A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been pr... more A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.
The evolution of sex determination mechanisms is often accompanied by reduction in dosage of gene... more The evolution of sex determination mechanisms is often accompanied by reduction in dosage of genes on a whole chromosome. Under these circumstances, negatively acting regulatory genes would tend to double the expression of the genome, which produces compensation of the single-sex chromosome and increases autosomal gene expression. Previous work has suggested that to reduce the autosomal expression to the female
Immunostaining of chromosomes shows that the male-specific lethal (MSL) proteins are associated w... more Immunostaining of chromosomes shows that the male-specific lethal (MSL) proteins are associated with all female chromosomes at a low level but are sequestered to the X chromosome in males. Histone-4 Lys- 16 acetylation follows a similar pattern in normal males and females, being higher on the X and lower on the autosomes in males than in females. However, the staining
Two types of transgene silencing were found for the Alcohol dehydrogenase (Adh) transcription uni... more Two types of transgene silencing were found for the Alcohol dehydrogenase (Adh) transcription unit. Transcriptional gene silencing (TGS) is Polycomb dependent and occurs when Adh is driven by the white eye color gene promoter. Full-length Adh transgenes are silenced posttranscriptionally at high copy number or by a pulsed increase over a threshold. The posttranscriptional gene silencing (PTGS) exhibits molecular hallmarks typical of RNA interference (RNAi), including the production of 21--25 bp length sense and antisense RNAs homologous to the silenced RNA. Mutations in piwi, which belongs to a gene family with members required for RNAi, block PTGS and one aspect of TGS, indicating a connection between the two types of silencing.
1. Nat Genet. 1999 Feb;21(2):148-9. Less from more: cosuppression of transposable elements. Birch... more 1. Nat Genet. 1999 Feb;21(2):148-9. Less from more: cosuppression of transposable elements. Birchler JA, Pal-Bhadra M, Bhadra U. Comment on: Nat Genet. 1999 Feb;21(2):209-12. PMID: 9988259 [PubMed - indexed for MEDLINE]. Publication Types: Comment; News. ...
By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthes... more By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.
Genes normally resident in euchromatic domains are silenced when packaged into heterochromatin, a... more Genes normally resident in euchromatic domains are silenced when packaged into heterochromatin, as exemplified in Drosophila melanogaster by position effect variegation (PEV). Loss-of-function mutations resulting in suppression of PEV have identified critical components of heterochromatin, including proteins HP1, HP2, and histone H3 lysine 9 methyltransferase. Here, we demonstrate that this silencing is dependent on the RNA interference machinery, using tandem mini-white arrays and white transgenes in heterochromatin to show loss of silencing as a result of mutations in piwi, aubergine, or spindle-E (homeless), which encode RNAi components. These mutations result in reduction of H3 Lys9 methylation and delocalization of HP1 and HP2, most dramatically in spindle-E mutants.
Journal of controlled release : official journal of the Controlled Release Society, Jan 7, 2015
Diverse array of therapeutic regimens, drugs or siRNA, are commonly used to regress cardiac hyper... more Diverse array of therapeutic regimens, drugs or siRNA, are commonly used to regress cardiac hypertrophy, although, bystander effect and lower retention of bioactive molecules significantly reduce their functional clinical efficacy. Carvedilol, a widely used and effective anti-hypertrophic drug, simultaneously blocks β-adrenergic receptors non-specifically in various organs. Likewise, non-specific genome-wide downregulation of p53 expression by specific siRNA efficiently abrogates cardiac hypertrophy but results in extensive tumorigenesis affecting bystander organs. Therefore, delivery of such therapeutics had been a challenge in treating cardiovascular dysfunction. Cardiac tissue engineering was successfully accomplished in this study, by encapsulating such bioactive molecules with a stearic acid modified Carboxymethyl chitosan (CMC) nanopolymer conjugated to a homing peptide for delivery to hypertrophied cardiomyocytes in vivo. The peptide precisely targeted cardiomyocytes while CM...
Dosage compensation refers to the phenomenon that despite the difference in copy number of X chro... more Dosage compensation refers to the phenomenon that despite the difference in copy number of X chromosomes in males and females approximately equal expression results from the sex chromosomes. We describe evidence for a model that dosage compensation is caused by an 'inverse dosage effect’ that results from an altered stoichiometry of transcriptional regulators on the X versus the autosomes. This imbalance of regulators would cause a two-fold increase in target gene expression throughout the genome in the absence of any modification. The two-fold hyperactivation compensates the X chromosome. However, the MSL (male specific lethal) complex modifies this effect on the autosomes, which would otherwise double their expression, by becoming sequestered to the X chromosome together with a histone acetylase (MOF) and kinase (JIL1). This situation reduces the level of histone 4 Lys16 acetylation and H3 phosphorylation on the autosomes, thus bringing their expression down to near the femal...
