platonin and Disease-Models--Animal

Studies have found that Platonin has neuroprotective effect, but its molecular mechanism needs further study. We found that at the early stage of cerebral ischemia/reperfusion injury, Platonin treatment significantly reduced cerebral infarct lesions, improved neurological scores, and exerted neuroprotective effects. Our group has shown that NLRP3 inflammasomes activation is required to mediate neuronal injury during cerebral ischemia /reperfusion injury. The brain protective effect of Platonin is related to its ability to effectively regulate autophagy and NLRP3 inflammasomes-derived inflammation. Platonin treatment effectively induced autophagy (LC3II/I, p62) and reduced NLRP3 inflammasomes activation(NLRP3, cleaved-IL-1β，cleaved-IL-18, cleaved-caspase1). However, 3-MA (15 mg/kg) treatment downregulated the inhibitory effect of Platonin on NLRP3 inflammasomes. We also studied the location of BNIP3 in Platonin-mediated neuroprotection and found that Platonin induced the expression of autophagic protein BNIP3 and enhanced the co-immunoprecipitation of BNIP3 with LC3, and double-labeled immunofluorescence also showed enhanced co-localization of BNIP3 with LC3. Finally, si-BNIP3 transfection attenuated the co localization of BNIP3 with LC3, decreased the autophagy activity to a certain extent and blocked the inhibition of NLRP3 inflammasomes-derived inflammation by Platonin. This study demonstrated that Platonin may play a neuroprotection role in cerebral I / R injury by inhibiting NLRP3 inflammasomes activation through upregulating autophagy via BNIP3 / LC3 pathway.

Topics: Animals; Autophagy; Disease Models, Animal; Inflammasomes; Membrane Proteins; Microtubule-Associated Proteins; Mitochondrial Proteins; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Reperfusion Injury; Thiazoles

Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Brain Ischemia; Cell Death; Collagen; Disease Models, Animal; Free Radicals; Humans; Immunologic Factors; Infarction, Middle Cerebral Artery; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Neurons; Neuroprotection; Neuroprotective Agents; Phosphorylation; Platelet Aggregation; RAW 264.7 Cells; Stroke; Thiazoles; Time Factors

Traumatic hemorrhagic shock and subsequent resuscitation may promote bacteria translocation and cause endotoxemia, a two-hit process that will induce severe lung injury. The pathogenesis involves oxidative stress, neutrophil infiltration, and inflammatory response. Platonin, a potent antioxidant, possesses potent anti-inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in a two-hit model of traumatic hemorrhage/resuscitation and subsequent endotoxemia.. Adult male rats were randomized to receive traumatic hemorrhage/resuscitation plus lipopolysaccharide (HS/L) alone or HS/L plus platonin (200 μg/kg; n = 12 in each group). Sham groups were used simultaneously. At 6 hours after resuscitation, rats were killed and the levels of lung injury were assayed.. Rats treated with HS/L alone had severe lung injury as evidenced by significant alterations in lung function (i.e., arterial blood gas and alveolar-arterial oxygen difference) and histology. Significant increases in polymorphonuclear leukocytes/alveoli ratio (neutrophil infiltration index) and significant increases in the concentrations of inflammatory molecules (including chemokine, cytokine, and prostaglandin E2) and malondialdehyde (lipid peroxidation index) revealed that HS/L caused significant oxidative stress, neutrophil infiltration, and inflammatory response in rat lungs. Moreover, our data revealed that the levels of functional and histologic alteration as well as polymorphonuclear leukocytes/alveoli ratio and the concentrations of inflammatory molecules and malondialdehyde in rats treated with HS/L plus platonin (200 μg/kg) were significantly lower than those treated with HR/L alone.. Platonin mitigates lung injury in a two-hit model of traumatic hemorrhage/resuscitation and endotoxemia in rats.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Endotoxemia; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Thiazoles

Enhanced oxidative stress and inflammatory response are crucial in mediating the development of acute lung injury induced by haemorrhagic shock with resuscitation. Platonin, a potent antioxidant, possesses potent anti-inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in haemorrhagic shock/resuscitation rats.. Seventy-two adult male rats were randomized to receive haemorrhagic shock/resuscitation (HS), HS plus platonin (10, 50, or 100μg/kg intravenous injection immediately after resuscitation), sham instrumentation (Sham), or Sham plus platonin (100μg/kg) (n=12 in each group). Haemorrhagic shock was induced by blood drawing and mean blood pressure was maintained at 40-45mmHg for 120min. Then, resuscitation was achieved by shed blood/saline mixtures re-infusion. After monitoring for another 8h, rats were sacrificed.. Arterial blood gas and histological findings, in concert with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that haemorrhagic shock/resuscitation caused significant lung injury. Significant increases in concentrations of inflammatory molecules (chemokine, cytokine, and prostaglandin E(2)) as well as nitric oxide and malondialdehyde in lung tissues confirmed that haemorrhagic shock/resuscitation elicited inflammatory response and imposed oxidative stress in rats. Platonin at the dosages of 50 and 100μg/kg, but not 10μg/kg, significantly attenuated the inflammatory response and oxidative stress induced by haemorrhagic shock/resuscitation. Most important, platonin at the dosages of 50 and 100μg/kg, but not 10μg/kg, significantly mitigated the lung injury induced by haemorrhagic shock/resuscitation.. Platonin mitigates acute lung injury in haemorrhagic shock/resuscitation rats.

Topics: Acute Lung Injury; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Resuscitation; Shock, Hemorrhagic; Thiazoles; Treatment Outcome