Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the ...Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor（BDNF） has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone（7,8-DHF）,a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.展开更多
The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patie...The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients,but the specifi city of these antibodies is generally low,and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecifi c dysregulation of the immune system,but the literature in PSC points to the possible presence of specifi c antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC,with a particular emphasis on the prevalence,clinical relevance and possible pathogenetic importance of each individual marker.展开更多
The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction,which may be help guide neuroengineering to boost stem cell-based neural regeneration for ...The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction,which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury.Herein,we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge(NF-GS)scaffold might improve tissue repair efficacy.To test this,we engineered tropomyosin receptor kinase C(TrkC)-modified neural stem cell(NSC)-derived neural network tissue with robust viability within an NF-GS scaffold.When NSCs were genetically modified to overexpress TrkC,the NT-3 receptor,a functional neuronal population dominated the neural network tissue.The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord.Additionally,host nerve fibers regenerated into the graft,making synaptic connections with the donor neurons.Accordingly,motor function recovery was significantly improved in rats with spinal cord injury(SCI)that received TrkC-modified NSC-derived neural network tissue transplantation.Together,the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI.展开更多
Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,an...Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin rec展开更多
The one-bead-one-compound （OBOC） combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immu...The one-bead-one-compound （OBOC） combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immunoglobulin E （IgE） epitopes of the major shellfish allergen tropomyosin. OBOC peptide libraries with 8-12 amino acid residues were screened with serum samples from patients with shellfish allergy for IgE mimotopes of tropomyosin. Twenty-five mimotopes were identified from the screening and their binding reactivity to tropomyosin-specific IgE was confirmed by peptide ELISA. These mimotopes could be divided into seven clusters based on sequence homology, and epitope mapping by EpiSearch of the clustered mimotopes was performed to characterize and confirm the validity of mimotopes. Five out of six of the predicted epitopes were found to overlap with previously identified epitopes of tropomyosin. To further confirm the mimicry potential of mimotopes, BALB/c mice were immunized with mimotopes conjugated to keyhole limpet hemocyanin and assayed for their capacity to induce tropomyosin-specific antibodies. BALB/c mice that received mimotope immunization were found to have an elevated level of tropomyosin-specific immunoglobulin G, but not mice that received an irrelevant mimotope. This study pioneers the successful application of the OBOC libraries using whole sera to screen and identify multiple shrimp allergen mimotopes and validates their mimicry potential using in vitro, in vivo, and in silico methods.展开更多
Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,N...Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.展开更多
文摘Traumatic brain injury（TBI） is a major health problem worldwide.Following primary mechanical insults,a cascade of secondary injuries often leads to further neural tissue loss.Thus far there is no cure to rescue the damaged neural tissue.Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration.The neurotrophin brain-derived neurotrophic factor（BDNF） has significant effect in both aspects,promoting neuronal survival,synaptic plasticity and neurogenesis.Recently,the flavonoid 7,8-dihydroxyflavone（7,8-DHF）,a small Trk B agonist that mimics BDNF function,has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI.Compared to BDNF,7,8-DHF has a longer half-life and much smaller molecular size,capable of penetrating the blood-brain barrier,which makes it possible for non-invasive clinical application.In this review,we summarize functions of the BDNF/Trk B signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.
文摘The aetiology of primary sclerosing cholangitis (PSC) is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients,but the specifi city of these antibodies is generally low,and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecifi c dysregulation of the immune system,but the literature in PSC points to the possible presence of specifi c antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC,with a particular emphasis on the prevalence,clinical relevance and possible pathogenetic importance of each individual marker.
基金the Chinese National Natural Science Foundation of China(81891003)the National Key R&D Program of China(2017YFA0104700)and the 111 Project for Academic Exchange Program(B13037)to Y.S.Zeng+2 种基金the Foundation of Guangdong Province(2017B020210012)to Y.S.Zeng and X.Zengthe Co-innovation Foundation of Guangzhou City(201704020221)to Y.S.Zeng,X.Zeng,and G.Lithe Start-up Foundation of Guangdong Province(Grant No.2018A030310113)to G.Li.
文摘The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction,which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury.Herein,we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge(NF-GS)scaffold might improve tissue repair efficacy.To test this,we engineered tropomyosin receptor kinase C(TrkC)-modified neural stem cell(NSC)-derived neural network tissue with robust viability within an NF-GS scaffold.When NSCs were genetically modified to overexpress TrkC,the NT-3 receptor,a functional neuronal population dominated the neural network tissue.The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord.Additionally,host nerve fibers regenerated into the graft,making synaptic connections with the donor neurons.Accordingly,motor function recovery was significantly improved in rats with spinal cord injury(SCI)that received TrkC-modified NSC-derived neural network tissue transplantation.Together,the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI.
文摘Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin rec
文摘The one-bead-one-compound （OBOC） combinatorial peptide library is a powerful tool to identify ligand and receptor interactions. Here, we applied the OBOC library technology to identify mimotopes specific to the immunoglobulin E （IgE） epitopes of the major shellfish allergen tropomyosin. OBOC peptide libraries with 8-12 amino acid residues were screened with serum samples from patients with shellfish allergy for IgE mimotopes of tropomyosin. Twenty-five mimotopes were identified from the screening and their binding reactivity to tropomyosin-specific IgE was confirmed by peptide ELISA. These mimotopes could be divided into seven clusters based on sequence homology, and epitope mapping by EpiSearch of the clustered mimotopes was performed to characterize and confirm the validity of mimotopes. Five out of six of the predicted epitopes were found to overlap with previously identified epitopes of tropomyosin. To further confirm the mimicry potential of mimotopes, BALB/c mice were immunized with mimotopes conjugated to keyhole limpet hemocyanin and assayed for their capacity to induce tropomyosin-specific antibodies. BALB/c mice that received mimotope immunization were found to have an elevated level of tropomyosin-specific immunoglobulin G, but not mice that received an irrelevant mimotope. This study pioneers the successful application of the OBOC libraries using whole sera to screen and identify multiple shrimp allergen mimotopes and validates their mimicry potential using in vitro, in vivo, and in silico methods.
基金supported by grants from National Natural Science Foundation of China(Grants 81922064,81874290,81803755,and 91853109)Sichuan Science and Technology Program(Grants 2019YFSY0038 and 2019JDRC0091,China)
文摘Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.
