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Protective Mechanisms (protective + mechanism)
Selected AbstractsEvaluation of the immune response against Strongyloides venezuelensis in antigen-immunized or previously infected micePARASITE IMMUNOLOGY, Issue 3 2008A. FERNANDES Summary The present study was carried out to investigate the immune response against Strongyloides venezuelensis infection in Balb/c mice previously immunized with larva-antigens or primed with live-larvae. Our results indicate that all primed mice developed a strong protection against challenge infection that remained active for 45 days. In mice primed with live-larvae the challenge infection resulted in great reduction of migrating larvae and the worms were completely eliminated from the small intestine before maturation. The protection pattern did not alter when the primary infection was aborted by drug treatment. In these experimental groups, the challenge infection was accompanied by a type-2 predominant immune response, intense IgE and reactive IgG1 production, and granulocyte infiltration in skin, lungs and intestine. The challenge infection in antigen-immunized mice also resulted in great reduction of migrating larvae. However, the worms that reached the host intestine matured, produced eggs and were eliminated similarly to the ones from nonimmunized mice. Protective mechanisms after immunization with larva antigen were migrating larva-specific and associated with a strong and mixed Th1 and Th2 response, without tissue granulocyte infiltration. In conclusion, protective immunity induced by a previous infection or antigen-immunization are stage-specific and operate through different effector mechanisms. [source] Protective mechanisms of activated protein C in severe inflammatory disordersBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009Arne P Neyrinck The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure,function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 [source] Protective mechanisms of the common fibular nerve in and around the fibular tunnel: A new conceptCLINICAL ANATOMY, Issue 6 2009Ramadan M. El Gharbawy Abstract The most frequent site at which the common fibular nerve is affected by compression, trauma, traction, masses, and surgery is within and around the fibular tunnel. The aim of this study was to determine whether there were protective mechanisms at this site that guard against compression of the nerve. Twenty-six lower limbs of 13 preserved adult cadavers (11 males and two females) were used. Proximal to the entrance of the tunnel, three anatomical configurations seemed to afford the required protection for the nerve: reinforcement of the deep fascia; tethering of the common fibular nerve to both the tendon of the biceps femoris and the reinforced fascia; and the particular arrangement of the deep fascia, fibular head, and soleus and gastrocnemius muscles. At the entrance of the tunnel, contraction of the first segment of fibularis longus muscle could afford the required protection. In the tunnel, contraction of the second and third segments of fibularis longus muscle could guard against compression of the nerve. The tough fascia on the surface of fibularis longus muscle and the fascial band within it, which have long been accused of compression of the nerve, may actually be elements of the protective mechanisms. We conclude that there are innate, anatomical protective mechanisms which should be taken into consideration when decompressing the common fibular nerve. To preserve these mechanisms whenever possible, the technique should be planned and varied according to the underlying etiology. Clin. Anat. 22:738,746, 2009. © 2009 Wiley-Liss, Inc. [source] Dynamics of metal subcellular distribution and its relationship with metal uptake in marine musselsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2005Tania Y-T. Abstract We examined the dynamics of subcellular distribution of metals (Cd, Ag, and Zn) in the marine green mussel Perna viridis by partitioning the metals into the insoluble fraction (IF), heat-sensitive proteins (HSP), and metallothionein-like proteins (MTLP) during metal uptake and elimination. Variations in metal uptake and elimination then were correlated with the subcellular distributions of these metals. The IF and HSP were the first ligands to bind with the metals during the dissolved exposure, and more metals were found in the HSP when the metal influx rate was higher. However, to minimize toxicity, metals were redistributed from HSP to MTLP afterwards. The subcellular distribution of metals was dependent of the exposure route in the mussels. During dietary metal exposure, the metals attained equilibrium before they were assimilated and the metal assimilation efficiency was independent of the metal partitioning in different subcellular fractions. During the efflux, metals in the soluble fraction mediated depuration, whereas metals in the insoluble fraction acted as a final storage pool. Redistribution also may occur between the metal-sensitive and inactive pools without significant depuration as a secondary protective mechanism. We further demonstrated that the higher efflux rate of Ag and Cd was related to a higher partitioning in the MTLP and a lower partitioning in the IF. Our study shows that subcellular pools other than MTLP were involved in immediate metal handling in the bivalves. The wide dynamics of subcellular metal distribution suggests that the relevance of individual subcellular fractions is dependent on the exposure pathway. [source] Morphologic and Neurochemical Abnormalities in the Auditory Brainstem of the Genetically Epilepsy-prone Hamster (GPG/Vall)EPILEPSIA, Issue 7 2005Verónica Fuentes-Santamaría Summary:,Purpose: This study was performed to evaluate whether audiogenic seizures, in a strain of genetically epilepsy-prone hamsters (GPG/Vall), might be associated with morphologic alterations in the cochlea and auditory brainstem. In addition, we used parvalbumin as a