Redox homeostasis and cellular stress response in aging and neurodegeneration.

Decreased expression and/or activity of antioxidant proteins leads to oxidative stress, accelerated aging, and neurodegeneration. While overwhelming levels and uncontrolled/dysregulated actions of reactive oxygen species (ROS) lead to deleterious effects, tighter regulation of those plays an important role in cell signaling. Mutations causing protein misfolding and the overload of toxic products derived from the free radical oxidation of polyunsaturated fatty acids, cholesterol, and glucose contribute to the disruption of the cellular redox homeostasis. Collectively or individually, these effects create pro-oxidant conditions in cells. Oxidative stress can induce neuronal damage, modulate intracellular signaling, and can ultimately lead to neuronal death by apoptosis or necrosis. Emerging evidence indicates that homocysteine (Hcy), a non-protein amino acid naturally present in the plasma, is implicated as a risk factor for numerous diseases. In particular, increased levels of circulating Hcy have been recognized as an independent risk factor for the development of vascular disease(s). Recent findings emphasize a relationship between elevated Hcy levels and neurodegeneration, which can be observed in Alzheimer's and Parkinson's diseases. An integrated response exists in the brain to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are controlled by several genes termed "vitagenes." Among these, the heat-shock proteins (HSPs) form a highly conserved system that is responsible for the preservation and repair of the correct protein conformation. Recent studies have shown that the heat-shock response (HSR) contributes to cytoprotection in a number of human diseases including inflammation, cancer, aging, and neurodegenerative disorders. Given the broad cytoprotective properties of the HSR, interest mounts currently among investigators toward discovering and developing pharmacological agents capable of inducing HSR. L: -Acetylcarnitine (LAC) is proposed as a therapeutic agent for several neurodegenerative disorders and also current evidence suggests that the compound may play a critical role in the modulation of cellular stress response in health and disease conditions. Here, we review the emerging salient concepts highlighting the pathways of neurodegeneration and the role of LAC in modulating the redox-dependent mechanisms responsible for the upregulation of vitagenes in brain that leads to the enhancement of stress tolerance in brain.

Parp and cell death or protection in rat primary astroglial cell cultures under LPS/IFNgamma induced proinflammatory conditions.

The enzyme poly(ADP-ribose)polymerase (PARP) has a leader role in the DNA damage survey mechanisms by its nick-sensor function, but it is also involved in the early events of the programmed cell death, particularly during inflammatory injury, as a coactivator of NF-kB. In the present study, we evaluated the PARP involvement in the mechanisms of protection and/or cell death in rat astroglial cell cultures during the early phase of proinflammatory commitment after lipopolysaccharide and interferon gamma treatment. According with the recent findings that PARP-1 phosphorylation by MAPK/ERK-2 pathway seems to modulate PARP activation, in time course experiments we demonstrated that a very early PARP activation and expression is able to trigger a cell death pathway, DNA damage independent, during strong proinflammatory insults, maintaining its role of guardian of the genome stability only during the normal cell cycling.

Dermatología estética a través del tiempo / Aesthetic dermatology through the time

Estudios antropológicos, etnológicos y arqueológicos muestran la evolución del cuidado de la piel desde la prehistoria. La preocupación del hombre por su aspecto estético se inicia con la humanidad misma. A través del tiempo se buscaron fórmulas cada vez más efectivas, para prolongar las condiciones de juventud y belleza. El aspecto estético de la piel siempre se relacionó con la buena salud. En la actualidad el dermatólogo posee sobrados elementos para recuperar y resaltar la salud y el cuidado de la piel.

Anthropologists and archeologists have traced the evolution of skin care since prehistory. The human concern for his aesthetic appearance dates since the beginning of humanity. Through time, more and more efficient formulations were looked for to extend youthfulness and beauty. An aesthetic skin has always been synonymous with health and at the present time the dermatologist has many resources to improve and acentuate the good quality of the skin.

