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Putative Mechanism (putative + mechanism)
Selected AbstractsPutative Mechanism for Anticancer and Apoptosis-Inducing Properties of Plant-Derived Polyphenolic CompoundsIUBMB LIFE, Issue 3 2000S. M. Hadi Abstract Several plant-derived polyphenolic compounds are considered to possess anticancer and apoptosis-inducing properties in cancer cells. Such compounds are recognized as naturally occurring antioxidants but also exhibit prooxidant properties under appropriate conditions. Evidence in the literature suggests that the antioxidant properties of polyphenolics such as gallotannins, curcumin, and resveratrol may not fully account for their chemopreventive effects. We propose a mechanism for the cytotoxic action of these compounds against cancer cells that involves mobilization of endogenous copper and the consequent prooxidant action. [source] Current hypotheses for the underlying biology of amyotrophic lateral sclerosis,ANNALS OF NEUROLOGY, Issue S1 2009Jeffrey D. Rothstein MD The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression. Ann Neurol 2009;65 (suppl):S3,S9 [source] Managing amyotrophic lateral sclerosis: Slowing disease progression and improving patient quality of life,ANNALS OF NEUROLOGY, Issue S1 2009Benjamin Rix Brooks MD It is now possible to slow the disease progression of amyotrophic lateral sclerosis (ALS), but documented improvement in the quality of life of ALS patients has been difficult to quantitate. Putative mechanisms involved in motor neuron degeneration in ALS include oxidative damage, mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity. Several pharmacological agents that target these potential targets have demonstrated therapeutic potential in animal models with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Many treatments that have been moderately effective in this animal model have not been successfully translated into effective treatments for humans with ALS. Only the glutamate modulator riluzole has demonstrated efficacy in clinical trials and is approved for treating ALS. Combination treatments may represent a potential therapeutic strategy to more robustly prolong life and preserve function, but only vitamin E with riluzole has been formally studied in clinical trials, and to date, no combination treatments have been found to be more effective than currently available single agents. Ann Neurol 2009;65 (suppl):S17,S23 [source] 20-hydroxyecdysone and juvenile hormone influence tyrosine hydroxylase activity in Drosophila females under normal and heat stress conditionsARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 4 2009N. E. Gruntenko Abstract The effects of exogenous 20-hydroxyecdysone (20E) and the juvenile hormone (JH) on the activity of the tyrosine hydroxylase (TH), the first and rate-limiting DA biosynthetic enzyme, has been studied in young females of wild type D. virilis and D. melanogaster under normal conditions and under heat stress (38°C). Both 20E feeding of the flies and JH application led to a substantial rise in TH activity. A rise in JH and 20E levels was found not to prevent the response of TH to heat stress, but to change the intensity of its response to the stress exposure. Putative mechanisms of regulation of DA level by 20E and JH in Drosophila females are discussed. © 2009 Wiley Periodicals, Inc. [source] IFN-, induces apoptosis in mouse embryonic stem cells, a putative mechanism of its embryotoxicityDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 3 2000Gang-Ming Zou It has been reported that interferon (IFN)-, should inhibit in vitro mouse embryo growth by direct cell toxicity. However, the mechanism involved has not been clearly established. In the present study, this question was addressed using the embryonic stem (ES) cell model. It was found that IFN-, induces a dose-dependent apoptosis in ES cells, as assessed by trypan-blue staining, by Annexin-V labeling and DNA analysis. Moreover, IFN-, treatment cooperates with Fas-mediated apoptosis, a phenomenon that has been recently reported. As Bcl-2 oncoprotein functions as a death repressor molecule in an evolutionarily conserved cell death pathway, its expression was analyzed by flow cytometry. It was demonstrated that Bcl-2 is expressed in ES cells. When compared to untreated ES cells, IFN-,-treated, apoptotic cells expressed a lower Bcl-2 level and a normal level of Fas, whereas surviving cells expressed a normal level of Bcl-2 but a lower Fas expression. Altogether, these data suggest that IFN-, may influence early mouse embryo development by promoting apoptosis, which may constitute a novel mechanism of IFN-, embryotoxicity. [source] Alkaloids may not be responsible for endophyte-associated reductions in tall fescue decomposition ratesFUNCTIONAL ECOLOGY, Issue 2 2010Jacob A. Siegrist Summary 1. ,Fungal endophyte , grass symbioses can have dramatic ecological effects, altering individual plant physiology, plant and animal community structure and function, and ecosystem processes such as litter decomposition and nutrient cycling. 