bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of caloric restriction on development of the proximal growth plate and metaphysis of the caput femoris in spontaneously hypertensive rats: Microscopic and computer‐assisted image analyses
Authors: Kawahara Toshio , Shimokawa Isao , Tomita Masato , Hirano Toru , Shindo Hiroyuki 
Published: November 2002

AbstractWe previously demonstrated that caloric restriction (CR) reduced the prevalence of osteonecrosis in caput femoris of spontaneously hypertensive rats (SHR), a model of human Perthes' disease. The effects of CR on the development and pathology in the proximal femoral growth plate (GP) and adjacent structures in SHR were investigated by morphometric and computer‐assisted image analyses. From 6 weeks of age, the food intake of SHR was restricted to 65% of the mean intake of ad libitum fed control SHR (SHR‐AL). Wistar Kyoto rats (WKY), from which the SHR strain was isolated, fed ad libitum were also included as controls. CR reduced prevalence of chondromucinous degeneration and dysarray of cartilage cell columns in the GP, becoming prevalent between 10 and 20 weeks in the SHR‐AL group, attaining the same levels of the WKY group. Thicknesses of non‐calcifying cell columns in the GP were greater in the SHR‐AL than WKY group; CR slightly reduced the thickness, but incompletely. Thicknesses of calcifying cell columns did not significantly differ among the three groups. CR decreased volume density and mean thicknesses of the trabecular bone in areas adjacent to GPs, and was greater in the SHR‐AL than the WKY group. The present morphologic analysis suggested that CR ameliorates dysplastic changes of trabecular bones in areas adjacent to the GP, rather than modulating the ossification process in the GP. The CR paradigm might give insight into the pathogenesis of, and a therapeutic strategy for, human Perthes' disease. Microsc. Res. Tech. 59:306–312, 2002. © 2002 Wiley‐Liss, Inc.
Characterization of gene expression profile associated with energy restriction‐induced cold tolerance of heart
Authors: Wada Yasuhiko , Kayo Tsuyoshi , Koizumi Akio 
Published: November 2002

AbstractHypothermia is known to be a common feature of energy restriction (ER) and essential for a life‐prolonging effect of ER. The heart is sensitive to hypothermia, but the heart in ER mice acquires some adaptation to hypothermia. The aim of the present study was to characterize the gene expression profile associated with ER‐induced cold resistance of heart. We analyzed the expression of heart mRNA from ER (200 kJ/week) or control (400 kJ/week) B6 11‐month‐old male mice using cDNA array membranes including 588 genes. Eighty‐eight out of 588 genes were expressed in the heart. mRNAs increased by ER were glutathion S‐transferase Mu1, transcriptional factor 1 for heat shock gene (HSF1), and fetal myosin alkali light chain genes. mRNA decreased by ER were seven genes in four categories: (1) cell cycle or apoptosis‐related proteins (cyclin G and nucleoside diphosphate kinase B); (2) stress response proteins (oxidative stress‐induced protein); (3) DNA repair proteins (protein involved in DNA double‐strand break repair, Rad23 UV excision repair protein homologue and ubiquitin‐conjugating enzyme); and (4) cell‐surface antigens (lamimin receptor 1). These data suggest that the heart of ER mice adapts to hypothermia involving heat shock proteins and their transcriptional factors and by changing structure and property of myofibrils. It is also suggested that ER induces protection against oxidative stress and inhibits cell proliferation of “nonmuscle cells” in the heart. Gene expression analysis using cDNA array was useful for screening genes associated with ER‐induced cold adaptation. Microsc. Res. Tech. 59:313–316, 2002. © 2002 Wiley‐Liss, Inc.
Anti‐aging effects of caloric restriction: Involvement of neuroendocrine adaptation by peripheral signaling
Authors: Chiba Takuya , Yamaza Haruyoshi , Higami Yoshikazu , Shimokawa Isao 
Published: November 2002

AbstractMany hormonal signals from peripheral tissues contribute to the regulation of energy homeostasis and food intake. These regulators including leptin, insulin, and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in hypothalamic nuclei. The anti‐aging effects of caloric restriction have been explained from an evolutional viewpoint of the adaptive response of the neuroendocrine and metabolic response systems to maximize survival during periods of food shortage. In organisms, excess energy is stored in adipose tissues as a triglyceride preparation for such survival situations. Adipose tissue has recently been recognized as an endocrine organ, and leptin, as secreted by adipocyte, seems to be an especially important factor for the adaptive response to fasting and neuroendocrine alterations under caloric restriction. In this review, we discuss the potential involvement of neuroendocrine modulators in longevity and the anti‐aging effects of caloric restriction. Microsc. Res. Tech. 59:317–324, 2002. © 2002 Wiley‐Liss, Inc.
Lifespan extension by caloric restriction: An aspect of energy metabolism
Authors: Yamaza Haruyoshi , Chiba Takuya , Higami Yoshikazu , Shimokawa Isao 
Published: November 2002

