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Mechanistic Analysis (mechanistic + analysis)
Selected AbstractsREVIEW ARTICLE: Maternal Transmission of Asthma RiskAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2009Robert H. Lim Maternal asthma significantly increases the risk of asthma in offspring, but the mechanisms remain poorly defined. We review animal models used to study the maternal effect, focusing on a murine model developed in our laboratory. Mother mice rendered allergic to ovalbumin produce offspring that are more susceptible to allergic sensitization, seen as airway hyperresponsiveness and allergic airway inflammation after a sensitization protocol, which has minimal effects on newborns from normal mothers. Mechanistic analyses identify a role for interleukin-4 (based on pre-mating injection of neutralizing antibodies), dendritic cells and allergen-specific T cells (based on adoptive transfer experiments). Other maternal exposures (e.g. pollutant exposure and non-pulmonary allergy) can increase asthma susceptibility in offspring. This observation implies that the maternal transmission of asthma represents a final common pathway to various types of inflammatory stimuli. Identification of the shared molecular mechanisms in these models may allow better prevention and therapy. Current knowledge, gaps in knowledge and future directions are discussed. [source] Bacterial hydrolytic dehalogenases and related enzymes: Occurrences, reaction mechanisms, and applicationsTHE CHEMICAL RECORD, Issue 2 2008Tatsuo Kurihara Abstract Dehalogenases catalyze the cleavage of the carbon,halogen bond of organohalogen compounds. They have been attracting a great deal of attention partly because of their potential applications in the chemical industry and bioremediation. In this personal account, we describe occurrences, reaction mechanisms, and applications of bacterial hydrolytic dehalogenases and related enzymes, particularly L -2-haloacid dehalogenase, DL -2-haloacid dehalogenase, fluoroacetate dehalogenase, and 2-haloacrylate reductase. L -2-Haloacid dehalogenase is a representative enzyme of the haloacid dehalogenase (HAD) superfamily, which includes the P-type ATPases and other hydrolases. Structural and mechanistic analyses of this enzyme have yielded important insights into the mode of action of the HAD superfamily proteins. Fluoroacetate dehalogenase is unique in that it catalyzes the cleavage of the highly stable CF bond of a fluorinated aliphatic compound. In the reactions of L -2-haloacid dehalogenase and fluoroacetate dehalogenase, the carboxylate group of Asp performs a nucleophilic attack on the ,-carbon atom of the substrate, displacing the halogen atom. This mechanism is common to haloalkane dehalogenase and 4-chlorobenzoyl-CoA dehalogenase. DL -2-Haloacid dehalogenase is unique in that a water molecule directly attacks the substrate, displacing the halogen atom. The occurrence of 2-haloacrylate reductase was recently reported, revealing a new pathway for the degradation of unsaturated aliphatic organohalogen compounds. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 67,74; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20141 [source] Induction of G2/M phase arrest and apoptosis by a novel indoloquinoline derivative, IQDMA, in K562 cellsDRUG DEVELOPMENT RESEARCH, Issue 9 2006Yi-Hsiung Lin Abstract The indoloquinoline, IQDMA (N,-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine), was identified as a novel antineoplastic agent with broad spectrum of antitumor activities against several human cancer cells. IQDMA-induced G2/M arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitors (CDKIs), p21 and p27, and down-regulation of Cdk1and Cdk2. IQDMA had no effect on the levels of cyclin A, cyclin B1, cyclin D3, or Cdc25C. IQDMA also increased apoptosis, as characterized by apoptotic body formation, increase of the sub G1 population and poly (ADP-ribose) polymerase (PARP) cleavage. Further mechanistic analysis demonstrated that IQDMA upregulated FasL protein expression, and kinetic studies showed the sequential activation of caspases-8, -3, and -9. Both caspase-8 and caspase-3 inhibitors, but not a caspase-9-specific inhibitor, suppressed IQDMA-induced cell death. These molecular alterations provide an insight into IQDMA-caused growth inhibition, G2/M arrest, and apoptotic death of K562 cells. Drug Dev. Res. 67:743,751, 2006. © 2006 Wiley-Liss, Inc. [source] Kinetics and mechanistic analysis of caustic magnesia hydrationJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 8 2004Sônia DF Rocha Abstract The kinetics of magnesia hydration to produce magnesium hydroxide is crucial for process design and control, and for the production of an Mg(OH)2 powder with desirable particle morphology. In this study, highly pure magnesia has been hydrated in a batch reactor. The effects of the following variables were evaluated experimentally: temperature (308,363 K), reaction time (0.5,5 h), initial slurry density (1,25%wt) and particle size in the ranges ,212 + 75 µm and ,45 + 38 µm. Experimental data indicate increasing magnesia hydration rates with increasing temperature, as expected. In addition, it has been observed that the hydration of magnesia increases significantly up to about 4,5%wt initial slurry density, stabilising afterwards. On the other hand, the reaction was almost unaffected when magnesia with different particle sizes were hydrated because of similar specific surface areas involved. A reaction mechanism to explain the oxide dissolution and the hydroxide precipitation has been proposed, assuming no significant change in the initial solids size and dissolution rate as the controlling step. The calculated activation energy value of 62.3 kJ mol,1 corroborates the mechanism proposed in this study and compares well with values previously reported in the literature. Copyright © 2004 Society of Chemical Industry [source] Deficiency of CXCR2, but not other chemokine receptors, attenuates autoantibody-mediated arthritis in a murine modelARTHRITIS & RHEUMATISM, Issue 7 2010Jonathan P. Jacobs Objective Chemokines coordinate leukocyte trafficking in homeostasis and during immune responses. Prior studies of their role in arthritis have used animal models with both an initial adaptive immune response and an inflammatory effector phase. We undertook analysis of chemokines and their receptors in the effector phase of arthritis using the K/BxN mouse serum,transfer model. Methods A time-course microarray analysis of serum-transferred arthritis was performed, examining ankle tissue, synovial fluid, and peripheral blood leukocytes. Up-regulation of chemokines was confirmed by quantitative reverse transcriptase,polymerase chain reaction. The functional relevance of chemokine induction was assessed by transferring serum into mice deficient in CCR1,7, CCR9, CXCR2, CXCR3, CXCR5, CX3CR1, CCL2, or CCL3. Further mechanistic analysis of CXCR2 involved treatment of arthritic mice with a CXCR2 antagonist, bone marrow (BM) cell transfers with CXCR2+/, and CXCR2,/, donors and recipients, flow cytometry of synovial cells, and competition experiments measuring enrichment of CXCR2-expressing neutrophils in arthritic joints of mice with mixed CXCR2+/+ and CXCR2,/, BM cells. Results Gene expression profiling revealed up-regulation of the CXCR2 ligands CXCL1, CXCL2, and CXCL5 in the joint in parallel with disease activity. CXCR2,/, mice had attenuated disease relative to CXCR2+/, littermates, as did mice receiving the CXCR2 inhibitor, while deficiency of other chemokine receptors did not affect arthritis severity. CXCR2 was required only on hematopoietic cells and was widely expressed on synovial neutrophils. CXCR2-expressing neutrophils were preferentially recruited to arthritic joints in the presence of CXCR2-deficient neutrophils. Conclusion CXCR2 (but not other chemokine receptors) is critical for the development of autoantibody-mediated arthritis, exhibiting a cell-autonomous role in neutrophil recruitment to inflamed joints. [source] Mechanistic Exploration of the Intramolecular Hydroalkoxylation of Allenyl Alcohols Mediated by Organolanthanide Complexes: A DFT StudyCHEMISTRY - A EUROPEAN JOURNAL, Issue 17 2010Sven Tobisch Dr. An efficient route toward functionalised cyclic ethers: Computational mechanistic analysis indicates an operative LnO ,-bond insertion mechanism with a turnover-limiting cyclisation for the intramolecular hydroalkoxylation of allenyl alcohols (see scheme). [source] MECHANISMS OF CARDIOTOXIN III-INDUCED APOPTOSIS IN HUMAN COLORECTAL CANCER COLO205 CELLSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2006Chia-Houng Tsai SUMMARY 1Cardiotoxin III (CTX III) is a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom. This is the first report on the mechanism of the anticancer effect of CTX III in human colorectal cancer Colo205 cells. 2Cardiotoxin III-induced Colo205 cell apoptosis was confirmed by DNA fragmentation (DNA ladder and sub-G1 formation) with an IC50 of 4 mg/mL at 48 h. 3Further mechanistic analysis demonstrate that CTX III induced the loss of mitochondrial membrane potential (Dym), cytochrome c release from mitochondria into the cytosol and activation of capase-9, caspase 3, as well as markedly enhancing the expression of Bax, but not Bcl-2, protein in the cells. Moreover, the CTX III-induced apoptosis was significantly blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. 4However, CTX III did not generate the formation of reactive oxygen species and anti-oxidants, including N -acetylcysteine, and catalase could not block CTX III-induced apoptosis in the Colo205 cells. 5Taken together, these results suggest that CTX III may induce apoptosis through a mitochondrial- and caspase-dependent mechanism and alteration of Bax/Bcl-2 ratio in human colorectal Colo205 cancer cells. [source] | |||||||||||||