bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation
Authors: Ryan Kelli R , McCue David , Anderton Stephen M 
Published: April 2005

AbstractThe ability of autoreactive T cells to induce autoimmune pathology is dependent on their ability to respond to the level of autoantigen presented in the target organ. Emerging evidence suggests that at the population level, T cell sensitivity for self can be reduced by deletion of those cells bearing high-affinity T cell receptors (TCRs) or by sensory adaptation of individual cells. Here, we have investigated the mechanisms that prevent the induction of experimental autoimmune encephalomyelitis (EAE) when myelin basic protein (MBP)-reactive T cells are exposed to a strong, antigenic stimulus. Stimulation of MBP-reactive TCR transgenic T cells with a superagonist peptide led to extensive activation-induced cell death (AICD) through Fas signaling. Using T cells lacking Fas, we found that disruption of this deletional mechanism only partially increased EAE in response to superagonist, failing to restore susceptibility to the level found in response to the wild-type MBP peptide. A significant fraction of the MBP-reactive T cells was able to avoid AICD in response to superagonist, but these cells had a reduced sensitivity for an antigen that correlated with elevated levels of CD5. Therefore, when TCR affinity is fixed, autoreactive T cell sensitivity can be shifted to below a threshold for harm by a combination of AICD and sensory adaptation.
Asymmetrical protein kinase A activity establishes neutrophil cytoskeletal polarity and enables chemotaxis
Authors: Jones Samuel L , Sharief Yousuf 
Published: April 2005

AbstractNeutrophil chemotaxis requires precise spatial organization of the actin cytoskeleton and integrin activation to polarize the cell and enable migration. Protein kinase A (PKA) activity regulates integrin activation and actin cytoskeletal organization, suggesting that PKA is a key element in the mechanism regulating neutrophil chemotaxis. Our hypothesis is that asymmetrical PKA activity is critical for establishing neutrophil adhesive and cytoskeletal polarity required for migration during chemotaxis. To test this hypothesis, we first determined that global treatment with the PKA inhibitor KT5720 decreased formylated Met-Leu-Phe (fMLF)-induced migration. The ability of PKA inhibitors to reduce migration correlated with increased overall β2 integrin cell-surface expression, affinity activation, and cellular adhesion. We next determined whether asymmetrical PKA activity was sufficient to induce migration. Exposure to gradient of the PKA inhibitors KT5720 or H-89 or a stearated, cell-permeant peptide (St-Ht31), which inhibits PKA binding to anchorage proteins, stimulated neutrophil migration in a chemotaxis chamber. Global treatment with KT5720 abolished the ability of fMLF to polarize the neutrophil actin cytoskeleton. In contrast to global treatment with KT5720, a point source of KT5720 was sufficient to polarize the actin cytoskeleton. The ability of KT5720 and St-Ht31 to stimulate migration was abolished by pretreatment with the phosphatidylinositol-3 kinase (PI-3K) inhibitors wortmannin and LY294002. These data suggest that asymmetrical PKA activity is necessary and sufficient for actin cytoskeletal polarization and migration during neutrophil chemotaxis. In addition, our data suggest PI-3K is an effector of PKA during chemotaxis.
Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction
Authors: Giuliani Fabrizio , Hader Walter , Yong V Wee 
Published: April 2005

AbstractMinocycline, a tetracycline with anti-inflammatory properties, has been reported to down-regulate the activity of microglia, whose activation occurs in inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis and Alzheimer's disease. In these disorders, a T cell component is also evident, and we have demonstrated previously that the interaction of activated T cells with microglia led to the substantial increase in tumor necrosis factor α (TNF-α) levels. Here, we report that minocycline decreases TNF-α levels produced in human T cell-microglia interaction. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which resulted in the decreased ability of T cells to contact microglia. In correspondence, minocycline decreased the expression on T cells of the CD40 ligand (CD40L), a key molecule regulating the contact-mediated interaction of T cells with microglia. These results demonstrate that the mechanism of action of minocycline involves not only microglia but also T cells and their subsequent activation of microglia. The capacity of minocycline to down-regulate CD40L on T cells may provide a new means to target the CD40-CD40L pathway, which regulates several inflammatory processes.
Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture
Authors: Kim Min P , Zhou Min , Wahl Larry M 
Published: April 2005