2. ,Within the tall fescue (Schedonorus arundinaceus) , fungal endophyte (Neotyphodium coenophialum) symbiosis, fungal produced alkaloids are often invoked as the putative mechanism driving these ecological responses. Yet few measurements of alkaloids exist in the ecological literature. In this study, we quantified alkaloid levels in live, standing dead and decomposing endophyte-infected (E+) and ,free (E,) plant material and simultaneously evaluated the direct and indirect effects of endophyte presence on tall fescue decomposition. 3. ,Loline and ergot alkaloid levels were consistently high in live E+ (common toxic strain of N. coenophialum) tall fescue biomass throughout the sampling period (May,November 2007), whereas, E, live and standing dead material had non-detectable alkaloid concentrations. Standing dead E+ biomass had significantly reduced alkaloid levels (6,19x lower than the levels measured in the corresponding live E+ biomass) that were equivalent to E, live and dead for loline but were still somewhat higher than E, material for ergots. 4. ,In an effort to test the role of alkaloids in directly inhibiting decomposition, as has been suggested by previous studies, we conducted a litter bag experiment using green, alkaloid-laden E+ and alkaloid-free E, tall fescue plant material. We incubated E+ and E, litter bags in both E+ and E, tall fescue stands for 170 days, and measured mass loss, carbon and nitrogen content, and ergot and loline alkaloid concentrations over the incubation period. 5. ,Consistent with previous reports, both direct and indirect effects of endophyte presence on litter decomposition were observed: endophyte presence in the litter and surrounding microenvironment significantly reduced decomposition rates. Surprisingly, despite large differences in alkaloid content between E+ and E, litter from Day 0,Day 21 of the incubation, direct effects of the endophyte on litter decomposition, while significant, were relatively small (differences in mass loss between E+ and E, litter were never >3%). Alkaloids were gone from E+ material by day 56. 6. ,We propose that results from this study indicating alkaloids are largely absent in standing dead material (the typical input to the decomposition process), and that despite being present in our litter bag experiment, failed to produce large differences in mass loss between E+ and E, material questions the supposition that fungal produced alkaloids directly inhibit decomposition. Additional studies exploring the mechanisms behind the direct and indirect effects of endophytes on this ecosystem process are needed. [source] Granulocyte-macrophage colony-stimulating factor elicits bone marrow-derived cells that promote efficient colonic mucosal healingINFLAMMATORY BOWEL DISEASES, Issue 3 2010Eric Bernasconi PhD Abstract Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy is effective in treating some Crohn's disease (CD) patients and protects mice from colitis induced by dextran sulfate sodium (DSS) administration. However, its mechanisms of action remain elusive. We hypothesized that GM-CSF affects intestinal mucosal repair. Methods: DSS colitic mice were treated with daily pegylated GM-CSF or saline and clinical, histological, and inflammatory parameters were kinetically evaluated. Further, the role of bone marrow-derived cells in the impact of GM-CSF therapy on DSS colitis was addressed using cell transfers. Results: GM-CSF therapy reduced clinical signs of colitis and the release of inflammatory mediators. GM-CSF therapy improved mucosal repair, with faster ulcer reepithelialization, accelerated hyperproliferative response of epithelial cells in ulcer-adjacent crypts, and lower colonoscopic ulceration scores in GM-CSF-administered mice relative to untreated mice. We observed that GM-CSF-induced promotion of mucosal repair is timely associated with a reduction in neutrophil numbers and increased accumulation of CD11b+ monocytic cells in colon tissues. Importantly, transfer of splenic GM-CSF-induced CD11b+ myeloid cells into DSS-exposed mice improved colitis, and lethally irradiated GM-CSF receptor-deficient mice reconstituted with wildtype bone marrow cells were protected from DSS-induced colitis upon GM-CSF therapy. Lastly, GM-CSF-induced CD11b+ myeloid cells were shown to promote in vitro wound repair. Conclusions: Our study shows that GM-CSF-dependent stimulation of bone marrow-derived cells during DSS-induced colitis accelerates colonic tissue repair. These data provide a putative mechanism for the observed beneficial effects of GM-CSF therapy in Crohn's disease. (Inflamm Bowel Dis 2010;) [source] Benign hereditary chorea revisited: A journey to understandingMOVEMENT DISORDERS, Issue 16 2007Galit Kleiner-Fisman MD Abstract Benign hereditary chorea (BHC) has been characterized as an autosomal dominant disorder manifesting nonprogressive chorea without dementia. However, there has been controversy regarding its existence. Diagnosis has been based solely on clinical criteria with many patients and families demonstrating "atypical" features and until recently, no diagnostic test was