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51.
Abstract: The influence of putrescine, spermidine, spermine, and some aliphatic α,ω-diamines on the uptake of neurotransmitters by rat forebrain synaptosomes was investigated. Choline uptake was most effectively inhibited by spermine (IC50 = 0.22 m M ), less so by spermidine (IC50 = 4.0 m M ), but not by putrescine (IC50 > 100 m M ). At 10 m M, 1,3-diaminopropane, cadaverine, and 1,8-diaminooctane all inhibited choline uptake by 50% or more. Spermine and spermidine inhibited the uptake of dopamine with IC50 values of 2.7 and 2.2 m M , respectively. Putrescine was only slightly inhibitory (IC50 = 17.3 m M ) and the other diamines were inactive. The uptake of γ-aminobutyrate (GABA) was only slightly inhibited (15–40%) by the polyamines at 10 m M . With the exception of inhibition of glycine uptake by 1,8-diaminooctane (60%) and of glutamate uptake by cadaverine (35%) none of the polyamines, tested at 10 m M , affected the uptake of adenosine, glutamate, and glycine significantly. A possible modulatory role for polyamines in synaptic transmission through interaction by negatively charged groups of the synaptic membrane with the polycationic compounds is discussed. 相似文献
52.
Aruna S. Jaiswal Harekrushna Panda Brian K. Law Jay Sharma Jitesh Jani Robert Hromas Satya Narayan 《PloS one》2015,10(5)
Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients. 相似文献
53.
Perspectives of diverse constituencies need to be incorporated when developing conservation strategies. In Menri (Medicine Mountains) of the Eastern Himalayas, Tibetan doctors and professional botanists were interviewed about conservation
of useful plants. We compare these two perspectives and find they differ significantly in conservation priorities (Wilcoxon
Signed Ranks P < 0.05), both in how they prioritized, as well as the priorities themselves. Tibetan doctors first consider which plants
are most important to their medical practice and, then secondarily, the conservation status of these plants. Additionally,
perceptions of threatened medicinal plants differ among Tibetan doctors who received medical training in Lhasa, who were local
trained, and who were self-taught. In contrast, professional botanists came to a consensus among themselves by first considering
the conservation status of plants and then considering use. We conclude that, in order to effect community based conservation,
opinions from both Tibetan doctors and professional botanists should be considered in establishing conservation priorities
and sustainable conservation programs. Furthermore, we set our own research agenda based on combined perspectives. 相似文献
54.
Carbon storage and fluxes in ponderosa pine forests at different developmental stages 总被引:12,自引:0,他引:12
B.E. Law P.E. Thornton † J. Irvine P.M. Anthoni‡ S. Van Tuyl 《Global Change Biology》2001,7(7):755-777
We compared carbon storage and fluxes in young and old ponderosa pine stands in Oregon, including plant and soil storage, net primary productivity, respiration fluxes, eddy flux estimates of net ecosystem exchange (NEE), and Biome‐BGC simulations of fluxes. The young forest (Y site) was previously an old‐growth ponderosa pine forest that had been clearcut in 1978, and the old forest (O site), which has never been logged, consists of two primary age classes (50 and 250 years old). Total ecosystem carbon content (vegetation, detritus and soil) of the O forest was about twice that of the Y site (21 vs. 10 kg C m?2 ground), and significantly more of the total is stored in living vegetation at the O site (61% vs. 15%). Ecosystem respiration (Re) was higher at the O site (1014 vs. 835 g C m?2 year?1), and it was largely from soils at both sites (77% of Re). The biological data show that above‐ground net primary productivity (ANPP), NPP and net ecosystem production (NEP) were greater at the O site than the Y site. Monte Carlo estimates of NEP show that the young site is a source of CO2 to the atmosphere, and is significantly lower than NEP(O) by c. 100 g C m?2 year?1. Eddy covariance measurements also show that the O site was a stronger sink for CO2 than the Y site. Across a 15‐km swath in the region, ANPP ranged from 76 g C m?2 year?1 at the Y site to 236 g C m?2 year?1 (overall mean 158 ± 14 g C m?2 year?1). The lowest ANPP values were for the youngest and oldest stands, but there was a large range of ANPP for mature stands. Carbon, water and nitrogen cycle simulations with the Biome‐BGC model suggest that disturbance type and frequency, time since disturbance, age‐dependent changes in below‐ground allocation, and increasing atmospheric concentration of CO2 all exert significant control on the net ecosystem exchange of carbon at the two sites. Model estimates of major carbon flux components agree with budget‐based observations to within ± 20%, with larger differences for NEP and for several storage terms. Simulations showed the period of regrowth required to replace carbon lost during and after a stand‐replacing fire (O) or a clearcut (Y) to be between 50 and 100 years. In both cases, simulations showed a shift from net carbon source to net sink (on an annual basis) 10–20 years after disturbance. These results suggest that the net ecosystem production of young stands may be low because heterotrophic respiration, particularly from soils, is higher than the NPP of the regrowth. The amount of carbon stored in long‐term pools (biomass and soils) in addition to short‐term fluxes has important implications for management of forests in the Pacific North‐west for carbon sequestration. 相似文献
55.
