bluuebunny/crossref_metadata_2025 huggingface dataset:
l‐Carnitine and Neuroprotection in the Animal Model of Mitochondrial Dysfunction
Authors: BINIENDA ZBIGNIEW , PRZYBYLA‐ZAWISLAK BEATA , VIRMANI ASHRAF , SCHMUED LARRY
Published: July 2010

Abstract:We have shown previously that pretreatment with l‐carnitine (LC) prior to 3‐nitropropionic acid (3‐NPA) exposure, while not significantly attenuating succinate dehydrogenase (SDH) inhibition, prevented hypothermia and oxidative stress. The plant and fungal toxin, 3‐NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, SDH. Inhibition of SDH disturbs electron transport, leading to cellular energy deficits and oxidative stress‐related neuronal injury. In the study presented here, a neurohistological method was applied to examine the mitochondriotropic effect of LC pretreatment against 3‐NPA‐induced neurotoxicity. Twenty adult male Sprague‐Dawley rats randomly divided into two groups (n= 10/group) were injected twice with 3‐NPA at 30 mg/kg sc, at 2 days apart, or received LC pretreatment at 100 mg/kg, at 30‐40 min before 3‐NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro‐Jade B. Data analysis showed that LC was protective against 3‐NPA‐induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.
Effects of Metabolic Modifiers Such as Carnitines, Coenzyme Q10, and PUFAs against Different Forms of Neurotoxic Insults: Metabolic Inhibitors, MPTP, and Methamphetamine
Authors: VIRMANI ASHRAF , GAETANI FRANCO , BINIENDA ZBIGNIEW
Published: July 2010

Abstract: A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3‐nitropropionic acid (3‐NPA), rotenone, and 1‐methyl‐4‐phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as l‐carnitine (L‐C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L‐C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L‐C levels may also affect ATP levels. This endogenous compound, L‐C, together with its acetyl ester, acetyl‐l‐carnitine (ALC), also participates in the control of the mitochondrial acyl‐CoA/CoA ratio, peroxisomal oxidation of fatty acids, and production of ketone bodies. A deficiency of carnitine is known to have major deleterious effects on the CNS. We have examined L‐C and its acetylated derivative, ALC, as potential neuroprotective compounds using various known metabolic inhibitors, as well as against drugs of abuse such as methamphetamine.
Possible Neuroprotective Mechanism of Human Neuroglobin
Authors: WAKASUGI KEISUKE , KITATSUJI CHIHIRO , MORISHIMA ISAO
Published: July 2010

Abstract: Neuroglobin (Ngb) is a newly discovered hexacoordinate globin that is expressed in vertebrate brain and can reversibly bind oxygen. Expression of Ngb increases in response to oxygen deprivation and protects neurons from hypoxia in vitro and in vivo. Recent work on human Ngb has shed light on the mechanism of this neuroprotection by human Ngb, as discussed in this review. Human ferric Ngb has been found to act as a guanine nucleotide dissociation inhibitor for the α subunit of heterotrimeric G proteins. Moreover, other Ngb‐binding proteins also have been identified. These findings suggest that human Ngb may function as a regulator of signal transduction in the brain.
Saposin C: Neuronal Effect and CNS Delivery by Liposomes
Authors: CHU ZHENGTAO , SUN YING , KUAN CHIA YI , GRABOWSKI GREGORY A. , QI XIAOYANG
Published: July 2010

Abstract: Saposin C is one of four small lipid‐binding proteins that derive from a single precursor protein, named prosaposin (PSAP). PSAP has several neuronal effects, including neurite outgrowth stimulation, neuron preservation, and nerve regeneration enhancement. A minimal domain required for PSAP's neurotrophic function is located in the amino‐terminal half of saposin C. Genetic defects of the PSAP gene in humans and mice lead to a complex lysosomal storage disease. The skin fibroblasts from PSAP‐ and saposin C‐deficient patients have a massive accumulation of multivesicular bodies (MVBs). Incorporation of exogenous saposin C‐containing liposomes into the cultured PSAP−/− cells reduced the accumulated MVBs to normal levels. Internalized saposin C was localized to late endosomes and lysosomes. MVBs are crucial for maintaining the cellular homeostasis required for neuronal development and growth. PSAP−/− mice have a short life span (30 days) and central nervous system (CNS) neuronal degeneration. Similar to PSAP−/− fibroblasts, excessive MVBs accumulated in CNS neurons and brain tissues of PSAP‐null mice. Cultured cortical and hippocampal neurons from PSAP−/− mice had poor survival and displayed a neurite degenerative pattern. Delivery of saposin C ex vivo into cultured neurons and in vivo into brain neuronal cells in mice across the blood‐brain barrier was accomplished with intravenously administered dioleoylphosphatidylserine (DOPS) liposomes. These studies may yield a new therapeutic approach for neuron protection, preservation, and regeneration.
Brain‐Derived Neurotrophic Factor Is Neuroprotective against Human Immunodeficiency Virus‐1 Envelope Proteins
Authors: BACHIS ALESSIA , MOCCHETTI ITALO
Published: July 2010