AbstractCaloric restriction (CR) may retard aging processes and extend lifespan in organisms by altering energy‐metabolic pathways. In CR rodents, glucose influx into tissues is not reduced, as compared with control animals fed ad libitum (AL), although plasma concentrations of glucose and insulin are lower. Gene expression profiles in rodents have suggested that CR promotes gluconeogenesis and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower organisms such as yeasts and nematodes, incomplete blocks in steps of insulin/insulin‐like growth factor‐1 (IGF‐1) signal pathway extend lifespan. The life‐prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of which relate to sensing energy status and silencing genes. These findings stress the substantial role of energy metabolism on CR. Future studies on metabolic adaptation and gene silencing with regard to lower caloric intake will be warranted to understand the mechanisms of the anti‐aging and life‐prolonging effects of CR. Microsc. Res. Tech. 59:325–330, 2002. © 2002 Wiley‐Liss, Inc.
Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles
Authors: Furuyama Tatsuo , Yamashita Hitoshi , Kitayama Kazuko , Higami Yoshikazu , Shimokawa Isao , Mori Nozomu 
Published: November 2002

AbstractIn C. elegans, insulin‐like hormone signal pathway plays a significant role in longevity. In particular, daf‐16 gene product is indispensable factor for this lifespan‐extension. This signal pathway is critical for dauer formation, which is a similar state to hibernation in mammals. We examined the expression level of mammalian daf‐16 homologues, Foxo 1,3, and 4 (FKHR, FKHRL1, and AFX) mRNAs in the rat skeletal muscles during aging and in 30% caloric restricted of ad libitum fed. The expression level of AFX mRNA was significantly higher at 6 and 12 months than at 3 and 26 months, and FKHRL1 expression was significantly higher at 6 months than at 3 and 26 months but FKHR expression showed no significant change with age. We observed a characteristic expression of AFX and FKHR mRNAs to be significantly higher in the second day in caloric restriction by every‐other‐day feeding than in ad libitum fed. This suggests that caloric restriction may increase the expression of FKHR‐family genes and prevent the aging process in the skeletal muscles. Microsc. Res. Tech. 59:331–334, 2002. © 2002 Wiley‐Liss, Inc.
Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics
Authors: Lane Mark A. , Mattison Julie , Ingram Donald K. , Roth George S. 
Published: November 2002

AbstractFor nearly 70 years it has been recognized that reduction in caloric intake by 30–40% from ad libitum levels leads to a significant extension of mean and maximal lifespan in a variety of short‐lived species. This effect of caloric restriction (CR) on lifespan has been reported in nearly all species tested and has been reproduced hundreds of times under a variety of different laboratory conditions. In addition to prolonging lifespan, CR also prevents or delays the onset of age‐related disease and maintains many physiological functions at more youthful levels. Studies in longer‐lived species, specifically rhesus and squirrel monkeys, have been underway since the late 1980s. The studies in nonhuman primates are beginning to yield valuable information suggesting that the effect of CR on aging is universal across species and that this nutritional paradigm will have similar effects in humans. Even if CR can be shown to impact upon human aging, it is unlikely that most people will be able to maintain the strict dietary control required for this regimen. Thus, elucidation of the biological mechanisms of CR and development of alternative strategies to yield similar benefits is of primary importance. CR mimetics, or interventions that “mimic” certain protective effects of CR, may represent one such alternative strategy. Microsc. Res. Tech. 59:335–338, 2002. © 2002 Wiley‐Liss, Inc.
Diffusion parameters in the striatum of rats with 6‐hydroxydopamine‐induced lesions and with fetal mesencephalic grafts
Authors: Reum T. , Olshausen F. , Mazel T. , Voříšek I. , Morgenstern R. , Syková E. 
Published: November 2002