AbstractAngiotensin II (Ang II)-mediated hypertension increases the risk for acute coronary syndrome, a consequence of atherosclerotic plaque rupture, which may be caused by matrix metalloproteinases (MMPs). Here, we show that human primary monocytes stimulated with tumor necrosis factor α (TNF-α) and granulocyte macrophage-colony stimulating factor (GM-CSF) release Ang II, which is an integral component of the signal transduction pathway that leads to MMP-1 production. An Ang II-mediated increase in MMP-1 synthesis occurred only in conjunction with cytokine stimulation. Moreover, Ang II mediated its effect through the Ang II type 2 (AT2) receptor, as demonstrated by enhancement of MMP-1 production by an AT2 agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT2 antagonist. Additionally, exogenous Ang II caused a significant enhancement in MMP-1 production by cytokine-stimulated monocytes, and the most effective enhancement occurrred when Ang II was added 6 h after stimulation. Furthermore, Ang II and the AT2 agonist increased prostaglandin E2 (PGE2), which in turn mediated the increase in MMP-1, as shown by the inhibition of MMP-1 by indomethacin or aspirin. In contrast, the AT2 antagonist inhibited the PGE2 production induced by TNF-α and GM-CSF. Ang II, through its interaction with the AT2 receptor, has a central role in mediating the PGE2-dependent production of MMP-1 by monocytes stimulated with TNF-α and GM-CSF. These observations provide insight into the association between hypertension and acute coronary syndrome and a possible mechanism by which Ang-converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.
Antiobesity Effect of a Melanin-Concentrating Hormone 1 Receptor Antagonist in Diet-Induced Obese Mice
Authors: Mashiko Satoshi , Ishihara Akane , Gomori Akira , Moriya Ryuichi , Ito Makoto , Iwaasa Hisashi , Matsuda Masao , Feng Yue , Shen Zhu , Marsh Donald J. , Bednarek Maria A. , MacNeil Douglas J. , Kanatani Akio 
Published: April 2005

AbstractMelanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 μg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.
Potential Role for Human Cytochrome P450 3A4 in Estradiol Homeostasis
Authors: Yu Ai-Ming , Fukamachi Katsumi , Krausz Kristopher W. , Cheung Connie , Gonzalez Frank J. 
Published: April 2005

AbstractPreviously, a human CYP3A4-transgenic (Tg-CYP3A4) mouse line was reported to exhibit enhanced metabolism of midazolam by cytochrome P450 3A4 (CYP3A4) expressed in small intestine. Here we show that expression of CYP3A4 and murine cyp3a and cyp2b was both age and sex dependent. CYP3A4 was expressed in the livers of male and female Tg-CYP3A4 mice at 2 and 4 wk of age. Since 6 wk, CYP3A4 was undetectable in male livers, whereas it was constitutively expressed in female livers at decreased levels (3- to 5-fold). Pregnenolone 16α-carbonitrile markedly induced hepatic CYP3A4 expression, and the level was higher in females than males. Induction of intrinsic murine cyp3a and cyp2b was also sex dependent. Tg-CYP3A4 females were found to be deficient in lactation, leading to a markedly lower pup survival. The mammary glands of the Tg-CYP3A4 lactating mothers had underdeveloped alveoli with low milk content. Furthermore, β-casein and whey acidic protein mRNAs were expressed at markedly lower levels in Tg-CYP3A4 pregnant and nursing mouse mammary glands compared with wild-type mice. This impaired lactation phenotype was associated with significantly reduced serum estradiol levels in Tg-CYP3A4 mice. A pharmacokinetic study revealed that the clearance of iv administrated [3H]estradiol was markedly enhanced in Tg-CYP3A4 mice compared with wild-type mice. These results suggest that CYP3A4 may play an important role in estradiol homeostasis. This may be of concern for treatment of pregnant and lactating women because CYP3A4 gene expression and enzymatic activity can be potentially modified by CYP3A4 inhibitors or inducers in medications, supplements, beverages, and diet.
Human Growth Hormone-Releasing Factor (hGRF)1–29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog
Authors: Jetté Lucie , Léger Roger , Thibaudeau Karen , Benquet Corinne , Robitaille Martin , Pellerin Isabelle , Paradis Véronique , van Wyk Pieter , Pham Khan , Bridon Dominique P. 
Published: April 2005