available for confirmation. Since 2002, mutations in the thyroid transcription factor (TITF-1) gene have been identified as resulting in some cases of BHC. Additionally, the clinical spectrum has expanded to include abnormalities in thyroid and lung with the putative mechanism of disease resulting from gene haploinsufficiency and reduced protein product. This review summarizes both a historical perspective and our current understanding of BHC. © 2007 Movement Disorder Society [source] Type 2 diabetes, cardiovascular disease, and the evolutionary paradox of the polycystic ovary syndrome: A fertility first hypothesisAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 5 2009Stephen J. Corbett Worldwide, the high prevalence of the Polycystic Ovary Syndrome (PCOS), a heritable cause of ovarian infertility, is an evolutionary paradox, which provides insight into the susceptibility of well-fed human populations to cardiovascular disease and diabetes. We propose that PCOS, Type 2 diabetes (T2D) and the Metabolic Syndrome are modern phenotypic expressions of a metabolic genotype attuned to the dietary and energetic conditions of the Pleistocene. This metabolic "Fertility First" rather than "Thrifty" genotype persisted at high prevalence throughout the entire agrarian period,from around 12,000 years ago until 1800 AD,primarily, we contend, because it conferred a fertility advantage in an environment defined by chronic and often severe seasonal food shortage. Conversely, we argue that genetic adaptations to a high carbohydrate, low protein agrarian diet, with increased sensitivity to insulin action, were constrained because these adaptations compromised fertility by raising the lower bound of body weight and energy intake optimal for ovulation and reproduction. After 1800, the progressive attainment of dietary energy sufficiency released human populations from this constraint. This release, through the powerful mechanism of fertility selection, increased, in decades rather than centuries, the prevalence of a genotype better suited to carbohydrate metabolism. This putative mechanism for rapid and recent human evolution can explain the lower susceptibility to T2D of today's Europid populations. This hypothesis predicts that the increasing rates of diabetes and cardiovascular disease, which typically accompany economic development, will be tempered by natural, but particularly fertility, selection against the conserved ancestral genotypes that currently underpin them. Am. J. Hum. Biol. 2009. © 2009 Wiley-Liss, Inc. [source] Analysis of TPI gene promoter variation in three sub-Saharan Africa population samplesAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 1 2009Licínio Manco Population samples from Angola, Mozambique, and S. Tomé e Príncipe were screened for the TPI gene promoter variants -5A,G, -8G,A and -24T,G. Three haplotypes were identified in the three populations: the haplotype -5A-8G-24T (average frequency 65.3%) and two less common haplotypes -5G-8G-24T (average frequency 24.7%) and -5G-8A-24T (average frequency 10.0%). A population sample from Central Portugal showed the haplotype -5A-8G-24T in 139 chromosomes and one subject heterozygous for haplotype -5G-8A-24G. The exact test of sample differentiation among three groups of malaria-infected individuals classified according to the severity of the disease showed no significant differences. We confirmed TPI gene diversity in sub-Saharan Africa, but we could not detect any association between TPI promoter variation and a malarial protective effect. Larger scale epidemiological studies are thus required to clarify this putative mechanism of natural host defense against this worldwide public health problem. Am. J. Hum. Biol., 2009. © 2008 Wiley-Liss, Inc. [source] Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates,ANNALS OF NEUROLOGY, Issue 3 2009Stefano Pluchino MD Objective Transplanted neural stem/precursor cells (NPCs) display peculiar therapeutic plasticity in vivo. Although the replacement of cells was first expected as the prime therapeutic mechanism of stem cells in regenerative medicine, it is now clear that transplanted NPCs simultaneously instruct several therapeutic mechanisms, among which replacement of cells might not necessarily prevail. A comprehensive understanding of the mechanism(s) by which NPCs exert their therapeutic plasticity is lacking. This study was designed as a preclinical approach to test the feasibility of human NPC transplantation in an outbreed nonhuman primate experimental autoimmune encephalomyelitis (EAE) model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the standard laboratory rodent. Methods We examined the safety and efficacy of the intravenous (IV) and intrathecal (IT) administration of human NPCs in common marmosets affected by human myelin oligodendrocyte glycoprotein 1-125,induced EAE. Treatment commenced upon the occurrence of detectable brain lesions on a 4.7T spectrometer. Results EAE marmosets injected IV or IT with NPCs accumulated lower disability and displayed increased survival, as compared with sham-treated controls. Transplanted