay for testing inhibition of lipid peroxidation were employed to determine antioxidant property of the extracts. Furthermore, cytotoxicity of both extracts was tested by XTT assay in MDA-MB-435S (human breast carcinoma cell line) and Hep3B (human hepatocellular carcinoma). DNA protective efficiency of the extracts was also studied using UV-photolysed H(2)O(2)-driven oxidative damage to pBR322. Both extracts exhibited promising antioxidant potentials and marginal cytotoxicity to the tested cell lines. Simultaneously, the extracts showed considerably high DNA-protection against photolysed H(2)O(2)-induced oxidative damage in pBR322. The study concluded that A. fruticosa holds colossal and diverse therapeutic potentials which might be useful in development of drugs or their precursors, thereby holding immense clinical prospect.

Cr(VI) (hexavalent) is a very strong oxidant which causes high cytotoxicity through oxidative stress in tissue systems. Its abundance in groundwater and drinking water in several parts of the world has been noted to cause severe toxicity to both flora and fauna. This study evaluated the effects of aqueous extract of Phyllanthus amarus Schum. & Thon. against Cr(VI)-induced oxidative toxicity in vitro in MDA-MB-435S human breast carcinoma cells, along with an estimation of its antioxidant potential, inhibition of lipid peroxidation and determination of its polyphenolic composition. The extract showed significant (P

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.

Aims: The absolute white blood cell (WBC) count and neutrophil to lymphocyte (N/L) ratio are predictors of death/myocardial infarction in patients who have undergone coronary angiography. We hypothesized that a pre-procedural elevated WBC count and an elevated N/L ratio would be a predictor of development of significant ventricular arrhythmias in subjects undergoing percutaneous coronary intervention (PCI). Methods and Results: We retrieved the data for all patients developing ventricular arrhythmia during PCI between 1999 to 2009 from our cath lab database (from 30,798 records), a total of 70 patients (Group I), and tabulated their WBC counts and absolute neutrophil and lymphocyte counts as well as N/L ratios. We compared the data with a random group of age, gender, medications and pre-existing condition matched controls (n=70) (Group II). We also adjusted for amount of myocardium under jeopardy. Group I had a significantly higher total WBC count (means 14,344 Vs 6852; 95% CI; p=0.0004); neutrophil count (means 75.79% Vs 58.06%; 95% CI; p < 0.0001) and N/L ratio (means 3.79 Vs 1.56; 95% CI; p < 0.0001) [means compared with t test]. Conclusion: Our data suggests a pre-procedural elevated WBC count, neutrophils and elevated N/L ratio are predictors of significant ventricular arrhythmias in patients undergoing percutaneous coronary intervention (PCI).

Central nervous system (CNS) hemangiopericytomas are rare mesenchymal tumors of the brain. In the absence of randomized clinical trials or large studies, the only information we have about the natural history and the management is from isolated clinical case series. They have suggested that surgery is beneficial, with conflicting results on the role of complete resection and adjuvant radiation. We have conducted a systematic review of clinical case series of CNS hemangiopericytoma analyzing the biology of the tumor and the best follow-up and management strategy. Fifteen pertinent clinical case series on newly diagnosed CNS hemangiopericytoma were selected by a review of literature. A total of 523 patients were analyzed for age, sex, mode of recurrence and metastases, and survival after complete/incomplete resection with or without radiation. The mean age was found to be 44.17 (±3.59) years. The incidence was higher in male individuals younger than 45 years and in older female individuals. Complete resection and adjuvant radiation significantly improved survival in comparison with incomplete resection and no radiation, respectively (P

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), β-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-β), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

Prevention and treatment of various degenerative diseases using traditional medicines is increasingly generating interest, especially in geriatric clinical research. This study aimed to evaluate the free-radical scavenging properties and potential to prevent DNA damage (from oxidative stress) of 56 extracts (polar and non-polar) from 14 medicinal plants (from 12 families) used by diverse Indian tribes and ethnic groups. Although widely known for traditional uses, these plants have not been extensively used for clinical purposes. Scavenging of DPPH\bullet radical by all the extracts was evaluated to estimate their antioxidant potential and rank them accordingly. Extracts occupying the top 10 ranks were further evaluated and extensively screened for their antioxidant potential by estimation of their ABTS\bullet+-scavenging and Fe+3-reducing properties. A cumulative ranking system was designed for these 10 plant extracts based on the results of the 3 antioxidant assays. Simultaneously, protection of DNA against photolyzed H2O2-induced oxidative damage by all 56 extracts was studied in pBR322. Considerable anti-genotoxic potential was exhibited by the top 3 extracts on the cumulative rank table, thereby proving the results of all the experiments were congruent. This is a preliminary report, which may yield a roadmap for isolating the active components from these extracts and designing geriatric medicines.

