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I have been working in diverse field of biological research including microbiology (malaria), cardiovascular (ion channel, metabolic syndrome, cell signaling, restenosis/vascular wall remodeling), and blood cancer (leukemia).Arsenic trioxide/Trisenox (ATO or TX) has been used successfully for treatment of all age acute promyelocytic leukemia (APL) patients alone or combination with retinoic acid receptor alpha( RARalpha) in both induction and consolidated therapy.Cisplatin (CDDP) is an antitumor drug enhances toxicity of ATO and also kill APL cells.
1. Trisenox (TX) disrupts MDM2-DAXX-HAUSP cmplex, activated p53, cell cycle regulation and apoptosis in APL cells.
MDM2-DAXX-HAUSP complex is exciting target of many anticancer drugs such as Doxorubicin, VP16 , Berbene etc. In normal growing cancer cells, complex molecules are assiciated together to control expression of p53 through proteaosomal degradation & ubiquitylation mediated by several E3 ubiquitin ligases prominently MDM2 and MDM4. Normally cells get stressed due to oxidative stress, DNA damage, and infection/inflammation. In stressed cancer cells, stress signals are transmitted by protein kinases (ATM & ATR) & its downstream targets , CHK1& 2 phosphorylation leading to complex molecules disruption, MDM2 degradation, and accumulation of p53. TX is reduced expression of complex molecules expression and also effected association in APL cells.
2. Cisplatin induces cytotoxicity in APL cells
Cisplatin (CDDP) causes cytotoxicity in APL cells through DNA-adduct formation, oxidaive stress, DNA damage, transcriptional factors(p53 & AP-1) activation, cell cycle regulation, and apoptosis. It also regulates stress signals, MAPK signaling pathway in APL cell lines.
Kumar et al., 2018
DNA-Adduct formation
Molecular mechanism of cisplatin action in APL cells
Kumar et al., 2015
3. CDDP disrupts complex, activated p53, cell cycle arrest , and apoptosis in acute leukemia cells
CDDP is reduced expression of MDM2-DAXX-HAUSP complex molecules, changed association, and phosphorylation CHK1&2 leading to activation of p53. CDDP-induced p53 involved in cell cycle regulation and apoptosis in APL cells.
TRPC channel roles in neurite growth
4. TRPC channel regulates NGF-induced neurite growth
Transient receptor potential channel(TRPC) is calcium permeable channel involved in nerve growth factor(NGF) -induced neurite outgrowth in PC12 cells and rat hippocampal neuron . It is seven member of families and mainly TRPC1,5 & 6 regulated actively in NGF-induced neurite growth.
MCP-1 involves PKN1 phosphorylation and restenosis
5.MCP-1 actively involved in PKN1 mediated restenosis
Restenosis is a mutifacial process of thickening of arterial wall in response of injury. It involves smooth muscles cells proliferation, migration, and neointima formation regulated by complex signaling cascade. MCP-1, a chemokines widely expresssed at site of vascular injury participating in baloon injury -induced restenosis by protein kinase N1 phosphorylation in rat carotid artery model.
6. Malaria parasite life cycle :
Malaria is transmitted by female anopheles mosquitoes. Mosquitoes are injected sporozoites into human during blood sucking/meal. Sporozoites is transformed into merozoites in human liver and entered into blood .Some of merozoites differentiated into male and female gametophytes in blood and carried to mosquito stomach for completion of sexual reproduction. Finally , sporozoites are formed in midgut of mosquito and store in salivery gland and ready to transmit other people.
7. Moleular mechanism of free heme toxicity
Malaria parasite digestes hemoglobin and generated free heme ,which is toxic to parasite. Free heme generates ROS and produces oxidatve stress through interacting with parasite membrane and induces lipid peroxidation, protein carbonyl formation, and DNA damage leading to parasite death.
9. Bilirubin causes apoptosis like death in malaria parasite
Bilirubin , is an end product of heme metabolism in parasite.It prevents hemozoin formation, generated ROS, oxidative stress, DNA damage leading to drops in mitochondrial membrance potential , release of cytochrome C and caspase3 activation and intrisic pathway of apoptosis.
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