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91.
92.
Aditya Sharma Chandan K. Maurya Deepti Arha Amit K. Rai Sushmita Singh Salil Varshney Jonathan D. Schertzer Akhilesh K. Tamrakar 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):136-146
Chronic inflammation contributes to obesity mediated metabolic disturbances, including insulin resistance. Obesity is associated with altered microbial load in metabolic tissues that can contribute to metabolic inflammation. Different bacterial components such as, LPS, peptidoglycans have been shown to underpin metabolic disturbances through interaction with host innate immune receptors. Activation of Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) with specific peptidoglycan moieties promotes insulin resistance, inflammation and lipolysis in adipocytes. However, it was not clear how Nod1-mediated lipolysis and inflammation is linked. Here, we tested if Nod1-mediated lipolysis caused accumulation of lipid intermediates and promoted cell autonomous inflammation in adipocytes. We showed that Nod1-mediated lipolysis caused accumulation of diacylglycerol (DAG) and activation of PKCδ in 3T3-L1 adipocytes, which was prevented with a Nod1 inhibitor. Nod1-activated PKCδ caused downstream stimulation of IRAK1/4 and was associated with increased expression of proinflammatory cytokines such as, IL-1β, IL-18, IL-6, TNFα and MCP-1. Pharmacological inhibition or siRNA mediated knockdown of IRAK1/4 attenuated Nod1-mediated activation of NF-κB, JNK, and the expression of proinflammatory cytokines. These results reveal that Nod1-mediated lipolysis promoted accumulation of DAG, which engaged PKCδ and IRAK1/4 to augment inflammation in 3T3-L1 adipocytes. 相似文献
93.
Yogavel Manickam Nipun Malhotra Siddhartha Mishra Palak Babbar Abhishek Dusane Benoît Laleu Valeria Bellini Mohamed-Ali Hakimi Alexandre Bougdour Amit Sharma 《PLoS pathogens》2022,18(3)
Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional ‘single target–single drug’ approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3’-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins. 相似文献
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Pradeep Kumar Yadalam Santhiya Rengaraj Maryam H. Mugri Mohammed Sayed Amit Porwal Nasser Mesfer Alahmari Khaled M. Alzahrani Ali Robaian Hosam Ali Baeshen Shankargouda Patil 《Saudi Journal of Biological Sciences》2022,29(1):622-629
ObjectivesPeri-implantitis is a destructive inflammatory process that affects the soft and hard tissues around dental implants. porphyromonas gingivalis, an anaerobic gram-negative bacterium, appears to be the main culprit. Since there is no efficient and specific vaccine to treat peri-implantitis, the goal of our research has been to develop a multi-epitope vaccination utilizing an immunoinformatics approach that targeted P. gingivalis type I fim A.Materials and methodsP. gingivalis peptides 6JKZ and 6KMF are suitable for vaccine development. B- and T-cell epitopes from 6KMF and 6JKZ were detected and evaluated based on critical factors to produce a multi-epitope vaccine construct. It was assessed based on allergenicity, antigenicity, stability. The vaccine's dual major histocompatibility complex (MHC-I and MHC-II) binding epitopes allowed it to reach a larger population. P. gingivalis fimbriae induce immune subversion through TLR -CXCR4 receptor complex pathway. The ClusPro 2.0 server was used to do the molecular docking using TLR2 - CXCR4 and vaccine epitopes as receptor and ligand respectively.ResultsThe designed vaccine was non-allergenic and had a high antigenicity, solubility, and stability. The 3D structure of the vaccine revealed strong interaction with CXCR4(TLR2) using molecular docking. The vaccine-CXCR4 interface was more consistent, possibly because the vaccination has a higher affinity for the CXCR4-TLR2 complex.ConclusionThis study details the vaccine's distinct and sustained interaction with the CXCR4(TLR2) immunological receptor and its consistent and effective utterance in the bacterial system. As a result, our vaccine formulation will evoke a significant memory response and induce an adaptive immune response against P. gingivalis. 相似文献
96.
