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Hydroxychavicol, a Piper Betle leaf Component, Induces Apoptosis of CML Cells Through Mitochondrial Reactive Oxygen Species-Dependent JNK and Endothelial Nitric Oxide Synthase Activation and Overrides Imatinib Resistance
No full textAlcoholic extract of Piper betle (Piper betle L.) leaves was recently
found to induce apoptosis of CML cells expressing wild type and
mutated Bcr-Abl with imatinib resistance phenotype. Hydroxychavicol
(HCH), a constituent of the alcoholic extract of Piper betle
leaves, was evaluated for anti-CML activity. Here, we report that
HCH and its analogues induce killing of primary cells in CML
patients and leukemic cell lines expressing wild type and mutated
Bcr-Abl, including the T315I mutation, with minimal toxicity to normal
human peripheral blood mononuclear cells. HCH causes early
but transient increase of mitochondria-derived reactive oxygen
species. Reactive oxygen species-dependent persistent activation
of JNK leads to an increase in endothelial nitric oxide synthasemediated
nitric oxide generation. This causes loss of mitochondrial
membrane potential, release of cytochrome c from mitochondria,
cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose
polymerase leading to apoptosis. One HCH analogue was also
effective in vivo in SCID mice against grafts expressing the T315I
mutation, although to a lesser extent than grafts expressing wild
type Bcr-Abl, without showing significant bodyweight loss. Our
data describe the role of JNK-dependent endothelial nitric oxide
synthase-mediated nitric oxide for anti-CML activity of HCH and
this molecule merits further testing in pre-clinical and clinical settings
Induced Biofilm Cultivation Enhances Riboflavin Production by an Intertidally Derived Candida Famata
No full textThe aim of the investigation was to ascertain if surface attachment of Candida
famata and aeration enhanced riboflavin production. A newly designed polymethylmethacrylate
(PMMA) conico-cylindrical flask (CCF) holding eight equidistantly spaced rectangular
strips mounted radially on a circular disk allowed comparison of riboflavin production between
CCFs with hydrophobic surface (PMMA-CCF), hydrophilic glass surface (GS-CCF), and 500-
ml Erlenmeyer flask (EF). Riboflavin production (mg/l) increased from 12.79 to 289.96, from
54.44 to 238.14, and from 36.98 to 158.71 in the GS-CCF, EF, and PMMA-CCF, respectively,
when C. famata was grown as biofilm-induced cultures in contrast to traditional planktonic
culture. Production was correlated with biofilm formation and planktonic growth was suppressed
in cultivations that allowed higher biofilm formation. Enhanced aeration increased
riboflavin production in hydrophilic vessels. Temporal pattern of biofilm progression based on
two-channel fluorescence detection of extracellular polymeric substances and whole cells in a
confocal laser scanning microscope followed by application of PHLIP and ImageJ volume
viewer software demonstrated early maturity of a well-developed, stable biofilm on glass in
contrast to PMMA surface. A strong correlation between hydrophilic reactor surface, aeration
Identification and Characterization of Alba Family Protein from Human Malaria Parasite Plasmodium Falciparum
No full textCarnosic Acid Modulates Akt/IKK/NF-jB Signaling by PP2A and Induces Intrinsic and Extrinsic Pathway Mediated Apoptosis in Human Prostate Carcinoma PC-3 Cells
No full textThis study investigates the efficacy of carnosic
acid (CA), a polyphenolic diterpene, isolated from the plant
rosemary (Rosemarinus officinalis), on androgen-independent
human prostate cancer PC-3 cells. CA induced antiproliferative
effects in PC-3 cells in a concentration- and
time-dependent manner, which was due to apoptotic
induction as evident from flow-cytometry, DNA laddering
and TUNEL assay. Apoptosis was associated with the
activation of caspase-8, -9, -3 and -7, increase in Bax:Bcl-2
