bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Antioxidant Capacity in the Hydrophilic and Lipophilic Domains
Authors: LOTITO SILVINA B. , RENART M. LOURDES , FRAGA CÉSAR G.
Published: July 2009

Abstract: The antioxidant capacity of different types of red and white wines was assessed by different assays. Two assays were used to evaluate the antioxidant capacity in aqueous phase: (1) inhibition of the generation of 2,2′‐azinodi(3‐etilbencenotiazolin‐6‐sulfonate) (ABTS)‐derived radical; and (2) protection of vitamin E in human plasma. The results indicated that red wines were not all equally effective, and a comparison could be made among different types. The ABTS assay showed that Cabernet Sauvignon wines had the highest antioxidant capacity followed by Malbec wines. Red wines showed a protective capacity of 70‐90% in preventing SH‐groups oxidation, and, in addition, they were also effective in preventing the oxidative damage in lipid domains (30‐97% protection to liposomes, 20‐70% to vitamin E). The antioxidant capacity of the white wines was significantly lower, as evaluated by all the assays. Significant correlations were found for phenolics and catechin content with the antioxidant capacity of the studied wines.
Physiological Model of the Stimulative Effects of Alcohol in Low‐to‐Moderate Doses
Authors: ANTOSHECHKIN ANATOLY G.
Published: July 2009

Abstract: A physiological model of alcohol use is proposed, based on the observation that ethanol is a natural intracellular metabolite. It is suggested that ethanol synthesis is an intermediate step in the metabolic pathway of elimination of the excess of energy‐releasing substrates from mitochondria and the cytosol when the cell does not require additional energy. The process is first of all important for elimination of acetyl‐CoA from mitochondria. Ingested alcohol passes across plasma and mitochondrial membranes by diffusion and follows the endogenous ethanol pathway but in the reverse direction. This pathway is used when the cell needs additional energy. In that case, exogenous ethanol supplies the respiratory chain with electrons via NADH on the path of oxidation to acetaldehyde and then to acetate by alcohol and aldehyde dehydrogenases. After conversion to acetyl‐CoA, it goes into the citrate cycle and is thus used for energy production entirely. If citrate cycle activity is decreased constitutionally, acetyl‐CoA enters into citrate cycle too slowly and energy deficit arises, ethanol compensates for the energy deficit. Acetate then diffuses out of mitochondria. The less energy production in mitochondria, the more the cell is ready to accept alcohol as an energy source. Citrate cycle activity can be depressed as a result of single‐nucleotide polymorphisms of genes controlling some enzymes involved in the cycle, which influences the alcohol requirement.
Oxidative Stress and Inflammatory Reaction Modulation by White Wine
Authors: BERTELLI ALBERTO A.E. , MIGLIORI MASSIMILIANO , PANICHI VINCENZO , LONGONI BIANCAMARIA , ORIGLIA NICOLA , FERRETTI AGNESE , CUTTANO MARIA GIUSEPPA , GIOVANNINI LUCA
Published: July 2009

Abstract: Wine and olive oil, essential components of the Mediterranean diet, are considered important factors for a healthy life style. Tyrosol (T) and caffeic acid (CA) are found in both extra virgin olive oil and in white wine. Three white wines from the northeast Italy and four white wines from Germany were analyzed for their content of T and CA. These compounds were tested for their antioxidant activity and their capacity to modulate three different cytokines: IL‐1β, IL‐6, and TNF‐α, which are currently considered to be the major cytokines influencing the acute phase of the inflammatory response. Furthermore, the antioxidant activity of T and CA was analyzed by monitoring the oxidation of a redox‐sensitive probe by using laser scanning confocal microscopy. T and CA, applied at nanomolar range, were found to significantly reduce the generation of oxidants induced by azobis‐amidinopropanedihydrochloride. Peripheral blood mononuclear cells (PBMC) from healthy volunteers were incubated at 37°C for 12 hours with 100 ng LPS (E. coli and P. maltofilia). Increasing doses of T and CA (150 nM to 300 μM) were added and cell‐associated IL‐1β and TNF‐α were determined by immunoreactive tests after three freeze‐thaw cycles. IL‐6 release was also determined in cell surnatants. LPS‐stimulated PBMC showed a significant increase in cytokine release, while T and CA, used at nanomolar concentrations, were able to modulate their expression. Taken together, these results suggest a remarkable effect of white wine non‐alcoholic compounds on oxidative stress and inflammatory reaction.
Reduction of Myocardial Ischemia Reperfusion Injury with Regular Consumption of Grapes
Authors: CUI JIANHUA , CORDIS GERALD A. , TOSAKI ARPAD , MAULIK NILANJANA , DAS DIPAK K.
Published: July 2009

Abstract: Recently several polyphenolic antioxidants derived from grape seeds and skins have been implicated in cardioprotection. This study was undertaken to determine if the grapes were equally cardioprotective. Sprague Dawley male rats were given (orally) standardized grape extract (SGE) for a period of three weeks. Time‐matched control experiments were performed by feeding the animals 45 μg/100 of glucose plus 45 μg/100 g fructose per day for three weeks. After 30 days, rats were sacrificed, hearts excised and perfused via working‐mode. Hearts were made ischemic for 30 min followed by two hours of reperfusion. At 100 mg/kg and at 200 mg/kg, SGE provided significant cardioprotection as evidenced by improved post‐ischemic ventricular recovery and reduced amount of myocardial infarction. No cardioprotection was apparent when rats were given grape samples at a dose of 50 mg/100 g/day. In vitro studies demonstrated that the SGE could directly scavenge superoxide and hydroxyl radicals which are formed in the ischemic reperfused myocardium. The results demonstrate that the heats of the rats fed SGE reduced myocardial ischemia reperfusion injury by functioning as in vivo antioxidant.
Cardioprotective Abilities of White Wine
Authors: CUI JIANHUA , TOSAKI ARPAD , CORDIS GERALD A. , BERTELLI ALBERTO A.E. , BERTELLI ALDO , MAULIK NILANJANA , DAS DIPAK K.
Published: July 2009

