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51.
Annalisa Cavallini Suzanne Brewerton Amanda Bell Samantha Sargent Sarah Glover Clare Hardy Roger Moore John Calley Devaki Ramachandran Michael Poidinger Eric Karran Peter Davies Michael Hutton Philip Szekeres Suchira Bose 《The Journal of biological chemistry》2013,288(32):23331-23347
Neurofibrillary tangles, one of the hallmarks of Alzheimer disease (AD), are composed of paired helical filaments of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD. We used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes Ser(P)-202, Thr(P)-231, Ser(P)-235, and Ser(P)-396/404) were measured in cell lysates using AlphaScreen assays. GSK3α, GSK3β, and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all four epitopes. We further dissected the effects of GSK3α and GSK3β using pharmacological and genetic tools in hTau primary cortical neurons. Pathway analysis of the kinases identified in the screen suggested mechanisms for regulation of total tau levels and tau phosphorylation; for example, kinases that affect total tau levels do so by inhibition or activation of translation. A network fishing approach with the kinase hits identified other key molecules putatively involved in tau phosphorylation pathways, including the G-protein signaling through the Ras family of GTPases (MAPK family) pathway. The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies. 相似文献
52.
Ramachandran Prakasam Mitsuaki Fujimoto Ryosuke Takii Naoki Hayashida Eiichi Takaki Ke Tan Fangxu Wu Sachiye Inouye Akira Nakai 《FEBS letters》2013
The febrile response is elicited by pyrogenic cytokines including IL-6 in response to microorganism infections and diseases in vertebrates. Mammalian HSF1, which senses elevations in temperature, negatively regulates the response by suppressing pyrogenic cytokine expression. We here showed that HSF3, an avian ortholog of mammalian HSF1, directly binds to and activates IL-6 during heat shock in chicken cells. Other components of the febrile response mechanism, such as IL-1β and ATF3, were also differently regulated in mammalian and chicken cells. These results suggest that the febrile response is exacerbated by a feed-forward circuit composed of the HSF3-IL-6 pathway in birds. 相似文献
53.
Govindan Subramanian Shashidhar N. Rao 《Bioorganic & medicinal chemistry letters》2013,23(24):6667-6672
The performance of several structure-based design (SBD) approaches in predicting the binding affinity of diverse small molecule inhibitors co-crystallized to human renin was assessed to ascertain the modeling tool and method of choice required when dealing with structure-based lead optimization projects. Most of the SBD approaches investigated here were able to provide qualitative guidance, but quantitative accuracy as well as decisive discrimination between [in]actives is still not within reach. Such an outcome suggests that the current methods need improvement to capture the overall physics of the binding phenomenon for consistent applications in a lead optimization setting. 相似文献
54.
Sellappan Selvamurugan Rangasamy Ramachandran Periasamy Viswanathamurthi 《Biometals》2013,26(5):741-753
A series of hexa-coordinated ruthenium(II) complexes of the type [Ru(CO)(B)L n ] (n = 1–4; B = PPh3, AsPh3 or Py) have been synthesized by reacting dibasic quadridentate Schiff base ligands H2L n (n = 1–4) with starting complexes [RuHCl(CO)(EPh3)2(B)] (E = P or As; B = PPh3, AsPh3 or Py). The synthesized complexes were characterized using elemental and various spectral studies including UV–Vis, FT-IR, NMR (1H, 13C and 31P) and mass spectroscopy. An octahedral geometry was tentatively proposed for all the complexes based on the spectral data obtained. The experiments on antioxidant activity showed that the ruthenium(II) S-methylisothiosemicarbazone Schiff base complexes exhibited good scavenging activity against various free radicals (DPPH, OH and NO). The in vitro cytotoxicity of these complexes has been evaluated by MTT assay. The results demonstrate that the complexes have good anticancer activities against selected cancer cell line, human breast cancer cell line (MCF-7) and human skin carcinoma cell line (A431). The DNA cleavage studies showed that the complexes have better cleavage of pBR 322 DNA. 相似文献
55.
Peter Bellstedt Thomas Seiboth Sabine Häfner Henriette Kutscha Ramadurai Ramachandran Matthias Görlach 《Journal of biomolecular NMR》2013,57(1):65-72
NMR-based structure determination of a protein requires the assignment of resonances as indispensable first step. Even though heteronuclear through-bond correlation methods are available for that purpose, challenging situations arise in cases where the protein in question only yields samples of limited concentration and/or stability. Here we present a strategy based upon specific individual unlabeling of all 20 standard amino acids to complement standard NMR experiments and to achieve unambiguous backbone assignments for the fast precipitating 23 kDa catalytic domain of human aprataxin of which only incomplete standard NMR data sets could be obtained. Together with the validation of this approach utilizing the protein GB1 as a model, a comprehensive insight into metabolic interconversion ("scrambling”) of NH and CO groups in a standard Escherichia coli expression host is provided. 相似文献
56.