marker of neurons with high levels of activity to examine changes within neurons. Methods: Cochlear histology as well as parvalbumin immunohistochemistry were performed to assess possible abnormalities in the GPG/Vall hamster. Densitometry also was used to quantify levels of parvalbumin immunostaining within neurons and fibers in auditory nuclei. Results: In the present study, missing outer hair cells and spiral ganglion cells were observed in the GPG/Vall hamster. In addition, an increase was noted in the size of spiral ganglion cells as well as a decrease in the volume and cell size of the cochlear nucleus (CN), the superior olivary complex nuclei (SOC), and the nuclei of the lateral lemniscus (LL) and the inferior colliculus (IC). These alterations were accompanied by an increase in levels of parvalbumin immunostaining within CN, SOC, and LL neurons, as well as within parvalbumin-immunostained fibers in the CN and IC. Conclusions: These data are consistent with a cascade of atrophic changes starting in the cochlea and extending along the auditory brainstem in an animal model of inherited epilepsy. Our data also show an upregulation in parvalbumin immunostaining in the neuropil of the IC that may reflect a protective mechanism to prevent cell death in the afferent sources to this nucleus. [source] Selective down-regulation of the ,6-integrin subunit in melanocytes by UVB lightEXPERIMENTAL DERMATOLOGY, Issue 6 2005Sven Krengel Abstract:,In vivo, melanocytes bind to laminin (LM) molecules of the basement membrane (BM) via the integrins ,3,1 and ,6,1, and they adhere to neighbouring keratinocytes via E-cadherin. Only few studies have addressed the impact of ultraviolet (UV) light on the interaction of melanocytes with their microenvironment. In this report, we examined the influence of UVB irradiation on the expression of the most important melanocyte-adhesion molecules (E-, N-cadherin, ,2-, ,3-, ,5-, ,6-, ,V-, ,1-, ,3-integrins and ICAM-1) in vitro by flow cytometry. We were able to demonstrate that the ,6-integrin subunit is selectively and reversibly down-regulated by UVB in a dwzm 150ose-dependent manner. In comparison, keratinocytes lacked UVB-inducible alterations in the expression of ,6-integrin. In the presence of LM-1, the UVB-induced down-regulation of ,6-integrin in melanocytes was significantly reduced. Moreover, LM-1 increased the resistance of melanocytes to UVB-induced cell death, as measured by annexinV-binding analysis. This effect was reversed by preincubation with an ,6-integrin-blocking antibody. By immunofluorescence, we could demonstrate that UVB leads to a dose-dependent internalization of ,6-integrin, providing an obvious explanation for the down-regulation on the outer cell surface observed by flow cytometry. We suggest that adhesion to LM-1 through ,6-integrin represents a protective mechanism for melanocytes to withstand UVB damage. Through ,6-integrin internalization, sunburns might alter the interaction between melanocytes and the BM, resulting in apoptosis induced by loss of anchorage (anoikis). Repeated sunburns may then lead to the selection of a population of melanocytes which are capable of anchorage-independent survival, culminating in solar nevogenesis and melanoma development. [source] The molecular determinants of sunburn cell formationEXPERIMENTAL DERMATOLOGY, Issue 3 2001G. Murphy Abstract: Sunburn cell (SBC) formation in the epidermis is a characteristic consequence of ultraviolet radiation (UVR) exposure at doses around or above the minimum erythema dose. SBC have been identified morphologically and biologically as keratinocytes undergoing apoptosis. There is evidence that SBC formation is a protective mechanism to eliminate cells at risk of malignant transformation. The level of DNA photodamage is a major determinant of SBC induction by a process controlled by the tumor suppressor gene p53. However, extra-nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas. UVR triggers death receptors either by direct activation of these surface molecules or by inducing the release of their ligands such as CD95 ligand or tumor necrosis factor. Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C. Pathways which modify SBC formation are now extensively studied given the importance of apoptosis in eliminating irreparably damaged cells. A greater understanding of the mechanisms that induce and prevent UVR-induced apoptosis will contribute to our understanding of mechanisms relevant in genomic integrity. [source] Heat Shock Protein Expression is Increased in Cardiac and Skeletal Muscles of Fischer 344 Rats After Endurance TrainingEXPERIMENTAL PHYSIOLOGY, Issue 1 2000T. R. Samelman Heat shock proteins (HSPs) are expressed when cells are exposed to various types of stress and they may provide protection against cellular insult. Previous data have shown increases in HSP expression following acute exhaustive exercise in rats (Locke et al. 1990, 1995; Salo et al. 1991) and humans (Liu et al. 1999); however, it is not known if chronic exercise will increase resting levels of HSPs. The purpose of this study was to determine if basal protein levels of HSP 72/73 and HSP 60 are increased in cardiac and skeletal muscle of endurance trained Fischer 344 rats. Heart, soleus (SOL) and lateral gastrocnemius (LG) muscles were removed and hearts were sectioned into left ventricle (LV), right ventricle (RV) and atria (AT). Endurance training improved myocardial citrate synthase activity by 88, 90 and 77% and cytochrome c oxidase activity by 58, 51 and 89% in LV, RV and AT, respectively. LV and RV oxidative enzyme activities were greater when compared to AT for both trained and untrained rats (P < 0.05). HSP 72/73 expression was significantly greater (P < 0.05) in LV, RV and SOL from endurance trained versus from control rats (26, 45 and 67%, respectively). HSP 60 was also increased (P < 0.05) in LV, RV and SOL in trained relative to untrained rats. HSP 72/73 and HSP 60 were unchanged in AT and LG after training. These