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Synthesis and Characterization of Furo[3,2-h]Quinoliniums as Potent Non-Detergent Spermicides
No full text7-Aryl substituted furo[3,2-h]quinoliniums have been synthesised in two steps from 5-chloro-8-hydroxy-7-
iodo-quinoline through a tandem Sonogashira alkynylation-cyclization pathway using aryl acetylenes followed by quaternisation reaction with alkyl halides under microwave irradiation. The compounds have been characterized spectroscopically and assessed for their sperm-immobilizing efficacy in vitro by modified Sander–Cramer test. Most of the derivatives showed potent spermicidal effect with minimum effective concentration (MEC) ranging from 125�g/ml – 1mg/ml. The results were further confirmed by double fluoroprobe staining with syber14/PI (Propidium Iodide). The mode of spermicidal action was assessed by (a) Hypo-osmotic swelling tests and (b) Scanning electron microscopy. The compounds have been found to be nontoxic to lactobacillus in 36 hours of culture whereas mild to moderately effective on common vaginal pathogens. Taken together it can be inferred that the water-soluble salts prepared from facile technique are potential candidates
for spermicides and could further be utilized for the preparation of vaginal contraceptives
Clinical Significance of Markers of Collagen Metabolism in Rheumatic Mitral Valve Disease
No full textRheumatic Heart Disease (RHD), a chronic acquired heart disorder results from Acute Rheumatic Fever. It is a
major public health concern in developing countries. In RHD, mostly the valves get affected. The present study investigated whether extracellular matrix remodelling in rheumatic valve leads to altered levels of collagen metabolism markers and if such markers can be clinically used to diagnose or monitor disease progression.
This is a case control study comprising 118 subjects. It included 77 cases and 41 healthy controls. Cases were
classified into two groups- Mitral Stenosis (MS) and Mitral Regurgitation (MR). Carboxy-terminal propeptide of type I
procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), total Matrix Metalloproteinase-1(MMP-1) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) were assessed. Histopathology studies were performed on excised mitral valve leaflets. A p value ,0.05 was considered statistically significant. Plasma PICP and PIIINP concentrations increased significantly (p,0.01) in MS and MR subjects compared to controls but decreased gradually over a one year period post mitral valve replacement (p,0.05). In MS, PICP level and MMP-
1/TIMP-1 ratio strongly correlated with mitral valve area (r =20.40; r = 0.49 respectively) and pulmonary artery systolic pressure (r = 0.49; r =20.49 respectively); while in MR they correlated with left ventricular internal diastolic (r = 0.68; r =20.48 respectively) and systolic diameters (r = 0.65; r =20.55 respectively). Receiver operating characteristic curve analysis established PICP as a better marker (AUC = 0.95; 95% CI = 0.9120.99; p,0.0001). A cut-off .459 ng/mL for PICP provided 91% sensitivity, 90% specificity and a likelihood ratio of 9 in diagnosing RHD. Histopathology analysis revealed inflammation, scarring, neovascularisation and extensive leaflet fibrosis in diseased mitral valve.
Conclusions: Levels of collagen metabolism markers correlated with echocardiographic parameters for RHD diagnosis
Studies of protein folding and ligand binding dynamics in vitro and in cultured cells using fluorescence correlation spe correlation spectroscopy and allied biophysical techniques
No full textIn order to function, newly synthesized protein need to fold
properly. Denatured proteins, which have had essentially all of their native three-dimensional structure disrupted, can refold from their random disordered state into a well-defined unique structure, in which the biological activity is virtually completely restored. During folding, a protein needs to search different possible conformations to reach into its native functional state. A comprehensive understanding of the early stages of protein folding remains elusive to date and is a subject of extensive research efforts. The major bottlenecks to study the early events of protein folding arise from the lack of computational and experimental techniques to study the unfolded and initial intermediate states. Fluorescence correlation spectroscopy (FCS) has been emerging as an important technique with single molecule resolution to study the diffusional and conformational dynamics of the early events of protein folding. In the present work, the rat intestinal fatty acid binding protein (IFABP) has been used as a model system. IFABP is a 15 kDa predominantly β-sheet protein that belongs to the intracellular lipid binding protein (iLBP) family. Fatty acid binding proteins are transport proteins delivering fatty acids (FAs) from cellular periphery to their subcellular destinations. They have been shown to play important roles in lipid metabolism and organelle dynamics. We used a combination of fluorescence correlation spectroscopy and far-UV circular dichroism (CD) to understand how the early processes like chain collapse and secondary structure formation influence the late folding events like the stabilization of the secondary structure and aggregation. Acid-induced unfolded IFABP was found to collapse in the presence of low concentrations of added salt and aggregate at higher concentrations. The results suggested that backbone hydrogen bond formation, not only the overall hydrophobicity of IFABP, may play crucial roles in the early collapse. Next, we explored the formation of intermediate state in the process of protein folding. We unfolded the protein by lowering the pH of the solution condition and monitored the occurrence of the intermediate state at around pH 3. A combination of tryptophan