ratio, release of cytochrome-c and decrease in expression
of inhibitor of apoptosis (IAP) family of proteins. Apoptosis
was attenuated upon pretreatment with specific
inhibitors of caspase-8 (Z-IETD-fmk) and caspase-9 (ZLEHD-
fmk) suggesting the involvement of both intrinsic
and extrinsic apoptotic cascades. Further, apoptosis resulted
from the inhibition of IKK/NF-jB pathway as evident
from decreased DNA binding activity, nuclear translocation
of p50 and p65 and IjBa phosphorylation. The downregulation
of IKK/NF-jB was associated with inhibition of
Akt phosphorylation and its kinase activity with a concomitant
increase in the serine/threonine protein phosphatase
2A (PP2A) activity. Pharmacologic inhibition of PP2A
by okadaic acid and calyculin A, significantly reversed
CA-mediated apoptotic events in PC-3 cells indicating that
CA induced apoptosis by activation of PP2A through
modulation of Akt/IKK/NF-jB pathway. In addition, CA
induced apoptosis in another androgen refractory prostat cancer DU145 cells via intrinsic pathway as evidenced
from the activation of caspase 3, cleavage of PARP,
increase in Bax:Bcl-2 ratio and cytochrome-c release.
Carnosic acid, therefore, may have the potential for use in
the prevention and/or treatment of prostate cancer
S-allyl Cysteine in Combination with Clotrimazole Downregulates Fas Induced Apoptotic Events in Erythrocytes of Mice exposed to Lead
No full textBackground: Chronic lead (Pb2+) exposure leads to the reduced lifespan of erythrocytes. Oxidative stress and
K+ loss accelerate Fas translocation into lipid raft microdomains inducing Fas mediated death signaling in
these erythrocytes. Pathophysiological-based therapeutic strategies to combat against erythrocyte death
were evaluated using garlic-derived organosulfur compounds like diallyl disulfide (DADS), S allyl cysteine
(SAC) and imidazole based Gardos channel inhibitor clotrimazole (CLT).
Methods: Morphological alterations in erythrocytes were evaluated using scanning electron microscopy.
Events associated with erythrocyte death were evaluated using radio labeled probes, flow cytometry and activity
gel assay. Mass spectrometry was used for detection of GSH–4-hydroxy-trans-2-nonenal (HNE) adducts.
Fas redistribution into the lipid rafts was studied using immunoblotting technique and confocal
microscopy.
Results: Combination of SAC and CLT was better than DADS and CLT combination and monotherapy with
these agents in prolonging the survival of erythrocytes during chronic Pb2+ exposure. Combination therapy
with SAC and CLT prevented redistribution of Fas into the lipid rafts of the plasma membrane and downregulated
Fas-dependent death events in erythrocytes of mice exposed to Pb2+.
Conclusion and general significance: Ceramide generation was a critical component of Fas receptor-induced
apoptosis, since inhibition of acid sphingomyelinase (aSMase) interfered with Fas-induced apoptosis during
Pb2+ exposure. Combination therapy with SAC and CLT downregulated apoptotic events in erythrocytes by
antagonizing oxidative stress and Gardos channel that led to suppression of ceramide-initiated Fas aggregation
in lipid rafts. Hence, combination therapy with SAC and CLT may be a potential therapeutic option for
enhancing the lifespan of erythrocytes during Pb2+ toxicity
Association of XRCC1, XRCC3, and NAT2 Polymorphisms with the Risk of Oral Submucous Fibrosis among Eastern Indian Population
No full textArecanut and smokeless tobacco usage
is a major cause for oral submucous fibrosis (OSF) and its
subsequent development to oral squamous cell carcinoma
in South-east Asian population. Polymorphisms at
N-acetyltransferase 2 locus, coding for an enzyme catalyzing
acetylation of aromatic amines, might cause DNA
adduct formation because of improper acetylation of
these polyaromatic hydrocarbons. DNA repair enzymes
remove these adduct to prevent malignancy.