Abstract: To study if white wines, like red wine, can also protect the heart from ischemia reperfusion injury, ethanol‐free extracts of three different white wines (WW1, WW2 and WW3) (100 mg/100 g body weight) were given orally to Sprague Dawley rats (200 g body weight) for three weeks. Control rats were given water only for the same period of time. After three weeks, rats were anesthetized and sacrificed, and the hearts excised for the preparation of isolated working rat heart. All hearts were subjected to 30 min global ischemia followed by two hours of reperfusion. The results demonstrated that among the three different white wines, only WW2 showed cardioprotection as evidenced by improved post‐ischemic ventricular recovery compared to control. The amount of malonaldehyde production in white wine‐fed rat hearts were lower compared to that found in control hearts indicating reduced formation of the reactive oxygen species. In vitro studies using chemiluminescence technique revealed that these white wines scavenged both superoxide anions and hydroxyl radicals. The results of our study demonstrated that only WW2 white wine provided cardioprotection as evidenced by the improved the post‐ischemic contractile recovery and reduced myocardial infarct size. The cardioprotective effect of this white wine may be attributed, at least in part, from its ability to function as an in vivo antioxidant.
The in Vivo Antithrombotic Effect of Wine Consumption on Human Blood Platelets and Hemostatic Factors
Authors: MANSVELT ERNA P.G. , Van VELDEN DAVID P. , FOURIE ELBA , ROSSOUW MARIETJIE , Van RENSBURG SUSAN J. , SMUTS C. MARIUS
Published: July 2009

Abstract: We compared the in vivo effect of red vs. white wine consumption on platelet aggregation, responsiveness and membrane viscosity, plasma total antioxidant status, thromboxane B2 levels, and fibrinolysis. Diet and red wine had a synergistic effect in decreasing platelet aggregation. Red wine did not have a significantly more favorable effect on the fibrinolytic factors than white wine. The reduction in platelet membrane viscosity after red wine, which could contribute to the protective antithrombotic role of red wine, needs further explanation.
Therapeutic Potential of Implanted Tissue‐Engineered Bioartificial Muscles Delivering Recombinant Proteins to the Sheep Heart
Authors: LU Y. , SHANSKY J. , DEL TATTO M. , FERLAND P. , MCGUIRE S. , MARSZALKOWSKI J. , MAISH M. , HOPKINS R. , WANG X. , KOSNIK P. , NACKMAN M. , LEE A. , CRESWICK B. , VANDENBURGH H.
Published: July 2009

Abstract: Tissue‐engineered primary adult sheep muscle cells genetically engineered to express either rhVEGF or rhIGF‐1 secreted the bioactive proteins locally in the sheep heart for at least 30 days.
Manufacturing and Characterization of 3‐D Hydroxyapatite Bone Tissue Engineering Scaffolds
Authors: CHU T.‐M. G. , HOLLISTER S. J. , HALLORAN J. W. , FEINBERG S. E. , ORTON D. G.
Published: July 2009

Abstract: Internal architecture has a direct impact on the mechanical and biological behaviors of porous hydroxyapatite (HA) implants. However, traditional processing methods provide very minimal control in this regard. This paper reviews a novel processing technique developed in our laboratory for fabricating scaffolds with controlled internal architectures. The preliminary mechanical property and in vivo evaluation of these scaffolds are also presented.
TGF‐β1‐Stimulated Osteoblasts Require Intracellular Calcium Signaling for Enhanced α5 Integrin Expression
Authors: NESTI LEON J. , CATERSON E. J. , WANG MARK , CHANG RICHARD , CHAPOVSKY FELIX , HOEK JAN B. , TUAN ROCKY S.
Published: July 2009

Abstract: The osteoactive factor, transforming growth factor β1 (TGF‐β1), influences osteoblast activity and bone function. We recently characterized a Smad‐independent TGF‐β1‐induced Ca2+ signal in human osteoblasts (HOB) and demonstrated its importance in cell adhesion. Here, we further elucidate the role of the TGF‐β1 Ca2+ signal in the mechanics of HOB adhesion. Osteoblast interaction with fibronectin (FN) through α5β1 integrin is principally responsible for osteoblast‐substrate adhesion. Our results show that the TGF‐β1 intracellular Ca2+ signal is responsible, in part, for stimulation of α5 integrin expression, but not β1 integrin or FN expression. Increased α5 integrin protein and mRNA expression was seen as early as 12 h after TGF‐β1 treatment, but was inhibited by cotreatment with nifedipine, a Ca2+ channel blocker. TGF‐β1 increased both FN and β1 integrin protein production within 48 h, independent of nifedipine cotreatment. Immunofluorescence observations revealed that TGF‐β1 increased α5 integrin staining, clustering, and colocalization with the actin cytoskeleton, effects that were blocked by nifedipine. The TGF‐β1 Ca2+ signal, a pathway crucial for HOB adhesion, enhances α5 integrin expression, focal contact formation, and cytoskeleton reorganization. These early events are necessary for osteoblast adhesion; thus they determine the fate of the cell and ultimately affect bone function.
Bioreactors and Bioprocessing for Tissue Engineering
Authors: RATCLIFFE ANTHONY , NIKLASON LAURA E.
Published: July 2009

