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Studies On Bioactive Molecules From Neem Leaf Extract And Their Mechanism Of Action Against Gastric Ulcer
Full text linkBIOPHYSICAL STUDIES ON THE BINDING OF ISOQUINOLINE ALKALOIDS AND ANALOGS TO NUCLEIC ACIDS
No full textMECHANISM OF miRNA ACTIVITY REGULATION IN MAMMALIAN CELLS
No full textCells must be able to respond to changes in their microenvironment in order to
survive. Genes encode proteins and proteins dictate cell function. Information flows
from DNA to RNA to protein, according to the central dogma of molecular biology
and each of the steps are under stringent regulatory control to ensure cell fate and
function. Cells can control which genes get transcribed and which transcripts get
translated. Regulation of the two major steps — transcription and translation — is
critical to its adaptability. Regulation of transcription and translation occurs in both
prokaryotes and eukaryotes, but it is far more complex in eukaryotes.
MicroRNAs (miRNAs) are a class of small non-coding RNAs that posttranscriptionally
regulate gene expression via translational repression and/or mRNA
degradation. These tiny regulators search for cognate targets by base pairing with
the 3’UTR of the target mRNAs. Over the years, since its discovery the role of
miRNAs has become apparent in regulating developmental timing, host-pathogen
interactions as well as cell differentiation, proliferation, apoptosis, tumorigenesis,
etc. Just like any other regulatory element, the biogenesis, activity and turnover of
miRNAs themselves are under strict regulatory control.
Extensive research has established how miRNAs regulate target mRNAs by
translation repression. However, information regarding the effect of target mRNA on
biogenesis and stability of corresponding miRNAs is limited. In this study, we have
reported increased biogenesis of cognate miRNAs in presence of abundant amounts of target mRNA in both cells as well as cell-free in vitro system. These
miRNAs get loaded onto AGO2 to form functionally competent miRISCs. This
target-driven miRNA increase is proportional to the concentration of target mRNA
and is affected by the translatability of the target message. While investigating the
molecular mechanism of the phenomenon, we identified that increased pre-miRNA
processing by AGO2-associated DICER1 in presence of target mRNA, contributes
to this increased miRNP formation.
Compartmentalization of biological processes provides a mechanism of
regulation of the processes with exquisite spatial and temporal control. We have
observed that miRNA activity is compartmentalized on the rough Endoplasmic
Reticulum (rER) membranes in human cells and have explored the effects of this
compartmentalization on miRNA function. Probing further into the phenomenon of
target driven miRNA biogenesis, we identified the rER membranes as the site of
target mRNA-governed miRNA assembly in human cells.
It is likely that target driven miRNA biogenesis operates in addition to the
conventional process of repression by preformed miRNPs. Rather than
transcriptionally upregulating miRNA synthesis, modulating the final step of
biogenesis will serve as an immediate means to increase miRNA production. This
in turn will help the cell respond to specific and urgent cellular needs like rapid
target driven miR-122 biogenesis during starvation stress reversal in human hepatic
cells. Thus, we have identified an additional layer of post-transcriptional regulation
of gene expression that helps the cell to maintain requisite levels of mature forms of
respective miRNAs by modulating its synthesis depending on target availability
Non-invasive management of visceral leishmaniasis: design, development and evaluation of clinically applicable immunodiagnostic tool for field settings
No full textDiagnosis is a process of identifying a particular disease through signs and symptoms of a person. Clinical history of a person and physical examination may draw a conclusion that describes the reason for particular health problem. The literal meaning of diagnosis is “to distinguish” in Greek. Thus diagnosis is an act to discriminate or distinguish certain conditions (diseases) from others (healthy or other diseases). Medical diagnosis is most of the time very challenging because symptoms like fever, pain, weakness, etc. are common in many diseases mainly in infectious diseases. Therefore, pieces of information are collected and compared such as sign and symptoms of a person, endemic diseases in that area, season of the disease, etc. The first evidence of disease diagnosis is found in the treatise “Edwin Smith Papyrus” written by Imhotep, a polymath of ancient Egypt (27th century BC) (Figure 1.1). Babylonian scholar Esagil-kin-apli (11th Century BC) first introduced the reason, logic and symptoms for a disease in his diagnostic handbook “Sakikku” (Horstmanshoff, 2004). Hippocrates (460-370 BC), a famous Greek physician used biological samples such as urine, sweat, etc for diagnosis
Endless Possibilities Around Indole: Asymmetric Synthesis, Atropisomerism, Potential Applications to Medicinal Chemistry and Materials Science
No full textThis thesis has embodied potential applications of an important heterocycle indole in the field of asymmetric synthesis, axial chirality, biology, and study of their chiroptical properties. A brief updated review as chapter I covers all the recent aspects on the emerging values of indoles in the above mentioned research works
Garcinol loaded vitamin E TPGS emulsified PLGA nanoparticles: preparation, physicochemical characterization, in vitro and in vivo studies
Full text linkGarcinol (GAR) is a naturally occurring polyisoprenylated phenolic compound. It has been recently
investigated for its biological activities such as antioxidant, anti-inflammatory, anti ulcer, and
antiproliferative effect on a wide range of human cancer cell lines. Though the outcomes are very
promising, its extreme insolubility in water remains the main obstacle for its clinical application. Herein
we report the formulation of GAR entrapped PLGA nanoparticles by nanoprecipitation method using
vitamin E TPGS as an emulsifier. The nanoparticles were characterized for size, surface morphology,
surface charge, encapsulation efficiency and in vitro drug release kinetics. The MTT assay depicted a
