Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: DrugBank:EXPT01586 (
G418
)
2,237
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Gap junctions (GJs) play an important role in the regulation of cell response to many drugs. However, little is known about their mechanisms. Using an in vitro model of cytotoxicity induced by geneticin (
G418
), we explored the potential signalling mechanisms involved. Incubation of cells with
G418
resulted in cell death, as indicated by the change in cell morphology, loss of cell viability and activation of caspase-3. Before the onset of cell injury,
G418
induced reactive oxygen species (ROS) generation, activated oxidative sensitive kinase P38 and caused a shift of connexin 43 (Cx43) from non-phosphorylated form to hyperphosphorylated form. These changes were largely prevented by antioxidants, suggesting an implication of oxidative stress. Downregulation of Cx43 with inhibitors or siRNA suppressed the expression of
thioredoxin
-interacting protein (TXNIP), activated Akt and protected cells against the toxicity of
G418
. Further analysis revealed that inhibition of TXNIP with siRNA activated Akt and reproduced the protective effect of Cx43-inhibiting agents, whereas suppression of Akt sensitized cells to the toxicity of
G418
. Furthermore, interference of TXNIP/Akt also affected puromycin- and adriamycin-induced cell injury. Our study thus characterized TXNIP as a presently unrecognized molecule implicated in the regulatory actions of Cx43 on oxidative drug injury. Targeting Cx43/TXNIP/Akt signalling cascade might be a promising approach to modulate cell response to drugs.
...
PMID:A novel TXNIP-based mechanism for Cx43-mediated regulation of oxidative drug injury. 2615 5
The elevated intracellular Ca
2+
and oxidative stress are well-reported mechanisms behind renal tubular epithelial injury initiated by various insults. Given that TRPV4 and connexin43 (Cx43) channels are activated by a wide range of stimuli and regulate both intracellular Ca
2+
and redox status, we speculated an involvement of these channels in renal tubular cell injury. Here, we tested this possibility and explored the potential underlying mechanisms. Our results demonstrated that exposure of renal tubular epithelial cells to aminoglycoside
G418
led to cell death, which was attenuated by both TRPV4 and gap junction (Gj) inhibitor. Activation of TRPV4 caused cell damage, which was associated with an early increase in Cx43 expression and function. Inhibition of Cx43 with chemical inhibitor or siRNA largely prevented TRPV4 activation-induced cell damage. Further analysis revealed that TRPV4 agonists elicited a rise in intracellular Ca
2+
and caused a Ca
2+
-dependent elevation in TXNIP (a negative regulator of the antioxidant
thioredoxin
). In the presence of Gj inhibitor, however, these effects of TRPV4 were largely prevented. The depletion of intracellular Ca
2+
with Ca
2+
chelator BAPTA-AM or downregulation of TXNIP with siRNA significantly alleviated TRPV4 activation-initiated cell injury. Collectively, our results point to a critical involvement of TRPV4/Cx43 channel interaction in renal tubular cell injury through mechanisms involving a synergetic induction of intracellular Ca
2+
and oxidative stress. Channel interactions could be an important mechanism underlying cell injury. Targeting channels could have therapeutic potential for the treatment of acute tubular cell injury.
...
PMID:Gap junctions amplify TRPV4 activation-initiated cell injury via modification of intracellular Ca
2+
and Ca
2+
-dependent regulation of TXNIP. 3275 16