Abstract: Human immunodeficiency virus type 1 (HIV‐1)‐positive patients in the late phase of infection develop AIDS dementia complex, an array of neurological complications that include extrapyramidal symptoms, cognitive impairments, and psychiatric disturbances. Brains of these patients exhibit brain injury. The HIV‐1 envelope glycoprotein 120 (gp120) has been suggested to be a causal agent of neuronal loss; however, several strains of gp120 exist during the infection and the relative neurotoxic potential of each strain is presently unknown. Using cultured cerebellar granule neurons, we determined whether two strains of gp120, gp120IIIB and gp120BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively, induce cell death. Apoptotic cell death and activated caspase‐3 were evident within a few hours in neurons exposed to low nanomolar concentrations of either gp120IIIB or gp120BaL. However, the neurotoxic effect of gp120IIIB was more rapid and occurred at lower concentrations than that of gp120BaL, suggesting that cerebellar granule cells may be more sensitive to apoptotic signals activated by the CXCR4 receptor. The neurotrophin brain‐derived neurotrophic factor (BDNF) has been shown to block neuronal apoptosis. Therefore, we examined whether BDNF protects against both strains of gp120. Preexposure of cerebellar granule cells to BDNF prior to both gp120s decreased apoptosis and consequently enhanced their survival. These findings underlie the rationale for exploring the ability of BDNF to reduce HIV‐1‐mediated neuronal cell death in vivo.
Nicotinamide Modulates Energy Utilization and Improves Functional Recovery from Ischemia in the In Vitro Rabbit Retina
Authors: TAM DIAMOND , TAM MAJESTIC , MAYNARD KENNETH I.
Published: July 2010

Abstract: The central nervous system depends critically on a regular supply of oxygen and glucose for the formation of adenosine triphosphate (ATP) and the sustenance of its energy metabolism. Consequently, a significant reduction in the supply of oxygen and glucose to neuronal tissue causes an imbalance between the energy supply and demand, inducing the onset of neuronal ischemia and triggering many metabolic cascades leading to irreversible injury and cell death. Nicotinamide (NAm), an essential precursor to nicotinamide adenine dinucleotide (NAD+), which raises brain ATP levels, may improve cerebral blood flow and is neuroprotective against ischemia‐induced injury. We therefore chose to examine the metabolic and electrophysiologic/functional effects of NAm (0.1 mM, 1.0 mM, 10.0 mM) under normal, control, and ischemic conditions, as well as following the early stages of reperfusion (“return‐to‐control” conditions) using an in vitro rabbit retina model where blood flow effects are excluded. Under nonischemic, control conditions, the protective concentration of NAm (10.0 mM) increased glucose utilization (34%, P < 0.01) and decreased lactate production (44%, P < 0.01), but had no significant effect on electrophysiologic function. After 2 h of ischemia, glucose utilization was significantly decreased (41%, P < 0.01) and lactate production was unaffected by NAm (10 mM). Following 3 h of “reperfusion”, NAm (10 mM) significantly improved glucose utilization (217%, P < 0.01), lactate production (40%, P < 0.01), and electrophysiologic function (264%, P < 0.01) relative to controls. Thus, the functional neuroprotective effects of NAm may be independent of blood flow effects, but related, at least in part, to its improvement of tissue glucose utilization and lactate production.
Mechanisms of Disease: Motoneuron Disease Aggravated by Transgenic Expression of a Functionally Modified AMPA Receptor Subunit
Authors: KUNER ROHINI , GROOM ANTHONY J. , MÜLLER GERALD , KORNAU HANS‐CHRISTIAN , STEFOVSKA VANYA , BRESINK IRIS , HARTMANN BETTINA , TSCHAUNER KARSTEN , WAIBEL STEFAN , LUDOLPH ALBERT C. , IKONOMIDOU CHRYSANTHY , SEEBURG PETER H. , TURSKI LECHOSLAW
Published: July 2010

Abstract: To reveal whether increased Ca2+ permeability of glutamate AMPA channels triggered by the transgene for GluR‐B(N) induces decline in motor functions and neurodegeneration in the spinal cord, we evaluated growth, motor coordination, and spinal reflexes in transgenic GluR‐B(N) and wild‐type (wt) mice. To reveal whether the transgenic GluR‐B(N) expression aggravates the course of motoneuron disease in SOD1 mice, we mated heterozygous GluR‐B(N) and SOD1 [C57BL6Ico‐TgN(hSOD1‐G93A)1Gur] mice to generate double‐transgenic progeny. The phenotypic sequelae in mice carrying mutations were evaluated by monitoring growth, motor coordination, and survival. Neuronal degeneration was assessed by morphological and stereological analysis of spinal cord and brain. We found that transgenic expression in mice of GluR‐B(N)‐containing glutamate AMPA receptors with increased Ca2+ permeability leads to a late‐onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progressed over the entire life span, but manifested clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerated disease progression, aggravated severity of motor decline, and decreased survival. These observations reveal that moderate, but persistently elevated Ca2+ influx via glutamate AMPA channels causes degeneration of spinal motoneurons and motor decline over the span of life. These features resemble the course of sporadic amyotrophic lateral sclerosis (ALS) in humans and suggest that modified function of glutamate AMPA channels may be causally linked to pathogenesis of ALS.
N‐Acetyldopamine Inhibits Rat Brain Lipid Peroxidation Induced by Lipopolysaccharide
Authors: OXENKRUG GREGORY F. , REQUINTINA PURA J.
Published: July 2010