Dermis acelular porcina (sus scrofa) cargada con antioxidantes de larrea divaricata / Porcine (sus scrofa) acellular dermis load with antioxidants from larrea divaricata

Con el objeto de cargar con antioxidantes de Larrea divaricata una dermis acelular porcina para propósitos terapéuticos, se determinó el contenido de polifenoles y antocianinas de extractos puros, aislados y absorbidos en una dermis acelular porcina. Los valores para polifenoles totales y antocianinas fueron: a) Larrea divaricata: 58,77 + 1,55 mg ácido gálico / 100 g peso fresco, 400,00 + 9,55 mg cianidina 3-glucósido / 100 g peso fresco, repectivamente, b) dermis acelular porcina: 8,86 + 0,55 mg ac. gállico / 100 g peso fresco y 0,10+ 0,00 mg cianidina 3-glucósido / 100 g peso fresco; respectivamente, c) Larrea divaricata absorbida en dermis acelular porcina 45,92 + 0,90 mg ácido gálico / 100 g peso fresco y 155,92 + 5,90 mg cianidina 3-glucósido / 100 g peso fresco, respectivamente. Nosotros concluimos que es posible tener una dermis acelular porcina cargada con antioxidantes de Larrea divaricata para propósitos médicos.

The aim of the study was to evaluate loading with antioxidants from Larrea divaricata a porcine acellular dermis for therapeutic purposes, poliphenols and anthocianins of pure extracts, isolated and absorbed in pig acellular dermis was evaluated. The following values (total polyphenols and anthocianins) were obtained: a) Larrea divaricata: 58,77 + 1,55 mg gallic acid / 100 g fresh weight; 400,95 + 9,55 mg cianydin 3- glucosyde / 100 g fresh weight; respectively; b) porcine acellular dermis: 8,86 + 0,55 mg gallic acid / 100 g fresh weight and 0,10+ 0,00 mg cianydin 3-glucosyde / 100 g fresh weight; respectively, c) L. divaricata absorbed in porcine acellular dermis: 45,92 + 0,90 mg gallic acid / 100 g fresh weight and 155,92 + 5,90 mg cianydin 3-glucosyde / 100 g fresh weight, respectively. We concluded that it is possible to get a porcine acellular dermis loaded with antioxidants from Larrea divaricata for medical purposes.

Effects of cyanobacterial extracellular products and gibberellic acid on salinity tolerance in Oryza sativa L.

Salt stress is one of the most serious factors limiting the productivity of rice, the staple diet in many countries. Gibberellic acid has been reported to reduce NaCl-induced growth inhibition in some plants including rice. Most paddy soils have a natural population of Cyanobacteria, prokaryotic photosynthethic microorganisms, which synthesize and liberate plant growth regulators such as gibberellins that could exert a natural beneficial effect on salt stressed rice plants. The aim of this work was to evaluate the effect of the cyanobacterium Scytonema hofmanni extracellular products on the growth of rice seedlings inhibited by NaCl and to compare it with the effect of the gibberellic acid in the same stress condition. Growth (length and weight of the seedlings) and biochemical parameters (5-aminolevulinate dehydratase activity, total free porphyrin and pigments content) were evaluated. Salt exposure negatively affected all parameters measured, with the exception of chlorophyll. Chlrorophyll concentrations nearly doubled upon exposure to high salt. Gibberellic acid counteracted the effect of salt on the length and dry weight of the shoot, and on carotenoid and chlorophyll b contents. Extracellular products nullified the salt effect on shoot dry weight and carotenoid content; partially counteracted the effect on shoot length (from 54% to 38% decrease), root dry weight (from 59% to 41% decrease) and total free porphyrin (from 31 to 13% decrease); reduced by 35% the salt increase of chlorophyll a; had no effect on root length and chlorophyll b. Gibberellic acid and extracellular products increased 5-aminolevulinate dehydratase activity over the control without salt. When coincident with high salinity, exposure to either EP or GA3, resulted in a reversal of shoot-related responses to salt stress. We propose that Scytonema hofmanni extracellular products may counteract altered hormone homeostasis of rice seedlings under salt stress by producing gibberellin-like plant growth regulators.

