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ICB3E Induces INOS Expression by ROS-Dependent JNK and ERK Activation for Apoptosis of Leukemic Cells
No full textThe role of c-Jun N terminal Kinase (JNK) has
been well documented in various cellular stresses where it
leads to cell death. Similarly, extracellular signal-regulated
kinase (ERK) which was identified as a signalling molecule
for survival pathway has been shown recently to be
involved in apoptosis also. Recently we reported that
ICB3E, a synthetic analogue of Piper betle leaf-derived
apoptosis-inducing agent hydroxychavicol (HCH), possesses
anti-chronic myeloid leukemia (CML) acitivity in
vitro and in vivo without insight on mechanism of action.
Here we report that ICB3E is three to four times more
potent than HCH in inducing apoptosis of leukemic cells
without having appreciable effects on normal human
peripheral blood mononuclear cells, mouse fibroblast cell
line NIH3T3 and monkey kidney epithelial cell line Vero.
ICB3E causes early accumulation of mitochondria-derived
reactive oxygen species (ROS) in K562 cells. Unlike HCH,
ICB3E treatment caused ROS dependent activation of both JNK, ERK and induced the expression of iNOS leading to
generation of nitric oxide (NO). This causes cleavage of
caspase 9, 3 and PARP leading to apoptosis. Lack of
cleavage of caspase 8 and inability of blocking chimera
antibody to DR5 or neutralizing antibody to Fas to reverse
ICB3E-mediated apoptosis suggest the involvement of only
intrinsic pathway. Our data reveal a novel ROS-dependent
JNK/ERK-mediated iNOS activation pathway which leads
to NO mediated cell death by ICB3
Eapnerantiodivergent Syntheses of Pantolactone and Pantothenic Acid from D-Mannitol
No full textEfficient synthetic routes to both the enantiomers of pantolactone
and pantothenic acid have been developed starting from
D-mannitol-based D-glyceraldehyde acetonide through its conversion
into a protected pantoic acid intermediate followed by either
cyclization or amide bond formation with a β-amino ester, and subsequent
appropriate deprotection
A Functional Loop Spanning Distant Domains of Glutaminyl-tRNA Synthetase Also Stabilizes a Molten Globule State
No full textMolten globule and other disordered states of
proteins are now known to play important roles in many
cellular processes. From equilibrium unfolding studies of two
paralogous proteins and their variants, glutaminyl-tRNA
synthetase (GlnRS) and two of its variants [glutamyl-tRNA
synthetase (GluRS) and its isolated domains, and a GluRS−
GlnRS chimera], we demonstrate that only GlnRS forms a
molten globule-like intermediate at low urea concentrations.
We demonstrated that a loop in the GlnRS C-terminal
anticodon binding domain that promotes communication with
the N-terminal domain and indirectly modulates amino acid binding is also responsible for stabilization of the molten globule
state. This loop was inserted into GluRS in the eukaryotic branch after the archaea−eukarya split, right around the time when
GlnRS evolved. Because of the structural and functional importance of the loop, it is proposed that the insertion of the loop into
a putative ancestral GluRS in eukaryotes produced a catalytically active molten globule state. Because of their enhanced dynamic
nature, catalytically active molten globules are likely to possess broad substrate specificity. It is further proposed that the putative
broader substrate specificity allowed the catalytically active molten globule to accept glutamine in addition to glutamic acid,
leading to the evolution of GlnRS.
Many functional proteins fold into a well-defined threedimensional
structure. However, it is now clear that not
all proteins fold into a uniquely defined native state
conformation. Many are intrinsically unfolded, while others
can be partially folded or present in a molten globule-like
structure in which the fold is compact but the internal mobility
is significantly enhanced.1 The molten globule class of compact
states is ubiquitous in nature, and in many cases, they are
produced under mildly denaturing conditions.2 However, for
many proteins, a molten globule state has not yet been detected
under several denaturing conditions, indicating that they are
energetically far removed from the native state. The
physicochemical properties that stabilize a molten globule
state with respect to the native state have not been fully
elucidated, except in a few cases. The most important insight
has come from pairs of paralogs in which one protein forms the
molten globule state under mild denaturing conditions and the
other does not.3 A classic example is that of the lysozyme−
lactalbumin pair. It has been concluded that non-native
interactions of a small part of bovine α-lactalbumin play a
crucial role in the stabilization of the molten globule state.4 It is
not known whether non-native contacts of a small region in a
protein play important roles in the stabilization of the molten
globule state of other proteins as well. If thi
Epistatic Effects between Variants of Kappa-Opioid Receptor Gene and A118G ofmu-Mpioid Receptor Gene Increase Susceptibility to Addiction in Indian Population
No full textObjective: Unequivocal evidence suggests contribution of κ-opioid receptor (KOR) in addiction to drugs of
abuse. A study was undertaken to identify the single nucleotide polymorphisms (SNP) at selective areas of
kappa opioid receptor 1 (OPRK1) gene in heroin as well as in alcohol addicts and to compare them with
that in control population. The potential interaction of the identified KOR SNPs with A118G of μ opioid receptor
was also investigated.