Abstract
In vivo bioconjugation to the free thiol on Cys34 of serum albumin by a strategically placed reactive group on a bioactive peptide is a useful tool to extend plasma half-life. Three maleimido derivates of human GH-releasing factor (hGRF)1–29 were synthesized and bioconjugated to human serum albumin ex vivo. All three human serum albumin conjugates showed enhanced in vitro stability against dipeptidylpeptidase-IV and were bioactive in a GH secretion assay in cultured rat anterior pituitary cells. When the maleimido derivatives were individually administered sc to normal male Sprague Dawley rats, an acute secretion of GH was measured in plasma. The best compound, CJC-1295, showed a 4-fold increase in GH area under the curve over a 2-h period compared with hGRF1–29. CJC-1295, a tetrasubstituted form of hGRF1–29 with an added Nε-3-maleimidopropionamide derivative of lysine at the C terminus, was selected for further pharmacokinetic evaluation, where it was found to be present in plasma beyond 72 h. A Western blot analysis of the plasma of a rat injected with CJC-1295 showed the presence of a CJC-1295 immunoreactive species on the band corresponding to serum albumin, appearing after 15 min and remaining in circulation beyond 24 h. These results led to the identification of CJC-1295 as a stable and active hGRF1–29 analog with an extended plasma half-life.
Estrogen Can Act via Estrogen Receptor α and β to Protect Hippocampal Neurons against Global Ischemia-Induced Cell Death
Authors: Miller Nora R. , Jover Teresa , Cohen Hillel W. , Zukin R. Suzanne , Etgen Anne M. 
Published: April 2005

Abstract
Estradiol at physiological concentrations intervenes in apoptotic death cascades and ameliorates neuronal death in experimental models of focal and global ischemia. The cellular targets that mediate estradiol protection of hippocampal neurons in global ischemia are, however, unclear. The present study examined the hypothesis that estradiol protects hippocampal neurons in ovariectomized rats via estrogen receptor (ER)α and/or β. Estradiol (14 d pretreatment) afforded robust protection of CA1 neurons against global ischemia-induced death. The broad-spectrum ER antagonist ICI 182,780 (intracerebroventricularly, 0 and 12 h after ischemia) abolished estrogen protection, consistent with a role for ERs. To evaluate the potential roles of ERα vs. ERβ in estrogen protection, we administered subtype-selective agonists for 14 d before and 7 d after ischemia. The ERα-selective agonist propyl pyrazole triol (PPT, 10 mg/kg) and ERβ-selective agonist WAY 200070–3 (1 mg/kg) produced nearly complete protection of CA1 neurons in approximately 50% of the animals. PPT, but not WAY 200070–3, at doses used for protection, elicited lordosis, induced negative feedback inhibition of LH release, and reduced weight gain. These findings establish the efficacy of the PPT dose in neuroendocrine assays and specificity of WAY 200070–3 for ERβ. We also examined the ability of estradiol and neuronal injury to regulate ERα and ERβ expression. Both estradiol and global ischemia markedly increased ERα, but not ERβ, protein in CA1. These data indicate that estradiol can act via ERα and ERβ to protect CA1 neurons from global ischemia-induced death and that both estradiol and global ischemia modulate ERα expression in hippocampal CA1.
p38 Mitogen-Activated Protein Kinase (MAPK) Is a Key Mediator in Glucocorticoid-Induced Apoptosis of Lymphoid Cells: Correlation between p38 MAPK Activation and Site-Specific Phosphorylation of the Human Glucocorticoid Receptor at Serine 211
Authors: Miller Aaron L. , Webb M. Scott , Copik Alicja J. , Wang Yongxin , Johnson Betty H. , Kumar Raj , Thompson E. Brad 
Published: April 2005