Abstract: Bioreactor design in tissue engineering is complex, and at the early stages of its development. Design of biologically effective, yet scalable, devices requires intimate collaboration between engineers and biologists to ensure that all aspects are considered fully. Growth conditions, harvesting time, scale‐up, storage, and sterility issues all need to be considered and incorporated into the design of bioreactors. Each tissue‐engineered product will likely require individualized bioreactor design. However, without a comprehensive understanding of each of these components, bioreactor design and tissue growth to manufacture product will remain at a relatively rudimentary and limited level. Increased fundamental understanding of the issues can have a dramatic impact on the ability to generate tissue‐engineered product safely, economically, and in the numbers that are required to fully address the patient populations in need.
The Significance of Nitric Oxide Production in the Brain After Injury
Authors: KHALDI AHMAD , CHIUEH C. C. , BULLOCK M. ROSS , WOODWARD J. J.
Published: July 2009

Abstract: Glutamate toxicity has been implicated in many aspects of brain injury including traumatic, ischemic, and hemorrhagic damage. We have used in vitro as well as in vivo methods to measure NO production and to examine the role of NO in glutamate toxicity. In building our recombinant system, we used human kidney embryonic cells, HEK 293, as host for transfection of nNOS and NMDA receptor proteins. Cells cotransfected with NMDA and nNOS were more resistant to glutamate toxicity. This resistance correlated with NO production as measured by citrulline assay. Meanwhile, the production of NO did not significantly change the response of the NMDA receptor as seen by calcium studies. Moreover, in vivo, NO production was directly correlated with brain tissue oxygen tension in subarachnoid hemorrhage patients. These data and others point toward the importance of NO production in the response of brain to injury.
Possible Roles of Nitric Oxide in the Physiology and Pathophysiology of the Mammalian Cochlea
Authors: RUAN RUN‐SHENG
Published: July 2009

Abstract:Nitric oxide (NO) has been implicated as a mediator of vasodilation and neurotransmission in the mammalian cochlea. This is demonstrated by the presence of nitric oxide synthase (NOS) and nitric oxide (NO) in the blood vessels and the organ of Corti in the cochlea. It is not certain if the neurons in the spiral ganglion produce NO since no fluorescent signal could be detected by 4,5‐diaminofluorescein diacetate (DAF‐2DA), a fluorescent indicator of NO. To determine if NO/peroxynitrite plays any role in neurodestruction observed in ischemic cochlea of the guinea pig, the effects of NO donors, such asS‐nitrosocysteine (S‐NC) and nitroglycerine (NTG); peroxynitrite generators, such as 3‐morpholinosydnonimine (SIN‐1); peroxynitrite inhibitors, such as superoxide dismutase plus catalase (SOD/Cat); and NOS inhibitors, such asNG‐nitro‐l‐arginine methyl ether (l‐NAME) were tested on normal and ischemic cochleae. The level of NO in the cochlea after 20 to 120 minutes of ischemia was indicated by measurement of nitrites/nitrates in the perilymph. The evidence gathered from these experiments indicates that NO or peroxynitrite is not necessarily destructive to auditory hair cells, and in fact, exogenous NO may protect neural structures in the cochlea from damage under ischemic conditions.
Gö6976 Protects Mesencephalic Neurons from Lipopolysaccharide‐Elicited Death by Inhibiting p38 MAP Kinase Phosphorylation
Authors: JEOHN GWANG‐HO , COOPER CYNTHIA L. , JANG KYUNG‐JIN , KIM HYOUNG‐CHUN , HONG JAU‐SHYONG
Published: July 2009

Abstract:Glial activation is associated with inflammation‐related neuron degeneration in the brain. A variety of protein kinases are assumed to contribute to the expression of inflammation‐related products, such as nitric oxide (NO) and proinflammatory cytokines, however, the mechanisms of glial activation and glia‐mediated neurotoxicity remain unclear. We found that the indolocarbazole, Gö6976, originally known as a selective protein kinase C (PKC) inhibitor, protects neurons from glia‐mediated damage and suppresses lipopolysaccharide (LPS)‐induced microglial production of inflammatory factors. The purpose of the study we report here was to determine the mechanism underlying the neuroprotective effect of Gö6976 in mesencephalic neuron/glia cultures. Gö6976 suppressed LPS‐induced neurotoxicity in mesencephalic neuron/glia cultures and the protective effect of Gö6976 paralleled the suppression of p38 mitogen activated protein kinase (MAPK) activation and inhibition of NO production. Gö6976 did not directly inhibit the activity of p38 MAPK; rather, the inhibitor suppressed the phosphorylation of p38 MAPK, suggesting that the target of Gö6976 is a signaling event upstream of p38 MAPK. Although Gö6976 was originally known to be a selective PKC inhibitor, the neuroprotection was not mediated through its reputed effects on PKC activity. This paper demonstrates that the neuroprotective effect of Gö6976 against LPS‐induced damage is mediated through the inhibition of proinflammatory factors, such as NO from microglia, by inhibiting the phosphorylation of p38 MAPK.
Nitric Oxide‐Releasing Drugs
Authors: BURGAUD JEAN‐LUC , ONGINI ENNIO , DEL SOLDATO PIERO
Published: July 2009

Abstract:Nitric oxide (NO) deficiency has been implicated in many pathologic processes, thus providing a solid biological basis for the use of NO replacement therapy. Exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate sufficient NO for normal biological functions. This theory has opened up the possibility of designing new drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner. This objective has been achieved by grafting an organic nitrate structure onto existing drugs through chemical spacers, such as aliphatic, aromatic, or a heterocyclic chain. The approach has led to the synthesis of several new chemical entities whose pharmacologic profile challenges the parent drug, not only on the basis of new properties, but also with respect to a better safety profile. In this article, a specific class of NO donors is reviewed, the nitric oxide‐releasing non‐steroidal antiinflammatory drugs, NO‐NSAIDs. Recently discovered compounds, whose action depends on the combined properties of both the known drug and NO release, are illustrated. Two examples are described in detail: (1) nitric oxide‐releasing aspirin, which has demonstrable innovative properties for treatment of vascular disorders and cancer; (2) nitro‐derivatives of flurbiprofen that have shown encouraging results in models of Alzheimer's disease.
Mechanisms of Corticosteroid Resistance in Rheumatoid Arthritis
Authors: CHIKANZA IAN C.
Published: July 2009