NPCs persisted within the host central nervous system (CNS), but were also found in draining lymph nodes, for up to 3 months after transplantation and exhibited remarkable immune regulatory capacity in vitro. Interpretation Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in nonhuman primates without overt side effects. Immune regulation (rather than neural differentiation) is suggested as the major putative mechanism by which NPCs ameliorate EAE in vivo. Our findings represent a critical step toward the clinical use of human NPCs in MS. Ann Neurol 2009;66:343,354 [source] Can coenzyme Q10 improve vascular function and blood pressure?BIOFACTORS, Issue 1-4 2003Potential for effective therapeutic reduction in vascular oxidative stress Abstract Coenzyme Q10 (CoQ) is an endogenously synthesised compound that acts as an electron carrier in the mitochondrial electron transport chain. The presence of adequate tissue concentrations of CoQ may be important in limiting oxidative and nitrosative damage in vivo. Oxidative and nitrosative stress are likely to be elevated in conditions such as diabetes and hypertension. In these conditions elevated oxidative and nitrosative stress within the arterial wall may contribute to increased blood pressure and vascular dysfunction. The major focus of this review is the potential of CoQ to improve vascular function and lower blood pressure. Although there is substantial indirect support for the putative mechanism of effect of CoQ on the vascular system, to date there is little direct support for an effect of CoQ on in vivo markers of oxidative or nitrosative stress. The limited data available from studies in animal models and from human intervention studies are generally consistent with a benefit of CoQ on vascular function and blood pressure. The observed effects of CoQ on these endpoints are potentially important therapeutically. However, before any firm clinical recommendations can be made about CoQ supplementation, further intervention studies in humans are needed to investigate the effects of CoQ on vascular function, blood pressure and cardiovascular outcomes. The particularly relevant groups of patients for these studies are those with insulin resistance, type 2 diabetes, hypertension and the metabolic syndrome. [source] Paradoxical roles for lysyl oxidases in cancer,A prospectJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007Stacey L. Payne Abstract Lysyl oxidase (LOX) is an extracellular matrix (ECM) enzyme that catalyzes the cross-linking of collagens or elastin in the extracellular compartment, thereby regulating the tensile strength of tissues. However, recent reports have demonstrated novel roles for LOX, including the ability to regulate gene transcription, motility/migration, and cell adhesion. These diverse functions have led researchers to hypothesize that LOX may have multiple roles affecting both extra- and intracellular cell function(s). Particularly noteworthy is aberrant LOX expression and activity that have been observed in various cancerous tissues and neoplastic cell lines. Both down and upregulation of LOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LOX as a tumor suppressor, as well as a metastasis promoter gene,creating a conundrum within the LOX research field. Here, we review the body of evidence on LOX gene expression, regulation, and function(s) in various cancer cell types and tissues, as well as stromal,tumor cell interactions. Lastly, we will examine putative mechanisms in which LOX facilitates breast cancer invasion and metastasis. Taken together, the literature demonstrates the increasingly important role(s) that LOX may play in regulating tumor progression and the necessity to elucidate its myriad mechanisms of action in order to identify potentially novel therapeutics. J. Cell. Biochem. 101: 1338,1354, 2007. © 2007 Wiley-Liss, Inc. [source] Blood Pressure Regulation and Vegetarian DietsNUTRITION REVIEWS, Issue 1 2005Susan E. Berkow PhD Hypertension affects approximately 50 million individuals in the United States and approximately 1 billion worldwide. Although heredity plays a role in blood pressure variability, diet and lifestyle exert considerable influence in blood pressure regulation. This report reviews the evidence of the relationship between a vegetarian diet and blood pressure regulation and presents data as to the putative mechanisms of action. [source] Pain Processing: Paradoxes and PredictionsPAIN PRACTICE, Issue 1 2001William J. Martin PhD Abstract: During the last 25 years, there have been substantial advances in our understanding of the physiology and pathophysiology of pain. The development of animal models that more closely mimic clinical pain in humans has helped elucidate the putative mechanisms by which chronic pain develops and is maintained. However, our increased understanding of the neurobiology of pain has not translated into breakthrough treatments for pain management. As such, chronic pain is still primarily managed by drugs whose primary indication does not include pain (eg, antidepressants, anticonvulsants, antiarrhythmics, local