AbstractGlucocorticoids (GCs) induce apoptosis in lymphoid cells through activation of the GC receptor (GR). We have evaluated the role of p38, a MAPK, in lymphoid cell apoptosis upon treatment with the synthetic GCs dexamethasone (Dex) or deacylcortivazol (DAC). The highly conserved phosphoprotein p38 MAPK is activated by specific phosphorylation of its threonine180 and tyrosine182 residues. We show that Dex and DAC stimulate p38 MAPK phosphorylation and increase the mRNA of MAPK kinase 3, a specific immediate upstream activator of p38 MAPK. Enzymatic assays confirmed elevated activity of p38 MAPK. Pharmacological inhibition of p38 MAPK activity was protective against GC-driven apoptosis in human and mouse lymphoid cells. In contrast, inhibition of the MAPKs, ERK and cJun N-terminal kinase, enhanced apoptosis. Activated p38 MAPK phosphorylates specific downstream targets. Because phosphorylation of the GR is affected by MAPKs, we examined its phosphorylation state in our system. We found serine 211 of the human GR to be a substrate for p38 MAPK both in vitro and intracellularly. Mutation of this site to alanine greatly diminished GR-driven gene transcription and apoptosis. Our results clearly demonstrate a role for p38 MAPK signaling in the pathway of GC-induced apoptosis of lymphoid cells.
Involvement of the Diels–Alderases in the Biosynthesis of Natural Products
Authors: Oikawa Hideaki 
Published: April 2005

Abstract
Recent studies on a novel C–C bond formation enzyme, Diels–Alderase, show that this unusual enzyme is involved in the biosynthesis of secondary metabolites. In this account, I describe studies related to Diels–Alderases including biomimetic synthesis, the biological utilization of the Diels–Alder reaction, and natural Diels–Alderases. The function and catalytic mechanism of natural Diels–Alderases, such as solanapyrone synthase, lovastatin nonaketide synthase, and macrophomate synthase, are of great interest due to the diversity of molecular skeletons in natural Diels–Alder adducts. The first structure analysis of macrophomate synthase provided information on detailed mechanisms regarding active site organization among the substrates, metal and amino acid residues, and regarding how to avoid product inhibition.
Construction and Control of Self-Assembly of Amyloid and Fibrous Peptides
Authors: Mihara Hisakazu , Matsumura Sachiko , Takahashi Tsuyoshi 
Published: April 2005

Abstract
The aggregation of peptides and proteins into amyloid fibrils is most commonly associated with a variety of serious diseases such as Alzheimer’s disease and the transmissible spongiform encephalopathies (prion diseases). Amyloid-like fibrils are undesirable states for proteins as biomolecules, however, these are fascinating nanoconstructs because of their highly ordered tertiary structure in which numerous β-stranded polypeptide chains align regularly. These kinds of fibrous peptides have the potential to be engineered into ones revealing basic insights into amyloid formation and protein folding, as well as developing novel peptidyl nanoscale materials. We have demonstrated that de novo designed peptides undergo self-initiated structural transition and fibril formation, showing representative properties of amyloid. Cofibril formation from two, three, or four peptide species with well-designed amino acid sequences was achieved, so that the charged residues within the β-strands were complementary to each other. This homologous recognition mechanism can be applied for the inhibition of the fibril formation. Meanwhile, cofibril formation indicates a possibility of functionalizing the fibrils by co-assembling of peptides with various elements to develop a fibrous peptide material as a well-ordered nanoconstruct. Another designing approach demonstrated the production of unique straight nanofibers with defined widths. The fibrils may make a nanoscaffold onto which a variety of functional groups can be arranged. The studies on engineering fibrous peptides will afford insight into desease-related amyloid formation and will help to develop nanoscale fibrous constructs.
14 Step-15 Electron Reversible Redox Behavior of Tetrameric Oligomer of Oxo-Bridged Triruthenium Cluster
Authors: Hamaguchi Tomohiko , Nagino Haruko , Hoki Katsunori , Kido Hiroaki , Yamaguchi Tadashi , Breedlove Brian K , Ito Tasuku 
Published: April 2005

