2058 research outputs found
Sort by
Design, Synthesis And Evaluation of Anti- Inflammatory Activity of Gallic Acid Derivatives
No full textInflammation is the immunological defence mechanism exerted by the host in which the body fights against injury or infection from bacteria, viruses and other pathogens. The etiological features of inflammation as described in Latin are rubor (redness), calor (warmth), tumor (swelling) and dolor (pain) as described by Aurelius Cornelius, a Roman physician and medical writer who lived from about 30 B.C. to 45 A.D. The redness and swelling that occurs at the site of a wound is due to the broadening of blood vessels to create the passage for specialized immune cells and blood cells to enter the site of inflammation and combat the pathogens. Inflammation gradually gets wane following
the process and healing begins simultaneously for tissue regeneration. Inadequate or uncontrolled regulation of the inflammatory response mechanism can produce devastating effects and may generate different chronic diseases and severe tissue damage. After 1970s, non-steroidal anti-inflammatory drugs (NSAIDs) have been established to inhibit cyclooxygenase (COX), a class of physiological and pathophysiological inflammatory mediators which produces prostaglandins (PGs) [1]. Since then, the biosynthetic cascade of arachidonic acid (AA) has been the subject of intense research. COX and lipoxygenase (LOX) play a vital role in inflammation by controlling the intensity and duration of pain, as well as the occurrence of fever, swelling and heat of an affected area.Although steroidal anti-inflammatory drugs (SAIDs) and NSAIDs are currently used to treat acute inflammation, these drugs have severe genomic and nongenomic toxicities. These drugs are already
known for their gastrointestinal, renal and cardiovascular side effects. Recently, Vioxx and Celebrex, two effective drugs used to treat arthritis, were withdrawn for their cardiovascular toxicity. These cases provide examples of the unknown side effects produced by synthetic drugs, and suggest that an evaluation of the long-term effects of drugs may be required
Investtiigattiion on riibosome structure and dynamiics:: Mycobactteriium riibosome iin focus
No full textThis doctoral study deals primarily with the application of cryo-EM and single particle reconstruction technique to investigate three major aspects of translation machinery in prokaryotes. Kinetic studies indicate that in vivo, protein synthesis and ribosome biogenesis involves interaction of additional factors, capable of enhancing efficient assembly and protein synthesis. The first part of the study deals with the characterization of hitherto unknown association of cellular protein factors with the bacterial ribosome and functional importance of such interactions with the ribosome. Biochemical studies and a 3D cryo-EM map of a ribosome sample purified directly from cell extract revealed strong association of two cellular proteins namely Aldehyde alcohol dehydrogenase (AdhE) and Outer membrane protein C (OmpC) with E. coli 70S ribosome. Additional ribosome associated functions of these two proteins reflect multi-tasking activity of proteins within cell. The second part of the study deals with structural characterization of ribosome from bacteria that are of clinical importance to human health like Mycobacterium. The 12Å resolution 3D cryo-EM map of Mycobacterium smegmatis revealed unique additional structural components in the mycobacterial ribosome. Identification of several rRNA helices particularly a rRNA helix lying close to mRNA exit and extensions of ribosomal proteins around the peptide exit tunnel in M. smegmatis 70S ribosome structure reflects diversity of ribosome structure across bacterial kingdom and involvement of species specific structural elements in fine tuning the process of protein biosynthesis. The third part of the study addresses structure of the largest ribosomal protein S1 and its interaction with ribosomes from E. coli and M. smegmatis. Dynamic ribosome binding nature of S1 protein in a species specific manner has been explored. The study also presents a model of full length S1 protein from E. coli and interprets the organization of the domains and interaction of S1 with mRNA as well as ribosomal components
Conversion of Amyloid Fibrils of Cytochrome c to Mature Nanorods through a Honeycomb Morphology
No full textABSTRACT: Amyloid species with various morphologies have been found for different proteins and disease systems. In this article, we aim to ask if these morphologies are
unique to a particular protein or if they convert from one to another. Using a heme protein containing iron as the transition-metal activator of aggregation and a negatively
charged surfactant, partial unfolding of the protein and its aggregation have been induced. In the pathway of aggregation, we have observed the formation of several
morphological structures of a single protein, which were visualized directly using atomic force microscopy (AFM). These structures have been found to appear and disappear
with time, and their formation could be monitored under normal buffer conditions and at room temperature without requiring any sophisticated chemical or biological
methodologies. In addition, we have observed the formation of honeycomb-shaped morphology, which may serve as an intermediate. These amyloid-based nanostructures
may have the potential to be explored in therapeutics delivery and other biomedical applications
Frequent inactivation of SLIT2 and ROBO1 signaling in head and neck lesions: clinical and prognostic implications
No full textObjective. The protein SLIT2 and its receptor ROBO1 regulate different cellular processes, such as proliferation, apoptosis,and migration. In this study our aim is to understand the alterations of these genes during development of head and neck squamous cell carcinoma (HNSCC).
Materials and Methods. First, molecular alterations of the genes were analyzed in 30 dysplastic lesions, 128 primary HNSCC samples, and 1 HNSCC cell line. Then alterations were correlated with mRNA expression (n ¼ 22) and protein expression (n ¼29). Finally, the alterations were correlated with different clinicopathologic parameters and clinical outcomes of the patients.
