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Study of senescence and possible mechanisms involved in arsenic-induced carcinogenesis in humans
Full text linkArsenic (As) induces various patho-physiological outcomes in humans like cancers including skin cancers, peripheral neuropathy (PN) and respiratory diseases. Though reports
have shown that arsenic induced senescence (AIS) in vitro; population based studies on AIS and epigenetic regulation of AIS contributing to As-induced diseases remains unexplored. We investigated AIS, senescence-associated secretory phenotype (SASP) markers, telomere
length alteration, epigenetic regulation involving altered senescence associated miRNA (SAmiRs)
expression in arsenic exposed individuals with characteristic skin lesions and
peripheral neuropathy. We also made an attempt to check the genetic damage, overall health
status and telomere length in arsenic exposed children. Exposure assessment was done from
drinking water and urine collected from arsenic exposed (N=120) and unexposed (N=60)
individuals recruited from West Bengal, India. Senescence and telomere length alteration was
evaluated using SA β-gal activity, ELISA and quantification of senescence proteins,
alternative lengthening of telomere (ALT) associated proteins and telomerase activity.
Relative telomere length (RTL) and SA-miRs in AIS was determined by qPCR. The
downstream molecule of the miRNA associated with As-induced PN was quantified by
immuoblotting. In vitro studies were conducted with sodium arsenite exposed HEK 293 cells,
to revalidate the observations.
As-exposed individuals exhibited significantly increased senescent cells, upregulated
senescence inducers, p53/p21 and SASP markers when compared to unexposed controls. Asexposed
skin lesion group showed significantly increased RTL, which was telomeraseindependent
but exhibited an over-expression of ALT associated proteins. All the SA-miRs
assessed were upregulated in the As-exposed compared to controls, specifically miR-29a.
Further analysis found that highest expression of miR29a and peripheral myelin protein 22
(PMP22), a direct target of miR 29a, was among As-exposed individuals with PN. Analyzing
other intermediate players regulating PMP22 expression revealed up-regulation of β-catenin
and down-regulation of GSK-3β. Our findings suggest that up-regulation of β-catenin,
possibly by miR29a mediated negative regulation of β-catenin inhibitors, may play a
predominant role in expression of PMP22 which leads to formation of aggresomes. Further
work to validate this mechanism is in process in vitro. Arsenic exposed children showed
considerable genetic damage as measured by micronucleus assay in the three cell types and
also adverse health outcomes like decreased haemoglobin content and gastritis. Telomere
length of arsenic exposed children was slightly elevated though it did not reach the
significance level.
Our findings suggest that arsenic exposure induces senescence in vivo and telomeraseindependent
elongation of telomere length is strictly associated with As-induced skin lesions
in adults. Epigenetically, arsenic alters the expression of SA-miRs and the mir29a/beta
catenin/PMP22 axis might be responsible for arsenic induced PN. However, in children, the
telomere length increase and genetic damage in the three cell types and adverse health
outcomes suggested that children are equally at danger of arsenic poisoning
Direct Syntheses of Drug or Drug-like Molecules via Copper Mediated/Catalyzed C-H Activation
No full textSTRUCTURAL AND FUNCTIONAL STUDIES ON GABAA RECEPTOR SUBTYPES: A COMPUTATIONAL PATHWAY FOR DESIGNING NOVEL NON-SEDATIVE MODULATORS
Full text linkIn this stressful era, maintaining the proper balance of neuronal excitation and inhibition remains the central demand of human brain. To harmonize the optimal brain functioning, γ-Amino Butyric Acid type A Receptors (GABAA-Rs) play a vital role by mediating the fast inhibitory neurotransmissions. These GABA-gated chloride ion channels maintain the delicate balance between neuronal excitation and inhibition. The formation of GABAA-R uses repertoire of 19 different subunit subtypes α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3, out of which two α1, two β2 and one γ2 form the most abundant native GABAA-R structure. In the absence of heteropentameric human GABAA-R structure the structural biology remains yet to be fully explored. Manipulation of GABAergic transmission is aimed to provide the benefits in the treatment of a host of neurological and psychiatric disorders. We utilised the existing experimental data and carried out a computational study to obtain the structural details of different GABAA-Rs. This computational pathway sequentially proceeds for : i) obtaining the different GABAA-R states and subtypes; ii) understanding the logic of their existence and correlating structure-function details for each of them; iii) unravelling the complete journey of molecular events that fine tune the state dependent channel transitions in normal conditions including ligand unoccupied closed, open, uncapped receptive states and GABA occupied singly and doubly bound states; iv) understanding the nature of cross-talk between two orthosteric sites and third allosteric BZD-site when we brought it into consideration; v) identifying a set of governing rules/markers forming the structural basis of selective modulation for BZD-site agonists at α1- and α2-GABAA-R subtypes.
