Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggr...Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggregates that lead to neuronal cell death.Although years can pass from initial prion infection to clinical presentation of symptoms,onset of symptoms is typically followed by rapid neurological decline resulting in death.Prion diseases have been characterized in animals ranging from sheep and cattle to cervids and humans,with notable cross-species infections such as the variant Creutzfeldt-Jakob disease.Thus,prions present a health risk with the potential to disrupt major food sources as well affect human health through animal to human and human to human transmission events.While human to human prion transmission is rare and the immediate risks for a prion-facilitated pandemic are low,prions are a class of pathogens for which we are underprepared.In addition,prions,and prion disease-like approaches,have also been discussed in the context of biological weapons and toxins,adding another layer of complexity surrounding biosecurity and biodefense.These threats underscore the need for increased scrutiny and research on prions.Here,pharmaceutical and nonpharmaceutical prion-specific interventions are discussed.Recent advances in prion therapeutic development are also briefly highlighted,and a set of policy recommendations are given that aims to provide high level suggestions for the prevention and mitigation of prion diseases.展开更多
We investigated the role of hydrological features, such as water masses, fronts, eddies, and sea ice, in affecting the distribution of upper trophic level species in the Scotia Sea region during autumn. On board RV Po...We investigated the role of hydrological features, such as water masses, fronts, eddies, and sea ice, in affecting the distribution of upper trophic level species in the Scotia Sea region during autumn. On board RV Polarstern, we performed 365 30-min strip transects recording seabirds and marine mammals along the North Scotia Ridge and the South Sandwich Trench in March--April 2013. Among the 7 identified cetacean species recorded, the humpback whale Megaptera novaeangliae was the most abundant baleen whale （40 individuals）, and noteworthy were sightings of six southern right whales Eubalaena australis. Pinnipeds （3 species, 1650 individuals） were dominated by Antarctic fur seal Arctocephalus gazella （99%）, and seabirds （36 species, 18900 individuals） by Antarctic prion Pachyptila desolata （-50%）. The distribution of these top predators was highly patchy with the majority of observations concentrated in a few counts. This heterogeneity is likely a result of prey availability, and we discuss how hydrological features may have caused the patchiness.展开更多
Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein...Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.展开更多
PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.展开更多
BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness o...BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness of drugs and poor patient outcomes.Long noncoding RNAs(lncRNAs)have been implicated in various pathophysiological processes of tumor cells,including chemotherapy resistance,yet the roles of many lncRNAs in CRC remain unclear.AIM To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.METHODS Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance.Various bioinformatics tools were employed to elucidate molecular mechanisms.The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction.Functional assays,including MTT,wound healing,and Transwell,were conducted to investigate the functional implications of lncRNA alterations.Interactions between lncRNAs and trans-cription factors were examined using RIP and luciferase reporter assays,while Western blotting was used to confirm downstream pathways.Additionally,a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.RESULTS LncRNA prion protein testis specific(PRNT)was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2(HIPK2)expression.PRNT was demonstrated to sponge transcription factor zinc finger protein 184(ZNF184),which in turn could regulate HIPK2 expression.Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin,with overexpression leading to decreased sensitivity and decreased expression reducing resistance.Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT.The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.CONCLUSION The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184.This regulatory mechanism enhances CRC progression and resistance to oxaliplatin,positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.展开更多
Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scra...Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scrapie-infected mice,using western blotting,ELISA,co-immunoprecipitation,immunohistochemistry,immunofluorescence assays,and RT-PCR.Results Both CXCR3 levels and activation were significantly higher in the brains of scrapie-infected mice and prion-infected SMB-S15 cells.Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia.Morphological colocalization of PrPC/PrPSc with IP10/CXCR3 was observed in scrapie-infected mouse brains using immunohistochemistry and immunofluorescence.immunohistochemistry(IHC)analysis of whole brain sections further revealed increased accumulation of IP10/CXCR3 specifically in brain regions with higher levels of PrPSc deposits.Co-immunoprecipitation and biomolecular interaction assays revealed the molecular interactions between PrP and IP10/CXCR3.Notably,a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells than in the normal partner cell line,SMB-PS.Importantly,resveratrol treatment effectively suppressed prion replication in SMB-S15 cells,thereby restoring the accumulation and secretion pattern of cellular IP10 similar to that observed in SMB-PS cells.Conclusion Our data demonstrate that the activation of IP10/CXCR3 signaling in prion-infected brain tissues coincides with PrPSc deposition.Modulation of IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.展开更多
Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prio...Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.展开更多
羊痒病(scrap ie)是传染性海绵状脑病(TSE)的原型,目前在世界许多地方流行。该病是绵羊的一种缓慢发展的致死性中枢神经系统变性疾病,能引起绵羊和山羊中枢神经系统发生退化变性,病羊具有中枢神经系统变性、空泡化、星形胶质细胞增生等...羊痒病(scrap ie)是传染性海绵状脑病(TSE)的原型,目前在世界许多地方流行。该病是绵羊的一种缓慢发展的致死性中枢神经系统变性疾病,能引起绵羊和山羊中枢神经系统发生退化变性,病羊具有中枢神经系统变性、空泡化、星形胶质细胞增生等特点,病羊表现为共济失调、痉挛、麻痹、衰弱和严重的皮肤瘙痒,病畜死亡率达100%。该病是由正常的朊蛋白(P rP c)发生错误折叠而变成异常的蛋白形式(P rP sc)引起的。展开更多
文摘Prions are infectious conformations of certain naturally occurring proteins.These misfolded proteins can structurally alter healthy protein,creating misfolded copies that repeat the process and form protein aggregates that lead to neuronal cell death.Although years can pass from initial prion infection to clinical presentation of symptoms,onset of symptoms is typically followed by rapid neurological decline resulting in death.Prion diseases have been characterized in animals ranging from sheep and cattle to cervids and humans,with notable cross-species infections such as the variant Creutzfeldt-Jakob disease.Thus,prions present a health risk with the potential to disrupt major food sources as well affect human health through animal to human and human to human transmission events.While human to human prion transmission is rare and the immediate risks for a prion-facilitated pandemic are low,prions are a class of pathogens for which we are underprepared.In addition,prions,and prion disease-like approaches,have also been discussed in the context of biological weapons and toxins,adding another layer of complexity surrounding biosecurity and biodefense.These threats underscore the need for increased scrutiny and research on prions.Here,pharmaceutical and nonpharmaceutical prion-specific interventions are discussed.Recent advances in prion therapeutic development are also briefly highlighted,and a set of policy recommendations are given that aims to provide high level suggestions for the prevention and mitigation of prion diseases.
文摘We investigated the role of hydrological features, such as water masses, fronts, eddies, and sea ice, in affecting the distribution of upper trophic level species in the Scotia Sea region during autumn. On board RV Polarstern, we performed 365 30-min strip transects recording seabirds and marine mammals along the North Scotia Ridge and the South Sandwich Trench in March--April 2013. Among the 7 identified cetacean species recorded, the humpback whale Megaptera novaeangliae was the most abundant baleen whale （40 individuals）, and noteworthy were sightings of six southern right whales Eubalaena australis. Pinnipeds （3 species, 1650 individuals） were dominated by Antarctic fur seal Arctocephalus gazella （99%）, and seabirds （36 species, 18900 individuals） by Antarctic prion Pachyptila desolata （-50%）. The distribution of these top predators was highly patchy with the majority of observations concentrated in a few counts. This heterogeneity is likely a result of prey availability, and we discuss how hydrological features may have caused the patchiness.
基金Supported by Alberta Prion Research Institute,Canada(Project title:"Comprehensive Risk Assessment of CWD Transmission to Humans Using Non-human Primates")European Metrology Research Programme(EMRP)Researcher Grant:HLT10-Bi Origin(Metrology for the Biomolecular Origin of Disease)
文摘Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
基金Supported by Hebei Provincial Health Commission Youth Science and Technology Project,No.20210027.