In this hospital-based study, 100 controls and
88 OSF patients were genotyped at four polymorphic
sites on NAT2 481 (C > T; silent), 590 (G > A;
Arg197 > Gln), 803 (A > G; Lys268 > Arg), 857 (G > A;
Gly286 > Glu) and two on XRCC1 18067 (C > T Arg
194 > Trp), 28152 (G > A Arg 399 > Gln), and one of
XRCC3 26304 (C > T Thr 241 > Met) loci by PCR-RFLP
to determine the risk of the disease.
Heterozygous XRCC3 codon 241 [OR 2.07
(1.05–4.06)], homozygous variant of NAT C481T [OR
2.81 (1.09–7.21)], and both heterozygous and homozygous
variants of NAT codon 268 and 286 [OR 2.31 (1.20–
4.45) and 4.98 (1.87–13.14), and 6.12 (2.75–13.62) and
2.65 (1.04–6.72)] individually influenced susceptibility to
OSF in the population.
Gene–gene interaction analysis by multifactor
dimensionality reduction (MDR) revealed that
XRCC3 Thr 241 Met had the largest univariate effect
followed by XRCC3 Thr 241 Met – NAT2 A857G in men
that presents a highly synergistic interaction as one of the
potential combinations of single nucleotide polymorphisms
(SNPs) to increase the risk of OSF in men if exposed
to arecanut or smokeless tobacco usage. These
observations can speculate the impact of the studied
SNPs on the etiology of OSF
Interconnection of Salt-induced Hydrophobic Compaction and Secondary Structure Formation Depends on Solution Conditions
No full textEarly events of protein folding are difficult to follow.
The unfolded state may have extended and compact conformers, which interconvert at early microsecond.
Hydrophobic compaction and secondary structure formation do not occur simultaneously in aqueous solution.
They occur simultaneously in the presence of urea.
Hydrophobic collapse has been monitored at single molecular resolutio
Biophysical Studies on the Effect of the 13 Position Substitution of the Anticancer Alkaloid Berberine on Its DNA Binding
No full textThe structural effects and thermodynamics of
the DNA binding of six berberine analogues with alkyl chains
of varying length and a terminal phenyl group at the C-13
position were investigated. All the analogues bound DNA
noncooperatively in contrast to the cooperative binding of
berberine. The binding affinity was higher and the effect of the
chain length was only up to (CH2)3, after which the binding
affinity decreased slightly. Intercalative binding with strong
stabilization of the DNA helix was revealed. Binding resulted in
the weakening of the base stacking with moderate conformational changes within the B-form. The binding was entropy driven in
each case, the entropy contribution to the free energy increasing with the chain length up to the threshold (CH2)3. The
complexation was dominated by nonpolyelectrolytic forces in each case; polyelectrolytic forces contributed only a quarter to the
total free energy at 50 mM [Na+]. Overall, the phenylalkyl substitution at the C-13 position considerably enhanced the DNA
binding and was highest for the analogue with (CH2)3. Structural and thermodynamic data on the DNA binding aspects of the
substituted berberines are presented in comparison with berberine
Conformation and Cytotoxicity of a Tetrapeptide Constellated with Alternative D- and L-proline
No full textProline containing peptides are highly important due to their
natural abundance in various secondary structural elements like
turns (b turn and c turn etc.) in proteins. Here the conformation,
cytotoxicity and structure of a unique tetrapeptide composed of
alternative D- and L-proline residues are discussed. The peptide
showed a polyproline II like conformation in dilute aqueous
solution. The aqueous solution of the peptide self-assembled to
form spheroidal oligomers with a diameter of y90 nm. The
morphological features were confirmed by bright field confocal
images, TEM analysis and AFM. The alternative D- and Lproline
residues in the peptide showed toxicity towards cancer cell
lines and y50% cell death was recorded against three different
types of cancer cells (Neura 2a, HEK 293 and Hep G2)