Utilización de extractos de avena sativa l. en dermatitis / Utilization of avena sativa l. extract in dermatitis

Los polifenoles (flavonoides y antocianinas) están ampliamente distribuidos entre las diferentes especies vegetales. Estos poseen gran capacidad antioxidante; existiendo correlación positiva entre la actividad antioxidante y los polifenoles totales. El objetivo de este trabajo fue evaluar: 1° El contenido de polifenoles y antocianas totales de semillas, glumelas y extracto acuoso de Avena sativa L. 2° El efecto de la aplicación tópica de extracto acuoso de avena en 45 casos (10 mujeres y 35 hombres, entre 1 y 56 años de edad) con dermatitis atópica, dermatitis de contacto irritativa y dermatitis de contacto alérgica; y 30 controles normales (15 mujeres y 15 hombres, entre 1 y 60 años de edad). Tratamiento: aplicación de compresas del extracto crudo de avena en la piel dañada durante 5 minutos, seguida de la colocación de la biomasa (T°= 33 + 2°C) cubierta por una tela de gasa durante 5 minutos. Dicha biomasa se retira con el extracto de avena líquido. Entre 1 y 36 meses de iniciado el tratamiento se observó remisión de los síntomas cutáneos. El extracto acuoso, la biomasa de Avena sativa L., glumelas y semillas enteras contenían 6.12+0,45, 46,11+0,36, 212,81+0,19 y 286,60+0,50 mg/100 g ác. Gálico, respectivamente, de polifenoles totales.

Polyphenols (flavonoids and anthocyanins) are widely spread among the different vegetables species. They have a big antioxidant capacity. One important correlation exists between the antioxidant activity and the quantity of total polyphenols. The objective of this work was to evaluate: 1- the contents of polyphenols and anthocyanins of whole seeds, glumes and aqueous extract of Avena Sativa L., 2- the effects of topical application of aqueous extract of Avena sativa L. in 45 patients (10 females and 35 males, between 1 and 56 years olds) with Atopic Dermatitis, Contact Irritative Dermatitis and Contact Allergic Dermatitis, and 30 normal controls (15 females and 15 males, between 1 and 60 years olds). Treatment: were applications of compress of aqueous extract Avena Sativa L over the damaged skin for approximately five minutes, immediately after, one must cover with the biomass of oat (T° = 33 + 2 C°) and a clothe for five minutes. The biomass was removed using the Avena Sativa L. acqueous extract. Remissions of the cutaneous symptoms were noticed between 1 and 36 months after the beginning of the treatment. Aqueous extract, Avena Sativa L. biomass, glumes and whole seeds contents were: 6.12+0.45; 46.11+0.36, 212.81+0.19 y 286.60+0.50 mg/100 g gallic ac., respectively, of total polyphenols.

Redox modulation of heat shock protein expression by acetylcarnitine in aging brain: relationship to antioxidant status and mitochondrial function.

There is significant evidence to show that aging is characterized by a stochastic accumulation of molecular damage and by a progressive failure of maintenance and repair processes. Protective mechanisms exist in the brain which are controlled by vitagenes and include members of the heat shock system, heme oxygenase-I, and Hsp70 as critical determinants of brain stress tolerance. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and the present study reports that treatment for 4 months of senescent rats with acetyl-L-carnitine induces heme oxygenase-1 as well as Hsp70 and SOD-2. This effect was associated with upregulation of GSH levels, prevention of age-related changes in mitochondrial respiratory chain complex expression, and decrease in protein carbonyls and HNE formation. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases. Particularly, modulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.

Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity.