results indicate that endurance training increases the basal expression of stress proteins and this observation is consistent with the hypothesis that endurance training may activate a protective mechanism to stress. [source] Anti-inflammatory role of interleukin-15 in Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2005Manuel A Silva MD Abstract Background: Interleukin (IL)-15 is overexpressed in intestinal tissue with active Crohn's disease (CD). However, its role in the pathogenesis of the disease remains uncertain. We studied the effects of IL-15 on colonic mucosal proinflammatory cytokine response in vitro using organ culture of human colonic explants. Methods: Colonic tissue was obtained from (1) resections in pediatric CD patients (inflamed and noninflamed) and (2) rectal biopsies in patients with CD undergoing colonoscopy (n = 31) and controls (n = 9). In preliminary experiments, explants from the resections were cultured in the presence or absence of a simulated TH1 stimulation using ionomycin (Io) and phorbol-myristate-acetate (PMA), with or without IL-15, or in medium alone. Rectal biopsies were cultured in the same conditions as above, with or without adding a monoclonal anti-IL-15 neutralizing antibody (mAb). Levels of interferon (IFN)-,, tumor necrosis factor (TNF)-,, and IL-2R, were measured by enzyme-linked immunosorbent assay. Results: IL-15, in the absence of Io + PMA, did not induce the expression of IFN-,, TNF-,, or IL-2R,. Only inflamed explants from resections stimulated with Io + PMA expressed IFN-,, TNF-,, and IL-2R,. This TH1 stimulatory effect was inhibited by IL-15 in a dose-dependent fashion. In rectal biopsy explants, inflamed, noninflamed CD, and control tissue responded to stimulation with Io + PMA (P < 0.05) with increased IFN-, and TNF-, (P < 0.05). This response was again inhibited by IL-15. The inhibitory effect of IL-15 was specifically reversed by anti-IL-15 mAb (P < 0.05). The data for the CD group were also analyzed according to the severity of colonic inflammation and medication use. Conclusions: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated TH1 immune response. [source] Lyme borreliosis , an updateJOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, Issue 5 2007Elisabeth Aberer Summary Lyme borreliosis is the most common tick-borne, infectious disease in the northern hemisphere. Disease manifestations in the United States and Europe vary as a result of geographic distribution of different species within the genospecies Borrelia burgdorferi sensu lato, which in turn are host-specific. Certain toxigenic B. burgdorferi strains cause early disseminated disease. The ability of Borrelial organisms to break down the extracellular matrix also promotes dissemination. B. burgdorferi are eliminated by complement-mediated lysis and by T and B cell activity of the specific immune response. Yet, B. burgdorferi can evade humoral immunity by means of type of protective mechanism by which it adheres to the proteoglycan decorin in the joints and skin. A further factor in the persistence of the pathogen is altered antigen expression. Re-infection usually occurs with a different strain, although repeated infection with the same strain is also possible after a certain period of latency. New developments in serologic testing include the use of recombinant native antigen as well as antigens produced in vivo such as VlsE (variable major protein-like sequence, expressed) or decorin-binding protein A. Diagnosis continues to be complicated by seropositivity of healthy individuals, the persistence of antibodies after therapy, and a lacking humoral immune response in patients with erythema migrans. [source] Astaxanthin protects mesangial cells from hyperglycemia-induced oxidative signaling,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Emiko Manabe Abstract Astaxanthin (ASX) is a carotenoid that has potent protective effects on diabetic nephropathy in mice model of type 2 diabetes. In this study, we investigated the protective mechanism of ASX on the progression of diabetic nephropathy using an in vitro model of hyperglycemia, focusing on mesangial cells. Normal human mesangial cells (NHMCs) were cultured in the medium containing normal (5 mM) or high (25 mM) concentrations of D -glucose. Reactive oxygen species (ROS) production, the activation of nuclear transcription factors such as nuclear factor kappa B (NF,B) and activator protein-1 (AP-1), and the expression/production of transforming growth factor-beta 1 (TGF,1) and monocyte chemoattractant protein-1 (MCP-1) were evaluated in the presence or absence of ASX. High glucose (HG) exposure induced significant ROS production in mitochondria of NHMCs, which resulted in the activation of transcription factors, and subsequent expression/production of cytokines that plays an important role in the mesangial expansion, an important event in the pathogenesis of diabetic nephropathy. ASX significantly suppressed HG-induced ROS production, the activation of transcription factors, and cytokine expression/production by NHMCs. In addition, ASX accumulated in the mitochondria of NHMCs and reduced the production of ROS-modified proteins in mitochondria. ASX may prevent the progression of diabetic nephropathy mainly through ROS scavenging effect in mitochondria of mesangial cells and thus is expected to be very useful for the prevention of diabetic nephropathy. J. Cell. Biochem. 