Abstract
Pyrazine-bridged trimeric and tetrameric oligomers of triruthenium clusters, [{Ru3O(CH3CO2)6(CO)(py)}-(μ-pz)-{Ru3O(CH3CO2)6(CO)}-(μ-pz)-{Ru3O(CH3CO2)6(py)2}]+ (1) and [{Ru3O(CH3CO2)6(CO)(py)}-(μ-pz)-{Ru3O(CH3CO2)6(CO)}-(μ-pz)-{Ru3O(CH3CO2)6(py)}-(μ-pz)-{Ru3O(CH3CO2)6(dmap)2}]2+ (2), were prepared (pz = pyrazine, py = pyridine, dmap = 4-dimethylaminopyridine). Trimer 1 and tetramer 2 show closely spaced 11 step-12 electron and 14 step-15 electron reversible redox waves, respectively, in their cyclic voltammograms in CH3CN. These compounds were designed specifically to incorporate the above-mentioned electrochemical behavior, using the unique redox properties characteristic of triruthenium clusters: (i) each Ru3 cluster unit generally exhibits four reversible single electron waves from Ru3IV,III,III to Ru3II,II,II state; (ii) the redox potentials of the cluster units strongly depend on the basicity of the ancillary ligand; (iii) redox potentials of the Ru3 cluster units vary by 300–500 mV depending on the presence or the absence of a carbonyl ligand on the cluster unit; (iv) in the negative potential region, electronic interaction through the bridging pyrazine between adjacent Ru3 units containing a carbonyl ligand makes the difference in redox potential of each unit larger. 1 and 2 were synthesized by linking Ru3 cluster units with the desired ancillary ligand set in the appropriate order.
Kinetic Study of the Mechanism of Free-Radical Scavenging Action in Curcumin: Effects of Solvent and pH
Authors: Ohara Keishi , Mizukami Wataru , Tokunaga Aiko , Nagaoka Shin-ichi , Uno Hidemitsu , Mukai Kazuo 
Published: April 2005

Abstract
A kinetic study was performed for the free-radical scavenging actions of curcumin and half-curcumin, which has a half-structure of curcumin, in order to clarify the mechanism of free-radical-scavenging in curcumin. The second-order rate constants for radical-scavenging reactions of curcumin and half-curcumin were measured by a stopped-flow spectrophotometer in several organic solvents (methanol, ethanol, acetonitrile, chloroform, and benzene) and in aqueous Triton X-100 (5.0 wt %) micelle solutions at various pH. The difference in the rate constant and solvent dependence between curcumin and half-curcumin suggests that the enol structure with the intramolecular hydrogen-bond of curcumin strongly enhances the radical-scavenging activity. Furthermore, notable pH dependences were observed for the rate constants of curcumin and half-curcumin in micelle solutions, suggesting that the acid–base dissociation equilibrium of phenol-protons in curcumin and half-curcumin affects their radical-scavenging activities.
Biohydrogen Production from Sucrose Using the Light-Harvesting Function of Zinc Chlorophyll-a
Authors: Takeuchi Yumi , Amao Yutaka 
Published: April 2005

Abstract
A biohydrogen production system, has been developed that couples sucrose hydrolysis by invertase and glucose dehydrogenase (GDH) and hydrogen production with a platinum colloid as a catalyst. The system uses the visible light-harvesting function of artificial Zn chlorophyll-a (Zn Chl-a), prepared from Mg Chl-a (obtained from Spilurina). When a sample solution containing sucrose, invertase, nicotinamide adenine dinucreotide (NAD+), Zn Chl-a, methylviologen (MV2+, an electron carrier), and platinum colloid was irradiated, continuous hydrogen production was observed with the irradiation time. The amount of hydrogen production was about 10.5 μmol after 4 h of irradiation under the optimum condition.