Abstract: Corticosteroids (CSs) have potent immunosuppressive effects and are commonly used to treat a range of immunological and inflammatory diseases such as rheumatoid arthritis (RA). These effects are mediated by the ability of CSs to modulate gene expression. CSs act by binding to the CS receptor (CR), which exists as α and β isoforms. Only CRα binds CS. CRβ functions as an endogenous inhibitor of CS and is expressed in several tissues. The CS/CRα complex binds to the glucocorticosteroid response element in the nucleus and also interferes with AP‐1 and NF‐κB binding. Thus, CSs inhibit the transcription of AP‐1 and NF‐κB inducible genes, such as interleukin (IL)‐2, IL‐6, IL‐8, IL‐1β, and tumor necrosis factor (TNF) α, as well as T‐cell proliferation. In clinical practice, a proportion of RA patients do not respond adequately to CS therapy. On this basis, RA patients can be divided on clinical grounds and on the ability of CSs to inhibit concanavalin A (conA)‐induced peripheral blood T‐cell proliferation in vitro into CS‐sensitive (SS) and CS‐resistant (SR) subgroups. The in vitro defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms of the SR in RA patients remain unknown but may include the following: dysregulation of CRα function, alterations in the intracellular signaling mechanisms and/or utilization of various other cellular activation pathways, perturbations of the cytokine milieu, and inhibition of lipocortin. In SR subjects, CSs fail to significantly inhibit conA‐induced IL‐2 and IL‐4 secretion and LPS‐induced IL‐8, IL‐1β secretion in vitro. CS therapy fails to reduce the circulating levels of IL‐8, IL‐1β, and TNFα in SR RA patients. Peripheral blood mononuclear cells (PBMCs) from SR significantly overexpress activated NF‐κB and IκBα. In vitro CSs fail to significantly inhibit conA‐induced NF‐κB activation in PBMCs from SR RA patients. Our preliminary observations show enhanced CRβ expression by PBMCs from SR RA patients. It is most likely that other molecular mechanisms such as enhanced AP‐1 expression are involved, and we currently are investigating such possibilities.
Mechanisms of Glucocorticoid Action in Bone
Authors: CANALIS ERNESTO , DELANY ANNE M.
Published: July 2009

Abstract: Glucocorticoids cause profound effects on bone cell replication, differentiation, and function. Glucocorticoids increase bone resorption by stimulating osteoclastogenesis by increasing the expression of RANK ligand and decreasing the expression of its decoy receptor, osteoprotegerin. In accordance with the increase in bone resorption, glucocorticoids stimulate the expression of collagenase 3 by posttranscriptional mechanisms. The most significant effect of glucocorticoids in bone is an inhibition of bone formation. This is because of a decrease in the number of osteoblasts and their function. The decrease in cell number is secondary to a decrease in osteoblastic cell replication and differentiation, and an increase in the apoptosis of mature osteoblasts. Glucocorticoids decrease osteoblastic function directly and indirectly through the modulation of growth factor expression, receptor binding, or binding protein levels. Clinically, patients with glucocorticoid‐induced osteoporosis (GIOP) develop bone loss in the first few months of glucocorticoid exposure, and modest doses of glucocorticoids increase the risk of fractures of the spine and hip. Bisphosphonates inhibit bone resorption and prevent and revert the bone loss that follows glucocorticoid exposure. Anabolic agents, such as parathyroid hormone, stimulate bone formation and can increase bone mass in GIOP.
Cortisol, Dehydroepiandrosterone Sulfate, and Androstenedione Levels in Patients with Polymyalgia Rheumatica during Twelve Months of Glucocorticoid Therapy
Authors: CUTOLO M. , SULLI A. , PIZZORNI C. , CRAVIOTTO C. , PRETE C. , FOPPIANI L. , SALVARANI C. , STRAUB R. H. , SERIOLO B.
Published: July 2009

Abstract: This paper aims to evaluate adrenal gland hormone levels in patients with polymyalgia rheumatica (PMR) during glucocorticoid (GC) therapy. A lower than expected basal production of cortisol was found in active and glucocorticoid‐untreated PMR patients, particularly females. The abrupt onset of PMR with clinical features similar to those of the steroid‐withdrawal syndrome or adrenal insufficiency, as well as the clinical response to GC therapy in elderly people already age‐disposed to an inadequate adrenal and anti‐inflammatory response, might represent the most significant pathophysiological basis of the disease.
Modulation of Cell Growth and Apoptosis by Sex Hormones in Cultured Monocytic THP‐1 Cells
Authors: CUTOLO MAURIZIO , SULLI ALBERTO , CRAVIOTTO CHIARA , FELLI LAMBERTO , PIZZORNI CARMEN , SERIOLO BRUNO , VILLAGGIO BARBARA
Published: July 2009