103: 1925,1937, 2007. © 2007 Wiley-Liss, Inc. [source] Regulatory T cell activity in primary and persistent Epstein,Barr virus infectionJOURNAL OF MEDICAL VIROLOGY, Issue 5 2009P.J. Wingate Abstract Regulatory T cells (Treg) provide a balance to immune T cell activation thereby protecting the body from pathogen-induced immunopathology. Several persistent viruses induce Treg that subvert protective immune mechanisms and promote viral persistence. Epstein,Barr virus (EBV) generally infects children subclinically and persists thereafter, but primary infection in early adulthood may cause immunopathological damage manifest as infectious mononucleosis. In this study the role of Treg was investigated in acute infectious mononucleosis and healthy EBV seropositive donors. The proportion of CD4+CD25high T cells in blood from infectious mononucleosis patients was significantly lower than in seropositive donors (P,=,0.05). Using the FOXP3 marker for Treg the same frequency and extra-follicular distribution of Treg was noted in infectious mononucleosis and control tonsils. Regulatory cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-,, were significantly raised in infectious mononucleosis compared to seropositive donor plasma (P,=,0.0001, P,=,0.0004 respectively) although levels of IL-10 peaked earlier in infectious mononucleosis than TGF-,. Previous studies identified EBV latent membrane protein (LMP)-1-induced Treg activity [Marshall et al. (2003): J Immunol 170:6183,6189; Marshall et al. (2007): Brit J Haematol 139:81,89], and in this study a significant reduction in interferon-, production was found from infectious mononucleosis but not seropositive donor lymphocytes after stimulation with a recall antigen when LMP-1 peptide PRG was added (P,=,0.03). It is possible that Treg are important in controlling primary EBV infection to a subclinical level in most cases and that infectious mononucleosis represents a failure of this protective mechanism. J. Med. Virol. 81:870,877, 2009. © 2009 Wiley-Liss, Inc. [source] Hyperosmotic stress induces Axl activation and cleavage in cerebral endothelial cellsJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Imola Wilhelm Abstract Because of the relative impermeability of the blood-brain barrier (BBB), many drugs are unable to reach the CNS in therapeutically relevant concentration. One method to deliver drugs to the CNS is the osmotic opening of the BBB using mannitol. Hyperosmotic mannitol induces a strong phosphorylation on tyrosine residues in a broad spectrum of proteins in cerebral endothelial cells, the principal components of the BBB. Previously, we have shown that among targets of tyrosine phosphorylation are ,-catenin, extracellular signal-regulated kinase 1/2 and the non-receptor tyrosine kinase Src. The aim of this study was to identify new signalling pathways activated by hypertonicity in cerebral endothelial cells. Using an antibody array and immunoprecipitation we identified the receptor tyrosine kinase Axl to become tyrosine phosphorylated in response to hyperosmotic mannitol. Besides activation, Axl was also cleaved in response to osmotic stress. Degradation of Axl proved to be metalloproteinase- and proteasome-dependent and resulted in 50,55 kDa C-terminal products which remained phosphorylated even after degradation. Specific knockdown of Axl increased the rate of apoptosis in hyperosmotic mannitol-treated cells; therefore, we assume that activation of Axl may be a protective mechanism against hypertonicity-induced apoptosis. Our results identify Axl as an important element of osmotic stress-induced signalling. [source] Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivoJOURNAL OF NEUROCHEMISTRY, Issue 4 2006Angela L. Guillozet-Bongaarts Abstract The tangles of Alzheimer's disease (AD) are comprised of the tau protein displaying numerous alterations, including phosphorylation at serine 422 (S422) and truncation at aspartic acid 421 (D421). Truncation at the latter site appears to result from activation of caspases, a class of proteases that cleave specifically at aspartic acid residues. It has been proposed that phosphorylation at or near caspase cleavage sites could regulate the ability of the protease to cleave at those sites. Here, we use tau pseudophosphorylated at S422 (S422E) to examine the effects of tau phosphorylation on its cleavage by caspase 3. We find that S422E tau is more resistant to proteolysis by caspase 3 than non-pseudophosphorylated tau. Additionally, we use antibodies directed against the phosphorylation site and against the truncation epitope to assess the presence of these epitopes in neurofibrillary tangles in the aged human brain. We show that phosphorylation precedes truncation during tangle maturation. Moreover, the distribution of the two epitopes suggests that a significant length of time (perhaps as much as two decades) elapses between S422 phosphorylation and cleavage at D421. We further conclude that tau phosphorylation at S422 may be a protective mechanism that inhibits cleavage in vivo. [source] The Endogenous Amine 1-Methyl-1,2,3,4- Tetrahydroisoquinoline Prevents the Inhibition of Complex I of the Respiratory Chain Produced by MPP+JOURNAL OF NEUROCHEMISTRY, Issue 1 2000Juan Parrado Abstract : The endogenous monoamine 1-methyl-1,2,3,4-tetrahydroisoquinoline has been shown to prevent the neurotoxic effect of MPP+ and other endogenous neurotoxins, which produce a parkinsonian-like syndrome in humans. We have tested its potential protective effect in vivo by measuring the protection of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the neurotoxicity elicited by MPP+ in rat striatum by tyrosine hydroxylase immunocytochemistry. Because we know that cellular damage caused by MPP+ is primarily the result of mitochondrial respiratory inhibition at the complex I level, we have extended the study further to understand this protective mechanism. We found that the inhibitory effect on the mitochondrial respiration rate induced by MPP+ in isolated rat liver mitochondria and striatal synaptosomes was prevented by addition of 1-methyl-1,2,3,4-tetrahydroisoquinoline. This compound has no antioxidant capacity ; therefore, this property is not involved in its protective effect. Thus, we postulate that the preventive effect that 1-methyl-1,2,3,4-tetrahydroisoquinoline has on mitochondrial inhibition for MPP+ could be due to a "shielding effect," protecting the energetic machinery, thus preventing energetic failure. These results suggest that this endogenous amine may protect against the effect of several parkinsonism-inducing