Department of Bioscience & Bioengineering

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IIT Jodhpur

We have engineered nano-constructs composed of plant virus capsid proteins encapsulating indocyanine green complexed with albumin. Our results that demonstrate the effectiveness of these nano-constructs for fluorescence imaging of ovarian cancer cells in vitro. © 2017 OSA.

World University root node

Optics InfoBase Conference Papers

Virus-mimicking hybrid nanostructures containing indocyanine green and albumin for near infrared fluorescence imaging of ovarian cancer cells

Streptococcus mutans, an oral pathogen associated with dental caries, colonizes tooth surfaces as polymicrobial biofilms known as dental plaque. S. mutans expresses several virulence factors that allow the organism to tolerate environmental fluctuations and compete with other microorganisms. We recently identified a small hypothetical protein (90 amino acids) essential for the normal growth of the bacterium. Inactivation of the gene, SMU.2137, encoding this protein caused a significant growth defect and loss of various virulence-associated functions. An S. mutans strain lacking this gene was more sensitive to acid, temperature, osmotic, oxidative, and DNA damage-inducing stresses. In addition, we observed an altered protein profile and defects in biofilm formation, bacteriocin production, and natural competence development, possibly due to the fitness defect associated with SMU.2137 deletion. Transcriptome sequencing revealed that nearly 20% of the S. mutans genes were differentially expressed upon SMU.2137 deletion, thereby suggesting a pleiotropic effect. Therefore, we have renamed this hitherto uncharacterized gene as sprV (streptococcal pleiotropic regulator of virulence). The transcript levels of several relevant genes in the sprV mutant corroborated the phenotypes observed upon sprV deletion. Owing to its highly conserved nature, inactivation of the sprV ortholog in Streptococcus gordonii also resulted in poor growth and defective UV tolerance and competence development as in the case of S. mutans. Our experiments suggest that SprV is functionally distinct from its homologs identified by structure and sequence homology. Nonetheless, our current work is aimed at understanding the importance of SprV in the S. mutans biology. © 2017 American Society for Microbiology. All Rights Reserved.

Fulltext

Journal of Bacteriology

Pleiotropic regulation of virulence genes in Streptococcus mutans by the conserved small protein SprV

We examine the long-term behaviour of non-integrable, energy-conserved, 1D systems of macroscopic grains interacting via a contact-only generalized Hertz potential and held between stationary walls. We previously showed that in homogeneous configurations of such systems, energy is equipartitioned at sufficiently long times, thus these systems ultimately reach thermal equilibrium. Here we expand on our previous work to show that heterogeneous configurations of grains also reach thermal equilibrium at sufficiently long times, as indicated by the calculated heat capacity. We investigate the transition to equilibrium in detail and introduce correlation functions that indicate the onset of the transition. © 2017 IOP Publishing Ltd and SISSA Medialab srl.

Journal of Statistical Mechanics: Theory and Experiment

The equilibrium phase in heterogeneous Hertzian chains

Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer's disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPCactivated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4-/- and Nlrp3-/- mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis. © 2017 Freeman et al.

Journal of Experimental Medicine

NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Trigonella foenum-graecum (fenugreek) is an important medicinal plant, well known for its antiinflammatory properties. However, the underlying cellular and molecular mechanisms of its action remain largely unknown. The apoptosis associated speck like protein containing a caspase recruitment domain (CARD) (ASC) is central to inflammatory and cell death pathways in innate and adaptive immunity. Here, we show that fenugreek seed extract provides cytoprotection to bacterial lipopolysaccharide (LPS) inflammed and nanosilica-treated fibroblasts via a reactive oxygen species independent pathway. All atom molecular dynamics simulations of ASC-ligand complex reveal that individual phytochemicals in fenugreek can bind to ASC via specific non-covalent interactions. These data show that a synergistic effect of fenugreek phytochemicals with the ASC protein alters its molecular properties resulting in altered cellular function. Such information is crucial to the development of targeted therapeutic interventions for inflammatory diseases. © 1996-2017.

Department of Chemistry

Frontiers in Bioscience - Elite

Trigonella seed extract ameliorates inflammation via regulation of the inflammasome adaptor protein, ASC

Background &amp; Aims The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene−smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD. Methods We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10−/− and Nod2−/− mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction. Results We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P &lt; 5.0 × 10−5; heterogeneity Cochrane Q test P &gt;.05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke. Conclusions In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene−smoking interactions were confirmed in mice with disruption of Il10 and Nod2—variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants. © 2017 AGA Institute

Gastroenterology

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

Centromeres are unique chromosomal loci that promote the assembly of kinetochores, macromolecular complexes that bind spindle microtubules during mitosis. In most organisms, centromeres lack defined genetic features. Rather, they are specified epigenetically by a centromere-specific histone H3 variant, CENP-A. The Mis18 complex, comprising the Mis18α: Mis18β subcomplex and M18BP1, is crucial for CENP-A homeostasis. It recruits the CENP-A-specific chaperone HJURP to centromeres and primes it for CENP-A loading. We report here that a specific arrangement of Yippee domains in a human Mis18α:Mis18β 4:2 hexamer binds two copies of M18BP1 through M18BP1’s 140 N-terminal residues. Phosphorylation by Cyclin-dependent kinase 1 (CDK1) at two conserved sites in this region destabilizes binding to Mis18α:Mis18β, limiting complex formation to the G1 phase of the cell cycle. Using an improved viral 2A peptide co-expression strategy, we demonstrate that CDK1 controls Mis18 complex recruitment to centromeres by regulating oligomerization of M18BP1 through the Mis18α:Mis18β scaffold. © Pan et al.