Methods: Two hundred control subjects, one hundred thirty heroin and one hundred ten alcohol addicts, all
male and residing in Kolkata, a city in eastern India, volunteered for the study. Exons 3 and 4 of OPRK1 and
the SNP, A118G of mu opioid receptor 1 (OPRM1) in the DNA samples were genotyped by sequencing and
restriction fragment length polymorphism respectively. The SNPs identified in the population were analyzed
by odds ratio and its corresponding 95% confidence interval was estimated using logistic regression models.
SNP–SNP interactions were also investigated.
Results: Three SNPs of OPRK1, rs16918875, rs702764 and rs963549, were identified in the population, none of
which showed significant association with addiction. On the other hand, significant association was observed
for A118G with heroin addiction (χ2=7.268, P=0.0264) as well as with alcoholic addition (χ2=6.626,
P=0.0364). A potential SNP–SNP interaction showed that the odds of being addicted was 2.51 fold in heroin
subjects [CI (95%)=1.1524 to 5.4947, P=0.0206] and 2.31 fold in alcoholics [CI (95%)=1.025 to 5.24,
P=0.0433] with the OPRK1 (rs16918875) and A118G risk alleles than without either. A significant interaction
was also identified between GG/AG of A118G and GG of rs702764 [O.R (95%)=2.04 (1.279 to 3.287),
P=0.0029] in case of opioid population.
Conclusion: Our study suggests that set associations of polymorphisms may be important in determining the
risk profile for complex diseases such as addiction
Vaccination with Liposomal Leishmanial Antigens Adjuvanted with Monophosphoryl Lipid−Trehalose Dicorynomycolate (MPL-TDM)Confers Long-Term Protection against Visceral Leishmaniasis through a Human Administrable Route
No full textThe development of a long-term protective subunit vaccine
against visceral leishmaniasis depends on antigens and adjuvants that can
induce an appropriate immune response. The immunization of leishmanial
antigens alone shows limited efficacy in the absence of an appropriate
adjuvant. Earlier we demonstrated sustained protection against Leishmania
donovani with leishmanial antigens entrapped in cationic liposomes through
an intraperitoneal route. However, this route is not applicable for human
administration. Herein, we therefore evaluated the immune response and
protection induced by liposomal soluble leishmanial antigen (SLA)
formulated with monophosphoryl lipid−trehalose dicorynomycolate
(MPL-TDM) through a subcutaneous route. Subcutaneous immunization
of BALB/c mice with SLA entrapped in liposomes or with MPL-TDM
elicited partial protection against experimental visceral leishmaniasis. In
contrast, liposomal SLA adjuvanted with MPL-TDM induced significantly
higher levels of protection in liver and spleen in BALB/c mice challenged
10 days post-vaccination. Protection conferred by this formulation was
sustained up to 12 weeks of immunization, and infection was controlled for
at least 4 months of the challenge, similar to liposomal SLA immunization administered intraperitoneally. An analysis of cellular
immune responses of liposomal SLA + MPL-TDM immunized mice demonstrated the induction of IFN-γ and IgG2a antibody
production not only 10 days or 12 weeks post-vaccination but also 4 months after the challenge infection and a down regulation
of IL-4 production after infection. Moreover, long-term immunity elicited by this formulation was associated with IFN-γ
production also by CD8+ T cells. Taken together, our results suggest that liposomal SLA + MPL-TDM represent a good vaccine
formulation for the induction of durable protection against L. donovani through a human administrable route
Molecular and Functional Characterizations of the Stringent Response Related dksA gene of Vibrio cholerae
No full textOn October 21, 2010, a cholera outbreak was confirmed by the Haitian National Public Health Laboratory. By November 19, the outbreak had reached every department of the country, and by December 17, a total of 121,518 cases of cholera, resulting in 63,711 hospitalizations and 2,591 deaths, had been reported. By November 16, additional cases of cholera had been confirmed in the neighboring
Dominican Republic and in Florida. - A report by Centers for Disease Control and Prevention (CDC) of U.S. Department of Health and Human Services in Morbidity and Mortality Weekly Report on 24 December, 2010. Again, a cholera epidemic strikes a human population just recent. This time the cholera pidemic is in Haiti, a small country that has undergone large disasters. On January 12, 2010, a
huge earthquake killed over 3,00,000 people, leaving Haiti with a huge homeless population and
its main city, Port-au-Prince, devoid of most normal services and sanitary conditions. Many city residents left, but the more rural areas were not any better at supplying people with sanitary conditions. Many Haitians simply turned to their largest river in the country for water to drink, bathe, wash clothes, and swim in. This is a perfect environment for the development and spread of cholera
in Haiti. this occurs mainly in the developing world
A Genetic Network That Balances Two Outcomes Utilizes Asymmetric Recognition of Operator Sites
No full textStability and induction of the lysogenic state of bacteriophage l are balanced by a complex regulatory network. A
key feature of this network is the mutually exclusive cooperative binding of a repressor dimer (CI) to one of two pairs of binding
sites, OR1-OR2 or OR2-OR3. The structural features that underpin the mutually exclusive binding mode are not well understood.