Accordingly, to fulfil the deliberate demand of clinically efficacious α2-selective non-sedative modulator/s the underlying logic is systematically demarcated under single platform. The crux from the early stage modulatory pathways of subtype selective actions provides newer avenues to guide the designing of novel modulator/s having desired pharmacological endpoints in diseased states.
Overall, this channelled study is bound to track the structure-function-novel drug designing, based on the understanding of GABAA-R modulatory pathways
An investigation on podophyllotoxin biosynthetic pathway in Podophyllum hexandrum
No full textPtox is primarily obtained from a critically endangered medicinal plant P. hexandrum. It is used for
synthesis semi-synthetic anti cancer drug etoposide (VP-16-213), teniposide (VM-26) and etopophos which are well know against testicular and lung cancer treatment (Stahelin and von Wartburg, 1991). Due to the comparatively lesser content of ptox in P. hexandrum and the limited knowledge on the molecular mechanism of ptox biosynthesis, an in depth investigation on ptox biosynthetic pathway in P. hexandrum is the need of the hour with a view to obtain enhanced the ptox content using modern cutting-edge techniques. It was well established that MeJA treatment to the cell culture of P. hexandrum increased ptox content maximum after 12 days of culture (Bhattacharyya et al., 2012). A comparative whole
transcriptome analysis of control and 12 days MeJA treated culture was reported. It was revealed that
along with all ptox biosynthetic pathway genes and other related transcription factors, CAD was most
significantly up regulated (Bhattacharyya et al., 2013, 2016). Considering this, further downstream
studies were performed with the CAD, one of the important rate limiting enzymes of ptox biosynthetic pathway. CAD catalyzes the synthesis of coniferyl alcohol and sinapyl alcohol from CAld and sinapaldehyde respectively. Coniferyl alcohol can produce both lignin and lignan while sinapyl alcohol produces only lignin. It has been revealed that out of four CAD isoforms viz.
PhCAD1, PhCAD2, PhCAD3 and PhCAD4, isolated from P. hexandrum, PhCAD3 and PhCAD4 were characterized as ptox specific. Furthermore, four transgenic cell cultures and calli of P. hexandrum overexpressing CAD isoforms independently, were raised and the ptox content was noted
significantly enhanced by HPLC analysis in ptox specific CAD overexpressing lines. However, the molecular mechanism of MeJA induced ptox accumulation is yet to be
explored. Here, it has been demonstrated that MeJA induced ROS production stimulated ptox accumulation significantly. MeJA induced ROS increased the mRNA stability of three ROSresponsive genes namely, PhCAD3, PhCAD4, NAC3 resulting enhanced ptox content. It has also
been noted that, MeJA up regulated other ptox biosynthetic pathway genes, which are not affected by
the MeJA induced ROS, however, by the down regulation of five secondary metabolites biosynthesis specific miRNAs viz. miR172i, miR035, miR1438, miR2275 and miR8291.
