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Abhisek Mukherjee Karina Cuanalo-Contreras Abha Sood Claudio Soto 《Biochemistry and Biophysics Reports》2022
Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC50. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors. 相似文献
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Vijayaprasad?GopichandranEmail authorView authors OrcID profile Valerie?A.?Luyckx Nikola?Biller-Andorno Amy?Fairchild Jerome?Singh Nhan?Tran Abha?Saxena Pascal?Launois Andreas?Reis Dermot?Maher Mahnaz?Vahedi 《Implementation science : IS》2015,11(1):161
Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review. 相似文献
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Desmond CP Gaudieri S James IR Pfafferott K Chopra A Lau GK Audsley J Day C Chivers S Gordon A Revill PA Bowden S Ayres A Desmond PV Thompson AJ Roberts SK Locarnini SA Mallal SA Lewin SR 《Journal of virology》2012,86(2):1181-1192
Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease. 相似文献
65.
Sharma A Patrick B Li J Sharma R Jeyabal PV Reddy PM Awasthi S Awasthi YC 《Archives of biochemistry and biophysics》2006,452(2):165-173
It has been suggested that the alpha-class glutathione S-transferases (GSTs) protect various cell types from oxidative stress and lipid peroxidation (LPO). In order to examine the protective role of alpha-class GST isozyme hGSTA1-1 against doxorubicin (DOX)-induced lipid peroxidation, cytotoxicity, and apoptosis, human small cell lung cancer (SCLC) H69 cells were stably transfected with hGSTA1. Immunological and biochemical characterization of hGSTA1-transfected cells revealed the expression of functionally active hGSTA1-1 localized near the cellular plasma membranes. hGSTA1-transfected cells acquired significantly increased resistance to the DOX-induced cytotoxicity by suppressing lipid peroxidation levels in these cells. Overexpression of hGSTA1-1 in cells inhibited DOX-mediated depletion of GSH and higher GSH levels were found in DOX-treated hGSTA1-transfected cells as compared with empty vector-transfected controls. hGSTA1-1 overexpression also provided protection to cells from DOX-induced apoptosis by inhibiting phosphorylation of c-Jun-N-terminal kinases (JNK), caspase-3 activation, and by preserving the levels of anti-apoptotic protein Bcl-2. These results are consistent with the idea that the alpha-class GSTs provide protection against oxidative stress by attenuating lipid peroxidation and these enzymes can modulate signaling for apoptosis. 相似文献
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Autism is a neurological disorder of childhood with poorly understood etiology and pathology. We compared lipid peroxidation status in the plasma of children with autism, and their developmentally normal non-autistic siblings by quantifying the levels of malonyldialdehyde, an end product of fatty acid oxidation. Lipid peroxidation was found to be elevated in autism indicating that oxidative stress is increased in this disease. Levels of major antioxidant proteins namely, transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein) in the serum, were significantly reduced in autistic children as compared to their developmentally normal non-autistic siblings. A striking correlation was observed between reduced levels of these proteins and loss of previously acquired language skills in children with autism. These results indicate altered regulation of transferrin and ceruloplasmin in autistic children who lose acquired language skills. It is suggested that such changes may lead to abnormal iron and copper metabolism in autism, and that increased oxidative stress may have pathological role in autism. 相似文献
70.
Plants are the prime source of phytoconstituents that can act as potent agents for the prevention and treatment of various diseases. Heterospathe elata is a plant belonging to the Arecaceae family having numerous medicinal properties. The present study was undertaken to prepare crude extracts of Heterospathe elata leaves with solvents of different polarity dimethyl carbonate (DMC), isopropyl alcohol (IPA), hydro alcohol (HYA) and water (WTR) by using successive Soxhlet extraction method. Further, the antioxidant, antidiabetic, and anti-inflammatory activities were assessed by the spectrophotometric method and possible bioactive phytoconstituents from the hydro alcohol extract of Heterospathe elata leaves using GC/MS. In our study, it was found that the GC/MS analysis revealed the presence of nineteen bioactive phytoconstituents. The highest antioxidant activity was found in the water extract. In antidiabetic and anti-inflammatory activity highest potential was shown by hydro alcohol extract and the lowest was in the dimethyl carbonate extract. These findings support the Heterospathe elata leaves showed the high biological potential attributed to a high amount of bioactive phytoconstituents and could be utilized as value-added functional food and medicine. 相似文献