Abstract: The effects of N‐acetyldopamine, a sepiapterin reductase inhibitor, on lipopolysaccharide‐induced lipid peroxidation were examined in rat brain homogenates in vitro. Lipid peroxidation in the form of malondialdehyde (MDA) was evaluated by the measurement of thiobarbituric acid (TBA) reactive substances. N‐Acetyldopamine inhibited the formation of MDA in a concentration‐dependent manner. The effect was similar to that of N‐acetylserotonin, but stronger than that of the endogenous antioxidant agent, melatonin. Possible clinical applications of N‐acetyldopamine and its derivatives are discussed.
The In Vitro Effect of Estradiol and Testosterone on Iron‐Induced Lipid Peroxidation in Rat Brain and Kidney Tissues
Authors: REQUINTINA PURA J. , OXENKRUG GREGORY F.
Published: July 2010

Abstract: The effects of estradiol and testosterone on iron‐induced lipid peroxidation were compared in rat brain and kidney homogenates in vitro. Lipid peroxidation in the form of malondialdehyde (MDA) was evaluated by the measurement of thiobarbituric acid (TBA) reactive substances. Estradiol inhibited lipid peroxidation in both tissues studied in a dose‐dependent manner. The effect was five times stronger in brain than in kidney. Testosterone did not affect lipid peroxidation in either tissue. Estradiol‐induced inhibition of brain lipid peroxidation might contribute to the neuroprotective effect of estrogens.
Neuroprotective Effects of Neurotrophins and Melanocortins in Spinal Cord Injury
Authors: SHARMA HARI SHANKER
Published: July 2010

Abstract:Spinal cord injury (SCI) induces lifetime disability, and no suitable therapy is available to treat victims or to minimze their sufferings. Recently, neurotrophins and compounds acting at melanocortin receptors have been been identified as potential neuroprotective agents. In this investigation, the neuroprotective effects of neurotrophins and melanocortins on the pathophysiology of SCI were examined in a rat model. The SCI was produced by making a longitudinal incision into the right dorsal horn of the t10 segments under equithesin anesthesia. In separate groups, neurotrophins [BDNF or IGF‐1 (0.1‐1 μg/10 μL in saline)] or melanocortins (ME10092, ME10354, ME10393, ME10431, and ME10501, having affinities to melanocortin receptors; 1‐10 μg in saline) were applied topically over the traumatized cord segment within 5‐10 min after SCI and the rats were allowed to survive for 5 h. A focal SCI resulted in widespread disruption of the blood‐spinal cord barrier (BSCB) to Evans blue albumin (EBA),[131]iodine, or lanthanum tracers and exhibited profound edema formation and cell or tissue destruction. Topical application of BDNF, IGF‐1, or ME10501 (having high affinity to melanocortin‐4 receptor, MCR‐4) in high quantity markedly attenuated BSCB disruption, edema formation, and nerve cell, glial cell, and axonal injuries. On the other hand, low doses of neurotrophins or melanocortins were not effective in attenuating pathophysiology of SCI. These observations suggest that neurotrophins (BDNF and IGF‐1) and melanocortins (with high affinity to MCR‐4) are capable of inducing neuroprotection if applied shortly after trauma in high doses. Taken together, the results indicate that neurotrophins and melanocortins participate in the pathophysiology of spinal cord cell and tissue injury following trauma.
Novel Neuroprotective Tripeptides and Dipeptides
Authors: FADEN ALAN I. , KNOBLACH SUSAN M. , MOVSESYAN VILEN A. , LEA PAUL M. , CERNAK IBOLJA
Published: July 2010

Abstract:It has long been recognized that thyrotropin‐releasing hormone (TRH) and certain TRH analogues are neuroprotective in a variety of animal models of CNS trauma. In addition to these neuroprotective actions, TRH and most TRH analogues have other physiological actions that may not be desirable for treatment of acute injury, such as analeptic, autonomic, and endocrine effects. We have developed a series of dual‐substituted TRH analogues that have strong neuroprotective actions, but are largely devoid of these other physiological actions. In addition, we have developed a family of cyclized dipeptides (diketopiperazines), structurally somewhat related to a metabolic product of TRH, that appear even more effective as neuroprotective agentsin vitroandin vivo, and may have nootropic properties. Here, we review these novel tripeptide and dipeptide compounds.
Cocaine Induces a Differential Dose‐Dependent Alteration in the Expression Profile of Immediate Early Genes, Transcription Factors, and Caspases in PC12 Cells
Authors: IMAM SYED Z. , DUHART HELEN M. , SKINNER JOHN T. , ALI SYED F.
Published: July 2010