文摘BACKGROUND Colorectal cancer(CRC)is the third most common cancer and a significant cause of cancer-related mortality globally.Resistance to chemotherapy,especially during CRC treatment,leads to reduced effectiveness of drugs and poor patient outcomes.Long noncoding RNAs(lncRNAs)have been implicated in various pathophysiological processes of tumor cells,including chemotherapy resistance,yet the roles of many lncRNAs in CRC remain unclear.AIM To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance.METHODS Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance.Various bioinformatics tools were employed to elucidate molecular mechanisms.The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction.Functional assays,including MTT,wound healing,and Transwell,were conducted to investigate the functional implications of lncRNA alterations.Interactions between lncRNAs and trans-cription factors were examined using RIP and luciferase reporter assays,while Western blotting was used to confirm downstream pathways.Additionally,a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance.RESULTS LncRNA prion protein testis specific(PRNT)was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2(HIPK2)expression.PRNT was demonstrated to sponge transcription factor zinc finger protein 184(ZNF184),which in turn could regulate HIPK2 expression.Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin,with overexpression leading to decreased sensitivity and decreased expression reducing resistance.Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT.The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo.CONCLUSION The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184.This regulatory mechanism enhances CRC progression and resistance to oxaliplatin,positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.
基金supported by SKLID Development Grants(2021SKLID504,2019SKLID401,2019SKLID603,and 2016SKLID603)the National Natural Science Foundation of China(81772197,81401670,and 81630062)。
文摘Objective To analyze the relationship between Chemokine IP10 and its receptor CXCR3 during prion infection.Methods We investigated the increases in IP10 signals,primarily localized in neurons within the brains of scrapie-infected mice,using western blotting,ELISA,co-immunoprecipitation,immunohistochemistry,immunofluorescence assays,and RT-PCR.Results Both CXCR3 levels and activation were significantly higher in the brains of scrapie-infected mice and prion-infected SMB-S15 cells.Enhanced CXCR3 expression was predominantly observed in neurons and activated microglia.Morphological colocalization of PrPC/PrPSc with IP10/CXCR3 was observed in scrapie-infected mouse brains using immunohistochemistry and immunofluorescence.immunohistochemistry(IHC)analysis of whole brain sections further revealed increased accumulation of IP10/CXCR3 specifically in brain regions with higher levels of PrPSc deposits.Co-immunoprecipitation and biomolecular interaction assays revealed the molecular interactions between PrP and IP10/CXCR3.Notably,a significantly larger amount of IP10 accumulated within prion-infected SMB-S15 cells than in the normal partner cell line,SMB-PS.Importantly,resveratrol treatment effectively suppressed prion replication in SMB-S15 cells,thereby restoring the accumulation and secretion pattern of cellular IP10 similar to that observed in SMB-PS cells.Conclusion Our data demonstrate that the activation of IP10/CXCR3 signaling in prion-infected brain tissues coincides with PrPSc deposition.Modulation of IP10/CXCR3 signaling in the brain represents a potential therapeutic target for mitigating the progression of prion diseases.
基金funded in part by the Center on Emerging and Zoonotic Infectious Diseases(CEZID)of the National Institutes of General Medical Sciences underaward number P20GM130448.
文摘Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.
文摘羊痒病(scrap ie)是传染性海绵状脑病(TSE)的原型,目前在世界许多地方流行。该病是绵羊的一种缓慢发展的致死性中枢神经系统变性疾病,能引起绵羊和山羊中枢神经系统发生退化变性,病羊具有中枢神经系统变性、空泡化、星形胶质细胞增生等特点,病羊表现为共济失调、痉挛、麻痹、衰弱和严重的皮肤瘙痒,病畜死亡率达100%。该病是由正常的朊蛋白(P rP c)发生错误折叠而变成异常的蛋白形式(P rP sc)引起的。