high amount of cytotoxicity of GAR-NPs in B16F10, HepG2 and KB cells. A considerable amount of cell
apoptosis was observed in B16f10 and KB cell lines. In vivo cellular uptake of fluorescent NPs on B16F10
cells was also investigated. Finally the GAR loaded NPs were radiolabeled with technetium-99m with
>95% labeling efficiency and administered to B16F10 melanoma tumor bearing mice to investigate the
in vivo deposition at the tumor site by biodistribution and scintigraphic imaging study. In vitro cellular
uptake studies and biological evaluation confirm the efficacy of the formulation for cancer treatmen
A novel nanohybrid for cancer theranostics: folate sensitized Fe2O3 nanoparticles for colorectal cancer diagnosis and photodynamic therapy
No full textOrganic–inorganic nanohybrids are becoming popular for their potential biological applications, including
diagnosis and treatment of cancerous cells. The motive of this study is to synthesise a nanohybrid for the
diagnosis and therapy of colorectal cancer. Here we have developed a facile and cost-effective synthesis of folic acid (FA) templated Fe2O3 nanoparticles with excellent colloidal stability in water using a hydrothermal method for the theranostics applications. The attachment of FA to Fe2O3 was confirmed using various spectroscopic techniques including FTIR and picosecond resolved fluorescence studies. The nanohybrid (FA–Fe2O3) is a combination of two nontoxic ingredients FA and Fe2O3, showing remarkable
photodynamic therapeutic (PDT) activity in human colorectal carcinoma cell lines (HCT 116) via generation of intracellular ROS. The light induced enhanced ROS activity of the nanohybrid causes significant nuclear DNA damage, as confirmed from the comet assay. Assessment of p53, Bax, Bcl2, cytochrome c (cyt c) protein expression and caspase 9/3 activity provides vivid evidence for cell death via an apoptotic pathway. In vitro magnetic resonance imaging (MRI) experiments in folate receptor (FR) overexpressed cancer cells (HCT 116) and FR deficient human embryonic kidney cells (HEK 293) reveal the target specificity of the
nanohybrid towards cancer cells, and are thus pronounced MRI contrasting agents for the diagnosis of colorectal cance
Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells
No full textExtravasation and metastatic progression are two main reasons for the high mortality rate associated with cancer. The metastatic potential of cancer cells depends on a plethora of metabolic challenges prevailing
within the tumor microenvironment. To achieve higher rates of proliferation, cancer cells reprogram their metabolism, increasing glycolysis and biosynthetic activities. Just why this metabolic reprogramming predisposes cells towards increased oncogenesis remains elusive. The accumulation of myriad oncolipids in the tumor microenvironment has been shown to promote the invasiveness of cancer cells, with lysophosphatidic acid
(LPA) being one such critical factor enriched in ovarian cancer patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed and glycolysis is increased with long exposure to LPA in ovarian cancer cells compared with non-transformed epithelial cells. We sought to uncover the regulatory complexity underlying this oncolipidinduced
metabolic perturbation. Gene regulatory networking using RNASeq analysis identified the oncogene ETS-1 as a critical mediator of LPA-induced metabolic alterations for the maintenance of invasive phenotype.
Moreover, LPA receptor-2 specific PtdIns3K-AKT signaling
induces ETS-1 and its target matrix metalloproteases. Abrogation of ETS-1 restores cellular bioenergetics towards increased oxidative phosphorylation and reduced glycolysis, and this effect was reversed by the presence
of LPA. Furthermore, the bioenergetic status of LPA-treated ovarian cancer cells mimics hypoxia through induction of hypoxia-inducible factor-1a, which was found to transactivate ets-1. Studies in primary
tumors generated in syngeneic mice corroborated the in vitro findings. Thus, our study highlights the phenotypic changes induced by the prometastatic factor ETS-1 in ovarian cancer cells. The relationship between enhanced invasiveness and metabolic plasticity further illustrates the critical role of metabolic adaptation of cancer cells as a driver of tumor progression. These findings reveal oncolipid-induced metabolic predispositio
Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis
Full text linkEarlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal
plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that
mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine
through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host’s immune response which
could be developed as an inexpensive and nontoxic therapeutics either alone or in combination
Small molecule induced poly(A) single strand to self-structure conformational switching: evidence for the prominent role of H-bonding interactions
No full textAll messenger RNAs (mRNAs) have a polyadenylic acid tail that is added during post transcriptional RNA
processing. Investigation of the structure–function and interactions of polyadenylic acid is an important
area to target for cancer and related diseases. Jatrorrhizine and coptisine are two important isoquinoline
alkaloids that are structurally very similar, differing only in the substituents on the isoquinoline chromophore.
Here we demonstrate that these alkaloids differentially induce a self-structure in single stranded
poly(A) using absorbance, thermal melting and differential scanning calorimetry experiments.
Jatrorrhizine was found to be more effective than coptisine in binding to poly(A) from spectroscopy and
calorimetry data. Molecular modeling results suggested the involvement of more H-bonds in the
complexation of the former with poly(A). It appears that the presence of substituents on the alkaloid that
can form H-bonding interactions with the adenine nucleotides may play a critical role in the binding and
structural rearrangement of poly(A) into the self-structure. The atomic force microscopy data directly
visualized the poly(A) self-structured network. We propose a plausible mechanism of the small molecule induced self-structure formation in poly(A). The results presented here may help in the design of effective poly(A) targeted molecules for therapeutic use