Oxaliplatin(OXA)is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN).Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA)transports Ca^(2+)from the cytoplas...Oxaliplatin(OXA)is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN).Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA)transports Ca^(2+)from the cytoplasm into the endoplasmic reticulum(ER),thereby maintaining intracellular Ca^(2+)homeostasis.Schefflera kwangsiensis Merr.ex H.L.Li(SKM)is traditionally used to treat neuropathic pain conditions such as trigeminal neuralgia and sciatica,and its active component Schekwanglupaside C has been identified as a potent SERCA activator.In this study,an OIPN mouse model was established by intraperitoneal administration of OXA(4 mg·kg^(-1))on days 1,2,8,9,15,and 16.SERCA2b mRNA and protein expression in dorsal root ganglia(DRG)were evaluated by quantitative polymerase chain reaction(qPCR)and immunofluorescence.Mechanical allodynia was assessed using the Von Frey test.DRG neuronal excitability was examined by whole-cell current-clamp recordings,whereas oxidative stress and neuronal apoptosis/necrosis were assessed using the reactive oxygen species(ROS)-sensitive probe 2',7'-dichlorofluorescin diacetate(H2 DCFDA)and fluorescein isothiocyanate(FITC)/propidium iodide(PI)dual staining.This study identifies SERCA2b as a novel therapeutic target for OIPN.We observed that SERCA2b mRNA and protein levels were significantly downregulated during OIPN progression.Treatment with the SERCA agonist CDN1163(CDN),the ethyl acetate extract of SKM(SKM.Ext),or duloxetine(DLX)attenuated neuronal pathology,restored DRG neuron soma diameter,and reduced the expression of proinflammatory cytokines interleukin-1β(IL-1β)and tumor necrosis factorα(TNF-α).Pre-incubation of DRG neurons with CDN1163 or SKM.Ext for 1 h significantly attenuated OXA-induced hyperexcitability and reduced the abnormal increase in voltage-gated sodium channel(VGSC)current density.Inhibition of oxidative stress with N-acetyl-L-cysteine(NAC)significantly restored SERCA expression in OIPN,indicating that oxidative stress downregulates SERCA2b in DRG.Collectively,these findings demonstrate that activation of SERCA2b by CDN1163 or Schefflera kwangsiensis extract enhances SERCA2b expression,reduces DRG neuronal sensitization,and alleviates OIPN.This work supports SERCA2b as a novel therapeutic target for OXA-induced neuropathy and expands the potential clinical analgesic indications of Schefflera kwangsiensis.展开更多
Fixed carrier membrane exhibits attractive CO2 permeance and selectivity due to its transport mechanism of reaction selectivity （facilitated transport）. However, its performance needs improvement to meet cost target...Fixed carrier membrane exhibits attractive CO2 permeance and selectivity due to its transport mechanism of reaction selectivity （facilitated transport）. However, its performance needs improvement to meet cost targets for CO2 capture. This study attempts to develop membranes with multiple permselective mechanisms in order to enhance CO2 separation performance of fixed carder membrane. In this study, a novel membrane with multiplepermselective mechanisms of solubility selectivity and reaction selectivity was developed by incorporating CO2-selective adsorptive silica nanoparticles in situ into the tertiary amine containing polyamide membrane formed by interfacial polymerization （IP）. Various techniques were employed to characterize the polyamide and polyam-ide-silica composite membranes. The TGA result shows that nanocomposite membranes exhlbit superior-thermal stability than pure polyamide membranes. In addition, gas permeation experiments show that both nanocomposite membranes have larger CO2 permeance than pure polyamide membranes. The enhanced CO2/N2 separation performance for nanocomposite membranes is mainly due to the thin film thickness, and multiple permselective mechanisms of solubility selectivity and reaction selectivity.展开更多
AIM:To investigate the cytotoxic mechanism of caribbean maitotoxin(MTX-C) in mammalian cells.METHODS:We used whole-cell patch-clamp techniques and fluorescence calcium imaging to determine the cellular toxic mechanism...AIM:To investigate the cytotoxic mechanism of caribbean maitotoxin(MTX-C) in mammalian cells.METHODS:We used whole-cell patch-clamp techniques and fluorescence calcium imaging to determine the cellular toxic mechanisms of MTX-C in insulin secreting HIT-T15 cells,which is a system where the effects of MTX have been observed.HIT-T15 cells stably express L-type calcium current,making it a suitable model for this study.Using the fluorescence calcium indicator Indo-1 AM,we found that there is a profound increase in HIT-T15 intracellular free calcium 3 min after application of 200 nmol/L MTX-C.RESULTS:About 3 min after perfusion of MTX-C,a gradual increase in free calcium concentration was observed.This elevation was sustained throughout the entire recording period.Application of MTX-C did