Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene dise...Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.展开更多
Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,...Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive.In this study,we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer.Our findings revealed that hydrophilic bases,specifically G in single-stranded RNA(ssRNA)and single-stranded DNA(ssDNA),displayed a higher propensity to form hydrogen bonds with phospholipid head groups.Notably,ssRNA exhibited stronger binding energy than ssDNA.Furthermore,divalent ions,particularly Ca2+,facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids.Overall,our study provides valuable insights into the molecular mechanisms underlying nucleic acidphospholipid interactions,with potential implications for the nucleic acids in biotherapies,particularly in the context of lipid carriers.展开更多
Gene therapy offers potentially transformative strategies for major human diseases.However,one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissu...Gene therapy offers potentially transformative strategies for major human diseases.However,one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissue.Here,we report a novel virus-like nanoparticle,the bioorthgonal engineered viruslike recombinant biosome(reBiosome),for efficient gene therapies of cancer and inflammatory diseases.The mutant virus-like biosome(mBiosome)is first prepared by site-specific codon mutation for displaying 4-azido-L-phenylalanine on vesicular stomatitis virus glycoprotein of eBiosome at a rational site,and the reBiosome is then prepared by clicking weak acid-responsive hydrophilic polymer onto the mBiosome via bioorthogonal chemistry.The results show that the reBiosome exhibits reduced virus-like immunogenicity,prolonged blood circulation time and enhanced gene delivery efficiency to weakly acidic foci(like tumor and arthritic tissue).Furthermore,reBiosome demonstrates robust therapeutic efficacy in breast cancer and arthritis by delivering gene editing and silencing systems,respectively.In conclusion,this study develops a universal,safe and efficient platform for gene therapies for cancer and inflammatory diseases.展开更多
Dear Editor,Multiple experiments have established TNF-α-induced protein 3 (A20/TNFAIP3) as a critical regulator associated with rheumatoid arthritis(RA)[1,2].The lack of TNF-α-induced protein 3 (A20) promotes the NO...Dear Editor,Multiple experiments have established TNF-α-induced protein 3 (A20/TNFAIP3) as a critical regulator associated with rheumatoid arthritis(RA)[1,2].The lack of TNF-α-induced protein 3 (A20) promotes the NOD-like receptor protein 3 (NLRP3) inflammasome and induces spontaneous arthritis,while increase of A20 reduces the secretion of IL-1β and favors immunological tolerance[3,4]. Hence, we investigate the feasibility of recombinant adeno-associated virus 6 (rAAV6)-mediated A20 gene therapy in a collageninduced arthritis (CIA) model.展开更多
Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and...Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and postural instability,as well as non-motor symptoms,such as cognitive decline,pain,and depression(Bloem et al.,2021).展开更多
目的明确我院分离的流感嗜血杆菌(HI)氨苄西林耐药的基因。方法用 E 试验测定我院上呼吸道感染患儿鼻咽部分离300株 HI 对氨苄西林耐药情况;以 Nitrocefin 纸片检测β内酰胺酶;PCR 扩增及序列分析确定产酶株的基因型。结果31株氨苄西林...目的明确我院分离的流感嗜血杆菌(HI)氨苄西林耐药的基因。方法用 E 试验测定我院上呼吸道感染患儿鼻咽部分离300株 HI 对氨苄西林耐药情况;以 Nitrocefin 纸片检测β内酰胺酶;PCR 扩增及序列分析确定产酶株的基因型。结果31株氨苄西林耐药株均产β内酰胺酶,占总菌株数11%(32/300),PCR 检测出 TEM-1 31株,ROB-1 1株。结论产β内酰胺酶是 HI 对氨苄西林耐药的重要机制,TEM-1型是β内酰胺酶主要基因型,ROB-1型β内酰胺酶也首次被检出,值得关注和长期监测。展开更多
基金supported by Medical University of Silesia research grants,No.PCN-1-129/N/2/O(to AS)。
文摘Gene therapies,despite of being a relatively new therapeutic approach,have a potential to become an important alternative to current treatment strategies in glaucoma.Since glaucoma is not considered a single gene disease,the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells,especially,in intraocular-pressure-independent manner.The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tro pism to retinal ganglion cells,res ulting in long-term expression and low immunogenic profile.The gene thera py studies recruit inducible and genetic animal models of optic neuropathy,like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model.Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors(i.e.,brain derived neurotrophic factor,and its receptor TrkB),regulation of apoptosis and neurodegeneration(i.e.,Bcl-xl,Xiap,FAS system,nicotinamide mononucleotide adenylyl transferase 2,Digit3 and Sarm1),immunomodulation(i.e.,Crry,C3 complement),modulation of neuroinflammation(i.e.,e rythropoietin),reduction of excitotoxicity(i.e.,Com KIlα)and transcription regulation(i.e.,Max,Nrf2).On the other hand,some of gene therapy studies focus on lowering intra ocular pressure,by impacting genes involved in both,decreasing aqueous humor production(i.e.,aquaporin 1),and increasing outflow facility(i.e.,COX2,prostaglandin F2a receptor,RhoA/RhoA kinase signaling pathway,MMP1,Myocilin).The goal of this review is to summarize the current stateof-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12222506,12347102,and 12174184).
