Effect of lentiviral vector-mediated overexpression of hypoxia-inducible factor 1 alpha delivered by pluronic F-127 hydrogel on brachial plexus avulsion in rats
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摘要
Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α(hypoxia-inducible factor 1α overexpression lentivirus), gel(pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α(pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel +hypoxia-inducible factor 1α groups(in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area(labeled by CD31 around av ulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii(identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.
Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α(hypoxia-inducible factor 1α overexpression lentivirus), gel(pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α(pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel +hypoxia-inducible factor 1α groups(in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area(labeled by CD31 around av ulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii(identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.
Brachial plexus avulsion often results in massive motor neuron death and severe functional deficits of target muscles. However, no satisfactory treatment is currently available. Hypoxia-inducible factor 1α is a critical molecule targeting several genes associated with ischemia-hypoxia damage and angiogenesis. In this study, a rat model of brachial plexus avulsion-reimplantation was established, in which C5–7 ventral nerve roots were avulsed and only the C6 root reimplanted. Different implants were immediately injected using a microsyringe into the avulsion-reimplantation site of the C6 root post-brachial plexus avulsion. Rats were randomly divided into five groups: phosphate-buffered saline, negative control of lentivirus, hypoxia-inducible factor 1α(hypoxia-inducible factor 1α overexpression lentivirus), gel(pluronic F-127 hydrogel), and gel + hypoxia-inducible factor 1α(pluronic F-127 hydrogel + hypoxia-inducible factor 1α overexpression lentivirus). The Terzis grooming test was performed to assess recovery of motor function. Scores were higher in the hypoxia-inducible factor 1α and gel +hypoxia-inducible factor 1α groups(in particular the gel + hypoxia-inducible factor 1α group) compared with the phosphate-buffered saline group. Electrophysiology, fluorogold retrograde tracing, and immunofluorescent staining were further performed to investigate neural pathway reconstruction and changes of neurons, motor endplates, and angiogenesis. Compared with the phosphate-buffered saline group, action potential latency of musculocutaneous nerves was markedly shortened in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor1α groups. Meanwhile, the number of fluorogold-positive cells and ChAT-positive neurons, neovascular area(labeled by CD31 around av ulsed sites in ipsilateral spinal cord segments), and the number of motor endplates in biceps brachii(identified by α-bungarotoxin) were all visibly increased, as well as the morphology of motor endplate in biceps brachil was clear in the hypoxia-inducible factor 1α and gel + hypoxia-inducible factor 1α groups. Taken together, delivery of hypoxia-inducible factor 1α overexpression lentiviral vectors mediated by pluronic F-127 effectively promotes spinal root regeneration and functional recovery post-brachial plexus avulsion. All animal procedures were approved by the Institutional Animal Care and Use Committee of Guangdong Medical University, China.
引文
Ali ZS,Johnson VE,Stewart W,Zager EL,Xiao R,Heuer GG,Weber MT,Mallela AN,Smith DH(2016)Neuropathological characteristics of brachial plexus avulsion injury with and without concomitant spinal cord injury.J Neuropathol Exp Neurol 75:69-85.
Bensaid W,Triffitt JT,Blanchat C,Oudina K,Sedel L,Petite H(2003)Abiodegradable fibrin scaffold for mesenchymal stem cell transplantation.Biomaterials 24:2497-2502.
Benton RL,Maddie MA,Minnillo DR,Hagg T,Whittemore SR(2008)Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse.J Comp Neurol 507:1031-1052.
Bertelli JA,Mira JC(1993)Behavioral evaluating methods in the objective clinical assessment of motor function after experimental brachial plexus reconstruction in the rat.J Neurosci Meth 46:203-208.
Bertelli JA,Mira JC(1994)Brachial plexus repair by peripheral nerve grafts directly into the spinal cord in rats.Behavioral and anatomical evidence of functional recovery.J Neurosurg 81:107-114.
Bertelli JA,Taleb M,Mira JC,Calixto JB(1996)Muscle fiber type reorganization and behavioral functional recovery of rat median nerve repair with vascularized or conventional nerve grafts.Restor Neurol Neurosci 10:5-12.