Increased free radical generation and decreased efficiency of the reparative/degradative mechanisms both primarily contribute to age-related elevation in the level of oxidative stress and brain damage. Excess formation of reactive oxygen and nitrogen species can cause proteasomal dysfunction and protein overloading. The major neurodegenerative diseases are all associated with the presence of abnormal proteins. Different integrated responses exist in the brain to detect oxidative stress which is controlled by several genes termed vitagenes, including the heat shock protein (HSP) system. Of the various HSPs, heme oxygenase-I (HO-1), by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. The HO-1 gene is redox regulated and its expression is modulated by redox active compounds, including nutritional antioxidants. Given the broad cytoprotective properties of the heat shock response, there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. These findings have opened up new neuroprotective strategies, as molecules inducing this defense mechanism can be a therapeutic target to minimize the deleterious consequences associated with accumulation of conformationally aberrant proteins to oxidative stress, such as in neurodegenerative disorders and brain aging, with resulting prolongation of a healthy life span.

Effect of antioxidant diets on mitochondrial gene expression in rat brain during aging.

Age-related increase of reactive oxygen species (ROS) is particularly detrimental in postmitotic tissues. Calorie restriction (CR) has been shown to exert beneficial effects, consistent with reduced ROS generation by mitochondria. Many antioxidant compounds also mimic such effects. N-acetyl cysteine (NAC) provides thiol groups to glutathione and to mitochondrial respiratory chain proteins; thus, it may counteract both ROS generation and effects. In the present study we investigated, in different rat brain areas during aging (6, 12, and 28 months), the effect of 1-year treatment with CR and dietary supplementation with NAC on the expression of subunit 39 kDa and ND-1 (mitochondrial respiratory complex I), subunit IV (complex IV), subunit alpha of F0F1-ATP synthase (complex V) and of adenine nucleotide translocator, isoform 1 (ANT-1). The observed age-related changes of expression were prevented by the dietary treatments. The present study provides further evidence for the critical role of mitochondria in the aging process.

Protective effect of carnosine during nitrosative stress in astroglial cell cultures.

Formation of nitric oxide by astrocytes has been suggested to contribute, via impairment of mitochondrial function, to the neurodegenerative process. Mitochondria under oxidative stress are thought to play a key role in various neurodegenerative disorders; therefore protection by antioxidants against oxidative stress to mitochondria may prove to be beneficial in delaying the onset or progression of these diseases. Carnosine has been recently proposed to act as antioxidant in vivo. In the present study, we demonstrate its neuroprotective effect in astrocytes exposed to LPS- and INFgamma-induced nitrosative stress. Carnosine protected against nitric oxide-induced impairment of mitochondrial function. This effect was associated with decreased formation of oxidatively modified proteins and with decreased up-regulation oxidative stress-responsive genes, such as Hsp32, Hsp70 and mt-SOD. Our results sustain the possibility that carnosine might have anti-ageing effects to brain cells under pathophysiological conditions leading to degenerative damage, such as aging and neurodegenerative disorders.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia.

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.

Redox regulation in neurodegeneration and longevity: role of the heme oxygenase and HSP70 systems in brain stress tolerance.

Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed "vitagenes," among these, the heat shock system, a highly conserved mechanism responsible for the preservation and repair of cellular macromolecules, such as proteins, RNAs, and DNA. Recent studies have shown that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including ischemia and reperfusion damage, inflammation, cancer, as well as metabolic and neurodegenerative disorders. Recently, the involvement of the heme oxygenase (HO) pathway in antidegenerative mechanisms has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein. HO induction occurs together with the induction of other heat shock proteins during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms, via the heat shock response, through nutritional antioxidants or pharmacological compounds, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistently, by maintaining or recovering the activity of vitagenes, it is feasible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.

Increased expression of heat shock proteins in rat brain during aging: relationship with mitochondrial function and glutathione redox state.