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although rare, can be devastating. Conflicting reports have been published regarding the protective effect of systemic rituximab therapy and likely reduction in incidence of CNS relapse in post-rituximab era. Methods: We retrospectively identified all the DLBCL patients at our institute between 2004 and 2014 who received systemic rituximab-based chemo-therapy at initial presentation. Patients were categorized into two groups, “standard risk” with no risk factors and “high risk” with one or more of the following risk factors, elevated lactate dehydrogenase (LDH) (above the institute normal), international prognostic index (IPI) ≥3, involvement of testis, breast, bone, kidneys, adrenal gland, retroperitoneal lymph nodes, para-meninges, and bone marrow. Descriptive statistics were used to analyze inci-dence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results: A total of 122 patients received rituximab-based therapy at the initial diagnosis; 73 patients (60%) qualified for standard risk; 49 patients (40%) met the criteria for “high risk” based on the above definition. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapse. Thirty-one of 49 (63%) “high risk” patients received CNS prophylaxis, mainly intrathecal (IT) methotrexate. Five patients (4.0%) developed CNS relapse in the entire study population. Percentage of patients developed CNS relapse in high-risk patients was 10.2% (5/49). Median time to relapse was 8.76 months and median survival after CNS relapse was 9.16 months. Four out of five patients who developed CNS relapse received prophylaxis with IT. Conclusions: CNS relapse continued to be a rare but devas-tating complication in post rituximab era, however our study confirms that majority of the DLBCL patients do not need CNS directed therapy. Current CNS directed therapies are probably inadequate to prevent CNS relapse in high risk DLBCL patients, therefore further research to develop better agents is needed in this area.

The two newer antiplatelet drugs, prasugrel and ticagrelor have both been incorporated in various national guidelines and are both under consideration for approval or have already been approved by various drug regulatory authorities. However, superiority of any one remains controversial and

Background: Ctip2 is crucial for epidermal homeostasis and protective barrier formation in developing mouse embryos. Selective ablation of Ctip2 in epidermis leads to increased transepidermal water loss (TEWL), impaired epidermal proliferation, terminal differentiation, as well as altered lipid composition during development. However, little is known about the role of Ctip2 in skin homeostasis in adult mice. Methodology/Principal Findings: To study the role of Ctip2 in adult skin homeostasis, we utilized Ctip2 ep2/2 mouse model in which Ctip2 is selectively deleted in epidermal keratinocytes. Measurement of TEWL, followed by histological, immunohistochemical, and RT-qPCR analyses revealed an important role of Ctip2 in barrier maintenance and in regulating adult skin homeostasis. We demonstrated that keratinocytic ablation of Ctip2 leads to atopic dermatitis (AD)-like skin inflammation, characterized by alopecia, pruritus and scaling, as well as extensive infiltration of immune cells including T lymphocytes, mast cells, and eosinophils. We observed increased expression of T-helper 2 (Th2)-type cytokines and chemokines in the mutant skin, as well as systemic immune responses that share similarity with human AD patients. Furthermore, we discovered that thymic stromal lymphopoietin (TSLP) expression was significantly upregulated in the mutant epidermis as early as postnatal day 1 and ChIP assay revealed that TSLP is likely a direct transcriptional target of Ctip2 in epidermal keratinocytes. Conclusions/Significance: Our data demonstrated a cell-autonomous role of Ctip2 in barrier maintenance and epidermal homeostasis in adult mice skin. We discovered a crucial non-cell autonomous role of keratinocytic Ctip2 in suppressing skin inflammatory responses by regulating the expression of Th2-type cytokines. It is likely that the epidermal hyperproliferation in the Ctip2-lacking epidermis may be secondary to the compensatory response of the adult epidermis that is defective in barrier functions. Our results establish an initiating role of epidermal TSLP in AD pathogenesis via a novel repressive regulatory mechanism enforced by Ctip2.

The study was aimed at evaluating apoptosis induction potentials of methanolic and aqueous extracts of Rheum emodi Wall. ex Meissn. rhizome. The ability of the extracts to induce apoptosis in MDA-MB-435S (human breast carcinoma), Hep3B (human hepatocellular carcinoma) and PC-3 (human prostate cancer) cell lines were tested by ELISA to detect cellular DNA fragmentation. Results obtained from the present study confirm that the extracts target the cancerous cells towards apoptosis. The study concludes that R. emodi possess anticancer metabolites that can be isolated and used as precursors in development of anticancer drugs. Suppression of apoptosis might contribute to tumor development by means of accumulation of continuously proliferating cells. The strategy employed in this study, to induce apoptosis in the tumor cells, could be a potential target of therapeutic intervention of cancers.