fluorescence and far-UV CD were used to study the unfolding of its tertiary and secondary structures. FCS was used to delve into the molecular events occurring in concert during the unfolding process. We observed that this intermediate state is stable enough to unfold its secondary structure after the unfolding of its tertiary structure in the presence of denaturing solvent like urea. We also observed that the effect of TFE upon the intermediate state is much less than the native or completely unfolded states. We carried over our in vitro work into the cellular system relating the structure-function properties of IFABP. A cellular model for lipid toxicity was generated with increased dose of a LCFA like sodium oleate. This lipid toxicity induced cell stress caused changes in mitochondrial morphology, loss in mitochondrial membrane potential and subsequent apoptosis. With controlled expression of IFABP in the HeLa cells, the mitochondrial morphology was partially restored with protection from apoptosis. The above findings were validated in Caco-2 cells where in the cellular metabolic stress, a controlled expression of IFABP could restore mitochondrial morphology and provided protection from apoptosis. A part of the thesis work also carries the distribution of IFABP in subcellular compartments in the presence and absence of its FA ligand and its diffusion was monitored at single cell resolution under cholesterol depleted condition by using CLSM, FCS, TIRF and FACS. It was noticed that although IFABP’s localization near the plasma membrane did not reduce under membrane cholesterol depleted condition, and the protein could still bind to some integral part of the membrane while receiving and trafficking its FA ligands inside the cell. Thus it was presumed that this protein could have evolved to receive their lipid ligands from the cell plasma membrane in a membrane microdomain-independent phenomenon. This present work is just a preliminary approach in addressing this phenomenon and more work are to be done to explore the mechanism of ligand uptake at single cell resolution
Studies On Proteins - Nucleic Acids Interactions In Regulation Of Replication And Transcription
No full textNegative stranded RNA viruses are considered as one of the most dreaded virus group innature due to its broad spectrum of infectivity. Chandipura virus (CHPV), the virus of interest for this study belongs to the rhabdoviridae family. Viruses belonging to this family owe its name rhabdo, meaning rod-shaped in Greek, to the typical bullet shaped morphology.Similarities between CHPV and Vesicular Stomatitis Virus (VSV) in genetic makeup, polypeptide composition and life cycle lead to include CHPV into vesiculovirus genus within the virus order mononegaviridae. CHPV and other mononegavirales are characterized by non-segmented, single stranded RNA genome of anti-message sense (negative sense)
Porous Polyurea Network Showing Aggregation Induced White Light Emission, Applications as Biosensor and Scaffold for Drug Delivery
No full textWe have designed a urea functionalized novel nanoporous material, POP-PU, which showsaggregation induced white light emission in the presence of suitable polar solvents. This nanomaterial has been explored as a pseudowhite light
emitter where the polymeric luminogen moiety can interact with the suitable polar solvent, leading to charge transfer. Thus, solvent assisted rotational freezing of
nonrigid polymeric nanoparticles gives radiative emission and the whole solution emits white light with color temperature of 8533 K. This nanoporous material also
holds the pockets (donor−donor−acceptor array) for specific biomolecular interaction. Among three pyrimidine based nucleotide bases, only cytosine can amplify the PL emission intensity of POP-PU and the other two bases cannot,
suggesting its future potential as a biosensor. Further, this urea functionalized porous organic nanomaterial can be utilized as an efficient drug-delivery vehicle for
liver cancer diagnostics and therapy based on the specific biomolecular interaction at its surface
p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-kB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche
Get PDFIn the bone marrow (BM), hematopoietic progenitors
(HPs) reside in specific anatomical niches near osteoblasts
(Obs), macrophages (MFs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of
Ob NF-kB signaling. Consequently, Ob p62-deficient
mice lose bone, Ob Ccl4 expression, and HP chemotaxis
toward Cxcl12, resulting in egress of short-term
hematopoietic stem cells and myeloid progenitors.
Finally, Ccl4 expression and myeloid progenitor
egress are reversed by deficiency of the p62 PB1-
binding partner Nbr1. A functional ‘‘MF-Ob niche’’
is required for myeloid progenitor/short-term stem
cell retention, in which Ob p62 is required to maintain
NF-kB signaling repression, osteogenesis, and BM
progenitor retention
Fine tuning of virulence regulatory pathways in enteric bacteria in response to varying bile and oxygen concentrations in the gastrointestinal tract
No full textAfter entering the gastrointestinal (GI) tract on the way to their physiological site of infection, enteric bacteria
encounter a remarkable diversity in environmental conditions. There are gross differences in the physico-chemical parameters in different sections of the GI tract e.g. between the stomach, small intestine and large intestine. Furthermore, even within a certain anatomical site, there are subtle differences in the microenvironment e.g. between the lumen, mucous layer and epithelial surface. Enteric pathogens must not only survive passage through the rapidly changing environments encountered at different niches of the GI tract but must also appropriately
coordinate expression of virulence determinants in response to environmental cues at different stages of infection.