not elicit the L-type calcium current,but large cationiccurrents appeared after applying MTX-C to the extracellular solution.The current-voltage relationship of the cation current is approximately linear within the voltage range from-60 to 50 mV,but flattened at voltages at-80 and-100 mV.These results indicate that MTX-C induces a non-voltage activated,inward current under normal physiological conditions,which by itself or through a secondary mechanism results in a large amount of cationic influx.The biophysical mechanism of MTX-C is different to its isoform,pacific maitotoxin(MTX-P),when the extracellular calcium is removed.CONCLUSION:We conclude that MTX-C causes the opening of non-selective,non-voltage-activated ion channels,which elevates level of intracellular calcium concentration and leads to cellular toxicities.展开更多
Tetra(amino)azacalix[4]arene skeleton was functionalized at the bridging NH sites using various aromatic aldehydes via formation of imidazobenzimidazole fused heterocycles.X-ray single crystal analysis revealed distor...Tetra(amino)azacalix[4]arene skeleton was functionalized at the bridging NH sites using various aromatic aldehydes via formation of imidazobenzimidazole fused heterocycles.X-ray single crystal analysis revealed distorted 1,3-alternate conformations for the resulting macrocycles.Anthracenyl and pyrenyl modified imidazobenzimidazole fused aza-calix[4]arenes existed as dimers in the solid state,associated mainly through-stacking interactions between the planar polycyclic fluorophores.The tetrapyrenyl modified product was further used as a Zn^(2+)-selective sensor,which showed naked-eye detected color change and enhanced excimer emission.The stoichiometry between the sensor and Zn2+was determined to be 1:1 and the association constant was 1.1×10^(5)L/mol.The sensing process was highly selective and showed strong anti-interference with presence of other cations.The UV-vis spectral changes in the sensing process were completely reversible by alternate addition of Zn^(2+) and F^(-),showing an efficient“on-off-on”result.展开更多
基金supported by the Natural Science Foundation of Jiangsu Province of China(No.BK20221054)the National Natural Science Foundation of China(Nos.82204653,82373929,and82100585)+3 种基金the Major Program of Jiangsu Provincial Administration for Market Regulation(No.KJ2024014)“Double First-Class”University Project(No.CPU2022QZ30)the Open Fund Project of State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture(No.SKL2024Z0104)Tibet Autonomous Region Science and Technology Plan Project Key Project(No.XZ202301ZY0014G)。
文摘Oxaliplatin(OXA)is a widely used chemotherapeutic agent whose clinical utility is limited by OXA-induced peripheral neuropathy(OIPN).Sarco/endoplasmic reticulum Ca^(2+)-ATPase(SERCA)transports Ca^(2+)from the cytoplasm into the endoplasmic reticulum(ER),thereby maintaining intracellular Ca^(2+)homeostasis.Schefflera kwangsiensis Merr.ex H.L.Li(SKM)is traditionally used to treat neuropathic pain conditions such as trigeminal neuralgia and sciatica,and its active component Schekwanglupaside C has been identified as a potent SERCA activator.In this study,an OIPN mouse model was established by intraperitoneal administration of OXA(4 mg·kg^(-1))on days 1,2,8,9,15,and 16.SERCA2b mRNA and protein expression in dorsal root ganglia(DRG)were evaluated by quantitative polymerase chain reaction(qPCR)and immunofluorescence.Mechanical allodynia was assessed using the Von Frey test.DRG neuronal excitability was examined by whole-cell current-clamp recordings,whereas oxidative stress and neuronal apoptosis/necrosis were assessed using the reactive oxygen species(ROS)-sensitive probe 2',7'-dichlorofluorescin diacetate(H2 DCFDA)and fluorescein isothiocyanate(FITC)/propidium iodide(PI)dual staining.This study identifies SERCA2b as a novel therapeutic target for OIPN.We observed that SERCA2b mRNA and protein levels were significantly downregulated during OIPN progression.Treatment with the SERCA agonist CDN1163(CDN),the ethyl acetate extract of SKM(SKM.Ext),or duloxetine(DLX)attenuated neuronal pathology,restored DRG neuron soma diameter,and reduced the expression of proinflammatory cytokines interleukin-1β(IL-1β)and tumor necrosis factorα(TNF-α).Pre-incubation of DRG neurons with CDN1163 or SKM.Ext for 1 h significantly attenuated OXA-induced hyperexcitability and reduced the abnormal increase in voltage-gated sodium channel(VGSC)current density.Inhibition of oxidative stress with N-acetyl-L-cysteine(NAC)significantly restored SERCA expression in OIPN,indicating that oxidative stress downregulates SERCA2b in DRG.Collectively,these findings demonstrate that activation of SERCA2b by CDN1163 or Schefflera kwangsiensis extract enhances SERCA2b expression,reduces DRG neuronal sensitization,and alleviates OIPN.This work supports SERCA2b as a novel therapeutic target for OXA-induced neuropathy and expands the potential clinical analgesic indications of Schefflera kwangsiensis.