Results. ROBO1 had a comparatively high frequency of deletion (28.5%-54.2%) from dysplastic lesions and subsequent clinical stages than did SLIT2 (16.6-27%). On the contrary, SLIT2 had a high frequency (56.6%-81.2%) of promoter methylation from dysplastic lesions onward compared with ROBO1 (20%-32.8%). Interestingly, alterations of SLIT2 and ROBO1 were high in dysplastic lesions (80%), followed by comparable frequencies (92.5%-95.3%) in subsequent stages of tumor. Alterations of these genes showed concordance with their mRNA/protein expression and significant association with poor patient outcome.
Conclusions. Our data suggest that inactivation of SLIT2 and/or ROBO1 is one of the early events in development of dysplastic lesions of head and neck and has prognostic importance
Nanoparticle-Protein Interaction Studies Using Spectroscopic and Biophysical Methods
No full textThe interaction of nanoparticles with biological interfaces has been studied extensively, where it has been found that proteins form the most abundant class of biomolecules interacting with nanoparticles. Also, nanoparticles due to the huge potential that they offer are being constantly scrutinized for their role in various aspects of biomedical, therapeutic and biotechnological applications. As a matter of fact, the exposure of such particulate matter to living systems is increasing exponentially, raising serious concerns related to their safety. The toxicity due to nanoparticles may arise due to their potential to interact with any biological system, even crossing the most protected blood brain barrier. In addition, they can induce conformational changes in protein, can alter the fluidity of membranes, and may release reactive oxygen species (ROS) and cause severe damage to DNA. Since the potential of nanoparticles are luring, such deleterious manifestations need to be alleviated in order to tap the resource that nanoparticles provide. This is a huge challenge, since nanoparticles are as complex in structure as proteins.
Here, we have developed a novel synthetic approach for the surface modification of one of the most biocompatible magnetite nanoparticles with a more biocompatible surface modifying agent, poly(ethylene) glycol. The stability and the efficiency of the new procedure have been extensively analysed. The interaction of magnetite nanoparticles with different protein systems has been taken in to account. It was observed that bare magnetite nanoparticles affect the proteins differently than that of the surface modified ones. In one of the protein systems, the bare magnetite nanoparticles affect the redox state of the protein; induce intermediate formation and leads to aggregation. The surface modification of nanoparticles maintains the redox state and prevents the aggregation of the protein. In another protein system, the early aggregation kinetics was analysed in the presence of bare and surface modified nanoparticles. Whereas, bare nanoparticles speeds up the aggregation rate, surface modified nanoparticles are found to delay the rate of aggregation
Antimony-Resistant Leishmania donovani Exploits miR-466i to Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection
No full textInfection with antimony-resistant Leishmania donovani (SbRLD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (SbSLD) infection. SbRLD, but not SbSLD, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-kB in infected macrophages (Mfs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-kB. We now show that infection of Mfs from MyD882/2 mice with SbRLD gave rise to significantly higher intracellular parasite number coupled with elevated IL-10/IL-12 ratio in the culture supernatant as compared with infection in wild type (WT) Mfs. Τhese attributes were not seen with SbSLD in similar experiments. Further, SbRLD infection upregulated miR-466i, which binds with 39-untranslated region, leading to the downregulation of MyD88. Infection of MyD882/2 Mf or IL-122/2 Mf with SbRLD induced IL-10 surge at 4 h, whereas the same in WT Mf started from 12 h. Thus, absence of IL-12 in MyD882/2 mice favored early binding of NF-kB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD882/2 mice with SbRLD showed significantly higher organ parasites coupled with ill-defined and immature hepatic granulomas, whereas in WT mice there were less organ parasites and the granulomas were well defined. From the survival kinetics it was observed that SbRLD-infected MyD882/2 mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that SbRLD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage
Role of active site residues in catalytic activities of heme based adenylate cyclase from Leishmania major
No full textLeishmania promastigotes inhabit in the midgut of a sandfly, where they are densely packed together and the environment of these promastigotes is then likely to
become hypoxic or even anoxic. Interestingly, Leishmania can survive in low oxygen concentration, which is an exception from Trypanosoma brucei. Although some
transcriptional regulators (HIF genes) in mammals help to response in adaptive responses during hypoxia, Leishmania lacks hypoxic inducible factor (HIF) as well as
transcriptional regulation. Thus, the underlying mechanism remains unclear. From the past few decades globin proteins have taken a vernerable positions in the cellular and
molecular biology of the three kingdoms respectively. Recently, a novel class of the globin coupled heme-containing sensor proteins has been identified in bacteria. These proteins are different from well-known heme proteins, such as hemoglobin/myoglobin (O2 carriers), cytochrome P450/peroxidases (oxygen activators), and cytochrome
c/cytochrome b5 (mediators of electron transfer). Globin-based O2 sensor proteins usually consist of an N-terminal heme-containing O2 sensor domain and a C-terminal effector
domain. The structures of globin-based sensor proteins are changed upon binding of O2 with the heme domain. This structural change influences the effector domain for proper
functioning like activation or inhibition. Against these backgrounds, the magnificent search of the Leishmania (L. major, L. infantum and L. braziliensis) genome sequence
has revealed more than 41 heme-containing protein-coding genes. Recently our laboratory has discovered a globin coupled heme containing adenylate cyclase from L.
major called HemAC-Lm, which is likely to function in cellular adaptability under various O2 tension