Abstract: Several authors have reported the regulation of apoptotic phenomena by sex hormones in different cell lines, including T lymphocytes and mononuclear cells. Since androgens can modulate the programmed cell death in responsive cell lines, we decided to investigate the induction of apoptosis in THP‐1 cells following their differentiation into macrophage‐like cells and exposure to sex hormones. In addition, we decided to evaluate the proto‐oncogene Bax and Fas (CD 95) and cleaved PARP (poly‐adp‐ribose‐polymerase) expression in the same cultured cells. The results showed for the first time the dose‐/time‐dependent regulation of the apoptotic event in human monocytic THP‐1 cells treated with different concentrations of androgens. No significant changes were observed for estrogen‐treated and unstimulated control cells. In particular, the cells, after stimulation with androgens but not with estrogens, were found to be positive for the proto‐oncogene Bax, Fas, and for cleaved subunits of PARP expression as demonstrated with different assays including immunocytochemical assay and Western blot analysis. In conclusion, these results support the possibility of sex hormone modulation of apoptosis in macrophage‐like cells, with interesting therapeutic perspectives in rheumatoid arthritis.
Stress Hormones, Proinflammatory and Antiinflammatory Cytokines, and Autoimmunity
Authors: ELENKOV ILIA J. , CHROUSOS GEORGE P.
Published: July 2009

Abstract:Recent evidence indicates that glucocorticoids and catecholamines, the major stress hormones, inhibit the production of proinflammatory cytokines, such as interleukin (IL)‐12, tumor necrosis factor (TNF)‐α, and interferon (IFN)‐γ, whereas they stimulate the production of antiinflammatory cytokines, such as IL‐10, IL‐4, and transforming growth factor (TGF)‐β. Thus, systemically, an excessive immune response, through activation of the stress system, stimulates an important negative feedback mechanism, which protects the organism from an “overshoot” of proinflammatory cytokines and other products of activated macrophages with tissue‐damaging potential. Conversely, in certain local responses and under certain conditions, stress hormones actually may boost regional immune responses, through induction of TNF‐α, IL‐1, and IL‐8, and by inhibiting TGF‐β production. Therefore, conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, severe exercise, and pregnancy and the postpartum period, through modulation of the systemic or local pro/antiinflammatory cytokine balance, may suppress or potentiate autoimmune diseases activity and/or progression.
Immunological Responses Are Not Abnormal in Symptomatic Gulf War Veterans
Authors: EVERSON MICHAEL P. , SHI KE , ALDRIDGE PEGGY , BARTOLUCCI ALFRED A. , BLACKBURN WARREN D.
Published: July 2009

Abstract: The underlying etiology and pathogenesis of Gulf War veterans' illnesses continue to be under intense investigation. Reports have suggested the basis for these illnesses may be an altered immune system, but compelling evidence is lacking. We sought to determine whether in vitro immune responses were abnormal in symptomatic Gulf War veterans relative to matched controls. A randomized case‐control study was conducted by blinded comparison of laboratory measures of in vitro immune responses in blood samples obtained from veterans in an outpatient facility of a Veterans Affairs medical center. Symptomatic Gulf War veterans with otherwise undefined illnesses (52 symptomatic subjects), asymptomatic Gulf War veterans (31 asymptomatic controls), and veterans who had applied for disability compensation and had not participated in the Gulf War (21 disability controls) represented the volunteer sample. In vitro cellular and humoral immune responses were measured to detect functional abnormalities in antigen presenting cells (autologous mixed leukocyte reactions and expression of interleukin (IL)‐1β, IL‐6, IL‐10, and tumor necrosis factor‐α); T cells (lymphocyte proliferation using the polyclonal T‐cell activators phytohemagglutinin and Concanavalin A; primary immune responses in allogeneic mixed leukocyte reactions; secondary immune response using the recall antigens tetanus toxoid, Candida albicans, and anthrax vaccine; and soluble IL‐2 receptor expression); type‐1 T‐helper cells (gamma interferon expression); type‐2 T‐helper cells (IL‐4 and IL‐10 expression); and B cells (polyclonal B‐cell activator pokeweed mitogen‐induced immunoglobulin production). In general, immune response measures did not differ significantly between groups. Heightened responses observed in the disability control group (sporadically greater responses to one mitogen and two antigens) and the Gulf War participation control group (greater recall responses to anthrax vaccine) did not suggest impaired immune cell function in symptomatic veterans when compared with controls. We conclude that in vitro immunological responses are not abnormal in symptomatic Gulf War veterans.
Corticotropin‐Releasing Factor Modulates Cardiovascular and Pupillary Autonomic Reflexes in Man
Authors: PONGRATZ GEORG , ZIETZ BETTINA , GLÜCK THOMAS , SCHÖLMERICH JÜRGEN , STRAUB RAINER H.
Published: July 2009

Abstract:In two recent studies, we found autonomic nervous hyperreflexia in subjects with chronic inflammatory diseases, particularly, in those subjects with higher degrees of systemic inflammation. Since corticotropin‐releasing factor (CRF) is induced by inflammatory stimuli and acts within the brain to change neuroendocrine and autonomic activity, we investigated CRF modulation of standard autonomic nervous reflexes. Fifteen healthy subjects were administered 100 μg CRF i.v., which led to a short‐term increase of heart rate (p< 0.001) and a decrease in systolic and diastolic blood pressure (p< 0.050). These changes were accompanied by a reduction in heart rate variation at rest (p= 0.010) and during the respiratory sinus arrhythmia test (p= 0.019), and a reduction of pupillary latency time (p= 0.038). In further 21 normal subjects we studied the effect of prednisolone treatment on autonomic nervous function (100 mg/d during three days → CRF reduction), which resulted in an increase of heart rate (p< 0.001), increase of heart rate variation during the respiratory sinus arrhythmia test (p< 0.001), increase in pupillary latency time (p= 0.012), a increase in maximal pupillary area (p= 0.002), and a decrease in diastolic blood pressure (p= 0.002). In conclusion, induction of a low central CRF content by prednisolone leads to a marked hyperreflexia in respiratory sinus arrhythmia and hyporeflexia in the latency time test. It is obvious that CRF can regulate autonomic reflexes. Possibly, central CRF status may also influence autonomic reflexes during chronic inflammation due to chronically changed central CRF concentration.
Neuropeptides in Experimental and Degenerative Arthritis
Authors: NIISSALO S. , HUKKANEN M. , IMAI S. , TÖRNWALL J. , KONTTINEN Y. T.
Published: July 2009