Multiple nanosecond duration molecular dynamics simulations on the pore-lining M2 helix of the nicotinic acetylcholine receptor reveal how its structure and dynamics change as a function of environment. In water, the M2 helix partially unfolds to form a molecular hinge in the vicinity of a central Leu residue that has been implicated in the mechanism of ion channel gating. In a phospholipid bilayer, either as a single transmembrane helix, or as part of a pentameric helix bundle, the M2 helix shows less flexibility, but still exhibits a kink in the vicinity of the central Leu. The single M2 helix tilts relative to the bilayer normal by 12 degrees, in agreement with recent solid state NMR data (Opella et al., Nat Struct Biol 6:374-379, 1999). The pentameric helix bundle, a model for the pore domain of the nicotinic receptor and for channels formed by M2 peptides in a bilayer, is remarkably stable over a 2-ns MD simulation in a bilayer, provided one adjusts the pK(A)s of ionizable residues to their calculated values (when taking their environment into account) before starting the simulation. The resultant transbilayer pore shows fluctuations at either mouth which transiently close the channel. Proteins 2000;39:47-55. 相似文献
56.
Law Peter K. Haider Kh. Fang G. Jiang S. Chua F. Lim Y.T. Sim E. 《Molecular and cellular biochemistry》2004,263(1):173-178
Bioengineering the regenerative heart may provide a novel treatment for heart failure. On May 14, 2002, a 55-year-old man suffering from ischemic myocardial infarction received 25 injections carrying 465 million cGMP-produced pure myoblasts into his myocardium after coronary artery bypass grafting. As on August 28, 2002, his EKG was normal and showed no arrhythmia. His ejection fraction increased by 13%. He no longer experienced shortness of breath and angina as he did before the treatment. Three myogenesis mechanisms were elucidated with 17 human/porcine xenografts using cyclosporine as immunosuppressant. Some myoblasts developed to become cardiomyocytes. Others transferred their nuclei into host cardiomyocytes through natural cell fusion. As yet others formed skeletal myofibers with satellite cells. De novo production of contractile filaments augmented the heart contractility. Human myoblasts transduced with VEGF165 gene produced six times more capillaries in porcine myocardium than in placebo. Xenograft rejection was not observed for up to 20 weeks despite cyclosporine discontinuation at 6 weeks. Pros and cons of autografts vs. allografts are compared to guide future development of heart cell therapy. (Mol Cell Biochem 263: 173–178, 2004) 相似文献
57.
Plant and Soil - The measurement of optical density of acid hydrolysed oil palm leaves provides the basis for a quantitative determination of the cyanidin liberated. This in turn was shown to be... 相似文献
58.