To summarize, among the four isolated PhCAD isoforms only PhCAD3 and PhCAD4 favour ptox specifically than lignin, whereas PhCAD1 favours the lignin and ptox almost equally. MeJAenhanced the ptox content in P. hexandrum by up regulating the ptox specific ROS-responsive
PhCAD isoforms namely PhCAD3 and PhCAD4 via increasing the mRNA stability. MeJA also regulates other ROS non-responsive ptox biosynthetic genes by down regulation of ROS nonresponsive miRNAs
Correction: The biological in vitro effect and selectivity shown by a CoII complex of 2-(2- hydroxyphenylazo)-indole-30-acetic acid on three distinctly different cancer cells
No full textIn the original article, the units of the IC50 values were erroneously omitted from Table 2. To clarify this point, Table 2 is provided herein along with a modied table caption which states the units of the IC50 values (m
Tamarixetin 3‑O‑β‑D‑Glucopyranoside from Azadirachta indica Leaves: Gastroprotective Role through Inhibition of Matrix Metalloproteinase‑9 Activity in Mice
No full textNeem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies
have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-β-D-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC50 value of ca. 50 μM. Molecular docking and dynamics showed the
binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity
A benzimidazole-based chemodosimeter for the fluorometric detection of Zn and Cu via 1,5 proton shifts and C–N bond cleavage
No full textHere, we report the design and synthesis of the fluorescent probe APBHN, which was derived from 2-
(1H-benzo[d]imidazol-2-yl)benzenamine and is capable of detecting intracellular Zn and Cu ions in the
micromolar range. Single-crystal X-ray analysis revealed that the structure of the ligand comprises a fused
cyclic system with a pendent naphthol moiety. With the addition of Zn and Cu ions the inherent fluorescence
behaviour of the ligand APBHN is perturbed via a chemodosimetric change that involves a 1,5
proton shift followed by C–N bond cleavage. Upon detailed analysis, it was found that the ligand forms
1 : 1 and 1 : 2 (metal to ligand) complexes with the corresponding metal ions. The detection limits of Zn2+
and Cu2+ were 5.59 μM and 0.148 μM, respectively, with APBHN, which are lower than the WHO guidelines
(76 μM for Zn2+ and 31.5 μM for Cu2+) for drinking water. Moreover, APBHN could be used as a practical,
visible colorimetric test kit for both Zn2+ and Cu2+. APBHN can efficiently detect Zn2+ and Cu2+ in
liver carcinoma cells with insignificant cytotoxicit
Selective Binding of Genomic Escherichia coli DNA with ZnO Leads to White Light Emission: A New Aspect of Nano−Bio Interaction and Interface
No full textHere, we report for the first time, a novel and
intriguing application of deoxyribonucleic acid (DNA) in the
area of optics by demonstrating white light emission by tuning the emission of a nanomaterial, ZnO rods, exhibiting surface defects, in the presence of genomic Escherichia coli DNA with a comparatively high quantum efficiency. In order to understand the DNA specificity, we have also studied the interaction of ZnO with CT, and ML DNA, ss EC DNA, synthetic polynucleotides and different mononucleosides and bases. Further, in order to understand the effect of particle shape and defects present in ZnO, we have also extended our study with ZnO rods prepared at higher temperature exhibiting red emission and ZnO particles exhibiting yellow emission. Interestingly, none of the above studies resulted in white light emission from
ZnO−DNA complex. Our studies unequivocally confirmed that the concentration and the nature of DNA and ZnO together
plays a crucial role in obtaining CIE coordinates (0.33, 0.33) close to white light. The much enhanced melting temperature (Tm) of EC DNA and the energetics factors confirm enhanced hydrogen bonding of ZnO with EC DNA leading to a new emission band. Our experimental observations not only confirm the selective binding of ZnO to EC DNA but also open a new perspective for developing energy saving light emitting materials through nano-bio interactions
Exploring the interaction of phenothiazinium dyes methylene blue, new methylene blue,azure A and azure B with tRNA Phe: spectroscopic, thermodynamic, voltammetric and molecular modeling approach
No full textThis study focuses on the understanding of the interaction of phenothiazinium dyes methylene blue
(MB), new methylene blue (NMB), azure A (AZA) and azure B (AZB) with tRNAPhe with particular emphasis
on deciphering the mode and energetics of the binding. Strong intercalative binding to tRNAPhe was
observed for MB, NMB and AZB, bound by a partial intercalative mode. AZA has shown groove binding
characteristics. From spectroscopic studies binding affinity values of the order of 105 M�1 were deduced
for these dyes; the trend varied as MB 4 NMB 4 AZB 4 AZA. The binding was characterized by an
increase of thermal melting temperatures and perturbation in the circular dichroism spectrum of tRNA.
All the dyes acquired optical activity upon binding to tRNA. The binding was predominantly entropy
driven with a favorable enthalpy term that increased with temperature in all the cases. Dissection of the
Gibbs energy to polyelectrolytic and non-polyelectrolytic terms revealed a major role of the nonelectrostatic
forces in the binding. The small but significant heat capacity changes and the observed
enthalpy–entropy compensation phenomenon confirmed the involvement of multiple weak noncovalent
forces driving the interaction. The mode of binding was confirmed from quenching, viscosity and
cyclic voltammetric results. Using density functional theory, ground state optimized structures of the dyes
were calculated to provide insight into theoretical docking studies to correlate the experimental
approaches. The modeling results verified the binding location as well as the binding energy of
complexation. The results may provide new insights into the structure–activity relationship useful in the
design of effective RNA targeted therapeutic agents