ABSTRACT Changes in mitochondrial function at the cellular level is not fully understood under no... more ABSTRACT Changes in mitochondrial function at the cellular level is not fully understood under normal aging. Present study investigates glucose oxidation by glutamatergic and GABAergic neurons, and neurotransmitter cycling in adult and aged mice. Cortical glutamate level was found to be reduced in aged mice. The glucose oxidation by glutamatergic neurons was decreased in aged mice while GABAergic functions seems to be unperturbed.
Human DNA ligase1 (hLig1) is the major replicative enzyme in proliferating mammalian cells that j... more Human DNA ligase1 (hLig1) is the major replicative enzyme in proliferating mammalian cells that join Okazaki fragments of the lagging strand during DNA replication. Interruptions in the process of ligation cause DNA damage to accumulate, resulting in cytotoxicity and cell death. In the present study we demonstrate that pyrrolo[1,4] benzodiazepine (PBD) derivatives exhibit anticancer properties by targeting the nick sealing activity of hLig1 as opposed to the DNA interaction activity known for such compounds. Our in silico and in vitro assays demonstrate the binding of these molecules with amino acid residues present in the DNA binding domain (DBD) of the hLig1 enzyme. Two of these hLig1 inhibitors S010-015 and S010-018 demonstrated selective cytotoxicity against DLD-1 (colon cancer) and HepG2 (hepatic cancer) cells in a dose dependant manner. The molecules also reduced cell viability and colony formation at concentrations of ⩽20μM in DLD-1 and HepG2 cells and induced apoptotic cell death. In yet another significant finding, the molecules reduced the migration of cancer cells in wound healing experiments, indicating their anti-metastatic property. In summary, we report the anticancer activity of PBD derivatives against DLD-1 and HepG2 cells and propose a new molecular target for their activity.
Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and e... more Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.
ABSTRACT Changes in mitochondrial function at the cellular level is not fully understood under no... more ABSTRACT Changes in mitochondrial function at the cellular level is not fully understood under normal aging. Present study investigates glucose oxidation by glutamatergic and GABAergic neurons, and neurotransmitter cycling in adult and aged mice. Cortical glutamate level was found to be reduced in aged mice. The glucose oxidation by glutamatergic neurons was decreased in aged mice while GABAergic functions seems to be unperturbed.
Human DNA ligase1 (hLig1) is the major replicative enzyme in proliferating mammalian cells that j... more Human DNA ligase1 (hLig1) is the major replicative enzyme in proliferating mammalian cells that join Okazaki fragments of the lagging strand during DNA replication. Interruptions in the process of ligation cause DNA damage to accumulate, resulting in cytotoxicity and cell death. In the present study we demonstrate that pyrrolo[1,4] benzodiazepine (PBD) derivatives exhibit anticancer properties by targeting the nick sealing activity of hLig1 as opposed to the DNA interaction activity known for such compounds. Our in silico and in vitro assays demonstrate the binding of these molecules with amino acid residues present in the DNA binding domain (DBD) of the hLig1 enzyme. Two of these hLig1 inhibitors S010-015 and S010-018 demonstrated selective cytotoxicity against DLD-1 (colon cancer) and HepG2 (hepatic cancer) cells in a dose dependant manner. The molecules also reduced cell viability and colony formation at concentrations of ⩽20μM in DLD-1 and HepG2 cells and induced apoptotic cell death. In yet another significant finding, the molecules reduced the migration of cancer cells in wound healing experiments, indicating their anti-metastatic property. In summary, we report the anticancer activity of PBD derivatives against DLD-1 and HepG2 cells and propose a new molecular target for their activity.
Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and e... more Living organisms belonging to all three domains of life, viz., eubacteria, archaeabacteria, and eukaryotes encode one or more DNA ligases. DNA ligases are indispensable in various DNA repair and replication processes and a deficiency or an inhibition of their activity can lead to accumulation of DNA damage and strand breaks. DNA damage, specially strand breaks at unsustainable levels can lead to replication block and/or cell death. DNA ligases as potential anticancer targets have been realized only recently. There is enough rationale to suggest that ligases have a tremendous potential for novel therapeutics including anticancer and antibacterial therapy, specially when the world is facing acute problems of drug resistance and chemotherapy failure, with an immediate need for new therapeutic targets. Here, we review the current state of the art in the development of human ligase inhibitors, their structures, molecular mechanisms, physiological effects, and their potential in future cancer therapy. Citing examples, we focus on strategies for improving the activity and specificity of existing and novel inhibitors by using structure-based rational approaches. In the end, we describe potential new sites on the ligase I protein that can be targeted for the development of novel inhibitors. This is the first comprehensive review to compile all known human ligase inhibitors and to provide a rationale for the further development of ligase inhibitors for cancer therapy.
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Papers by Mohammad Shameem