leupeptins and decamethrin

Deltamethrin (DM), a type II synthetic pyrethroid insecticide, is widely used in agriculture and home pest control. The evaluation of their toxic effects is of major concern to public health. However, the molecular mechanism of DM-induced neurodegenerative disease is still far from clear. This study was designed to investigate the potential role of ubiquitin proteasome system (UPS) in DM-induced neurotoxicity where the proteasome inhibitor MG-132 could mitigate the neurotoxic effects.. Male Sprague-Dawley rats were divided into two batches. The first batch of rats was administrated with a single dose of DM (12.5 mg/kg) by intraperitoneal injections (i.p.) and the animals were then euthanized at 5, 24, and 48 h post injection. The second batch was treated as follow: control group, DM (12.5 mg/kg) groups for 24 h, MG-132 (0.5 mg/kg, i.p.) 2 h plus DM 24 h group, and MG-132 alone group. Ubiqutinatied proteins, DNA damage and apoptosis were investigated.. DM treatment induced the ubiquitinated proteins expression with the peaks at 5 h. Moreover, DM increased DNA damage, early apoptotic rate, the expression level of Cleaved Caspase-3, caspase-3 activity and decreased the expression level of Bcl-2 at DM 24 h group. Compared to DM 24 h group, MG-132 pretreatment significantly down-regulated ubiquitinated proteins, lowered the DNA damage and apoptosis by decreasing Caspase-3 and increasing Bcl-2 expression.. These results indicate that MG-132 effectively alleviates DM-induced DNA damage and apoptosis by inhibiting ubiquitinated proteins. UPS may play a role in DM-induced neurodegenerative disorders.

Topics: Animals; Apoptosis; Caspase 3; Hippocampus; Insecticides; Leupeptins; Male; Neurodegenerative Diseases; Neurotoxicity Syndromes; Nitriles; Proteasome Endopeptidase Complex; Protective Agents; Proteostasis; Pyrethrins; Rats; Rats, Sprague-Dawley; Ubiquitin; Ubiquitin-Protein Ligase Complexes

Deltamethrin (DM) insecticides are currently being promoted worldwide for mosquito control, because of the high efficacy, low mammalian toxicity and less environmental impact. Widespread and improper use of insecticides induced resistance, which has become a major obstacle for the insect-borne disease management. Resistance development is a complex and dynamic process involving many genes. To better understand the possible molecular mechanisms involved in DM resistance, a proteomic approach was employed for screening of differentially expressed proteins in DM-susceptible and -resistant mosquito cells. Twenty-seven differentially expressed proteins were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). Four members of the ubiquitin-proteasome system were significantly elevated in DM-resistant cells, suggesting that the ubiquitin-proteasome pathway may play an important role in DM resistance. Proteasome subunit beta type 6 (PSMB6) is a member of 20S proteasomal subunit family, which forms the proteolytic core of 26S proteasome. We used pharmaceutical inhibitor and molecular approaches to study the contributions of PSMB6 in DM resistance: the proteasome inhibitor MG-132 and bortezomib were used to suppress the proteasomal activity and siRNA was designed to block the function of PSMB6. The results revealed that both MG-132 and bortezomib increased the susceptibility in DM-resistant cells and resistance larvae. Moreover, PSMB6 knockdown decreased cellular viability under DM treatment. Taken together, our study indicated that PSMB6 is associated with DM resistance in mosquitoes and that proteasome inhibitors such as MG-132 or bortezomib are suitable for use as a DM synergist for vector control.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Boronic Acids; Bortezomib; Cell Proliferation; Cells, Cultured; Cloning, Molecular; Culicidae; Cysteine Proteinase Inhibitors; Drug Resistance; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation; Insect Proteins; Insecticides; Larva; Leupeptins; Nitriles; Phylogeny; Proteasome Endopeptidase Complex; Proteomics; Pyrazines; Pyrethrins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

To study the protective effect of MG-132 on hippocampus cells apoptosis induced by deltamethrin (DM), one kind of pyrethroid pesticide.. 40 Male wistar rats were randomly divided into four groups: olive oil control, DM treated alone (12.5 mg/kg), MG-132 (0.5 mg/kg) plus DM group, MG-132 treated 2h plus olive oil. After 24h treatment of DM, the hippocampus was taken out to detect the apoptotic cell rate, the level of bcl-2 and Caspase-3 activity.. Compared with DM treated alone group (27.29% +/- 2.41%), the apoptotic cell rate in MG-132 + DM group (19.94% +/- 2.07%) was increased (P < 0.05), bcl-2 expression was enhanced [(0.43 +/- 0.06) vs. (2.01 +/- 0.23)] (P < 0.05) and the activity of Caspase-3 was decreased significantly (P < 0.05) in MG-132 treated 2h plus DM group [(4.55 +/- 0.46) vs.(3.73 +/- 0.35)].. MG-132 can protect hippocampus cells against apoptosis induced by deltamethrin.

Topics: Animals; Apoptosis; Hippocampus; Insecticides; Leupeptins; Male; Neurons; Nitriles; Pyrethrins; Rats; Rats, Wistar