AbstractFunctional recovery after transplantation of dopaminergic cells into the lesioned striatum is dependent on widespread diffusion of the transmitter released by the graft. In the present study, we investigated the diffusion parameters of the extracellular space in the striatum of control, 6‐hydroxydopamine‐lesioned, intrastriatally grafted, and sham‐grafted rats in vivo. We used two types of grafts—single macrografts or multiple micrografts. The real‐time iontophoretic tetramethylammonium method enabled us to extract three extracellular space diffusion parameters: volume fraction, α, tortuosity, λ, and nonspecific uptake of tetramethylammonium, k′. Compared with controls (α = 0.19, λ = 1.59), in lesioned animals both α and λ were lower (α = 0.14, λ = 1.50). α and λ were increased inside macro‐and micrografts, where α = 0.24 and λ = 1.80, and in sham‐grafted areas, where α = 0.24 and λ = 1.72. In regions outside the grafts (α = 0.15, λ = 1.51) or in sham grafts (α = 0.14, λ = 1.49), the values of α and λ were similar to the values observed in lesioned striatum. Nonspecific uptake (k′) did not differ among the groups. Our results show that, compared with control, α and λ were decreased in dopamine‐depleted areas and increased in areas with grafts. Multiple but smaller graft deposits, in contrast to their enlarged capability for dopaminergic reinnervation, impair the conditions for diffusion and extrasynaptic transmission in a larger area of the striatum than do single macrografts, presumably because of more extensive tissue damage, cell loss, and astrogliosis. © 2002 Wiley‐Liss, Inc.
The DNA damaging agent etoposide activates a cell survival pathway involving α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors and mitogen‐activated protein kinases in hippocampal neurons
Authors: Lu Chengbiao , Fu Weiming , Zhao Daohong , Mattson Mark P. 
Published: November 2002

AbstractEtoposide, an inhibitor of topoisomerase II that induces DNA damage and can trigger cell death, is used as a chemotherapeutic agent. Because chemotherapies can result in neurological complications and because DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders, we studied the effects of etoposide on cultured hippocampal neurons. We found that etoposide induces neuronal apoptosis and that, prior to the cell death commitment point, there is an increase in whole‐cell α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA)‐induced current but no change in N‐methyl‐D‐aspartate (NMDA)‐induced current. Associated with the increase in AMPA‐induced current was an increase in the amounts of AMPA receptor subunits GluR1 and GluR4, whereas levels of the NMDA receptor subunit NR1 were unaffected by etoposide. AMPA receptor activation can result in excitotoxic cell death but can also activate signaling pathways that promote synaptic plasticity and cell survival. We found that etoposide increases the activation of p42 and p44 mitogen‐activated protein (MAP) kinases, and that activation of the MAP kinases by etoposide requires AMPA receptor activation. Pharmacological blockade of AMPA receptors and p42/p44 MAP kinases, but not of NMDA receptors, exacerbated etoposide‐induced cell death. These findings suggest that, although etoposide is neurotoxic, it also activates a cell survival pathway involving AMPA receptor‐mediated activation of p42/p44 MAP kinases. Agents that selectively inhibit the cell life or death pathways triggered by DNA damage may prove useful in the settings of cancer and neurodegenerative disorders, respectively. Published 2002 Wiley‐Liss, Inc.
Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage
Authors: Ho Pei I. , Ortiz Daniela , Rogers Eugene , Shea Thomas B. 
Published: November 2002

AbstractHomocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD). We examined the consequences of treatment of cultured murine cortical neurons with HC. Homocysteine‐induced increases in cytosolic calcium, reactive oxygen species, phospho‐tau immunoreactivity and externalized phosphatidyl serine (indicative of apoptosis). Homocysteine‐induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity, as evidenced by treatment with antagonists of the NMDA channel and metabotropic glutamate receptors, respectively. The NMDA channel antagonist MK‐801 reduced tau phosphorylation but not apoptosis after HC treatment, suggesting that HC‐mediated apoptosis was not due to calcium influx. Apoptosis after HC treatment was reduced by co‐treatment with 3‐aminobenazmidine (3ab), an inhibitor of poly‐ADP‐ribosome polymerase (PARP), consistent with previous reports that ATP depletion by PARP‐mediated repair of DNA strand breakage mediated HC‐induced apoptosis. Treatment with 3ab did not reduce tau phosphorylation, however, therefore hyperphosphorylation of tau may not contribute to HC‐induced apoptosis under these conditions. Inhibition of mitogen‐activated protein kinase by co‐treatment with the kinase inhibitor PD98059 inhibited tau phosphorylation but not apoptosis after HC treatment. HC accumulation reduces cellular levels of S‐adenosyl methionine (SAM); co‐treatment with SAM reduced apoptosis, suggesting that inhibition of critical methylation reactions may mediate HC‐induced apoptosis. These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes. © 2002 Wiley‐Liss, Inc.
Oligodendrogenesis is differentially regulated in gray and white matter of jimpy mice
Authors: Baracskay Karen L. , Duchala Cynthia S. , Miller Robert H. , Macklin Wendy B. , Trapp Bruce D. 
Published: November 2002