Abstract: Classical symptoms of both inflammatory and degenerative arthritides may contribute to neurogenic responses like wheal, flare, edema, and pain. Rheumatoid arthritis (RA) is an autoimmune disease with an immunogenetic background. Neurogenic inflammation has been considered to play an essential role in RA, in part because of the symmetrical involvement (cross‐spinal reflexes) and the predominant involvement of the most heavily innervated small joints of the hands and the feet (highly represented in the hominiculus). In contrast, osteoarthritis (OA) is considered to arise as a result of degeneration of the hyaline articular cartilage, which secondarily results in local inflammation and pain. However, it is possible that the age‐related and predominant (compared to nociceptive nerves) degeneration of the proprioceptive, kinesthetic and vasoregulatory nerves can represent the primary pathogenic events. This leads to progressive damage of tissue with extremely poor capacity for self‐regeneration. Inflammation, be it primary/autoimmune or secondary/degenerative, leads to peripheral sensitization and stimulation, which may further lead to central sensitization, neurogenic amplification of the inflammatory responses and activation of the neuro‐endocrine axis. Neuropeptides serve as messengers, which modulate and mediate the actions in these cascades. Accordingly, many neuropeptides have been used successfully as experimental treatments, most recently VIP, which effectively controlled collagen‐induced arthritis in mice. Therefore, it can safely be concluded that better treatment/control of disease activity and pain can be achieved by blocking the cascade leading to initiation and/or amplification of inflammatory process combined with effects on central nociceptive and neuroendocrine responses.
Psychoneuroimmunology
Authors: PROLO PAOLO , CHIAPPELLI FRANCESCO , FIORUCCI ADRIANO , DOVIO ANDREA , SARTORI MARIA LUISA , ANGELI ALBERTO
Published: July 2009

Abstract: Psychoneuroimmunology (PNI) investigates the relations between the psychophysiological and immunophysiological dimensions of living beings. PNI brings together researchers in a number of scientific and medical disciplines, including psychology, the neurosciences, immunology, physiology, pharmacology, psychiatry, behavioral medicine, infectious diseases, and rheumatology. All are scientists with profound interest in interactions between the nervous and immune systems, and the relation between behavior and health. Despite the variety in domains and approaches to research, the outcome common to all research endeavors is the discovery of new information, of uncovered facts, of novel evidence, which contributes to the continuing generation of knowledge. In this paper we discuss psychoneuroimmune aspects of some conditions that are not routinely immediately associated with immunity, such as the condition of being the caregiver of somebody suffering from dementia; the effect on the brain‐body modulations of aluminum, a metal that is not a component of the human body; and insomnia, a fairly common but disturbing disease, that even today lacks an effectual treatment.
Brain Functional Involvement by Perfusion SPECT in Systemic Sclerosis and Behçet's Disease
Authors: NOBILI F. , CUTOLO M. , SULLI A. , VITALI P. , VIGNOLA S. , RODRIGUEZ G.
Published: July 2009

Abstract: Involvement of the central nervous system is frequent in systemic immune‐mediated diseases, such as systemic lupus erythematosus, Behçet's disease (BD), and systemic sclerosis (SSc). Structural brain examinations, such as computed tomography and magnetic resonance imaging, may be useful in diagnosing and following‐up these cerebral syndromes in some cases, but they are more often inconclusive. Single photon emission computed tomography (SPECT) with perfusion tracers is a powerful method that can disclose brain involvement in many clinical situations, even in patients with subtle neurological symptoms. In fact, perfusion tracers can disclose regional hypoperfusion caused by both ischemia due to vascular narrowing and neuronal metabolic derangement due to direct neuronal damage. The latter phenomenon occurs because the blood flow to the brain is strictly regulated by metabolic demands, so that hypometabolism is reflected by hypoperfusion in most instances. SPECT findings in 42 mainly neurologically asymptomatic patients with SSc and in eight mainly neurologically symptomatic patients with BD are reported. SPECT was shown to be very sensitive and disclosed brain functional deficits in approximately half of SSc patients without neurological complaints and in all patients with BD, who had various neurological symptoms but usually inconclusive structural brain examinations.
Decreased Catecholamine‐Induced Cell Death in B Lymphocytes from Patients with Rheumatoid Arthritis
Authors: WAHLE M. , PIERER M. , KRAUSE A. , KÖLKER S. , BAERWALD C.G. O.
Published: July 2009

Abstract: The expression of β2‐adrenergic receptors (β2‐R) on B lymphocytes and agonist‐induced cAMP production is reduced in patients with rheumatoid arthritis (RA). To further study functional consequences of the diminished β2‐R density on B lymphocytes in RA patients, agonist‐induced cell death was evaluated and compared to healthy controls. B lymphocytes from patients with RA and healthy controls were activated with anti‐IgM‐antibody. Coincubation was carried out with isoprenaline (iso, 0.001‐10 μM). Apoptotic and necrotic cells were determined using Annexin‐V and propidium‐iodide staining. β2‐R‐induced cell death in B cells from healthy volunteers was stimulated after 24 h (medium, 21.2 ± 1.6%; iso, 34.6 ± 4.4%; increase 59.3 ± 10.1%). However, in RA patients the increase in cell death following β2‐R stimulation (21.8 ± 8.9%) was significantly impaired (p= 0.02). Our data demonstrate that catecholamine‐induced cell death after stimulation of β2‐R on B lymphocytes is decreased in RA patients, possibly contributing to the pathogenesis of the disease.
Psychoneuroimmunology in Oral Biology and Medicine
Authors: PROLO PAOLO , CHIAPPELLI FRANCESCO , CAJULIS ELAINA , BAUER JANET , SPACKMAN SUSAN , ROMEO HORACIO , CARROZZO MARCO , GANDOLFO SERGIO , CHRISTENSEN RUSSELL
Published: July 2009