compounds that are associated with progressive impairment of the mitochondrial function. [source] Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: Therapeutic implications for Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2002Kwok-Keung Tai Abstract It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO4 or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease. © 2002 Wiley-Liss, Inc. [source] Effects of Acamprosate on Excitatory Amino Acids During Multiple Ethanol Withdrawal PeriodsALCOHOLISM, Issue 3 2003Abdelkader Dahchour Background: Our previous studies on the effects of acamprosate on enhanced locomotion during repeated withdrawals are now extended to the effects of acamprosate on excitatory amino acids in the hippocampus during repeated ethanol withdrawals. Methods: In this study, Wistar rats were made ethanol dependent by 4 weeks of vapor inhalation. After this first cycle of chronic ethanol treatment, rats underwent repeated and alternate cycles of 24 hr withdrawals and 1 week of chronic ethanol treatment. The microdialysis technique was used together with high-performance liquid chromatography and electrochemical detection to quantify different amino acids such as aspartate and glutamate. Results: An intraperitoneal administration of acamprosate (400 mg/kg) to naïve rats did not alter aspartate or glutamate levels compared with the saline groups. During the first cycle of ethanol withdrawal, the administration of acamprosate (400 mg/kg, intraperitoneally) 2 hr after the commencement of ethanol withdrawal decreased both aspartate and glutamate microdialysate levels when compared with their respective saline group. Acamprosate administration also significantly decreased glutamate levels during the third withdrawal compared with the saline group, whereas no changes were seen in aspartate levels. Conclusion: The results of this work demonstrate that acamprosate reduced the excitatory amino acid glutamate increase observed during repeated ethanol withdrawal. These effects of acamprosate may provide a protective mechanism against neurotoxicity by reducing excitatory amino acids, particularly glutamate. [source] Analysis of Streptococcus mutans biofilm proteins recognized by salivary immunoglobulin AMOLECULAR ORAL MICROBIOLOGY, Issue 5 2009T. Sanui Introduction:, The purpose of this study was to examine the Streptococcus mutans biofilm cellular proteins recognized by immunoglobulin A (IgA) in saliva from various caries-defined populations. Methods:, Biofilm and planktonic S. mutans UA159 cells were prepared. The proteins were extracted, separated by two-dimensional gel electrophoresis, transferred to blotting membranes, and probed for IgA using individual saliva samples from three groups of subjects; those who developed 0 caries (no active caries), 5,9 caries (medium), or more than 10 caries (severe) over a 12-month interval. Results:, Several proteins were recognized by salivary IgA in all groups of saliva but spot distribution and intensity varied greatly between the groups, and some proteins were recognized more strongly in biofilm cells than in planktonic culture, and vice versa. Furthermore, 15 proteins were only recognized by saliva from the ,no active caries' group, and four proteins were recognized by saliva samples from subjects in all three groups. Specifically, antigen I/II was recognized less in biofilm cells by caries-free saliva compared with planktonic cells. However, salivary IgA antibody to antigen I/II was absent in blots using saliva from the ,medium caries' and ,severe caries' groups. Conclusion:, The bacterial molecules recognized by caries-free saliva are significant factors for S. mutans caries formation, and their inhibition could be a therapeutic target. In addition, saliva of caries-free subjects includes significant IgA antibody against antigen I/II of S. mutans, indicating a protective mechanism. However, microorganisms may protect themselves from host immune attack by forming biofilms and decreasing expression of antigen I/II. [source] Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progressNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2007J. M. Woulfe Neurodegenerative diseases are characterized pathologically by the abnormal accumulation of pathogenic protein species within the cell. Several neurodegenerative diseases feature intranuclear protein aggregation in the form of intranclear inclusion bodies. Studies of these intranuclear inclusions are providing important clues regarding the cellular pathophysiology of these diseases, as exemplified by recent progress in defining the genetic basis of a subset of frontotemporal dementia cases. The precise role of intranuclear inclusion bodies in disease pathogenesis is currently a focus of debate. The present review provides an overview of the diverse family of neurodegenerative diseases in which nuclear inclusions form part of the neuropathological spectrum. In addition, current pathogenetic concepts relevant to these diseases will be reviewed and arguments for and against a protective role for intranuclear inclusions will be presented. The relationship of pathological intranuclear inclusions to functional intranuclear bodies will also be discussed. Finally, by analogy with pathological intranuclear inclusions, I will speculate on the possibility that intranuclear protein aggregation may represent a constitutive cellular protective mechanism occurring in neurons under physiological conditions. [source] Molecular mechanisms of UV-induced apoptosisPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2000D. Kulms Sunburn cells, single standing cells with typical morphologic features occurring in UV-exposed skin, have been recognized as keratinocytes undergoing apoptosis following UV irradiation. Induction of apoptosis following UV exposure appears to be a protective mechanism, getting rid off severely damaged cells that bear the risk of malignant transformation. UV-mediated apoptosis is a highly complex process in which different