It is generally recognized that lipid peroxides play an important role in the pathogenesis of several diseases and that sulfhydryl groups are critically involved in cellular defense against endogenous or exogenous oxidants. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Oxidative damage plays a crucial role in the brain aging process and induction of Hsps is critically utilized by brain cells in the repair process following various pathogenic insults. In the present study, we investigated, in rats 6, 12, and 28 months old, the role of heat shock expression on aging-induced changes in mitochondrial and antioxidant redox status. In the brain expression of Hsp72 and Hsc70 increased with age up to 28 months; at this age the maximum induction was observed in the hippocampus and substantia nigra followed by cerebellum, cortex, septum and striatum. Hsps induction was associated with significant changes in glutathione (GSH) redox state and HNE levels. Interestingly, a significant positive correlation between decrease in GSH and increase in Hsp72 was observed in all brain regions examined during aging. Analysis of mitochondrial complexes showed a progressive decrease of Complex I activity and mRNA expression in the hippocampus and a significant decrease of Complex I and IV activities in the substantia nigra and septum. Our results sustain a role for GSH redox state in Hsp expression. Increase of Hsp expression promotes the functional recovery of oxidatively damaged proteins and protects cells from progressive age-related cell damage. Conceivably, heat shock signal pathway by increasing cellular stress resistance may represent a crucial mechanism of defence against free radical-induced damage occurring in aging brain and in neurodegenerative disorders.

Redox regulation of heat shock protein expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach.

Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer's disease (AD) is a progressive disorder with cognitive and memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis. Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress.Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction occurs together with the induction of other HSPs during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimer's disease, in fact, involves a chronic inflammatory response associated with both brain injury and beta-amyloid associated pathology. All of the above evidence suggests that stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as an antidegenerative mechanism potentially important in AD pathogenesis. These findings have offered new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes, such as the HO gene, conceivably may delay the aging process and decrease the occurrence of age-related neurodegenerative diseases.

Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine.

Recent studies suggest that NO and its reactive derivative peroxynitrite are implicated in the pathogenesis of multiple sclerosis (MS). Patients dying with MS demonstrate increased astrocytic inducible nitric oxide synthase activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong oxidant capable of damaging target tissues, particularly the brain, which is known to be endowed with poor antioxidant buffering capacity. Inducible nitric oxide synthase is upregulated in the central nervous system (CNS) of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. We have recently demonstrated in patients with active MS a significant increase of NOS activity associated with increased nitration of proteins in the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, in the present study, MS patients were treated for 6 months with acetylcarnitine and compared with untreated MS subjects or with patients noninflammatory neurological conditions, taken as controls. Western blot analysis showed in MS patients increased nitrosative stress associated with a significant decrease of reduced glutathione (GSH). Increased levels of oxidized glutathione (GSSG) and nitrosothiols were also observed. Interestingly, treatment of MS patients with acetylcarnitine resulted in decreased CSF levels of NO reactive metabolites and protein nitration, as well as increased content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that nitrosative stress is a major consequence of NO produced in MS-affected CNS and implicate a possible important role for acetylcarnitine in protecting brain against nitrosative stress, which may underlie the pathogenesis of MS.

Role of the JAK/STAT signal transduction pathway in the regulation of gene expression in CNS.

Over the last 20 years the JAK/STAT signal transduction pathway has been extensively studied. An enormous amount of data on different cell signal transduction pathways is now available. The JAK/STAT signal transduction pathway is one of the intracellular signaling pathways activated by cytokines and growth factors that was first studied in the hematopoietic system, but recent data demonstrate that this signal transduction is also greatly utilized by other systems. The JAK/STAT pathway is a signaling cascade that links the activation of specific cell membrane receptors to nuclear gene expression. This review is focused on the role of JAK/STAT signal transduction pathway activation in the central nervous system (CNS).

Molecular chaperones and their roles in neural cell differentiation.

During the development of the nervous system, a large number of neurons are eliminated through naturally occurring neuronal death. Many morphological and biochemical properties of such dying neurons are reminiscent not only of apoptosis, a type of death involving the action of genetically programmed events, but also of epigenetic phenomena such as oxidative stress. Increasing evidence demonstrates that oxidative stress alters the expression of antioxidant enzymes and enhances expression and/or DNA binding of numerous transcription factors, including heat shock factor. The latter is a transcription factor for specific promoter elements located upstream of the heat shock genes. Heat shock proteins (Hsps) are essential, highly conserved proteins that are needed for normal cell growth and maintenance, and expression of Hsps has been detected during embryogenesis in various organisms. Developmental profiles of Hsps indicate that they are differentially regulated during neural maturation, suggesting a role for Hsps in neural cell differentiation. Their putative function in cell remodeling during migration and differentiation, as well as during postnatal development, a time of extensive cell differentiation, is considered in the present review. Moreover, the function of Hsps in cell signaling, protein transport and the effect of heat shock on neural plate induction and brain development are discussed.