Blits B,Carlstedt TP,Ruitenberg MJ,de Winter F,Hermens WT,Dijkhuizen PA,Claasens JW,Eggers R,van der Sluis R,Tenenbaum L,Boer GJ,Verhaagen J(2004)Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor.Exp Neurol 189:303-316.
Breidenbach W,Terzis JK(1984)The anatomy of free vascularized nerve grafts.Clin Plast Surg 11:65-71.
Chai H,Wu W,So KF,Yip HK(2000)Survival and regeneration of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion.Neuroreport 11:1249-1252.
Chai X,Kong W,Liu L,Yu W,Zhang Z,Sun Y(2014)A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis.Neural Regen Res 9:1145-1153.
Chen HS,Zhou ZH,Li M,Wang JX,Liu BJ,Lu Y(2013)Contribution of brain-derived neurotrophic factor to mechanical hyperalgesia induced by ventral root transection in rats.Neuroreport 24:167-170.
Chin TY,Kiat SS,Faizul HG,Wu W,Abdullah JM(2017)The effects of minocycline on spinal root avulsion injury in rat model.Malays J Med Sci24:31-39.
Cho Y,Shin JE,Ewan EE,Oh YM,Pita-Thomas W,Cavalli V(2015)Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1alpha.Neuron 88:720-734.
Cibert-Goton V,Phillips JP,Shortland PJ(2015)Vascular changes associated with spinal root avulsion injury.Somatosens Mot Res 32:158-162.
Cullheim S,Carlstedt T,Linda H,Risling M,Ulfhake B(1989)Motoneurons reinnervate skeletal muscle after ventral root implantation into the spinal cord of the cat.J Neurosci 29:725-733.
Diniz IM,Chen C,Xu X,Ansari S,Zadeh HH,Marques MM,Shi S,Moshaverinia A(2015)Pluronic F-127 hydrogel as a promising scaffold for encapsulation of dental-derived mesenchymal stem cells.J Mater Sci-Mater Mater Med 26:153.
Fan X,Heijnen CJ,van der Kooij MA,Groenendaal F,van Bel F(2009)The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury.Brain Res Rev 62:99-108.
Fang XY,Zhang WM,Zhang CF,Wong WM,Li W,Wu W,Lin JH(2016)Lithium accelerates functional motor recovery by improving remyelination of regenerating axons following ventral root avulsion and reimplantation.J Neurosci 329:213-225.
Favier FB,Britto FA,Freyssenet DG,Bigard XA,Benoit H(2015)HIF-1-driven skeletal muscle adaptations to chronic hypoxia:molecular insights into muscle physiology.Cell Mol Life Sci 72:4681-4696.
Feng Y,Liu T,Li XQ,Liu Y,Zhu XY,Jankovic J,Pan TH,Wu YC(2014)Neuroprotection by Orexin-A via HIF-1alpha induction in a cellular model of Parkinson’s disease.Neurosci Lett 579:35-40.
Gessi S,Merighi S,Stefanelli A,Fazzi D,Varani K,Borea PA(2013)A(1)and A(3)adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes.Pharmacol Res 76:157-170.
Gu HY,Chai H,Zhang JY,Yao ZB,Zhou LH,Wong WM,Bruce I,Wu WT(2004)Survival,regeneration and functional recovery of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion.Eur J Neurosci 19:2123-2131.
Hallin RG,Carlstedt T,Nilsson-Remahl I,Risling M(1999)Spinal cord implantation of avulsed ventral roots in primates;correlation between restored motor function and morphology.Exp Brain Res 124:304-310.
Hao GL,Zhang TY,Zhang Q,Gu MY,Chen C,Zou L,Cao XC,Zhang GC(2018)Partial recovery of limb function following end-to-side screw anastomosis of phrenic nerve in rats with brachial plexus injury.Med Sci Monit 24:4832-4840.
Hao J,Wang X,Bi Y,Teng Y,Wang J,Li F,Li Q,Zhang J,Guo F,Liu J(2014)Fabrication of a composite system combining solid lipid nanoparticles and thermosensitive hydrogel for challenging ophthalmic drug delivery.Colloids Surf B Biointerfaces 114:111-120.