Hexavalent chromium Cr(VI) is a very strong oxidant which consequently causes high cytotoxicity through oxidative stress. Prevention of Cr(VI)-induced cellular damage has been sought in this study in aqueous and methanolic extracts ofLawsonia inermisLinn. (Lythraceae), commonly known asHenna. The extracts showed significant (P< .05) potential in scavenging free radicals (DPPH•and ABTS•+) and Fe3+, and in inhibiting lipid peroxidation. DNA damage caused by exposure of pBR322 to Cr(VI)-UV is markedly inhibited by both extracts in varying degrees. A distinct decline in Cr(VI)-induced cytotoxicity was noticed in MDA-MB-435S (human breast carcinoma) cells with an increase in dosage of both extracts individually. Furthermore, both extracts proved to contain a high content of phenolic compounds which were found to have a strong and significant (P< .05) positive correlation to the radical scavenging potential, lipid peroxidation inhibition capacity and cyto-protective efficiency against Cr(VI)-induced oxidative cellular damage. HPLC analysis identified some of the major phenolic compounds in both extracts, which might be responsible for the antioxidant potential and the properties of DNA and cyto-protection. This study contributes to the search for natural resources that might yield potent therapeutic drugs against Cr(VI)-induced oxidative cell damage.

The objective of this study was to determine antioxidant and cytotoxic efficacies of methanolic and aqueous extracts ofRheum emodiWall. ex Meissn. rhizome. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities, inhibitory effect on lipid peroxidation and Fe3+reducing antioxidant property have been used to investigate antioxidant properties of the extracts. Cytotoxicity of the extracts was tested on MDA-MB-435S and Hep3B cell lines. Both extracts displayed extensive cytotoxicity to the tested cell lines. The extracts were studied for their ability to protect pBR322 DNA from damage by UV induced photolysis of H2O2. The aqueous extract, though inferior to methanolic extract in its antioxidant potential exhibited efficiency in DNA protection, while the methanolic extract failed to protect the DNA. The amount of total polyphenolics in the extracts was measured by spectrophotometric method. The methanolic extract contained higher polyphenolic contents than aqueous extract. Significant positive correlations were observed (P< .05) between results of phenolic content estimation and that of antioxidant assays. Hence, high-performance liquid chromatography analysis was performed to identify few major phenolic compounds that might be responsible for these therapeutic properties. These results indicate that rhizome ofR. emodipossesses antioxidant and cytotoxic activities and therefore have therapeutic potential.

Cyanthillium cinereum(Less.) H. Rob. (Asteraceae) has been traditionally known for its medicinal properties, all aspects of which are yet to be exploited. This study was aimed at investigating the therapeutic potential of polar (methanolic and aqueous) and nonpolar (hexane and chloroform) crude extracts of the whole plant. Several parameters including free-radical (DPPH•, ABTS•+, H2O2and•OH) scavenging, reducing power, protection of DNA against oxidative damage, cytotoxicity, inhibition of oxidative hemolysis in erythrocytes, total phenolic content and inhibition of lipid peroxidation were examined. All the free-radical generating assay models demonstrated positive scavenging efficiency with differential but considerable magnitudes for the four extracts. However, only the hexane extract showed significant H2O2scavenging effect. Lipid peroxidation was estimated by thiobarbituric acid-malondialdehyde (MDA) reaction, and a high degree of inhibition was shown by all the extracts. Reducing power of the polar extracts was higher than the non-polar ones. All extracts showed a concentration-dependent increase in phenolic contents. Oxidative damage to erythrocytes was hindered by all extracts in diverse degrees. XTT assay showed that all extracts have mild cytotoxic property. The aqueous extract evidently demonstrated protective effect on pBR322 plasmid DNA against oxidative breakdown. These results suggested the potential ofC. cinereumas medicine against free-radical-associated oxidative damage and related degenerative diseases involving metabolic stress, genotoxicity and cytotoxicity.