Recent studies have demonstrated that CI is an asymmetric dimer. The functional importance of the asymmetry is not fully clear.
Due to the asymmetric nature of the CI dimer as well as its binding sites, there are two possible bound orientations. By fluorescence
resonance energy transfer measurements we showed that CI prefers one bound orientation. We also demonstrated that
the relative configuration of the binding sites is important for CI dimer-dimer interactions and consequent cooperative binding.
We proposed that the operator configuration dictates the orientations of the bound CI molecules, which in turn dictates CI cooperative
interaction between the OR1-OR2 or OR2-OR3, but not both. Modeling suggests that the relative orientation of the C- and
N-terminal domains may play an important role in the mutually exclusive nature of the cooperative binding. This work correlates
unique structural features of a transcription regulatory protein with the functional properties of a gene regulatory network
Identification and Characterization of the Enzymatic andIimmunoregulatory role of Plasmodial Macrophage Migration Inhibitory Factor in Host Pathology
No full textMalaria remains one of the world’s most devastating infectious diseases. Approximately 3 billion people, one half of the world’s population, live in at-risk regions for malaria infection.This leads to about 250 million malaria cases every year and nearly one million deaths (World
Malaria Report, WHO, 2011,
http://www.who.int/malaria/world_malaria_report_2011/en/index.html). The etiologic agent
Plasmodium falciparum (P. falciparum) is the major organism responsible for the majority of
deaths due to malaria, 90% of which occur in Africa with more than 85% in children under
the age of 5. The presence of widespread drug resistance is hampering the effectiveness of
most of the available drug arsenal (1, 2) with the notable exception of artemisinin-based
derivatives. In the battle to fight malaria, introduction of new drugs with novel mechanisms of
action is essential
Biophysical Studies on the Interaction of Phenathidyes with Deoxyribonucleic Acidsazinium
No full textIt was known for many years that living things inherit traits from their parents. These observations led to
agriculture, breeding and cultivation of plants of desirable characteristics. Firming up the details took quite
some time and researchers did not understand exactly how traits were passed to the next generation until the middle of the twentieth century. Now it is clear that genes carry our traits through generations and that genes are made of deoxyribonucleic acid (DNA). The history of DNA research began with Friedrich Miescher, a Swiss biologist, who in 1868 detected a phosphorus-containing substance from the nuclei of pus cells obtained from discarded surgical bandages. He named it ‘nuclein’ consisting of an acidic portion which we know today as DNA. Even though Miescher and many others following him suspected that nuclein might play a key role in cell inheritance, but their lack of chemical diversity compared to proteins ruled out such a possibility. But in 1943 Avery and his colleagues at the Hospital of the Rockefeller Institute for Medical Research used bacteria to provide the first evidence that DNA is the bearer of genetic information. In 1952 Hershey and Chase
showed that it is the DNA part of the T2 viral particle furnishing the genetic information for the replication of the virus. By 1952, much was known about DNA as the sole substance capable of storing practically all the information needed to create a living being. What was not yet known was how the elusive DNA looked like, or the mechanism by which genetic information is passed on to the next generation remained the single greatest unanswered question in biology till 1953. It was in that year that James Watson, an American geneticist, and Francis Crick, an English physicist worked at the Cavendish Laboratory, Cambridge and proposed a double helical structure for DNA. The sentence ‘This structure has novel features which are of considerable biological interest’ may be one of science’s most famous understatements that paved the way for a scientific breakthrough in the name of DNA [1]. This was the culmination of a brilliant piece of work and a discovery that has proven to be the key to molecular biology and modern biotechnology. Using information derived from a number of other scientific works like X-ray fibre diffraction patterns generated by Rosalind Franklin, Maurice Wilkins, and their associates at the Wheatstone Physics Laboratory, King’s College [2,3] and the chemical evidence on base complementarity of Chargaff (1950), Watson and Crick were able to intelligently assemble the information like pieces of a puzzle to produce their model of the structure of DNA
Development of Novel Catalysts for Synthesis of Heterocycles
No full textChirality plays a pivotal role in the fields of biological, chemical, pharmaceutical and material science. In recent years, fabulous progress has been achieved in the catalytic
asymmetric processes. Indeed, catalytic asymmetric synthesis has become the most desirable way of preparation of enantiomerically pure compounds. Synthesis of
asymmetric compounds in biological processes takes place through asymmetric catalysis. Such natural processes would go through the binding of the reactants to the
active sites of the enzymes followed by chirality transfer. In most of the chemical systems, one of the reactants is bound to the chiral catalyst and this acts upon the
other reactant present in the medium, to transfer chirality