Role of Glutathione in Chalcone Derivative Induced Apoptosis of Brugia malayi and its Possible Therapeutic Implication
PURPOSE: Oxidative stress is an essential component of innate response against microbes. The oxidative impact has a very subtle connection with apoptosis. Our previous work indicated presumptive evidence of apoptosis by the chalcone derivatives against the human lymphatic filarial parasite. Evidence suggests the involvement of glutathione-S-transferase (GST) in the mechanism of action of chalcone drugs. In the present study, we explored the implications of redox status in apoptosis of the parasite by this drug.
RESULTS: Treatment with the representative drug, 4t, significantly decreased GSH level and increased GST activity in the Brugia malayi microfilariae (Mf) in comparison to Mf without 4t treatment. Drug-induced loss of motility of the parasites was reversed by the treatment with GSH (41%) and NAC (19%). A significant fall in rGST activity was observed due to drug addition, which could be reversed by the addition of GSH co-substrate, but not with the re-addition of rGST, indicating a vital role of GSH. In silico study demonstrated a favorable drug-GST enzyme interaction. Oxidative stress was reflected by increased protein carbonylation and intracellular reactive oxygen species level, in the drug-treated parasite. Mitochondrial oxygen consumption was reduced by the drug, which was reversed on the addition of GSH. Mitochondrial dysfunction was confirmed by MTT and cytochrome c assay. Apoptosis was confirmed by the inhibition in PARP activity.
CONCLUSION: We conclude that the depletion of GSH by chalcone with concomitant mitochondrial dysfunction revealed a novel rationale of apoptosis in the parasite. Such a mechanism might have wide therapeutic implications.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
|---|---|
| Enthalten in: |
Acta parasitologica - 66(2021), 2 vom: 10. Juni, Seite 406-415 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bhoj, P S [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
5S5A2Q39HX |
|---|
| Anmerkungen: |
Date Completed 30.07.2021 Date Revised 30.07.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s11686-020-00291-2 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM316078808 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM316078808 | ||
| 003 | DE-627 | ||
| 005 | 20231225160313.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s11686-020-00291-2 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1053.xml |
| 035 | |a (DE-627)NLM316078808 | ||
| 035 | |a (NLM)33037957 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bhoj, P S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Role of Glutathione in Chalcone Derivative Induced Apoptosis of Brugia malayi and its Possible Therapeutic Implication |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.07.2021 | ||
| 500 | |a Date Revised 30.07.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: Oxidative stress is an essential component of innate response against microbes. The oxidative impact has a very subtle connection with apoptosis. Our previous work indicated presumptive evidence of apoptosis by the chalcone derivatives against the human lymphatic filarial parasite. Evidence suggests the involvement of glutathione-S-transferase (GST) in the mechanism of action of chalcone drugs. In the present study, we explored the implications of redox status in apoptosis of the parasite by this drug | ||
| 520 | |a RESULTS: Treatment with the representative drug, 4t, significantly decreased GSH level and increased GST activity in the Brugia malayi microfilariae (Mf) in comparison to Mf without 4t treatment. Drug-induced loss of motility of the parasites was reversed by the treatment with GSH (41%) and NAC (19%). A significant fall in rGST activity was observed due to drug addition, which could be reversed by the addition of GSH co-substrate, but not with the re-addition of rGST, indicating a vital role of GSH. In silico study demonstrated a favorable drug-GST enzyme interaction. Oxidative stress was reflected by increased protein carbonylation and intracellular reactive oxygen species level, in the drug-treated parasite. Mitochondrial oxygen consumption was reduced by the drug, which was reversed on the addition of GSH. Mitochondrial dysfunction was confirmed by MTT and cytochrome c assay. Apoptosis was confirmed by the inhibition in PARP activity | ||
| 520 | |a CONCLUSION: We conclude that the depletion of GSH by chalcone with concomitant mitochondrial dysfunction revealed a novel rationale of apoptosis in the parasite. Such a mechanism might have wide therapeutic implications | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Filarial parasite | |
| 650 | 4 | |a Glutathione | |
| 650 | 4 | |a Mitochondria | |
| 650 | 4 | |a Sulfonamide chalcone | |
| 650 | 7 | |a Chalcones |2 NLM | |
| 650 | 7 | |a Chalcone |2 NLM | |
| 650 | 7 | |a 5S5A2Q39HX |2 NLM | |
| 650 | 7 | |a Glutathione |2 NLM | |
| 650 | 7 | |a GAN16C9B8O |2 NLM | |
| 700 | 1 | |a Bahekar, S |e verfasserin |4 aut | |
| 700 | 1 | |a Khatri, V |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, N |e verfasserin |4 aut | |
| 700 | 1 | |a Togre, N S |e verfasserin |4 aut | |
| 700 | 1 | |a Goswami, K |e verfasserin |4 aut | |
| 700 | 1 | |a Chandak, H S |e verfasserin |4 aut | |
| 700 | 1 | |a Dash, D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Acta parasitologica |d 1989 |g 66(2021), 2 vom: 10. Juni, Seite 406-415 |w (DE-627)NLM09254536X |x 1896-1851 |7 nnns |
| 773 | 1 | 8 | |g volume:66 |g year:2021 |g number:2 |g day:10 |g month:06 |g pages:406-415 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s11686-020-00291-2 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 66 |j 2021 |e 2 |b 10 |c 06 |h 406-415 | ||