Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this s...Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this study,a reversible,intelligent,responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition.The“reversible thermosensitive(RTS)”hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvi-ronment by inhibiting extracellular calcium influx.After accurate implantation and following in situ gelation,the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue tem-perature drops to the predetermined transition temperature.Subsequent restoration of the blood supply allevi-ates further tissue injury.Before the temperature drops,the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm.The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells,mice mesenteric arterial rings,and vascular ultrasonic Doppler detection.Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change.Therefore,this RTS hydrogel holds therapeutic po-tential for diseases requiring timely detection of temperature change.展开更多
It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of ex-cessive calcium ion (Ca2+) entry in central neu-rons, which may activate degradative processes and thereby cause cell death. T...It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of ex-cessive calcium ion (Ca2+) entry in central neu-rons, which may activate degradative processes and thereby cause cell death. Therefore, NMD- ARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR ac-tivity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activ-ity can be controlled at a physiological level. The sodium ion (Na+) is the major cation in ex-tracellular space. With its entry into the cell, Na+ can act as a critical intracellular second mes-senger that regulates many cellular functions. Recent data have shown that intracellular Na+ can be an important signaling factor underlying the up-regulation of NMDARs. While Ca2+ influx during the activation of NMDARs down-regu-lates NMDAR activity, Na+ influx provides an essential positive feedback mechanism to over- come Ca2+-induced inhibition and thereby po-tentiate both NMDAR activity and inward Ca2+ flow. Extensive investigations have been con-ducted to clarify mechanisms underlying Ca2+- mediated signaling. This review focuses on the roles of Na+ in the regulation of Ca2+-mediated NMDAR signaling and toxicity.展开更多
Minocycline hydrochloride（MH）, a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to tar...Minocycline hydrochloride（MH）, a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase（MAPK） and phosphoinositide 3-kinase（PI3K）/Akt signaling pathways as well as inhibition of matrix metalloproteinases（MMPs）. Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate（NMDA） receptors, mitochondrial calcium uptake, poly（ADP-ribose） polymerase-1（PARP-1） enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.展开更多
基金National Key Research and Development Program of China(2020YFA0908200)National Natural Science Foundation of China(81772099,81801928 and 52103173)+3 种基金China Postdoctoral Science Foundation(2021M692105)Shanghai Municipal Health Commission(20204Y0354)Shanghai Municipal Key Clinical Specialty(shslczdzk00901)Young Physicians Innovation Team Project of the Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine(QC201902).
文摘Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature,leading to tissue necrosis.The timely discovery and synchronized treatment become pivotal.In this study,a reversible,intelligent,responsive thermosensitive hydrogel system is constructed employing both the gel–sol transition and the sol–gel transition.The“reversible thermosensitive(RTS)”hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvi-ronment by inhibiting extracellular calcium influx.After accurate implantation and following in situ gelation,the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue tem-perature drops to the predetermined transition temperature.Subsequent restoration of the blood supply allevi-ates further tissue injury.Before the temperature drops,the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm.The inhibition of calcium influx and vasospasm in vitro and in vivo is demonstrated using vascular smooth muscle cells,mice mesenteric arterial rings,and vascular ultrasonic Doppler detection.Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change.Therefore,this RTS hydrogel holds therapeutic po-tential for diseases requiring timely detection of temperature change.
文摘It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of ex-cessive calcium ion (Ca2+) entry in central neu-rons, which may activate degradative processes and thereby cause cell death. Therefore, NMD- ARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR ac-tivity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activ-ity can be controlled at a physiological level. The sodium ion (Na+) is the major cation in ex-tracellular space. With its entry into the cell, Na+ can act as a critical intracellular second mes-senger that regulates many cellular functions. Recent data have shown that intracellular Na+ can be an important signaling factor underlying the up-regulation of NMDARs. While Ca2+ influx during the activation of NMDARs down-regu-lates NMDAR activity, Na+ influx provides an essential positive feedback mechanism to over- come Ca2+-induced inhibition and thereby po-tentiate both NMDAR activity and inward Ca2+ flow. Extensive investigations have been con-ducted to clarify mechanisms underlying Ca2+- mediated signaling. This review focuses on the roles of Na+ in the regulation of Ca2+-mediated NMDAR signaling and toxicity.
文摘Minocycline hydrochloride（MH）, a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase（MAPK） and phosphoinositide 3-kinase（PI3K）/Akt signaling pathways as well as inhibition of matrix metalloproteinases（MMPs）. Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate（NMDA） receptors, mitochondrial calcium uptake, poly（ADP-ribose） polymerase-1（PARP-1） enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.
