Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various disea...Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.展开更多
Aim Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species. Substantial studies has been made in deciphering alterations in adult ne...Aim Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species. Substantial studies has been made in deciphering alterations in adult neurogenesis are closely related to human disorders, including neurodegenerative disease, cerebrovascular disease and traumatic brain injury （TBI）. The cellular and molecular mechanisms underlying adult neurogenesis in humans remain to be a mystery. A series of researches links neurogenesis to Nicotinamide phosphoribosyltransferase （NAMPT） , a rate-limiting enzyme for mammalian NAD salvage synthesis. Although P7C3 compounds have neuro- protective efficiency by enhancing the activity of NAMPT, most of them were verified in the animal disease model. Fortunately, novel cell culture methods, such as patients-derived or genome-edited pluripotent stem cells （hESCs） and three-dimensional （3 D） organoid culture system, bring hope to drug testing and further develop specific medi- cine for neurodegenesis-associated diseases.展开更多
In this paper the critical cooling rate, Rc, for the glass formation of Fe80P13C7 alloy has been determined using both Uhlmann＇s and Barandiaran-Colmenero＇s method. In Uhlmann＇s method, all kinds of the expres-sion...In this paper the critical cooling rate, Rc, for the glass formation of Fe80P13C7 alloy has been determined using both Uhlmann＇s and Barandiaran-Colmenero＇s method. In Uhlmann＇s method, all kinds of the expres-sions of △G^l-s （T） and η/（T） determined using the different modes and methods had been investigated. It is indicated that the Rc for the glass formation of FesoP13C7 alloy can be estimated to be 349 K/s by Uhlmann＇s method based on the appropriate expressions of △G^l-s（T） and η/（T）. The calculated result accords with our experimental result. The Rc for the glass formation of Fe80P13C7 alloy has also been determined to be 0.49 K/s using Barandiaran-Colmenero＇s method. This resultant Rc is unreasonable low and it indicates that Barandiaran-Colmenero＇s method does not suit to Fe-based alloy.展开更多
Protein p7 of HCV is a 63 amino acid channel forming membrane protein essential for the progression ofviral infection and the sensitivity of this channel to small-molecule inhibitors renders p7 a potentialtarget for n...Protein p7 of HCV is a 63 amino acid channel forming membrane protein essential for the progression ofviral infection and the sensitivity of this channel to small-molecule inhibitors renders p7 a potentialtarget for novel therapies against HCV infection. Previous biochemical experiments suggested that theHis17 of p7 is a pore-lining residue and solvated-exposed to participate in channel gating. However, arecent NMR structural identification of the p7 hexamer in dodecylphosphocholine （DPC） micellesindicated that the His17 is embedded into the protein matrix. In this work, we performed moleculardynamic simulations to bridge the controversial observations. Our results illustrated that byincorporating the cholesterol into DOPC membranes to mimic an actual membrane-like composition,the orientation of His17 in the hexameric bundles spontaneously access to the central pore region,indicating a versatile property of the p7 viroporin conformation that could be voluntarily influenced byits surrounding environments.展开更多
基金supported by National Natural Science Foundation of China,No.32102745(to XL).
文摘Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.
文摘Aim Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species. Substantial studies has been made in deciphering alterations in adult neurogenesis are closely related to human disorders, including neurodegenerative disease, cerebrovascular disease and traumatic brain injury （TBI）. The cellular and molecular mechanisms underlying adult neurogenesis in humans remain to be a mystery. A series of researches links neurogenesis to Nicotinamide phosphoribosyltransferase （NAMPT） , a rate-limiting enzyme for mammalian NAD salvage synthesis. Although P7C3 compounds have neuro- protective efficiency by enhancing the activity of NAMPT, most of them were verified in the animal disease model. Fortunately, novel cell culture methods, such as patients-derived or genome-edited pluripotent stem cells （hESCs） and three-dimensional （3 D） organoid culture system, bring hope to drug testing and further develop specific medi- cine for neurodegenesis-associated diseases.
基金supported by the National Natural Science Foundation of China (No. 50861007)the Project of Supporting Xinjiang Uyghur Autonomous Region by Science and Technology (No. 201191203)the Opening Subject from State Key Laboratory of Powder Metallurgy in Central South University
文摘In this paper the critical cooling rate, Rc, for the glass formation of Fe80P13C7 alloy has been determined using both Uhlmann＇s and Barandiaran-Colmenero＇s method. In Uhlmann＇s method, all kinds of the expres-sions of △G^l-s （T） and η/（T） determined using the different modes and methods had been investigated. It is indicated that the Rc for the glass formation of FesoP13C7 alloy can be estimated to be 349 K/s by Uhlmann＇s method based on the appropriate expressions of △G^l-s（T） and η/（T）. The calculated result accords with our experimental result. The Rc for the glass formation of Fe80P13C7 alloy has also been determined to be 0.49 K/s using Barandiaran-Colmenero＇s method. This resultant Rc is unreasonable low and it indicates that Barandiaran-Colmenero＇s method does not suit to Fe-based alloy.
基金financial support from the National Natural Science Foundation of China(Nos.21625302,21573217 and 91430110)
文摘Protein p7 of HCV is a 63 amino acid channel forming membrane protein essential for the progression ofviral infection and the sensitivity of this channel to small-molecule inhibitors renders p7 a potentialtarget for novel therapies against HCV infection. Previous biochemical experiments suggested that theHis17 of p7 is a pore-lining residue and solvated-exposed to participate in channel gating. However, arecent NMR structural identification of the p7 hexamer in dodecylphosphocholine （DPC） micellesindicated that the His17 is embedded into the protein matrix. In this work, we performed moleculardynamic simulations to bridge the controversial observations. Our results illustrated that byincorporating the cholesterol into DOPC membranes to mimic an actual membrane-like composition,the orientation of His17 in the hexameric bundles spontaneously access to the central pore region,indicating a versatile property of the p7 viroporin conformation that could be voluntarily influenced byits surrounding environments.
