TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid ... more TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of tar...
Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells c... more Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and pro...
European journal of medicinal chemistry, Jan 16, 2017
A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesize... more A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesized via microwave assisted click chemistry technique. Some of the aryl-substituted conjugates 17-19 show promising antibacterial properties against the tested Gram-positive (S. aureus and S. pyogenes) and Gram-negative bacteria (S. typhi) with potency higher than that of the parent antibiotics 1-3. 2D-QSAR modeling supports the observed biological properties.
Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and t... more Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). To facilitate development of novel therapies aimed at myelin repair, we set out to develop imaging agents that permit direct quantification of myelination in vivo. In this work, we designed and synthesized a series of fluorescent fluorinated myelin imaging agents that can be used for in vivo positron emission tomography (PET) imaging combined with subsequent post-mortem fluorescent cryoimaging. Structure-activity relationship (SAR) studies of the newly developed myelin imaging agents led us to identify a lead compound (TAFDAS, 21) that readily enters the brain and spinal cord and selectively binds to myelin. By conducting sequential PET and 3D cryoimaging in an SCI rat model, we demonstrated for the first time that PET and cryoimaging can be combined as a novel technique to image the spinal cord with high sensitivity and spatial resolution.
Myelination is one of the fundamental processes in vertebrates. A major challenge is to quantitat... more Myelination is one of the fundamental processes in vertebrates. A major challenge is to quantitatively image myelin distribution in the central nervous system. For this reason, we designed and synthesized a series of fluorinated radioligands that can be radiolabeled as radiotracers for positron emission tomography (PET) imaging of myelin. These newly developed radioligands readily penetrate the blood-brain barrier and selectively bind to myelin membranes in the white matter region. Structure-activity relationship studies of such ligands suggested that optimal permeability could be achieved with calculated lipophilicty in the range of 3-4. After radiolabeling with fluorine-18, the brain uptake and retention of each radioligand were determined by microPET/CT imaging studies. These pharmacokinetic studies led us to identify a lead compound ([(18)F]FMeDAS, 32) with promising in vivo binding properties, which was subsequently validated by ex vivo autoradiography.
The ethanolic extract of S. robusta resin (10 and 30 % w/w applied locally in excised and incised... more The ethanolic extract of S. robusta resin (10 and 30 % w/w applied locally in excised and incised wounds) produced a dose-dependent acceleration in wound contraction and increased hydroxyproline content and tensile strength of wounds in rats. The results demonstrate wound healing activity of ethanolic extract of S. robusta resin.
Ficus racemosa (Moraceae) is an endemic plant of India. Antioxidant property of the ethanolic ext... more Ficus racemosa (Moraceae) is an endemic plant of India. Antioxidant property of the ethanolic extract of ficus racemosa leaves was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, reducing power assay and nitric oxide assay. In DPPH assay, extract with IC50 value (47.46μg/mL) showed less but appreciable scavenging activity than standard ascorbic acid with IC50 value (43.46μg/mL). In reducing power assay, standard ascorbic acid stands for high reducing power ability than extract. Leaves of ficus racemosa exhibited higher inhibitory activity against Nitric oxide radical with IC50 value (49.89μg/mL) than standard Butylated hydroxyl toluene (BHT) with IC50 value (72.16μg/mL). The results of this study showed that ethanolic extract of ficus racemosa leaves possess good antioxidant activity and can be considered as potential source of plant antioxidant.
Industrialization and indiscriminate use of agrochemicals have increased the human health risk. R... more Industrialization and indiscriminate use of agrochemicals have increased the human health risk. Recent epidemiological studies raised a concern for male reproduction given their observations of reduced sperm counts and altered semen quality. Interestingly, environmental factors that include various metals, pesticides and their metabolites have been causally linked to such adversities by their presence in the semen at levels that correlate to infertility. The epidemiological observations were further supported by studies in animal models involving various chemicals. Therefore, in this review, we focused on male reproductive toxicity and the adverse effects of different environmental chemicals on male reproduction. However, it is beyond the scope of this review to provide a detailed appraisal of all of the environmental chemicals that have been associated with reproductive toxicity in animals. Here, we provided the evidence for reproductive adversities of some commonly encountered chemicals (pesticides/metals) in the environment. In view of the recent thrust for an alternate to animal models in research, we subsequently discussed the contributions of Drosophila melanogaster as an alternate animal model for quick screening of toxicants for their reproductive toxicity potential. Finally, we emphasized the genetic and molecular tools offered by Drosophila for understanding the mechanisms underlying the male reproductive toxicity.
