Project description:We have recently developed a Drosophila behavioral- and transcriptomic- based (systems) model of chronic pentylenetetrazole (PTZ) induced locomotor plasticity. Pharmacological validation using antiepileptic drugs (AEDs) shows that the model is predictive of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective activities. This model is however developed using male flies. The present submission relates to microarray gene expression profiling of fly heads after treatment of female Drosophila adults with PTZ for seven days subsequent withdrawal of PTZ for next seven days. Expression profiles have been generated at three time points during chronic PTZ treatment, namely 12 hrs, 2nd day and 7th day and at the end of withdrawal period, i.e., 14th day from the beginning of the treatment. Keywords: Drug response
Project description:Pentylenetetrazol (PTZ)-induced kindling in rodents is an established model of epileptogenesis. The molecular basis of the associated long-term plasticity is however not clear. Further, rodent models of kindling plasticity are not amenable to large-scale screening of compounds for identifying antiepileptogenic drugs. In this context, we have developed a fly model of chronic PTZ- and withdrawal-induced behavioral plasticity. In our model, the chronic treatment is given for 7 days, followed by 7 day long withdrawal. Gene expression profiles of fly heads secondary to chronic PTZ were examined to identify molecular correlates of behavior in our model. Expression profiling of fly heads at three time points in the 7 day long chronic PTZ - 12 hrs, 2nd day, and 7th day - showed a dynamic and widespread alteration of various functional categories of genes. Keywords: Time Series
Project description:We recently developed a fly model of pentylenetetrazol (PTZ)-induced long-term behavioral plasticity. Pharmacological validation suggests this model to be kindling-like. Hence, our model is of relevance in understanding the molecular pathogenesis of epileptogenesis as well as in screening potential antiepileptogenic agents. Levetiracetam (LEV) is considered to have antiepileptogenic activity. Our fly model also predicted similar activity in LEV. Since the mechanism of action of LEV is not clearly known, we have examined the gene expression profiles of fly heads secondary to three days long chronic LEV treatment in Drosophila. Our results provide novel insights in to the drug’s mode of action. Keywords: Drug Response
Project description:Kindling induced by Pentylenetetrazol is an established rodent model of epileptogenesis. The molecular basis of the long-term plasticity involved is however not clear. In addition, rodent models of kindling plasticity are not useful for large-scale screening of compounds to identify antiepileptogenic drugs. Given this, we have developed a fly model of chronic PTZ- and withdrawal-induced behavioral plasticity. In our fly model, the chronic PTZ treatment is given for 7 days. This is then followed by 7 day long withdrawal. Expression profiling of fly heads at three time points in the 7 day long withdrawal period – 8th day, 10th day, and 14th day from the beginning of the treatment - showed a dynamic and widespread alteration of various functional categories of genes. Keywords: time series
Project description:Osteoporosis affects millions of people worldwide, and current medications like bisphosphonates and denosumab are not effective enough in reversing bone loss. Moreover, these treatments have drawbacks, including jaw osteonecrosis and skin eczema. Hence, there is an urgent need for new drugs to treat osteoporosis. Drug library screening was performed by alkaline phosphatase (ALP) staining in osteoblasts to identify potential candidates for osteoporosis. qPCR, Western blot, ALP staining, alizarin red staining, and TRAP staining were conducted to assess the impact of ZM-306416 (ZM) on osteoblast and osteoclast differentiation in vitro. Additionally, RNA sequencing and pathway analysis were carried out to explore molecular mechanisms. Micro-CT scan and immunostaining were used to determine bone phenotypes in vivo. Drug library screening demonstrated that ZM enhances ALP activity in osteoblasts, indicating its potential as a pro-osteogenic agent. ZM exerts dual effects by promoting osteoblast differentiation through the Wnt/β-catenin signaling pathway and simultaneously inhibiting osteoclast differentiation by the NF-κB and MAPK signaling pathways. In an OVX mouse model, ZM effectively prevents bone loss by stimulating osteoblast formation and inhibiting osteoclast development. Our study revealed that ZM has a dual anti-osteoporosis effect by promoting osteoblastogenesis and inhibiting osteoclastogenesis, mediated via activation of Wnt/β-catenin signaling and suppression of NF-κB/MAPK cascades. These findings suggest that ZM could be a promising therapeutic strategy for alleviating osteoporosis.
Project description:Osteoporosis affects millions of people worldwide, and current medications like bisphosphonates and denosumab are not effective enough in reversing bone loss. Moreover, these treatments have drawbacks, including jaw osteonecrosis and skin eczema. Hence, there is an urgent need for new drugs to treat osteoporosis. Drug library screening was performed by alkaline phosphatase (ALP) staining in osteoblasts to identify potential candidates for osteoporosis. qPCR, Western blot, ALP staining, alizarin red staining, and TRAP staining were conducted to assess the impact of ZM-306416 (ZM) on osteoblast and osteoclast differentiation in vitro. Additionally, RNA sequencing and pathway analysis were carried out to explore molecular mechanisms. Micro-CT scan and immunostaining were used to determine bone phenotypes in vivo. Drug library screening demonstrated that ZM enhances ALP activity in osteoblasts, indicating its potential as a pro-osteogenic agent. ZM exerts dual effects by promoting osteoblast differentiation through the Wnt/β-catenin signaling pathway and simultaneously inhibiting osteoclast differentiation by the NF-κB and MAPK signaling pathways. In an OVX mouse model, ZM effectively prevents bone loss by stimulating osteoblast formation and inhibiting osteoclast development. Our study revealed that ZM has a dual anti-osteoporosis effect by promoting osteoblastogenesis and inhibiting osteoclastogenesis, mediated via activation of Wnt/β-catenin signaling and suppression of NF-κB/MAPK cascades. These findings suggest that ZM could be a promising therapeutic strategy for alleviating osteoporosis.
Project description:Strychnine (STR) is a convulsant agent. In an effort to develop a Drosophila model of kindling epileptogenesis, we have examined chronic STR induced alterations in gene expression profile of fly heads. Expression profiling of fly heads after 7 day long STR treatment revealed perturbations in various functional category of genes. Keywords: Drug Response
Project description:In order to identify genes affected in our model of PANK defficiency we profiled fly heads of female flies control or expressing fumble RNAi by the use of the tim-gal4 driver Female fly heads of the indicated strains were collected at 2 different circadian timepoints, RNA extracted, labeled and hybridized to Affymetrix oligonucleotide microarrays.