Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW003
Henna Khalid
Targeting tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a mediator of apoptosis (cell death) and death ligand belonging to the TNF superfamily, represents a promising approach in anti-cancer therapy due to its selectivity to target cancer cell populations yet not normal cells. However, resistance to TRAIL is a common occurrence in tumours, limiting the effects of TRAIL to a minority of TRAIL-sensitive tumours. Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme catalysing the post-translational conversion of arginine residues to citrulline within histones (citrullination), implicated in the epigenetic modulation of gene expression, with a potential role in tumourigenesis. This study aimed to determine whether the PAD4 inhibitor F-amidine may sensitize tumour cells to TRAIL-induced apoptosis. Expression of PAD4 mRNA was assessed in a panel of 18 cancer cell lines via real-time qRT-PCR to determine PAD4 sensitive cell lines. Prostate (LNCaP), breast (MCF-7), malignant glioma (U87-MG) and acute myeloid leukaemic (HL-60) cell lines were challenged with F-amidine in the presence or absence of death receptor 5 (DR5) agonists and nuclear morphology assessed via Hoechst 33342 staining. PAD4 mRNA expression was detected in 11 cancer cell lines from breast, prostate, leukaemic, glioma, neuroblastoma, myeloma, hepatocellular carcinoma and pluripotent embryonal carcinoma origin. F-amidine synergistically and significantly enhanced TRAIL responses within the PAD4 expressing TRAIL-resistant U87-MG cell line. PAD4 expressing TRAIL-sensitive HL-60 and resistant MCF-7 cell lines were not significantly sensitized to TRAIL-induced apoptosis. Significant synergistic TRAIL responses were observed in the TRAIL-resistant and PAD4 mRNA-negative LNCaP cell line, revealing that F-amidine may also potentiate TRAIL responses independent of PAD4 inhibition. Overall, this study presents some of the first evidence that PAD inhibitors may possess roles as novel TRAIL sensitizers in epigenetic anti-cancer therapy, potentially independent of PAD4 inhibition.
{"title":"PAD4 inhibitors: potential sensitizers of tumour cells to TRAIL-induced apoptosis","authors":"Henna Khalid","doi":"10.1093/BIOHORIZONS/HZW003","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW003","url":null,"abstract":"Targeting tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a mediator of apoptosis (cell death) and death ligand belonging to the TNF superfamily, represents a promising approach in anti-cancer therapy due to its selectivity to target cancer cell populations yet not normal cells. However, resistance to TRAIL is a common occurrence in tumours, limiting the effects of TRAIL to a minority of TRAIL-sensitive tumours. Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme catalysing the post-translational conversion of arginine residues to citrulline within histones (citrullination), implicated in the epigenetic modulation of gene expression, with a potential role in tumourigenesis. This study aimed to determine whether the PAD4 inhibitor F-amidine may sensitize tumour cells to TRAIL-induced apoptosis. Expression of PAD4 mRNA was assessed in a panel of 18 cancer cell lines via real-time qRT-PCR to determine PAD4 sensitive cell lines. Prostate (LNCaP), breast (MCF-7), malignant glioma (U87-MG) and acute myeloid leukaemic (HL-60) cell lines were challenged with F-amidine in the presence or absence of death receptor 5 (DR5) agonists and nuclear morphology assessed via Hoechst 33342 staining. PAD4 mRNA expression was detected in 11 cancer cell lines from breast, prostate, leukaemic, glioma, neuroblastoma, myeloma, hepatocellular carcinoma and pluripotent embryonal carcinoma origin. F-amidine synergistically and significantly enhanced TRAIL responses within the PAD4 expressing TRAIL-resistant U87-MG cell line. PAD4 expressing TRAIL-sensitive HL-60 and resistant MCF-7 cell lines were not significantly sensitized to TRAIL-induced apoptosis. Significant synergistic TRAIL responses were observed in the TRAIL-resistant and PAD4 mRNA-negative LNCaP cell line, revealing that F-amidine may also potentiate TRAIL responses independent of PAD4 inhibition. Overall, this study presents some of the first evidence that PAD inhibitors may possess roles as novel TRAIL sensitizers in epigenetic anti-cancer therapy, potentially independent of PAD4 inhibition.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW009
Justin Byrne, J. Pitchford
Global biodiversity, and its associated ecosystem services, are threatened due to species extinctions. Reintroducing locally extinct species may be a partial solution to this problem. However, the success and possible consequences of any artificial reintroduction will depend on its ecological community, and the reaction of that community to the species' extinction and reintroduction. Mathematical models can offer useful insights by identifying the key features of communities and reintroduced species most likely to result in successful reintroductions. Here we simulated extinctions and reintroductions for a range of theoretical food webs generated using an established bioenergetics model. This allows the probability of successful reintroductions to be quantified as a function of two important ecological factors: the connectance of the food web, and of the time between extinctions and reintroductions. Reintroduction success is measured across an ensemble of 1796 simulated communities, with connnectances of 0.05, 0.15 and 0.3, using three criteria: presence of the reintroduced species in the final community, unchanged species richness in the final community compared to the pre-extinction persistent community and the complete restoration of the community (including both species richness and equilibrium biomass distributions). Although only 12 reintroduced species fail to re-establish according to minimal criteria, the process of extinction and reintroduction frequently has a large effect on the community composition. Increasing time to reintroduction increases both the probability of species loss, and equilibrium biomass change in the community. Proportionally, these community-level impacts occur more frequently when the reintroduced species is a primary producer or top predator. These results indicate that ignoring broader measures of reintroduction success could seriously underestimate the impact of reintroductions on the ecological community. These quantitative results can be compared to empirical literature and may help reveal which factors are most important to the success of reintroductions.