R Qi Y Ozaki N Asazuma K Satoh Y Yatomi C L Law T Hato S Nomura 《Biochimica et biophysica acta》1999,1451(2-3):353-363
Using glutathione S-transferase Syk fusion proteins, we evaluated the mode of platelet FcgammaRII tyrosine phosphorylation induced by FcgammaRII cross-linking or anti-CD9 monoclonal antibodies (mAb). The N-terminal SH2 domain of Syk (Syk-N-SH2), the C-terminal SH2 domain of Syk (Syk-C-SH2), and the domain having both the N- and C-terminal SH2 of Syk (Syk-NC-SH2) all bound to tyrosine-phosphorylated FcgammaRII with FcgammaRII cross-linking. In the case of anti-CD9 mAb-induced platelet activation, only Syk-C-SH2 and Syk-NC-SH2 bound to tyrosine-phosphorylated FcgammaRII. Since the SH2 domain is specific for a particular structure containing phosphotyrosine, these findings suggest that only one tyrosine residue in the immunoreceptor tyrosine-based activation motif (ITAM) is phosphorylated with anti-CD9 mAb, and that both are phosphorylated with FcgammaRII cross-linking. Synthetic peptides corresponding to the ITAM of human platelet FcgammaRII with the N-terminal tyrosine residue phosphorylated (N-P) or the C-terminal tyrosine residue phosphorylated (C-P), were used. N-P more potently dissociated Syk-C-SH2 from tyrosine-phosphorylated FcgammaRII than C-P, suggesting that the N-terminal tyrosine residue is phosphorylated upon anti-CD9 mAb-induced activation. Furthermore, these findings imply that Syk-N-SH2 binds to the phosphorylated C-terminal tyrosine residue of ITAM, and Syk-C-SH2 to the N-terminal tyrosine. Taken together, our findings suggest that FcgammaRII-dependent platelet activation without FcgammaRII dimerization, such as with anti-CD9 mAb, is distinct from that induced by FcgammaRII cross-linking. 相似文献
59.
Cheuk-Yiu Law Chung-Wah Siu Katherine Fan Wing-Hon Lai Ka-Wing Au Yee-Man Lau Lai-Yung Wong Jenny C.Y. Ho Yee-ki Lee Hung-Fat Tse Kwong-Man Ng 《Biochemistry and Biophysics Reports》2016
Patients with Danon disease may suffer from severe cardiomyopathy, skeletal muscle dysfunction as well as varying degrees of mental retardation, in which the primary deficiency of lysosomal membrane-associated protein-2 (LAMP2) is considerably associated. Owing to the scarcity of human neurons, the pathological role of LAMP2 deficiency in neural injury of humans remains largely elusive. However, the application of induced pluripotent stem cells (iPSCs) may shed light on overcoming such scarcity.In this study, we obtained iPSCs derived from a patient carrying a mutated LAMP2 gene that is associated with Danon disease. By differentiating such LAMP2-deficient iPSCs into cerebral cortical neurons and with the aid of various biochemical assays, we demonstrated that the LAMP2-deficient neurons are more susceptible to mild oxidative stress-induced injury.The data from MTT assay and apoptotic analysis demonstrated that there was no notable difference in cellular viability between the normal and LAMP2-deficient neurons under non-stressed condition. When exposed to mild oxidative stress (10 μM H2O2), the LAMP2-deficient neurons exhibited a significant increase in apoptosis. Surprisingly, we did not observe any aberrant accumulation of autophagic materials in the LAMP2-deficient neurons under such stress condition.Our results from cellular fractionation and inhibitor blockade experiments further revealed that oxidative stress-induced apoptosis in the LAMP2-deficient cortical neurons was caused by increased abundance of cytosolic cathepsin L. These results suggest the involvement of lysosomal membrane permeabilization in the LAMP2 deficiency associated neural injury. 相似文献
60.
David Charles Boettiger Stephen Kerr Rossana Ditangco Tuti Parwati Merati Thuy Thi Thanh Pham Romanee Chaiwarith Sasisopin Kiertiburanakul Chung Ki Patrick Li Nagalingeswaran Kumarasamy Saphonn Vonthanak Christopher Lee Nguyen Van Kinh Sanjay Pujari Wing Wai Wong Adeeba Kamarulzaman Fujie Zhang Evy Yunihastuti Jun Yong Choi Shinichi Oka Oon Tek Ng Pacharee Kantipong Mahiran Mustafa Winai Ratanasuwan Annette Sohn Matthew Law 《PloS one》2014,9(9)