A pulsed nozzle Fourier transform microwave (PNFTMW) spectrometer has been recently fabri- cated ... more A pulsed nozzle Fourier transform microwave (PNFTMW) spectrometer has been recently fabri- cated at the Indian Institute of Science. The basic design is the same as that of Balle and Flygare. How - ever, recent advances in microwave and computer technologies have helped in designing a state -of-the- art PNFTMW spectrometer. The range of the spectro- meter is from 2
ABSTRACT Background: Ficus racemosa (Family: Moraceae) is traditionally used in various skin dise... more ABSTRACT Background: Ficus racemosa (Family: Moraceae) is traditionally used in various skin diseases, cuts, acute and chronic wounds and burns. Hence the present study has been designed to evaluate the burn healing potential of ficus racemosa leaves. Methodology: In present study ficus racemosa leaves extract was given in the form of transdermal patch. For which the ficus racemosa leaves extracted with ethanol and obtained extract was incorporated in chitosan polymer to make patch. 5% and 10% doses have been selected for treatment. Dermal burn wound model was used to determine burn healing activity. Wistar albino rats of either sex weighing between 180-200g were selected for the study. Burn wound was created by heating aluminum metal rod at 850 and held it on the shaved back of rats. Along with this, hydroxyproline level and histopathological study also carried out to support experimental results. Percentage wound contraction in burn model was significantly (p<0.01) increases in groups treated with 5% patch (95.41%) and 10% patch (98.52%) as compared to control (86.32%). Standard, 5% and 10% treated animals showed complete epithelization in 18, 21 and 19 days respectively. Hydroxyproline level increase significantly (p<0.01) in 5% (65.45 mg/g tissue) and 10% (80.35 mg/g tissue) patches as compared to control (39.26 mg/g tissue). Histopathological study showed better regeneration of skin as compared to control. The ficus racemosa leaves extract as transdermal patch have significant burn healing activity and further study on active fraction responsible for activity is needed.
TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid ... more TET2 is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of TET2 and neomorphic IDH1/2 mutations, here we report that IDH1/2 mutant–derived 2-hydroxyglutarate is synthetically lethal to TET dioxygenase–deficient cells. In addition, a TET-selective small-molecule inhibitor decreases cytosine hydroxymethylation and restricted clonal outgrowth of TET2 mutant but not normal hematopoietic precursor cells in vitro and in vivo. Although TET inhibitor phenocopied somatic TET2 mutations, its pharmacologic effects on normal stem cells are, unlike mutations, reversible. Treatment with TET inhibitor suppresses the clonal evolution of TET2-mutant cells in murine models and TET2-mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of tar...
Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells c... more Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and pro...
European journal of medicinal chemistry, Jan 16, 2017
A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesize... more A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesized via microwave assisted click chemistry technique. Some of the aryl-substituted conjugates 17-19 show promising antibacterial properties against the tested Gram-positive (S. aureus and S. pyogenes) and Gram-negative bacteria (S. typhi) with potency higher than that of the parent antibiotics 1-3. 2D-QSAR modeling supports the observed biological properties.
Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and t... more Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). To facilitate development of novel therapies aimed at myelin repair, we set out to develop imaging agents that permit direct quantification of myelination in vivo. In this work, we designed and synthesized a series of fluorescent fluorinated myelin imaging agents that can be used for in vivo positron emission tomography (PET) imaging combined with subsequent post-mortem fluorescent cryoimaging. Structure-activity relationship (SAR) studies of the newly developed myelin imaging agents led us to identify a lead compound (TAFDAS, 21) that readily enters the brain and spinal cord and selectively binds to myelin. By conducting sequential PET and 3D cryoimaging in an SCI rat model, we demonstrated for the first time that PET and cryoimaging can be combined as a novel technique to image the spinal cord with high sensitivity and spatial resolution.
Myelination is one of the fundamental processes in vertebrates. A major challenge is to quantitat... more Myelination is one of the fundamental processes in vertebrates. A major challenge is to quantitatively image myelin distribution in the central nervous system. For this reason, we designed and synthesized a series of fluorinated radioligands that can be radiolabeled as radiotracers for positron emission tomography (PET) imaging of myelin. These newly developed radioligands readily penetrate the blood-brain barrier and selectively bind to myelin membranes in the white matter region. Structure-activity relationship studies of such ligands suggested that optimal permeability could be achieved with calculated lipophilicty in the range of 3-4. After radiolabeling with fluorine-18, the brain uptake and retention of each radioligand were determined by microPET/CT imaging studies. These pharmacokinetic studies led us to identify a lead compound ([(18)F]FMeDAS, 32) with promising in vivo binding properties, which was subsequently validated by ex vivo autoradiography.