Cocaine is a widely used drug of abuse and psychostimulant that acts on the central nervous system by blocking the dopamine reuptake sites. PC12 cells, a rat pheochromocytoma clonal line, in the presence of nerve growth factor (NGF), multiply and differentiate into competent neurons that can synthesize, store, and secrete the neurotransmitter dopamine (DA). In the present study, we evaluated the effect of increasing doses of cocaine on the expression of immediate early genes (IEGs),c‐fosandc‐jun, and closely related transcription factors, SP‐1 and NF‐kβ, at 24 h after the exposure to cocaine (50, 100, 200, 500, 1000, 2500 μM) in NGF‐differentiated PC12 cells. Cocaine (50‐500 μM) resulted in significant induction of the expression ofc‐fos,c‐jun, SP‐1, and NF‐kβ. However, higher concentrations of cocaine (1000 and 2500 μM) resulted in the downregulation of these expressions after 24 h. To further understand the role of dose‐dependent changes in the mechanisms of cell death, we evaluated the protein expression of apoptotic markers. A concentration‐dependent increase in the expression of caspase‐9 and ‐3 was observed up to 500 μM cocaine. However, the higher dose did not show any expression. We also evaluated the effect of increasing doses of cocaine on DA concentration and the expression of dopamine transporter (DAT). A significant dose‐dependent decrease in the concentration of DA as well as the expression of DAT was observed 24 h after the exposure of PC12 cells to cocaine. Therefore, in the present study, we reported that cocaine has both upstream and downstream regulatory actions on some IEGs and transcription factors that can regulate the mechanism of cell death, and these effects on gene expression are independent of its action on the dopaminergic system.
Neuroprotection in the PNS: Erythropoietin and Immunophilin Ligands
Authors: HÖKE AHMET , KESWANI SANJAY C.
Published: July 2010

Abstract: Many illnesses that affect the peripheral nervous system (PNS) lead to distal axonal degeneration rather than loss of neuronal cell bodies. Strategies aimed at promoting survival of injured neurons (i.e., preventing cell death) may not be applicable to many PNS illnesses. We have developed in vitro and in vivo animal models to study mechanisms of acquired peripheral neuropathies and used these models to evaluate the therapeutic potential of novel compounds. In recent years, erythropoietin (EPO) has been recognized as a novel neuroprotectant in the central nervous system. In the PNS, we recently showed that Schwann cell‐derived EPO acts as an endogenous neuroprotectant and that it is most effective in preventing distal axonal degeneration seen in models of peripheral neuropathy. Similarly, we showed that immunophilin ligands are also neuroprotective in the PNS and prevent axonal degeneration seen in models of peripheral neuropathies. Both EPO and non‐immunosuppressive immunophilin ligands are in early clinical development for the treatment of acquired peripheral neuropathies.
Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling
Authors: SLIKKER WILLIAM , YOUNG JOHN F. , CORLEY RICHARD A. , DORMAN DAVID C. , CONOLLY RORY B. , KNUDSEN THOMAS B. , ERSTAD BRIAN L. , LUECKE RICHARD H. , FAUSTMAN ELAINE M. , TIMCHALK CHARLES , MATTISON DONALD R.
Published: July 2010

Abstract:A workshop was conducted on November 18‐19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.
The future of tropical forests
Authors: Wright S. Joseph
Published: July 2010

Five anthropogenic drivers–land use change, wood extraction, hunting, atmospheric change, climate change–will largely determine the future of tropical forests. The geographic scope and intensity of these five drivers are in flux. Contemporary land use change includes deforestation (∼64,000 km2 yr−1 for the entire tropical forest biome) and natural forests regenerating on abandoned land (∼21,500 km2 yr−1 with just 29% of the biome evaluated). Commercial logging is shifting rapidly from Southeast Asia to Africa and South America, but local fuelwood consumption continues to constitute 71% of all wood production. Pantropical rates of net deforestation are declining even as secondary and logged forests increasingly replace old‐growth forests. Hunters reduce frugivore, granivore and browser abundances in most forests. This alters seed dispersal, seed and seedling survival, and hence the species composition and spatial template of plant regeneration. Tropical governments have responded to these local threats by protecting 7% of all land for the strict conservation of nature—a commitment that is only matched poleward of 40°S and 70°N. Protected status often fails to stop hunters and is impotent against atmospheric and climate change. There are increasing reports of stark changes in the structure and dynamics of protected tropical forests. Four broad classes of mechanisms might contribute to these changes. Predictions are developed to distinguish among these mechanisms.
Physiological functions of mitochondrial fusion
Authors: Chen Hsiuchen , Chan David C.
Published: July 2010

In recent years, the dynamic nature of mitochondria has been discovered to be critical for their function. Here we discuss the molecular basis of mitochondrial fusion, its protective role in neurodegeneration, and its importance in cellular function. The mitofusins Mfn1 and Mfn2, GTPases localized to the outer membrane, mediate outer‐membrane fusion. OPA1, a GTPase associated with the inner membrane, mediates subsequent inner‐membrane fusion. Mutations in Mfn2 or OPA1 cause neurodegenerative diseases. Mouse models with defects in mitochondrial fusion genes have provided important avenues for understanding how fusion maintains mitochondrial physiology and neuronal function. Mitochondrial fusion enables content mixing within a mitochondrial population, thereby preventing permanent loss of essential components. Cells with reduced mitochondrial fusion, as a consequence, show a subpopulation of mitochondria that lack mtDNA nucleoids. Such mtDNA defects lead to respiration‐deficient mitochondria, and their accumulation in neurons leads to impaired outgrowth of cellular processes and ultimately neurodegeneration.
Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence
Authors: Kim You‐Mie , Seo Yong‐Hak , Park Chan‐Bae , Yoon Soo‐Han , Yoon Gyesoon
Published: July 2010