Abstract: Rheumatoid arthritis involves psychoneuroendocrine‐immunopathological comorbidities. In the stoma, patients with rheumatoid arthritis frequently show signs of periondontal disease consequent to elevated levels of crevicular proinflammatory cytokines. It is not clear whether rheumatoid arthritis may manifest in association with immunopathological manifestations of the oral soft mucosa. Oral lichen planus (OLP), first described by E. Wilson in 1859, is a T‐cell‐mediated inflammatory disease whose lesions characteristically lack B cells, plasma cells, immunoglobulin. or complement. It is increasingly well characterized and recognized as a model for psychoneuroimmunology research in oral biology and medicine. To date, we have shown an association between changes in hypothalamic‐pituitary‐adrenal (HPA) regulation, systemic markers of cellular immunity and mood states, with clinical stages of OLP (i.e., atrophic vs. erosive vs. bullous lesions). We report significant associations (p < 0.05) between the stage of OLP, HPA deregulation, and altered distribution and functional responses of naïve CD4+ cells. We emphasize the need to study in greater details the psychoneuroendocrine‐immune inter‐relationships in OLP, and we propose a novel neuroimmune hypothesis for OLP.
The Use of Pupillometry in Joint and Connective Tissue Diseases
Authors: BERTINOTTI LUCA , PIETRINI UMBERTO , DEL ROSSO ANGELA , CASALE ROBERTO , COLANGELO NICOLA , ZOPPI MASSIMO , MATUCCI‐CERINIC MARCO
Published: July 2009

Abstract:The central and peripheral nervous systems are variably affected in the rheumatic diseases. Automated standardized infrared pupillometry allows the safe, noninvasive assessment of the pupillary innervation. Pupillometry has already been used in studying the autonomic nervous system (ANS) in various rheumatic diseases. In systemic lupus erythematosus, the irideal parasympathetic branch of ANS was more affected then the sympathetic branch. In Sjögren's syndrome, signs of pupillary parasympathetic denervation have been reported. In rheumatoid arthritis, pupil parasympathetic dysfunction has been shown to correlate with ocular dryness. In systemic sclerosis (SSc), both sympathetic and parasympathetic irideal impairment have been demonstrated. Beside providing autonomic innervation, sensory nerves fibers are able to control iris diameter. Exogenous ocular instillation of substance P (SP), a sensory neuropeptide, can determine an omathropine‐resistant, non‐cholinergic myosis, acting on specific receptors present on the iris sphincter muscle. We first studied pupillary SP‐ergic responsiveness in SSc, evaluating substance P (SP)‐stimulated pupillary diameters by pupillometry. A higher basal and SP‐stimulated myosis was found in lSSc versus both dSSc and controls, whereas no differences existed between dSSc and controls. From the literature, the pupillary parasympathetic nervous system seems to be more affected than the sympathetic branch of ANS in the rheumatic diseases characterized by an inflammatory status. However, we found in SSc both sympathetic and parasympathetic pupil control to be equally impaired. From our experience, we conclude that pupillary nervous control is differently affected in the two subsets of SSc, and that the SP‐ergic system seems to be impaired only in lSSc.
Opioid Peptides Endomorphin‐1 and Endomorphin‐2 in the Immune System in Humans and in a Rodent Model of Inflammation
Authors: JESSOP DAVID S. , RICHARDS LOUISE J. , HARBUZ MICHAEL S.
Published: July 2009

Abstract:Endomorphin (EM)‐1 and EM‐2 are tetrapeptides with high affinity and selectivity for the μ‐opioid receptor. We have utilized specific radioimmunoassays to characterize EM‐1 and EM‐2 in immune tissues from normal human subjects and from rats with adjuvant arthritis (AA). PBLs from three normal human subjects contained 248, 13, and 303 pg EM‐1 per 100 million cells, whereas EM‐2 was measured in two subjects at 69 and 588 pg per 100 million cells. In AA rats, EM‐1 (but not EM‐2) contents in the spleen and thymus were elevated compared with levels in tissues from non‐AA controls. EM‐1 was detectable in five of eight samples of synovial tissue from inflamed hind paws, whereas EM‐2 was detectable in two of eight synovial extracts. Neither EM‐1 nor EM‐2 were detectable in synovial tissue from non‐AA rats. To our knowledge, this is the first report of endomorphins in normal human immune cells. Increased endomorphin expression or uptake in peripheral tissues in a rodent model of chronic inflammation provides potential for endomorphins to selectively modulate chronic inflammation in mammals.
Dissecting the Circuitry of Protein Kinase A and cAMP Signaling in Cancer Genesis
Authors: CHO‐CHUNG YOON S. , NESTEROVA MARIA , BECKER KEVIN G. , SRIVASTAVA RAKESH , PARK YUN GYU , LEE YOUL NAM , CHO YEE SOOK , KIM MEYOUNG‐KIN , NEARY CATHERINE , CHEADLE CHRIS
Published: July 2009