Henderson CE,Phillips HS,Pollock RA,Davies AM,Lemeulle C,Armanini M,Simmons L,Moffet B,Vandlen RA,Simpson LCctSL,Koliatsos VE,Rosenthal A,et al.(1994)GDNF:a potent survival factor for motoneurons present in peripheral nerve and muscle.Science 266:1062-1064.
Hu L,Wang JH,Wang ZL,Xie JY,Chen D,Ding F(2018)Combination of bone morphogenetic protein 2 and mutant hypoxia-inducible factor1alpha repairs steroid-induced avascular necrosis of the femoral head.Zhongguo Zuzhi Gongcheng Yanjiu 22:4440-4446.
Imanishi M,Tomita S,Ishizawa K,Kihira Y,Ueno M,Izawa-Ishizawa Y,Ikeda Y,Yamano N,Tsuchiya K,Tamaki T(2014)Smooth muscle cell-specific Hif-1alpha deficiency suppresses angiotensin II-induced vascular remodelling in mice.Cardiovasc Res 102:460-468.
Khan M,Khan H,Singh I,Singh AK(2017)Hypoxia inducible factor-1alpha stabilization for regenerative therapy in traumatic brain injury.Neural Regen Res 12:696-701.
Kizaka-Kondoh S,Inoue M,Harada H,Hiraoka M(2003)Tumor hypoxia:a target for selective cancer therapy.Cancer Sci 94:1021-1028.
Li D,Bai T,Brorson JR(2011)Adaptation to moderate hypoxia protects cortical neurons against ischemia-reperfusion injury and excitotoxicity independently of HIF-1alpha.Exp Neurol 230:302-310.
Li H,Wong C,Li W,Ruven C,He L,Wu X,Lang BT,Silver J,Wu W(2015)Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPsigma.Sci Rep 5:14923.
Li H,Wu W(2017)Microtubule stabilization promoted axonal regeneration and functional recovery after spinal root avulsion.Eur J Neurosci46:1650-1662.
Li J,Chen S,Zhao Z,Luo Y,Hou Y,Li H,He L,Zhou L,Wu W(2017)Effect of VEGF on inflammatory regulation,neural survival,and functional improvement in rats following a complete spinal cord transection.Front Cell Neurosci 11:381.
Mills KR(2005)The basics of electromyography.J Neurol Neurosurg Psychiatry 76 Suppl 2:ii32-35.
ELBadawy NE,Abdel-Latif RS,El-Hady HA(2017)Association between SERPINB2 gene expression by real time pcr in respiratory epithelial cells and atopic bronchial asthma severity.Egypt J Immunol 24:165-181.
Oliveira AL,Langone F(2000)GM-1 ganglioside treatment reduces motoneuron death after ventral root avulsion in adult rats.Neurosci Lett293:131-134.
Pandit NK,McGowan R(1998)Gelation of Pluronic F127-polyethylene glycol mixtures:relationship to PEG molecular weight.Drug Dev Ind Pharm 24:183-186.
Romeo-Guitart D,Fores J,Navarro X(2017)Boosted regeneration and reduced denervated muscle atrophy by NeuroHeal in a pre-clinical model of lumbar root avulsion with delayed reimplantation.Sci Rep 7:12028.
Sato K,Morimoto N,Kurata T,Mimoto T,Miyazaki K,Ikeda Y,Abe K(2012)Impaired response of hypoxic sensor protein HIF-1alpha and its downstream proteins in the spinal motor neurons of ALS model mice.Brain Res 1473:55-62.
Shan T,Ma J,Ma Q,Guo K,Guo J,Li X,Li W,Liu J,Huang C,Wang F,Wu E(2013)β2-AR-HIF-1alpha:a novel regulatory axis for stress-induced pancreatic tumor growth and angiogenesis.Curr Mol Med 13:1023-1034.
Shen YI,Song HG,Papa A,Burke J,Volk SW,Gerecht S(2015)Acellular hydrogels for regenerative burn wound healing:translation from a porcine model.J Invest Dermatol 135:2519-2529.