Metronidazole (MTZ), a nitroimidazole drug, is primarily used as an anti-protozoan or an anti-bacterial agent in humans, although its genotoxic and carcinogenic effects have been widely reported, particularly in aquatic organisms. MTZ may induce DNA damages through single-strand breaks, modification of bases, DNA-DNA and DNA-protein cross-links, ultimately leading to apoptosis or necrosis. Here, we have assessed the genotoxicity of MTZ in the peripheral erythrocytes of Channa punctatus, using micronucleation (MN) and binucleation (BN) as genotoxicity markers. The therapeutic potential of aqueous extract of Coriandrum sativum against MTZ-induced genotoxicity has also been examined. The results show significant (P

Antimycin A (AMA) treatment of cells blocks mitochondrial electron transport chain, and leads to elevated ROS generation, thereby causing damage to mtDNA, proteins and lipids, along with mitochondrial membrane depolarization, release of pro-apoptotic proteins into the cytoplasm, and induction of apoptosis. Prevention of such oxidative cellular damage by the aqueous extract of Phyllanthus amarus has been investigated in this study. The extract demonstrated significant potential in mitigating H(2)O(2)-induced membrane damage along with considerable recession in AMA-governed mitochondrial protein and lipid degradation in Hep3B cells. 8-OHdG analysis of mtDNA damage revealed substantial protective potential of the extract against mtDNA damage. SQ-PCR of selected mtDNA sequences confirmed the potential of the extract to alleviate levels of mtDNA damage. FACS analysis with JC-1 fluorescent dye established significant escalation of mitochondrial membrane potential by the extract in AMA-treated cells. Extract treatment resulted in a distinct decline in the degrees of AMA-induced release of cytochrome c and AIF into the cytoplasm along with consequent pacification of apoptosis. All protective efficiencies of the extract reported in this study were found to hold strong and significant (P0.05) positive correlation to its total phenolic contents, thereby proving that polyphenolic constituents of P. amarus aqueous extract mitigate oxidative stress-induced cellular degeneration and aging.

e19523 Gender specific mortality in diffuse large B cell lymphoma patients receiving R-CHOP Background: Significant gender specific mortality differences were observed in diffuse large B cell lymph...

INTRODUCTION CNS relapse in DLBCL carries poor prognosis. Some studies have suggested decreased incidence with rituximab, but there are several others reporting otherwise. We analyzed prospective studies in literature to understand the role of rituximab and CNS prophylaxis in DLBCL, in comparison to CHOP based therapy. METHOD Extensive searches using PUBMED, EMBASE, CENTRAL and major hematology conferences were conducted for prospective studies. The keywords “CNS”, “diffuse large B-cell lymphoma”, “relapse”, “prophylaxis”, “rituximab”, “CHOP” were used. Inclusion: (i) prospective or randomized trials (ii) Entire study population or a significant majority of patients were newly diagnosed DLBCL, (iii) no evidence of CNS involvement at baseline, (iv) use of rituximab-chemotherapy or CHOP-based chemotherapy, (v) have data relevant to our study. Exclusion: (i) retrospective studies, review article or case reports, (ii) exclusively testicular, mediastinal or double hit lymphoma, (iii) HIV positive patients. Data is presented as mean ± standard error of mean. Significant differences (at P RESULTS The study population characteristics are shown in Table. The mean incidence of CNS relapse with rituximab-chemotherapy (R-CHOP/R-CHOEP) was found to be 5.52% (3.21%-7.73%), while that with CHOP-based chemotherapy alone was 4.43% (3.53% -5.33%). No significant difference was observed by two-tailed unpaired t test (P = 0.94). The median time from diagnosis to CNS relapse was 6.5-7 months. The mean incidence of leptomeningeal, parenchymal and both relapses in the rituximab-chemotherapy group were 38.62(±1.93)%, 57.32(±3.06)%, 5.36(±1.79)% compared to 16.17(±0.44)%, 66.17(±0.44)%, 22.06(±0.41)% with chemotherapy alone. One-way ANOVA also showed that use of rituximab resulted in statistically significant (P CONCLUSION Rituximab hasn't significantly decreased overall incidence, but causes less parenchymal CNS relapse. CNS prophylaxis has a definite role in high risk population. There is significantly better survival after CNS relapse in the rituximab era. Abstract 1644. TABLE STUDY Age (yr) Sex (M:F) No. Stage 3/4 IPI int-high/ high (>=3 IPI or >=2 aa IPI) Extranodal (>=2) high LDH Follow up (m) Criteria for CNS prophylaxis Patients receiving CNS prophylaxis (IT=intrathecal, S=systemic) Chemo Tilly 2003 61-69 ACVBP vs CHOP : M 182 vs 177 F 141 vs 135 635 (501 DLBCL) 267 vs 253 210 vs 207 (aa IPI) 155 VS 156 231 VS 241 68 None for CHOP VS ACVBP (IV methotrexate, etop + IT mtx) 323 (ACVBP) 323 ACVBP vs 312 CHOP Feugier 2004 69 M 92 (CHOP-R) vs 107 (CHOP) 202 vs 197 161 vs 157 121 vs 120 61 vs 51 131 vs 132 24 NA no prophylaxis 202 R-CHOP Vs 197 CHOP Bernstein 2009 97/ 225 for CHOP were >60 yrs NR 899 aggressive lymphoma 191/ 225 CHOP 95/ 225 CHOP 81/225 CHOP 146/ 225 CHOP 20 years none for CHOP 121 IT MTX or radiation (24 Gy) 225 CHOP vs ProMACE-CytaBOM vs mBACOD vs MACOP-B Boehme 2009 68 648 vs 569 1217 (944 DLBCL) 687 507 212 602 24 bone marrow, testes, sinuses, orbits, oral cavity, tongue, salivary glands. 475/1217 (IT-MTX) 608 RCHOP Vs 609 CHOP Kim 2012 59.5 NR 564 276 192 193 NR 10.5 ≥1 risk factor 59 IT RCHOP Kumar 2012 56 (prophylaxis) VS 58 (no prophylaxis) male: 74 vs 476 female: 43 vs 396 989 85 vs 454 55 vs 240 66 vs 220 57 vs 372 30 High risk site involvement : orbit, testis, peripheral blood, vertebra, bone marrow, nasal/paranasal sinuses 117/989 IT- 84/117 (AraC/MTX) S--33/117 (MTX) R-CHOP Holte 2013 54 97 vs 59 156 (145 DLBCL) 150 156 41 151 36 everyone 156/156 (S- Ara-c+ MTX) 1 dose of IT-MTX RCHOEP Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