{"title":"Species reintroduction and community-level consequences in dynamically simulated ecosystems","authors":"Justin Byrne, J. Pitchford","doi":"10.1093/BIOHORIZONS/HZW009","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW009","url":null,"abstract":"Global biodiversity, and its associated ecosystem services, are threatened due to species extinctions. Reintroducing locally extinct species may be a partial solution to this problem. However, the success and possible consequences of any artificial reintroduction will depend on its ecological community, and the reaction of that community to the species' extinction and reintroduction. Mathematical models can offer useful insights by identifying the key features of communities and reintroduced species most likely to result in successful reintroductions. Here we simulated extinctions and reintroductions for a range of theoretical food webs generated using an established bioenergetics model. This allows the probability of successful reintroductions to be quantified as a function of two important ecological factors: the connectance of the food web, and of the time between extinctions and reintroductions. Reintroduction success is measured across an ensemble of 1796 simulated communities, with connnectances of 0.05, 0.15 and 0.3, using three criteria: presence of the reintroduced species in the final community, unchanged species richness in the final community compared to the pre-extinction persistent community and the complete restoration of the community (including both species richness and equilibrium biomass distributions). Although only 12 reintroduced species fail to re-establish according to minimal criteria, the process of extinction and reintroduction frequently has a large effect on the community composition. Increasing time to reintroduction increases both the probability of species loss, and equilibrium biomass change in the community. Proportionally, these community-level impacts occur more frequently when the reintroduced species is a primary producer or top predator. These results indicate that ignoring broader measures of reintroduction success could seriously underestimate the impact of reintroductions on the ecological community. These quantitative results can be compared to empirical literature and may help reveal which factors are most important to the success of reintroductions.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW002
K. Baker
Type 1 diabetes mellitus (T1DM) is a chronic life-threatening condition whose incidence in the UK has doubled every 20 years since 1945 (Diabetes UK, 2010). Whilst intensive insulin therapy has been shown to reduce the incidence of long-term vascular complications in T1DM patients, it has also been shown to increase the risk of severe hypoglycaemia by 3-fold. Clinical islet transplantation has progressed considerably over the past decade, yet issues regarding the toxic effects of immunosuppression drugs and the paucity of pancreatic donor supplies remain. To provide an effective long-term therapy for heightened glycaemic control, many studies are investigating the potential of bioartificial islet encapsulation strategies and artificial bihormonal closed-loop systems. Following consideration of the basis of pancreatic transplantation, this article takes an indepth look at both the benefits and limitations of bioartificial and artificial therapies and compares their potential in terms of providing an effective long-term solution to patients suffering with T1DM.