Abstract  Diverse metabolic alterations, including mitochondrial dysfunction, have often been reported as characteristic phenotypes of senescent cells. However, the overall consequence of senescent metabolic features, how they develop, and how they are linked to other senescent phenotypes, such as enlarged cell volume, increased granularity, and oxidative stress, is not clear. We investigated the potential roles of glycogen synthase kinase 3 (GSK3), a multifunctional kinase, in the development of the metabolic phenotypes in cell senescence. The inactivation of GSK3 via phosphorylation is commonly observed in diverse cell senescences. Furthermore, subcytotoxic concentration of GSK3 inhibitor was sufficient to induce cellular senescence, accompanied by augmented anabolism, such as enhanced protein synthesis, and increased glycogenesis and lipogenesis, in addition to mitochondrial dysfunction. Anabolism was accomplished through glycogen synthase, eIF2B, and SREBP1. These metabolic features seem to contribute to an increase in cellular mass by increasing glycogen granules, protein mass, and organelles. Taken together, our results suggest that GSK3 is one of the key modulators of metabolic alteration, leading the cells to senescence.
Redefining the role of mitochondria in exercise: a dynamic remodeling
Authors: Bo Hai , Zhang Yong , Ji Li Li
Published: July 2010

Exercise induced adaptations in muscle are highly specific and dependent upon the type of exercise, as well as its frequency, intensity, and duration. Mitochondria are highly dynamic organelles. Fusion and fission reactions lead to a continuous remodeling of the mitochondrial network, which range from reticulum of elongated and branched filaments to collections of individual organelles. Mitochondrial network dynamics are sensitive to various physiological and pathological stimuli, and mitochondrial morphological changes are no epiphenomena, but central to cell function and survival. There is a strong correlation between mitochondrial network morphology, dynamic‐related protein, and energy metabolism. It is expected that alteration in cellular energy status during exercise can also be achieved through mitochondrial network dynamics. In this review, we describe mitochondrial network remodeling response to acute and endurance exercise, which is accompanied by bioenergetics and redox regulation. In addition, potential mechanisms for metabolic and redox signaling involved in mitochondrial dynamic regulation are also reviewed.
MELAS and l‐arginine therapy: pathophysiology of stroke‐like episodes
Authors: Koga Yasutoshi , Povalko Nataliya , Nishioka Junko , Katayama Koujyu , Kakimoto Noriko , Matsuishi Toyojiro
Published: July 2010

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) is a maternally inherited multisystem mitochondrial disorder. Although many molecular and cellular mechanisms have been discovered leading to mitochondrial cytopathy, the pathogenic mechanism of stroke‐like episodes seen in MELAS has not been clarified yet. According to the muscle and brain pathology and vascular physiology, mitochondrial angiopathy, or endothelial dysfunction, were proposed to play an important role for developing stroke‐like episodes. Based on a hypothesis of mitochondrial angiopathy theory, we use l‐arginine in MELAS patients and report its usefulness. This review aims to give a general idea on the actual knowledge about the possible pathogenic mechanism of stroke‐like episodes, including clinical symptoms that lead to stroke‐like episodes, muscle, or brain pathology, molecular cellular functions, neuroimagings including MRI, MRS, and SPECT, and the proposed site of action of l‐arginine therapy on MELAS patients. Currently, l‐arginine therapy may be the most promising for the treatment of stroke‐like episodes in MELAS.
Mitochondrial dysfunction in insulin insensitivity: implication of mitochondrial role in type 2 diabetes
Authors: Wang Chih‐Hao , Wang Ching‐Chu , Wei Yau‐Huei
Published: July 2010

Abundant evidence has been accumulated to suggest that mitochondrial dysfunction is associated with type 2 diabetes. Research findings from this and other laboratories have supported the notion that impaired mitochondrial function is a cause of insulin insensitivity in myocytes and adipocytes as a result of insufficient supply of energy or defects in the insulin signaling pathway. We demonstrated that inhibition of respiration and oxidative phosphorylation by respiratory inhibitors or knockdown of genes involved in mitochondrial biogenesis can impair the differentiation of preadipocytes and response of adipocytes to insulin. Moreover, defective mitochondria also cause a decrease in adiponectin secretion that leads to decline glucose utilization of other tissues. Besides, it has been elucidated that some environmental factors, pollutants, and mitochondrial toxins are involved in the pathogenesis of type 2 diabetes. Taken together, we suggest that mitochondrial dysfunction plays a role in the pathophysiology of insulin insensitivity, and that activation of mitochondrial biogenesis may be an effective strategy in the prevention or treatment of insulin resistance and type 2 diabetes.
Mass Transfer and Nutrient Absorption in a Simulated Model of Small Intestine
Authors: Tharakan A. , Norton I.T. , Fryer P.J. , Bakalis S.
Published: July 2010

Abstract:  There is an increasing need to understand how food formulations behave in vivo from both food and pharma industries. A number of models have been proposed for the stomach, but few are available for the other parts of the gastrointestinal tract. An experimental rig that simulates the segmentation motion occurring in the small intestine has been developed. The objective of developing such an experimental apparatus was to study mass transport phenomena occurring in the lumen and their potential effect on the concentration of species available for absorption. When segmentation motion was applied the mass transfer coefficient in the lumen side was increased up to a factor of 7. The viscosity of the lumen, as influenced by guar gum concentration, had a profound effect on the mass transfer coefficient. The experimental model was also used to demonstrate that glucose available for absorption, resulting from starch hydrolysis, can be significantly reduced by altering the lumen viscosity. Results suggest that absorption of nutrients could be controlled by mass transfer.