AbstractThe factors that regulate oligodendrogenesis have been studied extensively in optic nerve, where oligodendrocyte production and myelination quickly follow colonization of the nerve by progenitor cells. In contrast, oligodendrocyte production in the cerebral cortex begins approximately 1 week after progenitor cell colonization and continues for 3–4 weeks. This and other observations raise the possibility that oligodendrogenesis is regulated by different mechanisms in white and gray matter. The present study examined oligodendrocyte production in the developing cerebral cortex of jimpy (jp) and jimpymsd (msd) mice, which exhibit hypomyelination and oligodendrocyte death due to mutations in and toxic accumulations of proteolipid protein, the major structural protein of CNS myelin. Proliferation of oligodendrocyte progenitors and production of myelinating oligodendrocytes was reduced in jp cerebral cortex when compared to wild‐type (wt) and msd mice. The incidence of oligodendrocyte cell death was similar in jp and msd cortex, but total dying oligodendrocytes were greater in msd. We confirm previous reports of increased oligodendrocyte production in white matter of both jp and msd mice. The jp mutation, therefore, reduces oligodendrocyte production in cerebral cortex but not in white matter. These data provide additional evidence that oligodendrogenesis is differentially regulated in white matter and gray matter and implicate PLP/DM20 as a modulator of these differences. © 2002 Wiley‐Liss, Inc.
Time course assessment of methylmercury effects on C6 glioma cells: submicromolar concentrations induce oxidative DNA damage and apoptosis
Authors: Belletti Silvana , Orlandini Guido , Vettori Maria Vittoria , Mutti Antonio , Uggeri Jacopo , Scandroglio Renato , Alinovi Rossella , Gatti Rita 
Published: November 2002

AbstractOrganic mercury is a well‐known neurotoxicant although its mechanism of action has not been fully clarified. In addition to a direct effect on neurons, much experimental evidence supports an involvement of the glial component. We assessed methylmercury hydroxide (MeHgOH) toxicity in a glial model, C6 glioma cells, exposed in the 10−5–10−8 M range. The time course of the effects was studied by time‐lapse confocal microscopy and supplemented with biochemical data. We have monitored cell viability and proliferation rate, reactive oxygen species (ROS), mitochondrial transmembrane potential, DNA oxidation, energetic metabolism and modalities of cell death. The earliest effect was a measurable ROS generation followed by oxidative DNA damage paralleled by a partial mitochondrial depolarization. The effect on cell viability was dose dependent. TUNEL, caspase activity and real‐time morphological observation of calcein‐loaded cells showed that apoptosis was the only detectable mode of cell death within this concentration range. N‐acetyl‐cysteine (NAC) or reduced glutathione (GSH) completely prevent the apoptotic effect of MeHgOH. The lowest effective MeHgOH concentration was 10−7 M for ROS and DNA OH‐adducts generation. The effect of submicromolar concentrations of MeHgOH on C6 cells could be relevant in the developmental neurotoxicity caused by low dose, long‐term exposures, such as those of food origin. In addition, we have shown that the same concentrations are effective in the induction of DNA oxidative damage, with further potential pathogenetic implications. © 2002 Wiley‐Liss, Inc.
JNK3 contributes to c‐jun induction and apoptosis in 4‐hydroxynonenal‐treated sympathetic neurons
Authors: Bruckner Shane R. , Estus Steven 
Published: November 2002

Abstract4‐Hydroxynoneal (HNE), an end product of lipid peroxidation, induces apoptosis in many cell types, including neural cells. HNE toxicity is often accompanied by activation of the c‐Jun N‐terminal kinase/stress‐activated protein kinase (JNK/SAPK) pathway. Here we have evaluated the hypothesis that the primary JNK associated with neurons, JNK3, contributes to HNE‐induced neuronal apoptosis. First, we demonstrate that HNE induces caspase‐dependent apoptosis in sympathetic neurons. Second, we show that HNE‐induced c‐Jun phosphorylation and c‐jun induction are attenuated in JNK3‐deficient neurons. Third, we show that HNE neurotoxicity is significantly inhibited by JNK3 deficiency. In summary, these results indicate that JNK3 plays a critical role in HNE‐induced c‐Jun activation and apoptosis in sympathetic neurons. © 2002 Wiley‐Liss, Inc.
Bone morphogenetic protein‐6 is a neurotrophic factor for calbindin‐positive striatal neurons
Authors: Gratacòs E. , Gavaldà N. , Alberch J. 
Published: November 2002