eLife

CDK-regulated dimerization of M18BP1 on a Mis18 hexamer is necessary for CENP-A loading

Seven hexacoordinated cis-dioxidomolybdenum(VI) complexes [MoO2L1–7] (1‐7) derived from various tetradentate diamino bis(phenolato) “salan” ligands, N,N′-dimethyl-N,N′-bis-(2-hydroxy-3-X-5-Y-6-Z-benzyl)-1,2-diaminoethane {(X = Br, Y = Me, Z = H (H2L1); X = Me, Y[dbnd]Cl, Z = H (H2L2); X = iPr, Y = Cl, Z = Me (H2L3)} and N,N′-bis-(2-hydroxy-3-X–5-Y-6-Z-benzyl)-1,2-diaminopropane {(X = Y = tBu, Z = H (H2L4); X = Y = Me, Z = H (H2L5); X = iPr, Y[dbnd]Cl, Z = Me (H2L6); X = Y = Br, Z = H (H2L7)} containing O‐[sbnd]N donor atoms, have been isolated and structurally characterized. The formation of cis-dioxidomolybdenum(VI) complexes was confirmed by elemental analysis, IR, UV–vis and NMR spectroscopy, ESI-MS and cyclic voltammetry. X-ray crystallography showed the O2N2 donor set to define an octahedral geometry in each case. The complexes (1–7) were tested for their in vitro antiproliferative activity against HT-29 and HeLa cancer cell line. IC50 values of the complexes in HT-29 follow the order 6 &lt; 7 &lt;&lt; 1 &lt; 2 &lt; 5 &lt;&lt; 3 &lt; 4 while the order was 6 &lt; 7 &lt; 5 &lt; 1 &lt;&lt; 3 &lt; 4 &lt; 2 in HeLa cells. Some of the complexes proved to be as active as the clinical referred drugs, and the greater potency of 6 and 7 (IC50 values of 6 are 2.62 and 10.74 μM and that of 7 is 11.79 and 30.48 μM in HT-29 and HeLa cells, respectively) may be dependent on the substituents in the salan ligand environment coordinated to the metal. © 2017 Elsevier Inc.

Journal of Inorganic Biochemistry

Synthesis, structure and cytotoxicity of a series of Dioxidomolybdenum(VI) complexes featuring Salan ligands

The study reports the synthesis and characterization of gelatin-tamarind gum (TG) based filled hydrogels for drug delivery applications. In this study, three different types of carbon nanotubes (CNTs) were incorporated within the dispersed TG phase of the filled hydrogels. The prepared hydrogels were thoroughly characterised using bright field microscope, FESEM, FTIR spectroscopy, differential scanning calorimeter, and mechanical tester. The swelling and the drug (salicylic acid) release properties of the filled hydrogels were also evaluated. The micrographs revealed the formation of biphasic systems. The internal phase appeared as agglomerates, and the CNTs were confined within the dispersed TG phase. FTIR and XRD studies revealed that CNTs promoted associative interactions among the components of the hydrogel, which promoted the formation of large crystallite size. The mechanical study indicated better resistance to the breakdown of the architecture of the CNT-containing filled hydrogels. Drug release studies, both passive and iontophoretic, suggested that the non-Fickian diffusion of the drug was prevalent during its release from hydrogel matrices. The prepared hydrogels were cytocompatible with human keratinocytes. The results suggested the probable use of such hydrogels in wound healing, tissue engineering and drug delivery applications. © 2017 Elsevier Ltd

Journal of the Mechanical Behavior of Biomedical Materials

Reinforcing the inner phase of the filled hydrogels with CNTs alters drug release properties and human keratinocyte morphology: A study on the gelatin- tamarind gum filled hydrogels

There is a need for high performance scaffold in tissue engineering. Keeping this perspective in mind, the present study delineates the preparation and physico-chemical characterization of soluble eggshell protein (SEP) modified silk fibroin (SF)-polyvinyl alcohol (PVA) scaffold and its application in bone tissue engineering. The SF/PVA scaffold were prepared by salt leaching and modified with eggshell protein. Micro-architecture and porosity analysis revealed that all the scaffolds were having desired pore size (230-360 μm), interconnected porous network and 90% porosity. The scaffolds were found with suitable swelling behavior and biodegradability to support cell proliferation till replaces native osseous tissue. In vitro cytocompatibility and differentiation study showed that SEP(SF-PVA) supports viability, proliferation and differentiation of cord blood derived human mesenchymal stem cell. Further, in vivo study in mice model showed that the scaffolds are non-immunogenic and support tissue growth. In conclusion, SEP modified SF-PVA scaffold could be a better option for tissue engineering. © 2017 Trans Tech Publications, Switzerland.