Abstract: Expression of the RIα subunit of the cAMP‐dependent protein kinase type I (PKA‐I) is enhanced in human cancer cell lines, in primary tumors, in transformed cells, and in cells upon stimulation of growth. Signaling via the cAMP pathway may be complex, and the biological effects of the pathway in normal cells may depend upon the physiological state of the cells. However, results of different experimental approaches such as antisense exposure, 8‐Cl‐cAMP treatment, and gene overexpression have shown that the inhibition of RIα/PKA‐I exerts antitumor activity in a wide variety of tumor‐derived cell lines examined in vitro and in vivo. cDNA microarrays have further shown that in a sequence‐specific manner, RIα antisense induces alterations in the gene expression profile of cancer cells and tumors. The cluster of genes that define the “proliferation‐transformation” signature are down‐regulated, and those that define the “differentiation‐reverse transformation” signature are up‐regulated in antisense‐treated cancer cells and tumors, but not in host livers, exhibiting the molecular portrait of the reverted (flat) phenotype of tumor cells. These results reveal a remarkable cellular regulation, elicited by the antisense RIα, superimposed on the regulation arising from the Watson‐Crick base‐pairing mechanism of action. Importantly, the blockade of both the PKA and PKC signaling pathways achieved with the CRE‐transcription factor decoy inhibits tumor cell growth without harming normal cell growth. Thus, a complex circuitry of cAMP signaling comprises cAMP growth regulatory function, and deregulation of the effector molecule by this circuitry may underlie cancer genesis and tumor progression.
Deficient Protein Kinase A in Systemic Lupus Erythematosus
Authors: KAMMER GARY M.
Published: July 2009

Abstract: Systemic lupus erythematosus (SLE) is an idiopathic autoimmune disease characterized by impaired T lymphocyte immune effector functions. We have identified a disorder of signal transduction in SLE T cells involving the cyclic AMP/protein kinase A (cAMP/PKA) pathway. Cyclic AMP‐stimulated PKA‐catalyzed protein phosphorylation is markedly diminished owing to profound deficiencies of both type I (PKA‐I) and type II (PKA‐II) isozyme activities. Deficient PKA‐I isozyme is characterized by a significant reduction in the amount of type I regulatory beta subunit (RIβ) steady state mRNA by competitive polymerase chain reaction. This is associated with a 30% decrease in RIα protein and a 65% reduction in RIβ protein. Indeed, T cells from ∼25% of SLE subjects have no detectable RIβ protein. Transient transfection of T cells not expressing RIβ protein with autologous SLE RIβ cDNA bypassed the block in translation, reconstituting PKA activity and augmenting IL‐2 production. Of importance was the initial identification of novel RIα mRNA mutations characterized by heterogeneous transcript mutations, including deletions, transitions, and transversions. Most mutations are clustered adjacent to GAGAG motifs and CT repeats. By contrast, deficient PKA‐II activity is the result of spontaneous dissociation of the cytosolic RIIβ2C2 holoenzyme, aberrant RIIβ translocation to the nucleus from the cytosol, and retention of RIIβ in the nucleus. In conclusion, distinct mechanisms account for deficient PKA‐I and PKA‐II isozyme activities in SLE T cells.
The Role of Cyclic AMP and Its Effect on Protein Kinase A in the Mitogenic Action of Thyrotropin on the Thyroid Cell
Authors: DREMIER S. , COULONVAL K. , PERPETE S. , VANDEPUT F. , FORTEMAISON N. , VAN KEYMEULEN A. , DELEU S. , LEDENT C. , CLÉMENT S. , SCHURMANS S. , DUMONT J. E. , LAMY F. , ROGER P. P. , MAENHAUT C.
Published: July 2009

Abstract: Cyclic AMP has been shown to inhibit cell proliferation in many cell types and to activate it in some. The latter has been recognized only lately, thanks in large part to studies on the regulation of thyroid cell proliferation in dog thyroid cells. The steps that led to this conclusion are outlined. Thyrotropin activates cyclic accumulation in thyroid cells of all the studied species and also phospholipase C in human cells. It activates directly cell proliferation in rat cell lines, dog, and human thyroid cells but not in bovine or pig cells. The action of cyclic AMP is responsible for the proliferative effect of TSH. It accounts for several human diseases: congenital hyperthyroidism, autonomous adenomas, and Graves' disease; and, by default, for hypothyroidism by TSH receptor defect. Cyclic AMP proliferative action requires the activation of protein kinase A, but this effect is not sufficient to explain it. Cyclic AMP action also requires the permissive effect of IGF‐1 or insulin through their receptors, mostly as a consequence of PI3 kinase activation. The mechanism of these effects at the level of cyclin and cyclin‐dependent protein kinases involves an induction of cyclin D3 by IGF‐1 and the cyclic AMP‐elicited generation and activation of the cyclin D3‐CDK4 complex.
Cyclic AMP and the Reverse Transformation Reaction
Authors: PUCK THEODORE T. , WEBB PATRICIA , JOHNSON ROBERT
Published: July 2009

Abstract: Traditional methods for cancer treatment have been aimed at killing the cancer cells. Unfortunately this approach all too often is accompanied by harmful killing of normal cells. The present paper describes an experimental program in our laboratory in which cancer cells are treated so as to revert to normal cell behavior. This process, which we have named reverse transformation, appears to offer considerable hope in the treatment of a large number of malignancies.
Protein Kinase A and Chromosomal Stability
Authors: MATYAKHINA LUDMILA , LENHERR SARA M. , STRATAKIS CONSTANTINE A.
Published: July 2009

Abstract: All malignant human tumors contain chromosomal rearrangements. Among them, the majority of solid tumors show chromosomal instability, caused by abberations in chromosomal segregation during cell division. Chromosomal instability, defined as increased probability of formation of novel chromosomal mutations compared to that of normal or control cells, appears to be a feature of tumorigenesis in vivo and in vitro (in cancer cell lines). Several enzymatic kinases are involved in maintaining proper chromosomal segregation and regulating cell cycle progression. One such kinase, cAMP‐dependent protein kinase A (PKA), has a functional role in many aspects of cell signaling, metabolism, and proliferation. In this review, we will discuss the potential participation of PKA in chromosomal stability. This role includes the association of PKA with the centrosome, microtubules, and the anaphase‐promoting complex/cyclosome (ACP/C), all key aspects of proper chromosomal segregation.