According to the mitochondrial theory of aging, accrual of mutations in mitochondrial DNA (mtDNA) plays the paramount function in the cellular pathology of aging and in development of age-related degenerative ailments. Reactive oxygen species (ROS), which are byproducts of oxidative phosphorylation (OX-PHOS) in aerobic (mitochondrial) respiration, cause oxidative stress-induced damage to mtDNA. This damaged DNA, whose normal role is to encode proteins many of which are players in the electron transport chain (ETC), now codes for defective proteins. Such faulty proteins lead to a considerable impairment in the efficacy of ETC, thereby generating more ROS, which cause further damage to mtDNA in turn, leading to further defects in proteins, aggravated ETC dysfunction, and even more ROS. Hence, a ‘vicious cycle’ propagates that ultimately directs tissue cells towards structural and functional decline, or in other words, degeneration and aging. However, in spite of a wide acceptance of this theory, there have simultaneously been a considerable number of criticisms against it. This review is aimed at discussing the paradigm of aging and degenerative diseases in light of the mitochondrial paraphernalia, with reference to the evidences in support as well as in antagonism to the mitochondrial theory of aging.Keywords: Aging; Degenerative diseases; mtDNA mutations; ROS; Cell death.© 2011 JSR Publications. ISSN: 2070-0237 (Print); 2070-0245 (Online). All rights reserved.doi:10.3329/jsr.v3i1.5078 J. Sci. Res. 3 (1), 176-186 (2011)

BACKGROUND We evaluated mean QRS duration improvement immediately after cardiac resynchronization therapy (CRT) in patients with non-ischemic cardiomyopathy (NICM), with a left bundle branch block (LBBB) pattern on electrocardiogram (ECG), owing to obligatory right ventricular pacing or as a new finding; and to what extent. METHODS AND RESULTS We tabulated ECGs of 18 subjects, 24 hours before and after receiving CRT, for both groups. The percentage decreases of QRS duration in all groups were statistically similar (p

The study was aimed to evaluate antioxidant activity of methanolic and aqueous extracts of Bergenia ciliata (Haw.) Sternb.rhizome. Total phenolic content was determined in both extracts. Free radical (DPPH● and ●OH) scavenging potential of the extracts revealed that both extracts to be active radical scavengers. Reducing (Fe+3-Fe+2) power and lipid peroxidation inhibition efficiency (TBARS assay) of both extracts were also evaluated and both extracts showed promising activity in preventing lipid peroxidation and might prevent oxidative damages to biomolecules. Furthermore, the ability of the extracts to protect DNA (pBR322) against UV-induced photolysed H2O2 – oxidative damage was analysed. Both the extracts were able to protect DNA from oxidative damage. The results obtained suggest that extracts of B. ciliata have promising therapeutic potential and could be considered as potential source for drug development by pharmaceutical industries.