Practical Application:  To address health‐related diseases such as obesity, novel foods that provide advanced functions are required. To achieve the full potential offered by the latest developments in the field of food material science, a fundamental understanding of the behavior of food structures in vivo is required. Using the developed gut model we have demonstrated that absorption of nutrients can be controlled by mass transfer limitations.
Do Statins Improve Heart Failure Outcome in Post–Myocardial Infarction Patients With Moderate to Severe Left Ventricular Dysfunction?
Authors: Sankaranarayanan Rajiv , Maini Sameer , James Michael Anthony , Burtchaell Stephanie , Chatterjee Amit K.
Published: July 2010

The authors conducted this retrospective cohort study to assess the influence of statins on heart failure (HF) outcome by enrolling 500 consecutive acute myocardial infarction patients, majority (339 of 500) with moderate to severe left ventricular dysfunction (ejection fraction <40%) between March 2000 and March 2002 with 5.5‐year mean follow‐up. They were retrospectively analyzed according to whether they were discharged on a statin, and their HF outcome was evaluated independent of overt clinical ischemic events. Mortality in the statin group was 71 of 249 (28.5%; median survival 252 days) vs 48 of 90 (53%; median survival, 141.5 days; P<.001) in the no‐statin group. Univariate analysis showed fewer HF readmissions (statin group, 7% vs no‐statin group, 32%; P<.001) and HF deaths (statin group, 4% vs no‐statin group, 13%; P=.002). Multivariate analysis by logistic regression showed that these effects due to statins are independent of cholesterol levels, age, sex, drugs, revascularization, and implantable cardioverter‐defibrillator (ICD) or cardiac resynchronization therapy. Statins have an important role in independently improving HF outcome in post–myocardial infarction patients with left ventricular ejection fraction <40%. Congest Heart Fail. 2010;16:181–186. © 2010 Wiley Periodicals, Inc.
Lens opacity and refractive influences on the measurement of retinal vascular fractal dimension
Authors: Li Haitao , Mitchell Paul , Liew Gerald , Rochtchina Elena , Kifley Annette , Wong Tien Y. , Hsu Wynne , Lee Mong L. , Zhang Yong P. , Wang Jie J.
Published: July 2010

Acta Ophthalmol. 2010: 88: e234–e240

Purpose:  To examine the influence of lens opacity and refraction on the measurement of retinal vascular fractal dimension (Df).

Methods:  Optic disc photographs (right eyes) of 3654 baseline Blue Mountains Eye Study participants (aged 49–97 ) were digitized. Retinal vascular Df was quantified using a computer‐based program. Summated severity scores for nuclear, cortical and posterior subcapsular (PSC) cataract were assessed from lens photographs. Refraction data were converted to spherical equivalent refraction (SER), as sum spherical plus 0.5 cylinder power. Axial length was measured at 10‐year follow‐up examinations using an IOL master.

Results:  Mean Df of the retinal vasculature was 1.444 ± 0.023 for 2859 eligible participants. Increasing lens opacity scores were associated with significant reduction in Df (β = −0.0030, p < 0.0001). Both cortical and PSC cataract involving central lens area were associated with reduced Df, after controlling for confounding factors (ptrend ≤ 0.0105). Increasing myopia severity was associated with reduced Df after adjusting for lens opacity scores and other confounders (ptrend < 0.0001). The slope of Df decrease per SER reduction was 0.0040 in eyes with SER ≤ −4D, compared to −0.0016 in eyes with SER > −4D. For axial length quintiles, there were no significant differences in mean Df in all groups except a reduction in the fifth quintile (axial length ≥24.15 mm) (all p < 0.05).

Conclusion:  Ocular media opacity independently influenced retinal vascular Df measurement, but we found no evidence supporting any refractive axial magnification effect on this measure. Myopic refraction ≤−4D was associated with a reduction in Df, suggesting rarefaction of retinal vasculature associated with high myopia.
Quercetin and naringenin reduce abnormal development of mouse embryos produced by hydroxyurea
Authors: Pérez-Pastén Ricardo , Martínez-Galero Elizdath , Chamorro-Cevallos Germán
Published: July 2010

Objectives

There is limited evidence about the impact of quercetin and naringenin on embryonic development. The purpose of this work was to evaluate in vitro their direct teratogenic potential as well as their protective activity against teratogenesis mediated by oxidative damage on mouse embryos.

Methods

Quercetin and naringenin toxicity on whole mouse cultured embryos, as well as their ability to protect embryos against hydroxyurea-induced insult were evaluated.

Key findings

Quercetin 100 µm and naringenin 300 µm produced significant reduction of developmental and growth parameters, in comparison with those of the control group. Embryos exposed to the concurrent administration of quercetin or naringenin with hydroxyurea (2 µm, 2 h) were significantly protected from growth and developmental retardation, and abnormalities induced by hydroxyurea. Interestingly, embryos exposed to hydroxyurea and dimethyl sulfoxide 0.1%, the vehicle employed to dissolve flavonoids, also showed significant damage amelioration.