Su H,Yuan Q,Qin D,Yang X,Wong WM,So KF,Wu W(2013)Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury.BMC Surg 13:21.
Sun Y,Chen X,Zhang X,Shen X,Wang M,Wang X,Liu WC,Liu CF,Liu J,Liu W,Jin X(2017)β2-adrenergic receptor-mediated HIF-1αupregulation mediates blood brain barrier damage in acute cerebral ischemia.Front Mol Neurosci 10:257.
Vleggeert-Lankamp CL(2007)The role of evaluation methods in the assessment of peripheral nerve regeneration through synthetic conduits:a systematic review.J Neurosurg 107:1168-1189.
Wang L,Jiang M,Duan D,Zhao Z,Ge L,Teng X,Liu B,Liu B,Chen P,Lu M(2014)Hyperthermia-conditioned OECs serum-free-conditioned medium induce NSC differentiation into neuron more efficiently by the upregulation of HIF-1 alpha and binding activity.Transplantation 97:1225-1232.
Wang L,Yuzhou L,Yingjie Z,Jie L,Xin Z(2015)A new rat model of neuropathic pain:complete brachial plexus avulsion.Neurosci Lett 589:52-56.
Wu HF,Cen JS,Zhong Q,Chen L,Wang J,Deng DY,Wan Y(2013)The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127.Biomaterials 34:1686-1700.
Bensaid W,Triffitt JT,Blanchat C,Oudina K,Sedel L,Petite H(2003)Abiodegradable fibrin scaffold for mesenchymal stem cell transplantation.Biomaterials 24:2497-2502.
Benton RL,Maddie MA,Minnillo DR,Hagg T,Whittemore SR(2008)Griffonia simplicifolia isolectin B4 identifies a specific subpopulation of angiogenic blood vessels following contusive spinal cord injury in the adult mouse.J Comp Neurol 507:1031-1052.
Bertelli JA,Mira JC(1993)Behavioral evaluating methods in the objective clinical assessment of motor function after experimental brachial plexus reconstruction in the rat.J Neurosci Meth 46:203-208.
Bertelli JA,Mira JC(1994)Brachial plexus repair by peripheral nerve grafts directly into the spinal cord in rats.Behavioral and anatomical evidence of functional recovery.J Neurosurg 81:107-114.
Bertelli JA,Taleb M,Mira JC,Calixto JB(1996)Muscle fiber type reorganization and behavioral functional recovery of rat median nerve repair with vascularized or conventional nerve grafts.Restor Neurol Neurosci 10:5-12.
Blits B,Carlstedt TP,Ruitenberg MJ,de Winter F,Hermens WT,Dijkhuizen PA,Claasens JW,Eggers R,van der Sluis R,Tenenbaum L,Boer GJ,Verhaagen J(2004)Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor.Exp Neurol 189:303-316.
Breidenbach W,Terzis JK(1984)The anatomy of free vascularized nerve grafts.Clin Plast Surg 11:65-71.
Chai H,Wu W,So KF,Yip HK(2000)Survival and regeneration of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion.Neuroreport 11:1249-1252.
Chai X,Kong W,Liu L,Yu W,Zhang Z,Sun Y(2014)A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis.Neural Regen Res 9:1145-1153.
Chen HS,Zhou ZH,Li M,Wang JX,Liu BJ,Lu Y(2013)Contribution of brain-derived neurotrophic factor to mechanical hyperalgesia induced by ventral root transection in rats.Neuroreport 24:167-170.
Chin TY,Kiat SS,Faizul HG,Wu W,Abdullah JM(2017)The effects of minocycline on spinal root avulsion injury in rat model.Malays J Med Sci24:31-39.
Cho Y,Shin JE,Ewan EE,Oh YM,Pita-Thomas W,Cavalli V(2015)Activating injury-responsive genes with hypoxia enhances axon regeneration through neuronal HIF-1alpha.Neuron 88:720-734.
Cibert-Goton V,Phillips JP,Shortland PJ(2015)Vascular changes associated with spinal root avulsion injury.Somatosens Mot Res 32:158-162.