The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known... more The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known about its involvement in mitotic cell cycle progression. In this study, we established evidence of the regulatory role of Ago-1 in cell cycle control in association with the G2/M cyclin, cyclin B. Immunostaining of early embryos revealed that the maternal effect gene Ago-1 is essential for proper chromosome segregation, mitotic cell division, and spindle fiber assembly during early embryonic development. Ago-1 mutation resulted in the up-regulation of cyclin B-Cdk1 activity and down-regulation of p53, grp, mei-41, and wee1. The increased expression of cyclin B in Ago-1 mutants caused less stable microtubules and probably does not produce enough force to push the nuclei to the cortex, resulting in a decreased number of pole cells. The role of cyclin B in mitotic defects was further confirmed by suppressing the defects in the presence of one mutant copy of cyclin B. We identified involvement of 2 novel embryonic miRNAs--miR-981 and miR--317-for spatiotemporal regulation of cyclin B. In summary, our results demonstrate that the haploinsufficiency of maternal Ago-1 disrupts mitotic chromosome segregation and spindle fiber assembly via miRNA-guided control during early embryogenesis in Drosophila. The increased expression of cyclin B-Cdk1 and decreased activity of the Cdk1 inhibitor and cell cycle checkpoint proteins (mei-41 and grp) in Ago-1 mutant embryos allow the nuclei to enter into mitosis prematurely, even before completion of DNA replication. Thus, our results have established a novel role of Ago-1 as a regulator of the cell cycle.
A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conju... more A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI50 values in the range of <0.1–3.6 μM. Some of these PBD conjugates (6a–c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated
A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for the... more A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. Interestingly, these chalcone derivatives induced G(0)/G(1)-phase cell-cycle arrest, down-regulation of G(1)-phase cell-cycle regulatory proteins such as cyclin D1 and cyclin E1, and up-regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF-κB, and up-regulation of caspase-9. One of these chalcone derivatives, 3 d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies.
A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been pr... more A series of 2,5-diaryloxadiazole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates have been prepared and evaluated for their anticancer activity. These conjugates have shown promising activity with GI50 values ranging from &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.1 to 0.29 microM. It is observed that some of these conjugates particularly 4a, 4d, 4i and 4l exhibit significant anticancer activity. Some detailed biological assays relating to the cell cycle aspects associated to Bax and caspases have been examined with a view to understand the mechanism of action of these conjugates.
The evolution of sex determination mechanisms is often accompanied by reduction in dosage of gene... more The evolution of sex determination mechanisms is often accompanied by reduction in dosage of genes on a whole chromosome. Under these circumstances, negatively acting regulatory genes would tend to double the expression of the genome, which produces compensation of the single-sex chromosome and increases autosomal gene expression. Previous work has suggested that to reduce the autosomal expression to the female
Immunostaining of chromosomes shows that the male-specific lethal (MSL) proteins are associated w... more Immunostaining of chromosomes shows that the male-specific lethal (MSL) proteins are associated with all female chromosomes at a low level but are sequestered to the X chromosome in males. Histone-4 Lys- 16 acetylation follows a similar pattern in normal males and females, being higher on the X and lower on the autosomes in males than in females. However, the staining
Two types of transgene silencing were found for the Alcohol dehydrogenase (Adh) transcription uni... more Two types of transgene silencing were found for the Alcohol dehydrogenase (Adh) transcription unit. Transcriptional gene silencing (TGS) is Polycomb dependent and occurs when Adh is driven by the white eye color gene promoter. Full-length Adh transgenes are silenced posttranscriptionally at high copy number or by a pulsed increase over a threshold. The posttranscriptional gene silencing (PTGS) exhibits molecular hallmarks typical of RNA interference (RNAi), including the production of 21--25 bp length sense and antisense RNAs homologous to the silenced RNA. Mutations in piwi, which belongs to a gene family with members required for RNAi, block PTGS and one aspect of TGS, indicating a connection between the two types of silencing.
1. Nat Genet. 1999 Feb;21(2):148-9. Less from more: cosuppression of transposable elements. Birch... more 1. Nat Genet. 1999 Feb;21(2):148-9. Less from more: cosuppression of transposable elements. Birchler JA, Pal-Bhadra M, Bhadra U. Comment on: Nat Genet. 1999 Feb;21(2):209-12. PMID: 9988259 [PubMed - indexed for MEDLINE]. Publication Types: Comment; News. ...
By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthes... more By applying a methodology, a series of benzothiazole-pyrrole based conjugates (4a-r) were synthesized and evaluated for their antiproliferative activity. Compounds such as 4a, 4c, 4e, 4g-j, 4m, 4n, 4o and 4r exhibited significant cytotoxic effect in the MCF-7 cell line. Cell cycle effects were examined for these conjugates at 2 μM as well as 4 μM concentrations and FACS analysis show an increase of G2/M phase cells with concomitant decrease of G1 phase cells thereby indicating G2/M cell cycle arrest by them. Interestingly 4o and 4r are effective in causing apoptosis in MCF-7 cells. Moreover, 4o showed down regulation of oncogenic expression of Ras and its downstream effector molecules such as MEK1, ERK1/2, p38 MAPK and VEGF. The apoptotic aspect of this conjugate is further evidenced by increased expression of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in the highly malignant breast cancers.