Angiopoietin‐2, its soluble receptor Tie‐2, and metabolic syndrome components in a population‐based sample 下载免费PDF全文
57.
Cesar Meleza Bobbie Thomasson Chidambaram Ramachandran Jason W. O'Neill Klaus Michelsen Mei-Chu Lo 《Analytical biochemistry》2016
Prostaglandin D2 synthase (PGDS) catalyzes the isomerization of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2). PGD2 produced by hematopoietic prostaglandin D2 synthase (H-PGDS) in mast cells and Th2 cells is proposed to be a mediator of allergic and inflammatory responses. Consequently, inhibitors of H-PGDS represent potential therapeutic agents for the treatment of inflammatory diseases such as asthma. Due to the instability of the PGDS substrate PGH2, an in-vitro enzymatic assay is not feasible for large-scale screening of H-PGDS inhibitors. Herein, we report the development of a competition binding assay amenable to high-throughput screening (HTS) in a scintillation proximity assay (SPA) format. This assay was used to screen an in-house compound library of approximately 280,000 compounds for novel H-PGDS inhibitors. The hit rate of the H-PGDS primary screen was found to be 4%. This high hit rate suggests that the active site of H-PGDS can accommodate a large diversity of chemical scaffolds. For hit prioritization, these initial hits were rescreened at a lower concentration in SPA and tested in the LAD2 cell assay. 116 compounds were active in both assays with IC50s ranging from 6 to 807 nM in SPA and 82 nM to 10 μM in the LAD2 cell assay. 相似文献
58.
Annamalai Muthusamy Huliyar Narasimhamurthy Nagendra Prasad Erathodi Ramachandran Sanjay Mattu Radhakrishna Rao Kapaettu Satyamoorthy 《In vitro cellular & developmental biology. Plant》2016,52(6):598-607
The production of specific secondary metabolites in vitro can be improved through medium supplementation with secondary metabolite precursors, plant growth regulators (PGRs), and abiotic and biotic elicitors. In the present study, node and internode explants of Phyllanthus amarus and P. urinaria collected from Karkala region, Udupi District, Karnataka, India, were inoculated aseptically onto Murashige and Skoog (MS) medium for callus induction. Uniform calluses were inoculated onto MS medium fortified with one of two precursor’s cinnamic acid (CA) or phenylalanine (PA), or with naphthalene acetic acid (NAA). After 30 d of treatment, calluses from treatment and control groups were harvested and quantitatively analyzed for three lignans (phyllanthin, hypophyllanthin and niranthin) and an antioxidant (ellagic acid). Increased amounts of the lignans and ellagic acid were obtained through supplementation with CA, PA, and NAA, and higher ellagic acid was present at higher amounts than the three lignans. These results demonstrated that the Phyllanthus species collected from Karkala region (designated “Accessions3”) show substantial response to CA, PA, and NAA treatment and represent a potential source of donor plants with higher amounts of lignans and antioxidants. These plants can be cultivated on a large scale both in vitro and in vivo for production of important bioactive compounds. Production of these compounds can be further enhanced through induction of somaclonal variant plants with higher amounts of bioactive molecule production and through production of transgenic plants overexpressing genes related to lignan- and phenolic-compound biosynthesis. 相似文献
59.
To establish the relationship between thyroid hormone and cyclic Adenosine monophosphate (cAMP) during lacertilian tail regeneration, cAMP phosphodiesterase, the hydrolytic enzyme of cAMP, was assayed in the tail regenerate, liver, and skeletal muscle of control (group A), chemically thyroidectomized (group B), and thyroidectomized and T4-replaced (group C) animals during various periods of tail regeneration. Enzyme activity was elevated in all three tissues of group B animals. Animals of group C showed an intermediate level of enzyme activity between controls (group A) and experimental animals (group B). These observations suggest a possible regulatory role of thyroxine in maintaining optimum levels of phosphodiesterase. The retardation in regeneration observable in the hypothyroid group of animals may be correlated with low levels of tissue cAMP. However, the operation of other influencing factors on phosphodiesterase during regeneration can be surmised from the observed tendency to exhibit similar patterns of phase-specific modulations in enzyme activity. Our observations are discussed in terms of phase-specific involvement of cAMP in regeneration, as well as its role in other metabolic aspects and the possible mode of indirect control exerted by thyroxine on lacertilian tail regeneration. © 1996 Wiley-Liss, Inc. 相似文献
60.