The ethanolic extract of S. robusta resin (10 and 30 % w/w applied locally in excised and incised... more The ethanolic extract of S. robusta resin (10 and 30 % w/w applied locally in excised and incised wounds) produced a dose-dependent acceleration in wound contraction and increased hydroxyproline content and tensile strength of wounds in rats. The results demonstrate wound healing activity of ethanolic extract of S. robusta resin.
Ficus racemosa (Moraceae) is an endemic plant of India. Antioxidant property of the ethanolic ext... more Ficus racemosa (Moraceae) is an endemic plant of India. Antioxidant property of the ethanolic extract of ficus racemosa leaves was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, reducing power assay and nitric oxide assay. In DPPH assay, extract with IC50 value (47.46μg/mL) showed less but appreciable scavenging activity than standard ascorbic acid with IC50 value (43.46μg/mL). In reducing power assay, standard ascorbic acid stands for high reducing power ability than extract. Leaves of ficus racemosa exhibited higher inhibitory activity against Nitric oxide radical with IC50 value (49.89μg/mL) than standard Butylated hydroxyl toluene (BHT) with IC50 value (72.16μg/mL). The results of this study showed that ethanolic extract of ficus racemosa leaves possess good antioxidant activity and can be considered as potential source of plant antioxidant.
Industrialization and indiscriminate use of agrochemicals have increased the human health risk. R... more Industrialization and indiscriminate use of agrochemicals have increased the human health risk. Recent epidemiological studies raised a concern for male reproduction given their observations of reduced sperm counts and altered semen quality. Interestingly, environmental factors that include various metals, pesticides and their metabolites have been causally linked to such adversities by their presence in the semen at levels that correlate to infertility. The epidemiological observations were further supported by studies in animal models involving various chemicals. Therefore, in this review, we focused on male reproductive toxicity and the adverse effects of different environmental chemicals on male reproduction. However, it is beyond the scope of this review to provide a detailed appraisal of all of the environmental chemicals that have been associated with reproductive toxicity in animals. Here, we provided the evidence for reproductive adversities of some commonly encountered chemicals (pesticides/metals) in the environment. In view of the recent thrust for an alternate to animal models in research, we subsequently discussed the contributions of Drosophila melanogaster as an alternate animal model for quick screening of toxicants for their reproductive toxicity potential. Finally, we emphasized the genetic and molecular tools offered by Drosophila for understanding the mechanisms underlying the male reproductive toxicity.
A pulsed nozzle Fourier transform microwave (PNFTMW) spectrometer has been recently fabri- cated ... more A pulsed nozzle Fourier transform microwave (PNFTMW) spectrometer has been recently fabri- cated at the Indian Institute of Science. The basic design is the same as that of Balle and Flygare. How - ever, recent advances in microwave and computer technologies have helped in designing a state -of-the- art PNFTMW spectrometer. The range of the spectro- meter is from 2
ABSTRACT Background: Ficus racemosa (Family: Moraceae) is traditionally used in various skin dise... more ABSTRACT Background: Ficus racemosa (Family: Moraceae) is traditionally used in various skin diseases, cuts, acute and chronic wounds and burns. Hence the present study has been designed to evaluate the burn healing potential of ficus racemosa leaves. Methodology: In present study ficus racemosa leaves extract was given in the form of transdermal patch. For which the ficus racemosa leaves extracted with ethanol and obtained extract was incorporated in chitosan polymer to make patch. 5% and 10% doses have been selected for treatment. Dermal burn wound model was used to determine burn healing activity. Wistar albino rats of either sex weighing between 180-200g were selected for the study. Burn wound was created by heating aluminum metal rod at 850 and held it on the shaved back of rats. Along with this, hydroxyproline level and histopathological study also carried out to support experimental results. Percentage wound contraction in burn model was significantly (p<0.01) increases in groups treated with 5% patch (95.41%) and 10% patch (98.52%) as compared to control (86.32%). Standard, 5% and 10% treated animals showed complete epithelization in 18, 21 and 19 days respectively. Hydroxyproline level increase significantly (p<0.01) in 5% (65.45 mg/g tissue) and 10% (80.35 mg/g tissue) patches as compared to control (39.26 mg/g tissue). Histopathological study showed better regeneration of skin as compared to control. The ficus racemosa leaves extract as transdermal patch have significant burn healing activity and further study on active fraction responsible for activity is needed.
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Papers by Anand Dev .Tiwari