Genes normally resident in euchromatic domains are silenced when packaged into heterochromatin, a... more Genes normally resident in euchromatic domains are silenced when packaged into heterochromatin, as exemplified in Drosophila melanogaster by position effect variegation (PEV). Loss-of-function mutations resulting in suppression of PEV have identified critical components of heterochromatin, including proteins HP1, HP2, and histone H3 lysine 9 methyltransferase. Here, we demonstrate that this silencing is dependent on the RNA interference machinery, using tandem mini-white arrays and white transgenes in heterochromatin to show loss of silencing as a result of mutations in piwi, aubergine, or spindle-E (homeless), which encode RNAi components. These mutations result in reduction of H3 Lys9 methylation and delocalization of HP1 and HP2, most dramatically in spindle-E mutants.
Journal of controlled release : official journal of the Controlled Release Society, Jan 7, 2015
Diverse array of therapeutic regimens, drugs or siRNA, are commonly used to regress cardiac hyper... more Diverse array of therapeutic regimens, drugs or siRNA, are commonly used to regress cardiac hypertrophy, although, bystander effect and lower retention of bioactive molecules significantly reduce their functional clinical efficacy. Carvedilol, a widely used and effective anti-hypertrophic drug, simultaneously blocks β-adrenergic receptors non-specifically in various organs. Likewise, non-specific genome-wide downregulation of p53 expression by specific siRNA efficiently abrogates cardiac hypertrophy but results in extensive tumorigenesis affecting bystander organs. Therefore, delivery of such therapeutics had been a challenge in treating cardiovascular dysfunction. Cardiac tissue engineering was successfully accomplished in this study, by encapsulating such bioactive molecules with a stearic acid modified Carboxymethyl chitosan (CMC) nanopolymer conjugated to a homing peptide for delivery to hypertrophied cardiomyocytes in vivo. The peptide precisely targeted cardiomyocytes while CM...
Dosage compensation refers to the phenomenon that despite the difference in copy number of X chro... more Dosage compensation refers to the phenomenon that despite the difference in copy number of X chromosomes in males and females approximately equal expression results from the sex chromosomes. We describe evidence for a model that dosage compensation is caused by an 'inverse dosage effect’ that results from an altered stoichiometry of transcriptional regulators on the X versus the autosomes. This imbalance of regulators would cause a two-fold increase in target gene expression throughout the genome in the absence of any modification. The two-fold hyperactivation compensates the X chromosome. However, the MSL (male specific lethal) complex modifies this effect on the autosomes, which would otherwise double their expression, by becoming sequestered to the X chromosome together with a histone acetylase (MOF) and kinase (JIL1). This situation reduces the level of histone 4 Lys16 acetylation and H3 phosphorylation on the autosomes, thus bringing their expression down to near the femal...
The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known... more The role of Ago-1 in microRNA (miRNA) biogenesis has been thoroughly studied, but little is known about its involvement in mitotic cell cycle progression. In this study, we established evidence of the regulatory role of Ago-1 in cell cycle control in association with the G2/M cyclin, cyclin B. Immunostaining of early embryos revealed that the maternal effect gene Ago-1 is essential for proper chromosome segregation, mitotic cell division, and spindle fiber assembly during early embryonic development. Ago-1 mutation resulted in the up-regulation of cyclin B-Cdk1 activity and down-regulation of p53, grp, mei-41, and wee1. The increased expression of cyclin B in Ago-1 mutants caused less stable microtubules and probably does not produce enough force to push the nuclei to the cortex, resulting in a decreased number of pole cells. The role of cyclin B in mitotic defects was further confirmed by suppressing the defects in the presence of one mutant copy of cyclin B. We identified involvement of 2 novel embryonic miRNAs--miR-981 and miR--317-for spatiotemporal regulation of cyclin B. In summary, our results demonstrate that the haploinsufficiency of maternal Ago-1 disrupts mitotic chromosome segregation and spindle fiber assembly via miRNA-guided control during early embryogenesis in Drosophila. The increased expression of cyclin B-Cdk1 and decreased activity of the Cdk1 inhibitor and cell cycle checkpoint proteins (mei-41 and grp) in Ago-1 mutant embryos allow the nuclei to enter into mitosis prematurely, even before completion of DNA replication. Thus, our results have established a novel role of Ago-1 as a regulator of the cell cycle.
A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conju... more A series of 3,5-diaryl-isoxazoline/isoxazole linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared. These conjugates showed potent anticancer activity with GI50 values in the range of <0.1–3.6 μM. Some of these PBD conjugates (6a–c) with promising anticancer activity were further investigated on the cell cycle distribution. Moreover, these PBD conjugates exhibited G0/G1 arrest, enhancement in the levels of p53 protein as well as mitochondrial-mediated
A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for the... more A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. Interestingly, these chalcone derivatives induced G(0)/G(1)-phase cell-cycle arrest, down-regulation of G(1)-phase cell-cycle regulatory proteins such as cyclin D1 and cyclin E1, and up-regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF-κB, and up-regulation of caspase-9. One of these chalcone derivatives, 3 d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies.
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Papers by Manika Pal-Bhadra