anesthetics). These adjuvant analgesics have come into favor despite the fact that the mechanisms through which these drugs provide pain relief remain either largely unknown or are not selective for a single target. Moreover, the efficacy of adjuvant analgesics in animal models of pain is often validated only after case studies or clinical trials have been reported. This retrospective validation of "novel" analgesics in animal models of pain raises a question of the predictive validity of these models. This article reviews the use of several adjuvant and standard analgesics currently used to treat difficult-to-manage pain. What can these drugs teach us about the development of novel pain medicines? Within this context, the use of animal models of pain to predict analgesic efficacy in clinical pain conditions is considered. [source] Stress and Pregnancy Loss: Role of Immune Mediators, Hormones and NeurotransmittersAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2001Petra Clara Arck This review highlights recent studies investigating the impact of stress on pregnancy health or loss. Spontaneous abortion is the most common adverse pregnancy outcome, and stress has been suggested to be abortogenic in mice and humans. A wealth of information has been published on the effect of stress on the nervous, endocrine and immune systems during the past two decades. Stress- and/or pregnancy-related hormones (corticotropin releasing hormone, adrenocorticotropin, prolactin, and progesterone) might interact with peripheral and local immuncompetent cells, such as certain T cell subsets, mast cells or NK cells, and result in changes of cytokine production. Since a well-balanced interaction of nervous, endocrine and immune system is crucial for the maintenance of successful pregnancy, putative mechanisms and recent observations on stress-triggered pregnancy failure have been reviewed. [source] Theoretical evaluation of magnetoreception of power-frequency fieldsBIOELECTROMAGNETICS, Issue 5 2010Jacques Vanderstraeten Abstract Several effects of power-frequency (50/60,Hz) magnetic fields (PF-MF) of weak intensity have been hypothesized in animals and humans. No valid mechanism, however, has been proposed for an interaction between PF-MF and biological tissues and living beings at intensities relevant to animal and human exposure. Here we proposed to consider PF-MF as disrupters of the natural magnetic signal. Under exposure to these fields, an oscillating field exists that results from the vectorial summation of both the PF-MF and the geomagnetic field. At a PF-MF intensity (rms) of 0.5,µT, the peak-to-peak amplitude of the axis and/or intensity variations of this resulting field exceeds the related discrimination threshold of magnetoreception (MR) in migrating animals. From our evaluation of the 50/60,Hz responsiveness of the putative mechanisms of MR, single domain particles (Kirschvink's model) appear unable to transduce that oscillating signal. On the contrary, radical pair reactions are able to, as well as interacting multidomain iron,mineral platelets and clusters of superparamagnetic particles (Fleissner/Solov'yov's model). It is, however, not yet known whether the reception of 50/60,Hz oscillations of the natural magnetic signal might be of consequence or not. Bioelectromagnetics 31:371,379, 2010. © 2010 Wiley-Liss, Inc. [source] Heparin regulates colon cancer cell growth through p38 mitogen-activated protein kinase signallingCELL PROLIFERATION, Issue 1 2010G. Chatzinikolaou Objectives:, Heparin acts as an extracellular stimulus capable of activating major cell signalling pathways. Thus, we examined the putative mechanisms utilized by heparin to stimulate HT29, SW1116 and HCT116 colon cancer cell growth. Materials and methods:, Possible participation of the mitogen-activated protein kinase (MAPK) cascade on heparin-induced HT29, SW1116 and HCT116 colon cancer cell growth was evaluated using specific MAPK cascade inhibitors, Western blot analysis, real-time quantitative PCR and FACS apoptosis analysis. Results:, Treatment with a highly specific p38 kinase inhibitor, SB203580, significantly (50,70%) inhibited heparin-induced colon cancer cell growth, demonstrating that p38 MAPK signalling is involved in their heparin-induced proliferative response. This was shown to be correlated with increased (up to 3-fold) phosphorylation of 181/182 threonine/tyrosine residues on p38 MAP kinase. Furthermore, heparin inhibited cyclin-dependent kinase inhibitor p21WAF1/CIP1 and p53 tumour suppressor gene and protein expression up to 2-fold or 1.8-fold, respectively, and stimulated cyclin D1 expression up to 1.8-fold, in these cell lines through a p38-mediated mechanism. On the other hand, treatment with heparin did not appear to affect HT29, SW1116 and HCT116 cell levels of apoptosis. Conclusions:, This study demonstrates that an extracellular glycosaminoglycan, heparin, finely modulates expression of genes crucial to cell cycle regulation through specific activation of p38 MAP kinase to stimulate colon cancer cell growth. [source] | |||||||||||||