molecular pathways are involved. These include DNA damage, activation of the tumor suppressor gene p53, triggering of cell death receptors either directly by UV or by autocrine release of death ligands, mitochondrial damage and cytochrome C release. Detailed knowledge about the interplay between these pathways will increase our understanding of photocarcinogenesis. This review briefly discusses recent findings concerning the molecular mechanisms underlying UV-induced apoptosis. [source] Neuroprotective effects of Brazilian green propolis and its main constituents against oxygen-glucose deprivation Stress, with a gene-expression analysisPHYTOTHERAPY RESEARCH, Issue 10 2009Yoshimi Nakajima Abstract Our purpose was to investigate the neuroprotective effects (and the underlying mechanism) exerted by water extract of Brazilian green propolis (WEP) and its main constituents against the neuronal damage induced by oxygen-glucose deprivation (OGD)/reoxygenation in retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus). Cell damage was induced by OGD 4 h plus reoxygenation 18 h exposure. In RGC-5, and also in PC12 (rat pheochromocytoma, neuronal cells), WEP and some of its main constituents attenuated the cell damage. At the end of the period of OGD/reoxygenation, RNA was extracted and DNA microarray analysis was performed to examine the gene-expression profile in RGC-5. Expression of casein kinase 2 (CK2) was down-regulated and that of Bcl-2-related ovarian killer protein (Bok) was up-regulated following OGD stress, results that were confirmed by quantitative reverse transcriptase-PCR (qRT-PCR). These effects were normalized by WEP. Our findings indicate that WEP has neuroprotective effects against OGD/reoxygenation-induced cell damage and that certain constituents of WEP (caffeoylquinic acid derivatives, artepillin C, and p -coumaric acid) may be partly responsible for its neuroprotective effects. Furthermore, the protective mechanism may involve normalization of the expressions of antioxidant- and apoptosis-related genes (such as CK2 and Bok, respectively). Copyright © 2009 John Wiley & Sons, Ltd. [source] Proteome analysis of the responses of Panax ginseng C. A. Meyer leaves to high light: Use of electrospray ionization quadrupole-time of flight mass spectrometry and expressed sequence tag dataPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 12 2003Myung Hee Nam Abstract We performed comparative proteomic analyses in order to understand the physiological responses of ginseng (Panax ginseng C. A. Meyer) to high light (HL). As a first step, we analyzed the proteins expressed in ginseng leaves. Proteins extracted from leaves were separated by two-dimensional polyacrylamide gel electrophoresis. Protein spots were identified by tandem mass spectra analysis using electrospray ionization quadrupole-time of flight mass spectrometry (ESI Q-TOF MS). We used a ginseng expressed sequence tag (EST) database as well as a nonredundant protein database from NCBI to identify proteins. Eighty-one proteins were identified using the nr protein database, 51 of which were also verified from the ginseng EST database. An additional 66 proteins were identified only from the ginseng EST database. Proteins that function in energy metabolism, protein stabilization, and protection against oxidative stress were abundant. To understand the light responses of ginseng leaves, we studied time dependent changes in expressed proteins produced by 0,4 h of HL exposure. Six HL-responsive proteins were identified: three proteins were up-regulated (cytosolic small heat-shock protein, cytosolic ascorbate peroxidase, and putative major latex-like protein) and three proteins were down-regulated (Rieske Fe/S protein, putative 3-beta hydroxysteroid dehydrogenase/isomerase-like protein, and oxygen-evolving enhancer-like protein). Our results show that the ginseng EST database combined with ESI Q-TOF MS analysis can be used to identify ginseng proteins and to elucidate the protective mechanism of ginseng against HL induced damage. [source] Autoregulation of the cerebral circulation during sleep in newborn lambsTHE JOURNAL OF PHYSIOLOGY, Issue 3 2005Daniel A. Grant Autoregulation is a vital protective mechanism that maintains stable cerebral blood flow as cerebral perfusion pressure changes. We contrasted cerebral autoregulation across sleep,wake states, as little is known about its effectiveness during sleep. Newborn lambs (n= 9) were instrumented to measure cerebral blood flow (flow probe on the superior sagittal sinus) and cerebral perfusion pressure, then studied during active sleep (AS), quiet sleep (QS) and quiet wakefulness (QW). We generated cerebral autoregulation curves by inflating an occluder cuff around the brachiocephalic artery thereby lowering cerebral perfusion pressure. Baseline cerebral blood flow was higher (P < 0.05) and cerebral vascular resistance lower (P < 0.05) in AS than in QW (76 ± 8% and 133 ± 15%, respectively, of the AS value, mean ±s.d.) and in QS (66 ± 11% and 158 ± 30%). The autoregulation curve in AS differed from that in QS and QW in three key respects: firstly, the plateau was elevated relative to QS and QW (P < 0.05); secondly, the lower limit of the curve (breakpoint) was higher (P < 0.05) in AS (50 mmHg) than QS (45 mmHg); and thirdly, the slope of the descending limb below the breakpoint was greater (P < 0.05) in AS than QS (56% of AS) or QW (56% of AS). Although autoregulation functions in AS, the higher breakpoint and greater slope of the descending limb may place the brain at risk for vascular compromise should hypotension occur. [source] The Effect of Hyperbaric Oxygen Therapy on Erectile Function Recovery in a Rat Cavernous Nerve Injury ModelTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2008Alexander Müller MD ABSTRACT Introduction., Cavernosal oxygenation appears to be important for preservation of erectile tissue health. Hyperbaric oxygen therapy (HBOT) has been shown to improve tissue oxygenation and has