There are some common themes in the responses of enteric pathogens to environmental cues, there are also
distinct differences that may reflect differences in basic pathogenesis mechanisms. The role of bile and oxygen
concentration in spatiotemporal regulation of virulence genes in selected enteric pathogens has been reviewed
Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection
No full textThe efflux of antimony through multidrug resistance protein (MDR)-1 is the key factor in the failure of metalloid treatment in kalaazar patients infected with antimony-resistant Leishmania donovani (SbRLD). Previously we showed that MDR-1 upregulation in SbRLD infection is IL-10–dependent. Imipramine, a drug in use for the treatment of depression and nocturnal enuresis in children,
inhibits IL-10 production from SbRLD-infected macrophages (SbRLD-Mfs) and favors accumulation of surrogates of antimonials. It inhibits IL-10–driven nuclear translocation of c-Fos/c-Jun, critical for enhanced MDR-1 expression. The drug upregulateshistone deacetylase 11, which inhibits acetylation of IL-10 promoter, leading to a decrease in IL-10 production from SbRLDMfs. It abrogates SbRLD-mediated p50/c-Rel binding to IL-10 promoter and preferentially recruits p65/RelB to IL-12 p35 and p40 promoters, causing a decrease in IL-10 and overproduction of IL-12 in SbRLD-Mfs. Histone deacetylase 11 per se does not influence IL-12 promoter activity. Instead, a imipramine-mediated decreased IL-10 level allows optimal IL-12 production in
SbRLD-Mfs. Furthermore, exogenous rIL-12 inhibits intracellular SbRLD replication, which can be mimicked by the presence of Ab to IL-10. This observation indicated that reciprocity exists between IL-10 and IL-12 and that imipramine tips the balance toward an increased IL-12/IL-10 ratio in SbRLD-Mfs. Oral treatment of infected BALB/c mice with imipramine in combination with sodium stibogluconate cleared organ SbRLD parasites and caused an expansion of the antileishmanial T cell repertoire where sodium
stibogluconate alone had no effect. Our study deciphers a detailed molecular mechanism of imipramine-mediated regulation of IL-10/IL-12 reciprocity and its impact on SbRLD clearance from infected hosts
Comparative evaluation of genotoxicity by micronucleus assay in the buccal mucosa over comet assay in peripheral blood in oral precancer and cancer patients
No full textEarly detection and quantification of DNA damage in oral
premalignancy or malignancy may help in management of
the disease and improve survival rates. The comet assay
has been successfully utilised to detect DNA damage in oral
premalignant or malignancy. However, due to the invasive
nature of collecting blood, it may be painful for many
unwilling patients. This study compares the micronucleus
(MN) assay in oral buccal mucosa cells with the comet
assay in peripheral blood cells in a subset of oral habitinduced precancer and cancer patients. For this, MN assay of exfoliated epithelial cells was compared with comet assay of peripheral blood leucocytes among 260 participants, including those with oral lichen planus (OLP; n = 52), leukoplakia (LPK; n = 51), oral submucous fibrosis (OSF;n = 51), oral squamous cell carcinoma (OSCC; n = 54) and normal volunteers (n = 52). Among the precancer groups,
LPK patients showed significantly higher levels of DNA
damage as reflected by both comet tail length (P < 0.0001)
and micronuclei (MNi) frequency (P = 0.0009). The DNA
damage pattern in precancer and cancer patients was OLP
< OSF < LPK < OSCC, and with respective oral habits, it
was multiple habits > cigarette + khaini > cigarette smokers
> areca + khaini > areca. There was no significant difference in the comet length and MNi frequency between males and females who had oral chewing habits. An overall significant correlation was observed between MNi frequency
and comet tail length with r = 0.844 and P < 0.0001. Thus,
the extent of DNA damage evaluation by the comet assay in
peripheral blood cells is perfectly reflected by the MN assay on oral exfoliated epithelial cells, and MNi frequency can be used with the same effectiveness and greater efficiency in early detection of oral premalignant conditions
Genetically modified organisms and visceral leishmaniasis
No full textVaccination is the most effective method of preventing infectious diseases. Since the eradication of small pox in 1976, many other potentially life compromising if not threatening diseases have been dealt with subsequently.This eventwas a major leap not only in the scientific
world already burdened with many diseases but also in the mindset of the common man who became more receptive to novel treatment options. Among the many protozoan
diseases, the leishmaniases have emerged as one of the largest parasite killers of the world, second only to malaria. There are three types of leishmaniasis namely cutaneous (CL), mucocutaneous (ML), and visceral (VL), caused by a group of more than 20 species of Leishmania parasites.Visceral leishmaniasis, also known as kala-azar is the most severe form and almost fatal if untreated. Since the first attempts at leishmanization,we have killed
parasite vaccines, subunit protein, or DNA vaccines, and now we have live recombinant carrier vaccines and live attenuated parasite vaccines under various stages of development.Although some research has shown promising results, many more potential genes need to be evaluated as live attenuated vaccine candidates. This mini-review attempts to summarize the success and failures of genetically modified organisms used in vaccination
against some of major parasitic diseases for their application in leishmaniasis