Cullheim S,Carlstedt T,Linda H,Risling M,Ulfhake B(1989)Motoneurons reinnervate skeletal muscle after ventral root implantation into the spinal cord of the cat.J Neurosci 29:725-733.
Diniz IM,Chen C,Xu X,Ansari S,Zadeh HH,Marques MM,Shi S,Moshaverinia A(2015)Pluronic F-127 hydrogel as a promising scaffold for encapsulation of dental-derived mesenchymal stem cells.J Mater Sci-Mater Mater Med 26:153.
Fan X,Heijnen CJ,van der Kooij MA,Groenendaal F,van Bel F(2009)The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury.Brain Res Rev 62:99-108.
Fang XY,Zhang WM,Zhang CF,Wong WM,Li W,Wu W,Lin JH(2016)Lithium accelerates functional motor recovery by improving remyelination of regenerating axons following ventral root avulsion and reimplantation.J Neurosci 329:213-225.
Favier FB,Britto FA,Freyssenet DG,Bigard XA,Benoit H(2015)HIF-1-driven skeletal muscle adaptations to chronic hypoxia:molecular insights into muscle physiology.Cell Mol Life Sci 72:4681-4696.
Feng Y,Liu T,Li XQ,Liu Y,Zhu XY,Jankovic J,Pan TH,Wu YC(2014)Neuroprotection by Orexin-A via HIF-1alpha induction in a cellular model of Parkinson’s disease.Neurosci Lett 579:35-40.
Gessi S,Merighi S,Stefanelli A,Fazzi D,Varani K,Borea PA(2013)A(1)and A(3)adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes.Pharmacol Res 76:157-170.
Gu HY,Chai H,Zhang JY,Yao ZB,Zhou LH,Wong WM,Bruce I,Wu WT(2004)Survival,regeneration and functional recovery of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion.Eur J Neurosci 19:2123-2131.
Hallin RG,Carlstedt T,Nilsson-Remahl I,Risling M(1999)Spinal cord implantation of avulsed ventral roots in primates;correlation between restored motor function and morphology.Exp Brain Res 124:304-310.
Hao GL,Zhang TY,Zhang Q,Gu MY,Chen C,Zou L,Cao XC,Zhang GC(2018)Partial recovery of limb function following end-to-side screw anastomosis of phrenic nerve in rats with brachial plexus injury.Med Sci Monit 24:4832-4840.
Hao J,Wang X,Bi Y,Teng Y,Wang J,Li F,Li Q,Zhang J,Guo F,Liu J(2014)Fabrication of a composite system combining solid lipid nanoparticles and thermosensitive hydrogel for challenging ophthalmic drug delivery.Colloids Surf B Biointerfaces 114:111-120.
Henderson CE,Phillips HS,Pollock RA,Davies AM,Lemeulle C,Armanini M,Simmons L,Moffet B,Vandlen RA,Simpson LCctSL,Koliatsos VE,Rosenthal A,et al.(1994)GDNF:a potent survival factor for motoneurons present in peripheral nerve and muscle.Science 266:1062-1064.
Hu L,Wang JH,Wang ZL,Xie JY,Chen D,Ding F(2018)Combination of bone morphogenetic protein 2 and mutant hypoxia-inducible factor1alpha repairs steroid-induced avascular necrosis of the femoral head.Zhongguo Zuzhi Gongcheng Yanjiu 22:4440-4446.
Imanishi M,Tomita S,Ishizawa K,Kihira Y,Ueno M,Izawa-Ishizawa Y,Ikeda Y,Yamano N,Tsuchiya K,Tamaki T(2014)Smooth muscle cell-specific Hif-1alpha deficiency suppresses angiotensin II-induced vascular remodelling in mice.Cardiovasc Res 102:460-468.
Khan M,Khan H,Singh I,Singh AK(2017)Hypoxia inducible factor-1alpha stabilization for regenerative therapy in traumatic brain injury.Neural Regen Res 12:696-701.
Kizaka-Kondoh S,Inoue M,Harada H,Hiraoka M(2003)Tumor hypoxia:a target for selective cancer therapy.Cancer Sci 94:1021-1028.