Alzheimer's disease research enters a "new cycle": how significant?

Recent evidence suggests a link between the aberrant re-expression of cell cycle proteins in adult neurons of the Alzheimer's disease brain and the process of apoptotic degeneration. Here we will discuss this unexpected phenomenon as related to the mechanisms of beta-amyloid toxicity, and its significance for therapeutic possibilities.

Regional distribution of heme oxygenase, HSP70, and glutathione in brain: relevance for endogenous oxidant/antioxidant balance and stress tolerance.

It is generally recognized that lipid peroxides play an important role in the pathogenesis of several diseases and that sulfhydryl groups are critically involved in cellular defense against endogenous or exogenous oxidants. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Heme oxygenase (HO) is a stress protein that has been implicated in defense mechanisms against agents that may induce oxidative injury, such as endotoxins, cytokines and heme and its induction represents a common feature in a number of neurodegenerative diseases. In the present report we studied regional distribution of heme oxygenase (HO) activity and protein expression, together with that of Hps70, in brain of C57BL6 mice. Endogenous lipid peroxidation was investigated on the basis of the analysis of ultra weak chemiluminescence, hydro peroxides and lipid soluble fluorescent products, and compared to the regional distribution of thiols, antioxidant enzymes and trace metals. Our results show that levels of HO activity and expression of inducible Hsp70 and the ratio of GSH/GSSG in the different brain regions examined were positively correlated with the content of peroxides. Substantia Nigra was the brain area exhibiting the highest levels of HO-2, constitutive and inducible Hsp70, GSSG, peroxides, iron, and calcium, in contrast with the lowest content in GSH, GSH/GSSG ratio and glutathione reductase activity, compared to the other cerebral regions examined. Among these, cortex showed the lowest levels of HO-2, Hsp70, GSSG and peroxides that were associated with the highest levels of GSH and GSH/GSSG ratio. These data support the hypothesis that the glutathione redox state and basal peroxides can directly participate in the signaling pathways of heat shock protein expression and hence of stress tolerance.

Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers.

Heme oxygenase-1 (HO-1) is a redox-sensitive inducible protein that provides efficient cytoprotection against oxidative stress. Curcumin, a polyphenolic natural compound that possesses anti-tumor and anti-inflammatory properties, has been reported recently to induce potently HO-1 expression in vascular endothelial cells (Free Rad Biol Med 28:1303-1312, 2000). Here, we extend our previous findings by showing that caffeic acid phenethyl ester (CAPE), another plant-derived phenolic agent, markedly increases heme oxygenase activity and HO-1 protein in astrocytes. The effect seems to be related to the peculiar chemical structures of curcumin and CAPE, because analogous antioxidants containing only portions of these two molecules were totally ineffective. At a final concentration of 30 microM, both curcumin and CAPE maximally up-regulated heme oxygenase activity while promoting marked cytotoxicity at higher concentrations (50-100 microM). Similar results were obtained with Curcumin-95, a mixture of curcuminoids commonly used as a dietary supplement. Incubation of astrocytes with curcumin or CAPE at concentrations that promoted maximal heme oxygenase activity resulted in an early increase in reduced glutathione followed by a significant elevation in oxidized glutathione contents. A curcumin-mediated increase in heme oxygenase activity was not affected by the glutathione precursor and thiol donor N-acetyl-L-cysteine. These data suggest that regulation of HO-1 expression by polyphenolic compounds is evoked by a distinctive mechanism which is not necessarily linked to changes in glutathione but might depend on redox signals sustained by specific and targeted sulfydryl groups. This study identifies a novel class of natural substances that could be used for therapeutic purposes as potent inducers of HO-1 in the protection of tissues against inflammatory and neurodegenerative conditions.