Conclusions

These results indicate that quercetin and naringenin have not only a minor toxic effect on development, but also a protective effect against hydroxyurea-induced embryonic damage.
Biological activity of the essential oil of Kadsura longipedunculata (Schisandraceae) and its major components
Authors: Mulyaningsih Sri , Youns Mahmoud , El-Readi Mahmoud Z , Ashour Mohamed L , Nibret Endalkachew , Sporer Frank , Herrmann Florian , Reichling Jürgen , Wink Michael
Published: July 2010

Objectives

The aim was to determine the chemical composition of the essential oil of Kadsura longipedunculata and the biological activity of the oil and its major components.

Methods

The essential oil from stem bark of Kadsura longipedunculata was analysed by capillary gas chromatography (GLC/FID) and gas chromatography–mass spectrometry (GLC/MS). The ability of the oil to reduce diphenylpicrylhydrazine (DPPH•) was used to evaluate the antioxidant activity. Inhibition of both lipoxygenase and prostaglandin E2 was used to assess the anti-inflammatory activity. Antimicrobial activity was studied in vitro against a range of bacteria and fungi using diffusion and microdilution methods. Inhibition of trypanosome proliferation was assessed using resazurin as vital stain. The in-vitro cytotoxicity of the essential oil on six human cancer cell lines (HepG2, MIA PaCa-2, HeLa, HL-60, MDA-MB-231 and SW-480) was examined using the MTT assay.

Key findings

Fifty compounds, representing 97.63% of total oil, were identified. δ-Cadinene (21.79%), camphene (7.27%), borneol (6.05%), cubenol (5.12%) and δ-cadinol (5.11%) were found to be the major components of the oil. The oil exerted a good antimicrobial activity against all Gram-positive bacteria tested, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. Streptococcus pyogenes and S. agalactiae were the most sensitive bacteria with a minimal inhibitory concentration (MIC) of 60 µg/ml oil. The essential oil showed a moderate fungicidal activity against yeasts, but it did not show any activity against Gram-negative bacteria. The essential oil showed a good trypanocidal activity in Trypanosoma b. brucei with an IC50 value of 50.52 ± 0.029 µg/ml. Radical scavenging activity had an IC50 value of 3.06 ± 0.79 mg/ml. 5-Lipoxygenase inhibition (IC50 = 38.58 µg/ml) and prostaglandin E2 production inhibition (28.82% at 25 µg/ml) accounted for anti-inflammatory activity of the oil. The oil exhibited some degree of cytotoxic activity against MIA PaCa-2, HepG-2 and SW-480 cell lines with IC50 values of 133.53, 136.96 and 136.62 µg/ml, respectively. The oil increased caspase 3/7 activity (an indicator of apoptosis) 2.5–4 fold in MIA Paca-2 cells. Camphene and borneol did not show antioxidant activity. However, both compounds exhibited some degree of antimicrobial, trypanocidal, anti-inflammatory and cytotoxic activity.

Conclusions

This investigation provided evidence for, and confirmed the efficacy of, K. longipedunculata, a traditionally used Chinese medicinal plant for the treatment of inflammation and infection.
The essential oil ofCroton nepetaefoliusselectively blocks histamine-augmented neuronal excitability in guinea-pig celiac ganglion
Authors: Leal-Cardoso José Henrique , Lahlou Saad , Weinreich Daniel , Caldas Magalhães Pedro Jorge
Published: July 2010

Objectives

Croton nepetaefolius is a medicinal plant useful against intestinal disorders. In this study, we elucidate the effects of its essential oil (EOCN) on sympathetic neurons, with emphasis on the interaction of EOCN- and histamine-induced effects.

Methods

The effects of EOCN and histamine were studied in guinea-pig celiac ganglion in vitro.

Key findings

Histamine significantly altered the resting potential (Em) and the input resistance (Ri) of phasic neurons (from −56.6 ± 1.78 mV and 88.6 ± 11.43 MΩ, to −52.9 ± 1.96 mV and 108.6 ± 11.00 MΩ, respectively). Em, Ri and the histamine-induced alterations of these parameters were not affected by 200 µg/ml EOCN. The number of action potentials produced by a 1-s (two-times threshold) depolarising current and the current threshold (Ith) for eliciting action potentials (rheobase) were evaluated. Number of action potentials and Ith were altered by histamine (from 2.6 ± 0.43 action potentials and 105.4 ± 11.15 pA to 6.2 ± 1.16 action potentials and 67.3 ± 8.21 pA, respectively). EOCN alone did not affect number of action potentials and Ith but it fully blocked the histamine-induced modifications of number of action potentials and Ith. All the effects produced by histamine were abolished by pyrilamine.

Conclusions

EOCN selectively blocked histamine-induced modulation of active membrane properties.
Effect ofγ-glutamylcysteine ethylester on the levels ofc-fosmRNA expression, glutathione and reactive oxygen species formation in kainic acid excitotoxicity
Authors: Turunc Ezgi , Kanit Lutfiye , Yalcin Ayfer
Published: July 2010

Objectives

The aim of this study was to investigate the effect of γ-glutamylcysteine ethylester (GCEE), a precursor of glutathione biosynthesis, on the levels of glutathione, formation of reactive oxygen species and c-fos mRNA expression in rat hippocampus and cortex in kainic acid-induced excitotoxicity.