Li D,Bai T,Brorson JR(2011)Adaptation to moderate hypoxia protects cortical neurons against ischemia-reperfusion injury and excitotoxicity independently of HIF-1alpha.Exp Neurol 230:302-310.
Li H,Wong C,Li W,Ruven C,He L,Wu X,Lang BT,Silver J,Wu W(2015)Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPsigma.Sci Rep 5:14923.
Li H,Wu W(2017)Microtubule stabilization promoted axonal regeneration and functional recovery after spinal root avulsion.Eur J Neurosci46:1650-1662.
Li J,Chen S,Zhao Z,Luo Y,Hou Y,Li H,He L,Zhou L,Wu W(2017)Effect of VEGF on inflammatory regulation,neural survival,and functional improvement in rats following a complete spinal cord transection.Front Cell Neurosci 11:381.
Mills KR(2005)The basics of electromyography.J Neurol Neurosurg Psychiatry 76 Suppl 2:ii32-35.
ELBadawy NE,Abdel-Latif RS,El-Hady HA(2017)Association between SERPINB2 gene expression by real time pcr in respiratory epithelial cells and atopic bronchial asthma severity.Egypt J Immunol 24:165-181.
Oliveira AL,Langone F(2000)GM-1 ganglioside treatment reduces motoneuron death after ventral root avulsion in adult rats.Neurosci Lett293:131-134.
Pandit NK,McGowan R(1998)Gelation of Pluronic F127-polyethylene glycol mixtures:relationship to PEG molecular weight.Drug Dev Ind Pharm 24:183-186.
Romeo-Guitart D,Fores J,Navarro X(2017)Boosted regeneration and reduced denervated muscle atrophy by NeuroHeal in a pre-clinical model of lumbar root avulsion with delayed reimplantation.Sci Rep 7:12028.
Sato K,Morimoto N,Kurata T,Mimoto T,Miyazaki K,Ikeda Y,Abe K(2012)Impaired response of hypoxic sensor protein HIF-1alpha and its downstream proteins in the spinal motor neurons of ALS model mice.Brain Res 1473:55-62.
Shan T,Ma J,Ma Q,Guo K,Guo J,Li X,Li W,Liu J,Huang C,Wang F,Wu E(2013)β2-AR-HIF-1alpha:a novel regulatory axis for stress-induced pancreatic tumor growth and angiogenesis.Curr Mol Med 13:1023-1034.
Shen YI,Song HG,Papa A,Burke J,Volk SW,Gerecht S(2015)Acellular hydrogels for regenerative burn wound healing:translation from a porcine model.J Invest Dermatol 135:2519-2529.
Su H,Yuan Q,Qin D,Yang X,Wong WM,So KF,Wu W(2013)Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury.BMC Surg 13:21.
Sun Y,Chen X,Zhang X,Shen X,Wang M,Wang X,Liu WC,Liu CF,Liu J,Liu W,Jin X(2017)β2-adrenergic receptor-mediated HIF-1αupregulation mediates blood brain barrier damage in acute cerebral ischemia.Front Mol Neurosci 10:257.
Vleggeert-Lankamp CL(2007)The role of evaluation methods in the assessment of peripheral nerve regeneration through synthetic conduits:a systematic review.J Neurosurg 107:1168-1189.
Wang L,Jiang M,Duan D,Zhao Z,Ge L,Teng X,Liu B,Liu B,Chen P,Lu M(2014)Hyperthermia-conditioned OECs serum-free-conditioned medium induce NSC differentiation into neuron more efficiently by the upregulation of HIF-1 alpha and binding activity.Transplantation 97:1225-1232.
Wang L,Yuzhou L,Yingjie Z,Jie L,Xin Z(2015)A new rat model of neuropathic pain:complete brachial plexus avulsion.Neurosci Lett 589:52-56.
Wu HF,Cen JS,Zhong Q,Chen L,Wang J,Deng DY,Wan Y(2013)The promotion of functional recovery and nerve regeneration after spinal cord injury by lentiviral vectors encoding Lingo-1 shRNA delivered by Pluronic F-127.Biomaterials 34:1686-1700.