文摘Recently,lipid nanoparticles(LNPs)have been extensively investigated as non-viral carriers of nucleic acid vaccines due to their high transport efficiency,safety,and straightforward production and scalability.However,the molecular mechanism underlying the interactions between nucleic acids and phospholipid bilayers within LNPs remains elusive.In this study,we employed the all-atom molecular dynamics simulation to investigate the interactions between single-stranded nucleic acids and a phospholipid bilayer.Our findings revealed that hydrophilic bases,specifically G in single-stranded RNA(ssRNA)and single-stranded DNA(ssDNA),displayed a higher propensity to form hydrogen bonds with phospholipid head groups.Notably,ssRNA exhibited stronger binding energy than ssDNA.Furthermore,divalent ions,particularly Ca2+,facilitated the binding of ssRNA to phospholipids due to their higher binding energy and lower dissociation rate from phospholipids.Overall,our study provides valuable insights into the molecular mechanisms underlying nucleic acidphospholipid interactions,with potential implications for the nucleic acids in biotherapies,particularly in the context of lipid carriers.
基金supported by the National Natural Science Foundation of China(Grant No.81874303 and No.82173752 W.L.Lu).
文摘Gene therapy offers potentially transformative strategies for major human diseases.However,one of the key challenges in gene therapy is developing an effective strategy that could deliver genes into the specific tissue.Here,we report a novel virus-like nanoparticle,the bioorthgonal engineered viruslike recombinant biosome(reBiosome),for efficient gene therapies of cancer and inflammatory diseases.The mutant virus-like biosome(mBiosome)is first prepared by site-specific codon mutation for displaying 4-azido-L-phenylalanine on vesicular stomatitis virus glycoprotein of eBiosome at a rational site,and the reBiosome is then prepared by clicking weak acid-responsive hydrophilic polymer onto the mBiosome via bioorthogonal chemistry.The results show that the reBiosome exhibits reduced virus-like immunogenicity,prolonged blood circulation time and enhanced gene delivery efficiency to weakly acidic foci(like tumor and arthritic tissue).Furthermore,reBiosome demonstrates robust therapeutic efficacy in breast cancer and arthritis by delivering gene editing and silencing systems,respectively.In conclusion,this study develops a universal,safe and efficient platform for gene therapies for cancer and inflammatory diseases.
基金supported by the National Natural Science Foundation of China (81871789, 82172387)the Natural Science Foundation of Jiangsu Province (BK20180052)the Gusu Health Talents Program (GSWS2020023)。
文摘Dear Editor,Multiple experiments have established TNF-α-induced protein 3 (A20/TNFAIP3) as a critical regulator associated with rheumatoid arthritis(RA)[1,2].The lack of TNF-α-induced protein 3 (A20) promotes the NOD-like receptor protein 3 (NLRP3) inflammasome and induces spontaneous arthritis,while increase of A20 reduces the secretion of IL-1β and favors immunological tolerance[3,4]. Hence, we investigate the feasibility of recombinant adeno-associated virus 6 (rAAV6)-mediated A20 gene therapy in a collageninduced arthritis (CIA) model.
基金supported by the National Natural Science Foundation of China (32160204)Major Science and Technology Projects of Hainan Province (ZDKJ2021032)STI 2030—Major Projects (2022ZD0208602)。
文摘Parkinson's disease(PD)is a prevalent neurodegenerative disorder that affects millions of individuals worldwide.Symptoms of PD typically manifest as movement impairments,including bradykinesia,rigidity,tremors,and postural instability,as well as non-motor symptoms,such as cognitive decline,pain,and depression(Bloem et al.,2021).
文摘目的明确我院分离的流感嗜血杆菌(HI)氨苄西林耐药的基因。方法用 E 试验测定我院上呼吸道感染患儿鼻咽部分离300株 HI 对氨苄西林耐药情况;以 Nitrocefin 纸片检测β内酰胺酶;PCR 扩增及序列分析确定产酶株的基因型。结果31株氨苄西林耐药株均产β内酰胺酶,占总菌株数11%(32/300),PCR 检测出 TEM-1 31株,ROB-1 1株。结论产β内酰胺酶是 HI 对氨苄西林耐药的重要机制,TEM-1型是β内酰胺酶主要基因型,ROB-1型β内酰胺酶也首次被检出,值得关注和长期监测。