基金Supported by the National Natural Science Foundation of China （20836006）, the National Basic Research Program （2009CB623405）, the Science ＆ Technology Pillar Program of Tianjin （10ZCKFSH01700）, the Programme of Introducing Talents of Discipline to Universities （B06006）, and the Cheung Kong Scholar Program for Innovative Teams of the Ministry of Education （IRT0641）.
文摘Fixed carrier membrane exhibits attractive CO2 permeance and selectivity due to its transport mechanism of reaction selectivity （facilitated transport）. However, its performance needs improvement to meet cost targets for CO2 capture. This study attempts to develop membranes with multiple permselective mechanisms in order to enhance CO2 separation performance of fixed carder membrane. In this study, a novel membrane with multiplepermselective mechanisms of solubility selectivity and reaction selectivity was developed by incorporating CO2-selective adsorptive silica nanoparticles in situ into the tertiary amine containing polyamide membrane formed by interfacial polymerization （IP）. Various techniques were employed to characterize the polyamide and polyam-ide-silica composite membranes. The TGA result shows that nanocomposite membranes exhlbit superior-thermal stability than pure polyamide membranes. In addition, gas permeation experiments show that both nanocomposite membranes have larger CO2 permeance than pure polyamide membranes. The enhanced CO2/N2 separation performance for nanocomposite membranes is mainly due to the thin film thickness, and multiple permselective mechanisms of solubility selectivity and reaction selectivity.
文摘AIM:To investigate the cytotoxic mechanism of caribbean maitotoxin(MTX-C) in mammalian cells.METHODS:We used whole-cell patch-clamp techniques and fluorescence calcium imaging to determine the cellular toxic mechanisms of MTX-C in insulin secreting HIT-T15 cells,which is a system where the effects of MTX have been observed.HIT-T15 cells stably express L-type calcium current,making it a suitable model for this study.Using the fluorescence calcium indicator Indo-1 AM,we found that there is a profound increase in HIT-T15 intracellular free calcium 3 min after application of 200 nmol/L MTX-C.RESULTS:About 3 min after perfusion of MTX-C,a gradual increase in free calcium concentration was observed.This elevation was sustained throughout the entire recording period.Application of MTX-C did not elicit the L-type calcium current,but large cationiccurrents appeared after applying MTX-C to the extracellular solution.The current-voltage relationship of the cation current is approximately linear within the voltage range from-60 to 50 mV,but flattened at voltages at-80 and-100 mV.These results indicate that MTX-C induces a non-voltage activated,inward current under normal physiological conditions,which by itself or through a secondary mechanism results in a large amount of cationic influx.The biophysical mechanism of MTX-C is different to its isoform,pacific maitotoxin(MTX-P),when the extracellular calcium is removed.CONCLUSION:We conclude that MTX-C causes the opening of non-selective,non-voltage-activated ion channels,which elevates level of intracellular calcium concentration and leads to cellular toxicities.
基金supported by National Natural Science Foundation of China(Nos.21971223 and 21772178).
文摘Tetra(amino)azacalix[4]arene skeleton was functionalized at the bridging NH sites using various aromatic aldehydes via formation of imidazobenzimidazole fused heterocycles.X-ray single crystal analysis revealed distorted 1,3-alternate conformations for the resulting macrocycles.Anthracenyl and pyrenyl modified imidazobenzimidazole fused aza-calix[4]arenes existed as dimers in the solid state,associated mainly through-stacking interactions between the planar polycyclic fluorophores.The tetrapyrenyl modified product was further used as a Zn^(2+)-selective sensor,which showed naked-eye detected color change and enhanced excimer emission.The stoichiometry between the sensor and Zn2+was determined to be 1:1 and the association constant was 1.1×10^(5)L/mol.The sensing process was highly selective and showed strong anti-interference with presence of other cations.The UV-vis spectral changes in the sensing process were completely reversible by alternate addition of Zn^(2+) and F^(-),showing an efficient“on-off-on”result.