neuromodulatory effects. Aim., This study was designed to define the effects of HBOT on erectile function (EF) and cavernosal tissue in the rat cavernous nerve (CN) injury model. Methods., Four groups of Sprague-Dawley rats were studied: rats with bilateral CN crush, HBOT treated (Crush+/HBOT+); bilateral CN-crush/no HBOT (C+/H,); no crush/no HBOT (C,/H,); and no crush/HBOT (C,/H+). HBOT was delivered daily for 90 minutes at three atmospheres for 10 days commencing the day of CN crush. Main Outcome Measures., Ten days after CN injury, the animals underwent CN stimulation measuring the maximal intracavernosal pressure/mean arterial pressure (ICP/MAP) ratios. Corporal tissue was harvested pre-sacrifice, and immunohistochemically stained for nerve growth factor (NGF), endothelial nitric oxide synthase (eNOS), and cluster of differentiation molecule (CD31). Histologic analysis was performed for Masson's trichrome to assess the smooth muscle,collagen ratio. Terminal deoxynucleotidyl transferase Biotin-dUTP Nick End Labeling assay was used to define apoptotic indices (AIs). Results., The C+/H, group had significantly lower ICP/MAP ratios compared with C,/H, rats, (31% vs. 70%, P < 0.001). C+/H+ rats had significantly higher ICP/MAP ratio recovery compared with the C+/H, group (55% vs. 31%, P = 0.005). NGF and eNOS staining densities were higher in C+/H+ rats compared with C+/H, rats (P < 0.05 and P < 0.001, respectively). No difference was seen in CD31 expression. Staining density for MT displayed a trend toward higher smooth muscle preservation after HBOT. AIs were significantly increased by HBOT (P < 0.05). Conclusion., HBOT following a CN injury improved EF preservation in this model, supporting the cavernosal oxygenation concept as protective mechanism for EF. The effects appear to be mediated via preservation of neurotrophic and endothelial factor expression. Müller A, Tal R, Donohue JF, Akin-Olugbade Y, Kobylarz K, Paduch D, Cutter SC, Mehrara BJ, Scardino PT, and Mulhall JP. The effect of hyperbaric oxygen therapy on erectile function recovery in a rat cavernous nerve injury model. J Sex Med 2008;5:562,570. [source] Association of CASP8 D302H polymorphism with reduced risk of aggressive prostate carcinomaTHE PROSTATE, Issue 6 2010Jessica Lubahn Abstract BACKGROUND Because of the dramatically different clinical course of aggressive and indolent prostate carcinoma (PCa), markers that distinguish between these phenotypes are of critical importance. Apoptosis is an important protective mechanism for unrestrained cellular growth and metastasis. Therefore, dysfunction in this pathway is a key step in cancer progression. As such, genetic variants in apoptosis genes are potential markers of aggressive PCa. Recent work in breast carcinoma has implicated the histidine variant of CASP8 D302H (rs1045485) as a protective risk allele. METHODS We tested the hypothesis that the H variant was protective for aggressive PCa in a pooled analysis of 796 aggressive cases and 2,060 controls. RESULTS The H allele was associated with a reduced risk of aggressive PCa (ORper allele,= 0.67, 95% CI: 0.54,0.83, Ptrend,=,0.0003). The results were similar for European-Americans (ORper allele,=,0.68; 95% CI: 0.54,0.86) and African-Americans (ORper allele,=,0.61; 95% CI: 0.34,1.10). We further determined from the full series of 1,160 cases and 1,166 controls in the Prostate, Lung, Colorectal, Ovarian (PLCO) population that the protective effect of the H allele tended to be limited to high-grade and advanced PCa (all cases ORper allele,=,0.94; 95% CI: 0.79,1.11; localized, low-grade disease ORper allele,=,0.98; 95% CI: 0.79,1.23; and aggressive disease ORper allele,=,0.73; 95% CI: 0.50,1.07). CONCLUSION These results suggest that histidine variant of CASP8 D302H is a protective allele for aggressive PCa with potential utility for identification of patients at differential risk for this clinically significant phenotype. Prostate 70: 646,653, 2010. © 2009 Wiley-Liss, Inc. [source] Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritisARTHRITIS & RHEUMATISM, Issue 3 2010Beatriz Caramés Objective Autophagy is a process for turnover of intracellular organelles and molecules that protects cells during stress responses. We undertook this study to evaluate the potential roles of Unc-51,like kinase 1 (ULK1), an inducer of autophagy, Beclin1, a regulator of autophagy, and microtubule-associated protein 1 light chain 3 (LC3), which executes autophagy, in the development of osteoarthritis (OA) and in cartilage cell death. Methods Expression of ULK1, Beclin1, and LC3 was analyzed in normal and OA human articular cartilage and in knee joints of mice with aging-related and surgically induced OA, using immunohistochemistry and Western blotting. Poly(ADP-ribose) polymerase (PARP) p85 expression was used to determine the correlation between cell death and autophagy. Results ULK1, Beclin1, and LC3 were constitutively expressed in normal human articular cartilage. ULK1, Beclin1, and LC3 protein expression was reduced in OA chondrocytes and cartilage, but these 3 proteins were strongly expressed in the OA cell clusters. In mouse knee joints, loss of glycosaminoglycans (GAGs) was observed at ages 9 months and 12 months and in the surgical OA model, 8 weeks after knee destabilization. Expression of ULK1, Beclin1, and LC3 decreased together with GAG loss, while PARP p85 expression was increased. Conclusion Autophagy may be a protective or homeostatic mechanism in normal cartilage. In contrast, human OA and aging-related and surgically induced OA in mice are associated with a reduction and loss of ULK1, Beclin1, and LC3 expression and a related increase in apoptosis. These results suggest that compromised autophagy represents a novel mechanism in the development of OA. [source] Nitrite reduction: a ubiquitous function from a pre-aerobic pastBIOESSAYS, Issue 8 2009Francesca Cutruzzolà Abstract In eukaryotes, small amounts of nitrite confer cytoprotection against ischemia/reperfusion-related