Amit Kumar Solanki Abhishek Acharya Himani Kaushik Bharti Bhatia Lalit C Garg 《Bioinformation》2021,17(6):628
Beta toxin from Clostridium perfringens after being secreted in gut is capable of causing necrotic enteritis in humans and several other animal species and does not respond to routinely used antibiotics. Therefore, there is a need to design an effective inhibitor for the Clostridium perfringens beta toxin (CPB) using cutting edge drug discovery technologies. Hence, potential CPB inhibitors were identified using computer aided screening of compounds from the ZINC database. Further, we document the molecular docking analysis of Clostridium perfringens beta toxin model (that revealed 4 binding pockets, A-D) with the identified potential inhibitors. We show that ZINC291192 [N-[(1-methylindol-3-yl) methyl eneamino]-7,10-dioxabicyclo[4.4.0]deca-2,4,11-triene-8- carboxamide] has optimal binding features with calculated binding energy of -10.38 kcal/mol and inhibition constant of 24.76 nM for further consideration. 相似文献
97.
Evidence for photosynthetic independence of viral multiplication in cyanophage LPP-1 infected cyanobacterium Phormidium uncinatum 总被引:1,自引:0,他引:1
P.S. Bisen Surabhi Audholia H.D. Shukla Amit Gupta D.P. Singh 《FEMS microbiology letters》1988,52(3):225-228
Abstract Pigment decomposition, oxygen evolution and CO2 fixation were measured in the cyanobacterium Phormidium uncinatum after infection with cyanophage LPP-1, under light and dark conditions. A gradual decrease in para benzoquinone supported O2 evolution, chlorophyll a and phycocyanin level were noticed after 6 h of infection. These results demonstrated decreased photosynthetic activity of the host P. uncinatum prior to the start of LPP-1 multiplication. Metabolic inhibitor investigations confirmed that the cyanophage LPP-1 multiplication was independent of host photosynthesis. 相似文献
98.
Drink composition, voluntary drinking, and fluid balance in exercising, trained, heat-acclimatized boys 总被引:2,自引:0,他引:2
Rivera-Brown Anita M.; Gutierrez Randall; Gutierrez Juan Carlos; Frontera Walter R.; Bar-Or Oded 《Journal of applied physiology》1999,86(1):78-84
This study examinedthe effects of beverage composition on the voluntary drinking pattern,body fluid balance, and thermoregulation of heat-acclimatized trainedboys exercising intermittently in outdoor conditions (wet bulb globetemperature 30.4 ± 1.0°C). Twelve boys (age 13.4 ± 0.4 yr) performed two 3-h sessions, each consisting of four20-min cycling bouts at 60% maximal aerobic power alternating with25-min rest. One of two beverages was assigned: unflavored water (W) orflavored water plus 6% carbohydrate and 18 mmol/l Na (CNa). Drinkingwas ad libitum. Total intake was higher(P < 0.05) during CNa (1,943 ± 190 g) compared with W (1,470 ± 143 g). Euhydration wasmaintained with CNa (+0.18% body wt), but a mild dehydration resultedwith W (0.94% body wt; P < 0.05). Sweat loss, much higher than previously published for children of similar age, was similar between conditions (CNa = 1,644.7 ± 117.5; W = 1,750.2 ± 152.7 g). The increase in rectaltemperature (CNa = 0.86 ± 0.3; W = 0.76 ± 0.1°C), heartrate, and all perceptual variables did not differ between conditions.In conclusion, a flavored carbohydrate-electrolyte drink preventsvoluntary dehydration in trained heat-acclimatized boys exercising in atropical climate despite their large sweat losses. Because hydrationchanges were minor, the thermoregulatory strain observed was similarbetween conditions. 相似文献
99.
Fiber optic in vivo imaging in the mammalian nervous system 总被引:4,自引:0,他引:4
The compact size, mechanical flexibility, and growing functionality of optical fiber and fiber optic devices are enabling several new modalities for imaging the mammalian nervous system in vivo. Fluorescence microendoscopy is a minimally invasive fiber modality that provides cellular resolution in deep brain areas. Diffuse optical tomography is a non-invasive modality that uses assemblies of fiber optic emitters and detectors on the cranium for volumetric imaging of brain activation. Optical coherence tomography is a sensitive interferometric imaging technique that can be implemented in a variety of fiber based formats and that might allow intrinsic optical detection of brain activity at a high resolution. Miniaturized fiber optic microscopy permits cellular level imaging in the brains of behaving animals. Together, these modalities will enable new uses of imaging in the intact nervous system for both research and clinical applications. 相似文献
100.