Methods

Sprague–Dawley rats were used and divided into four groups: control, kainic acid (10 mg/kg), GCEE (10 mg/kg) and kainic acid (10 mg/kg) + GCEE (10 mg/kg). Kainic acid and GCEE were administered to the rats intraperitoneally. The levels of glutathione and the expressions of c-fos mRNA in hippocampus and cortex tissues were determined using spectrophotometric and reverse transcription followed real-time PCR methods, respectively. Formation of reactive oxygen species was determined using dichlorofluorescin fluorescence in brain synaptosomes treated with kainic acid or GCEE in vitro.

Key findings

Kainic acid treatment significiantly upregulated the expression of c-fos mRNA in the hippocampus and cortex when compared to the control group. GCEE treatment significantly decreased the levels of c-fos mRNA in the cortex when compared to the kainic acid-treated group. GCEE treatment against kainic acid significantly increased the levels of glutathione in the cortex and hippocampus, and decreased the levels of formation of reactive oxygen species when compared to kainic acid-treated synaptosomes.

Conclusions

The increased levels of glutathione and the reduced levels of reactive oxygen species formation lead us to conclude that GCEE may be beneficial as a potential antioxidant against neurodegenerative processes where excitotoxicity is involved.
Suppression of tumour necrosis factor-αbySchizonepeta tenuifoliawater extract via inhibition of IκBαdegradation and Jun N-terminal kinase/stress-activated protein kinase activation
Authors: Kang Hee , Han Sang-Woo , Hong Joung-Woo , Sohn Nak-Won
Published: July 2010

Objectives

The anti-inflammatory effects of an aqueous extract of Schizonepeta tenuifolia on lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in vivo and in vitro have been investigated.

Methods

C57BL/6 mice were orally administered phosphate-buffered saline (control) or S. tenuifolia water extract (50, 200, 500 or 1000 mg/kg) for 10 days before intraperitoneal administration of LPS (1.3 mg/kg). Blood samples were obtained 1 h after LPS challenge, followed by determination of TNF-α and IL-6 levels. Peritoneal macrophages from thioglycollate-injected mice were obtained and stimulated with LPS and S. tenuifolia water extract for viability assay, cytokine analysis, real-time RT PCR and Western blotting.

Key findings

Oral administration of S. tenuifolia water extract to mice significantly reduced LPS-induced serum levels of TNF-α, but not IL-6. When peritoneal macrophages were treated in vitro with S. tenuifolia water extract, the inhibition of LPS-induced TNF-α was more pronounced than that of IL-6 at the level of secreted protein and mRNA. S. tenuifolia water extract reduced the degradation of IκBα and the nuclear relocation of p65 NF-κB, but the phosphorylation of IκBα was not affected. Inhibition of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) by S. tenuifolia water extract led secondarily to the inhibition of phospho-c-Jun and phospho-ATF-2.

Conclusions

These results indicated that the downregulation of TNF-α by S. tenuifolia water extract may have involved the inhibition of both IκBα degradation and activation of c-Jun and ATF-2 involving suppression of JNK/SAPK.
Effects of Nanostructured Additives on Boundary Lubrication for Potential Artificial Joint Applications
Authors: Pendleton Alice , Kar Prasenjit , Kundu Subrata , Houssamy Sahar , Liang Hong
Published: July 2010

Water-based fluids containing nanostructured fullerene C60 and 18-crown ether-6 were investigated. The effects of those nanostructured additives on the tribological performance of titanium and its alloys as potential biomaterials were analyzed. Experimentally, tribology tests were conducted using a Ti–6Al–4V ball against a disk made of pure titanium as a simplified model of the material rubbing pair. Lubrication mechanisms were studied by comparing the nanostructures, viscosities, and frictions. Results showed that the fullerene C60 in deionized water provided the lowest viscosity and friction. Crown ether, on the other hand, provided high friction and shear. Our analysis indicated that the fullerene was weakly interacted with water compared with the crown ether, resulting in an extended low friction in the boundary lubrication regime. The crown ether required extra energy in order to slide or roll. This led to a high friction. This finding opens the possibilities for lubrication design and optimization for biological and engineering applications in general.
Tribological Behaviors of PTFE-Based Composites Filled With Nanoscale Lamellar Structure Expanded Graphite
Authors: Yang Yu-lin , Jia Zhi-ning , Chen Jin-jiang , Fan Bing-li
Published: July 2010

This paper provides a polytetrafluoroethylene (PTFE)/nano-EG solid self-lubricating composite that exhibits very low friction coefficient and wear rate. In present study, the influences of the content of expanded graphite with nanoscale lamellar structure (nano-EG) in PTFE/nano-EG composite, normal contact pressure, and sliding velocity on tribological properties were studied by using the MMU-5G friction and wear tester sliding against AISI-1045 steel. Meanwhile, the property of nano-EG was characterized by utilizing a field emission scanning electron microscope. Compared with that of pure PTFE, the addition of nano-EG into PTFE matrix effectively improved the antifriction and wear resistance properties of PTFE/nano-EG composite. The highest wear resistance was found for the PTFE/nano-EG composite filled with 15wt % nano-EG. The morphologies of worn surface of the ANSI-1045 steel and composites were observed using a confocal laser scanning microscopy (CLSM) and a scanning electron microscope (SEM) to examine composite microstructures and to study modes of failure. The images of CLSM and SEM indicate that the property of transfer film generated on the surface of mating pair is likely responsible for the lower wear rate observed in these experiments.