tissue damage in vivo, possibly via reduction to nitric oxide (NO) and inhibition of mitochondrial function. Several hemeproteins are involved in this protective mechanism, starting with deoxyhemoglobin, which is capable of reducing nitrite. In facultative aerobic bacteria, such as Pseudomonas aeruginosa, nitrite is reduced to NO by specialized heme-containing enzymes called cd1 nitrite reductases. The details of their catalytic mechanism are summarized below, together with a hypothesis on the biological role of the unusual d1 -heme, which, in the reduced state, shows unique properties (very high affinity for nitrite and exceptionally fast dissociation of NO). Our results support the idea that the nitrite-based reactions of contemporary eukaryotes are a vestige of earlier bacterial biochemical pathways. The evidence that nitrite reductase activities of enzymes with different cellular roles and biochemical features still exist today highlights the importance of nitrite in cellular homeostasis. [source] Protective effect of binaphthyl diselenide, a synthetic organoselenium compound, on 2-nitropropane-induced hepatotoxicity in ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2010Mohammad Ibrahim Abstract Organoselenides have been documented as promising pharmacological agents against a number of diseases associated with oxidative stress. Here we have investigated, for the first time, the potential antioxidant activity of binaphthyl diselenide ((NapSe)2; 50,mg,kg,1, p.o.) against the 2-nitropropane (2-NP)-induced hepatoxicity in rats, using different end points of toxicity (liver histopathology, plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatinine). In addition, in view of the association of oxidative stress with 2-NP exposure, hepatic lipid peroxidation, ascorbic acid levels, ,-aminolevulinate dehydratase (,-ALA-D) and catalase (CAT) activities were evaluated. 2-NP caused an increase of AST, ALT and hepatic lipid peroxidation. 2-NP also caused hepatic histopathological alterations and ,-ALA-D inhibition. (NapSe)2 (50,mg,kg,1) prevented 2-NP-induced changes in plasmatic ALT and AST activities and also prevented changes in hepatic histology, ,-ALA-D and lipid peroxidation. Results presented here indicate that the protective mechanism of (NapSe)2 against 2-NP hepatotoxicity is possibly linked to its antioxidant activity. Copyright © 2010 John Wiley & Sons, Ltd. [source] Interaction of hydrogen sulfide with ion channelsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2010Guanghua Tang Summary 1. Hydrogen sulfide (H2S) is a signalling gasotransmitter. It targets different ion channels and receptors, and fulfils its various roles in modulating the functions of different systems. However, the interaction of H2S with different types of ion channels and underlying molecular mechanisms has not been reviewed systematically. 2. H2S is the first identified endogenous gaseous opener of ATP-sensitive K+ channels in vascular smooth muscle cells. Through the activation of ATP-sensitive K+ channels, H2S lowers blood pressure, protects the heart from ischemia and reperfusion injury, inhibits insulin secretion in pancreatic , cells, and exerts anti-inflammatory, anti-nociceptive and anti-apoptotic effects. 3. H2S inhibited L-type Ca2+ channels in cardiomyocytes but stimulated the same channels in neurons, thus regulating intracellular Ca2+ levels. H2S activated small and medium conductance KCa channels but its effect on BKCa channels has not been consistent. 4. H2S-induced hyperalgesia and pro-nociception seems to be related to the sensitization of both T-type Ca2+ channels and TRPV1 channels. The activation of TRPV1 and TRPA1 by H2S is believed to result in contraction of nonvascular smooth muscles and increased colonic mucosal Cl, secretion. 5. The activation of Cl, channel by H2S has been shown as a protective mechanism for neurons from oxytosis. H2S also potentiates N -methyl- d -aspartic acid receptor-mediated currents that are involved in regulating synaptic plasticity for learning and memory. 6. Given the important modulatory effects of H2S on different ion channels, many cellular functions and disease conditions related to homeostatic control of ion fluxes across cell membrane should be re-evaluated. [source] Prediabetes and the big baby,DIABETIC MEDICINE, Issue 1 2008D. R. Hadden Abstract The concept of prediabetes has come to the fore again with the worldwide epidemic of Type 2 diabetes. The careful observations of W. P. U. Jackson and his colleagues in Cape Town, South Africa 50 years ago still deserve attention. Maternal hyperglycaemia cannot be the only cause of fetal macrosomia, and the pathophysiological reason for the unexplained stillbirth in late diabetic pregnancy still eludes us. The biochemical concepts of ,facilitated anabolism' and ,accelerated starvation' were developed by Freinkel as explanations of the protective mechanisms for the baby during the stresses of pregnancy. Some of these nutritional stresses may also occur in the particular form of early childhood malnutrition known in Africa as kwashiorkor, where subcutaneous fat deposition, carbohydrate intolerance, islet hyperplasia and sudden death may follow a period of excess carbohydrate and deficient protein intake. Different feeding practices in different parts of the world make comparisons uncertain, but there is evidence for insulin resistance in both the macrosomic fetus of the hyperglycaemic mother and in the child with established kwashiorkor. These adaptive changes in early development may play both a physiological and a pathological role. Worldwide studies of hyperglycaemia in pregnancy are gradually establishing acceptable diagnostic criteria, appropriate screening procedures and an evidence base for treatment. Nevertheless the challenge of prediabetes and the big baby is still with us,in Jackson's words,,diabetes mellitus is a fascinating condition,the more we know about it the less we understand it'. [source] | |||||||||||||||||||||||||||||||