AbstractBone morphogenetic proteins (BMPs) are a set of members of the transforming growth factor‐β superfamily recently described as promoting the differentiation of several neuronal populations within the basal ganglia. This study examined whether a member of this family, BMP‐6, could exert neurotrophic effects on the neurons of the striatum, in which BMP‐6 mRNA had been previously detected during development. Here we show that BMP‐6 increases the number and differentiation of calbindin‐positive neurons in vitro. Indeed, BMP‐6 increased the total area, the perimeter, and the degree of arborization of this neuronal population. This trophic factor promoted dendritic growth without modifying axonal length or soma area. Furthermore, BMP‐6 increased the number of glial fibrillary acidic protein‐positive cells while decreasing the number of nestin‐positive cells. The suppression of cell proliferation or glial development by the antimitotic fluorodeoxyuridine removed the effects on striatal neurons, suggesting the involvement of astroglial cells in the differentiation induced by BMP‐6. The current results confirm the relevance of BMPs in the development of the striatum and emphasize the crucial importance of the trophic interaction between glial and neuronal cells. © 2002 Wiley‐Liss, Inc.
Role of c‐Jun concentration in neuronal cell death
Authors: Rössler Oliver G. , Steinmüller Lars , Giehl Klaus M. , Thiel Gerald 
Published: November 2002

AbstractA dimer of the basic region leucine zipper proteins c‐Jun and c‐Fos constitutes the classical activator protein‐1 (AP‐1) transcription factor. c‐Jun is thought to play essential roles in many important cellular pathways, including the control of proliferation and cell death. To investigate the roles of c‐Jun and c‐Fos concentrations in the regulation of neuronal cell death, we generated conditional alleles by fusing c‐Jun and c‐Fos to the ligand binding domain of the murine estrogen receptor (ER), with the aim of controlling the biological activities of c‐Jun and c‐Fos by the synthetic ligand 4‐hydroxytamoxifen (4OHT). Transient transfection experiments revealed an increase in AP‐1 activity following transfection of an expression vector encoding a c‐Jun/estrogen receptor fusion protein (c‐JunER) and stimulation with 4OHT. In contrast, a c‐Fos/estrogen receptor fusion protein (c‐FosER) was only weakly active in HT22 immortalized hippocampal cells and in PC12 pheochromocytoma cells. Highest levels of AP‐1 activity were obtained by cotransfection of c‐FosER and c‐JunER and stimulation with 4OHT. Using retroviral gene transfer, we generated HT22 and PC12 cells expressing either c‐JunER or c‐FosER. The AP‐1 activity was moderately increased in 4OHT‐treated HT22 and PC12 cells expressing c‐JunER, whereas no biological activity was observed in cells expressing c‐FosER. We tested the influcence of 4OHT‐activated c‐JunER or c‐FosER upon cell survival and cell death by quantification of mitochondrial reduction capacity of 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide to formazan dye crystals. We did not observe any 4OHT‐dependent decrease in cell survival in cells expressing c‐JunER or c‐FosER. Likewise, the number of pycnic nuclei did not increase in HT22 or PC12 cells expressing c‐JunER or c‐FosER. We conclude that an increase in the c‐Jun concentration is not sufficient to trigger neuronal cell death. We propose that it is not the concentration of c‐Jun that is critical for cell survival but rather the concentration of active, i.e., phosphorylated c‐Jun. © 2002 Wiley‐Liss, Inc.
Fragile X mental retardation protein in plasticity and disease
Authors: Todd Peter K. , Malter James S. 
Published: November 2002

AbstractFragile X syndrome is the most common cause of mental retardation known to be inherited. The syndrome results from the suppressed expression of a single protein, the fragile X mental retardation protein (FMRP). Understanding the function and regulation of FMRP can, therefore, offer insights into both the pathophysiology of fragile X syndrome and the molecular mechanisms of learning and memory. We provide an overview of current concepts of how FMRP functions in the nervous system, with special emphasis on recent evidence that FMRP has a role in metabotropic glutamate receptor‐activated protein translation and synaptic plasticity. © 2002 Wiley‐Liss, Inc.