{"title":"Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus","authors":"K. Baker","doi":"10.1093/BIOHORIZONS/HZW002","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW002","url":null,"abstract":"Type 1 diabetes mellitus (T1DM) is a chronic life-threatening condition whose incidence in the UK has doubled every 20 years since 1945 (Diabetes UK, 2010). Whilst intensive insulin therapy has been shown to reduce the incidence of long-term vascular complications in T1DM patients, it has also been shown to increase the risk of severe hypoglycaemia by 3-fold. Clinical islet transplantation has progressed considerably over the past decade, yet issues regarding the toxic effects of immunosuppression drugs and the paucity of pancreatic donor supplies remain. To provide an effective long-term therapy for heightened glycaemic control, many studies are investigating the potential of bioartificial islet encapsulation strategies and artificial bihormonal closed-loop systems. Following consideration of the basis of pancreatic transplantation, this article takes an indepth look at both the benefits and limitations of bioartificial and artificial therapies and compares their potential in terms of providing an effective long-term solution to patients suffering with T1DM.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW004
C. Ezeabara, C. U. Okeke
{"title":"Taxonomic significance of transverse sections of roots of six Citrus species","authors":"C. Ezeabara, C. U. Okeke","doi":"10.1093/BIOHORIZONS/HZW004","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW004","url":null,"abstract":"","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW007
C. Dowle
Clostridium difficile infection (CDI) is the most common aetiology of hospital acquired infections, the leading cause of nosocomial diarrhoea and a significant clinical and economic burden. Recommended treatment for CDI is prescription of broadspectrum antibiotics. Antibiotic treatment disrupts natural gut microbiota allowing C. difficile to colonize. Clostridium difficile is also resistant to antibiotics and may persist in the gastrointestinal tract for months causing recurrent disease. There is a pressing need for alternate therapies. Faecal microbiota transplantation (FMT) is a promising treatment option whereby healthy donor faecal samples are infused into a patient thus, theoretically, restoring normal bowel conditions. Until recently there has been a paucity of randomized controlled trials and reports of FMT efficacy have been limited to case studies and series. Here, a meta-analysis of 684 patients treated with FMT across 23 independent studies was conducted, reporting a mean resolution rate of 90.4%. Three RCTs are included that, although methodologically limited, appear to verify reports of high efficacy in case reports with minimal adverse effects. FMT appears to be a safe, highly efficacious and affordable treatment option. Future research should focus on potential long-term safety concerns and optimizing protocols for donor screening, patient selection and FMT administration.
{"title":"Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection","authors":"C. Dowle","doi":"10.1093/BIOHORIZONS/HZW007","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW007","url":null,"abstract":"Clostridium difficile infection (CDI) is the most common aetiology of hospital acquired infections, the leading cause of nosocomial diarrhoea and a significant clinical and economic burden. Recommended treatment for CDI is prescription of broadspectrum antibiotics. Antibiotic treatment disrupts natural gut microbiota allowing C. difficile to colonize. Clostridium difficile is also resistant to antibiotics and may persist in the gastrointestinal tract for months causing recurrent disease. There is a pressing need for alternate therapies. Faecal microbiota transplantation (FMT) is a promising treatment option whereby healthy donor faecal samples are infused into a patient thus, theoretically, restoring normal bowel conditions. Until recently there has been a paucity of randomized controlled trials and reports of FMT efficacy have been limited to case studies and series. Here, a meta-analysis of 684 patients treated with FMT across 23 independent studies was conducted, reporting a mean resolution rate of 90.4%. Three RCTs are included that, although methodologically limited, appear to verify reports of high efficacy in case reports with minimal adverse effects. FMT appears to be a safe, highly efficacious and affordable treatment option. Future research should focus on potential long-term safety concerns and optimizing protocols for donor screening, patient selection and FMT administration.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW005
H. R. Warren, M. Hejmadi
Resistance to chemotherapy is a major obstacle in clinical oncology. Hypoxia is a hallmark of solid tumours as a result of poorly structured tumour neovasculature and is known to be a key contributor to cancer malignancy and reduced drug effectiveness. Hypoxia-inducible factor-1 (HIF-1) mediates the hypoxic response, bringing about adaptive responses to the change in microenvironment. This study investigated the effect of 24 h hypoxia on the sensitivity of SH-SY5Y neuroblastoma cells to 5-fluorouracil (5-FU). Cytotoxicity, apoptosis and membrane integrity cell-based assays were carried out to observe changes in cell viability alongside apoptotic and necrotic cell death to determine the molecular mechanisms underlying reduced drug sensitivity. Hypoxic cells showed no change in cell viability to 5-FU in comparison to normoxic controls, suggesting that hypoxia conferred reduced drug sensitivity. As a measure of apoptosis, caspase-3/7 levels were significantly higher in hypoxic cells treated with increasing 5-FU concentrations. However, this was associated with less cell necrosis, suggesting that despite increased hypoxia-induced apoptosis, a significant decrease in uncontrolled cell death accounted for the change in viability observed. This finding also implies that alternative cell survival mechanisms could also be activated.
{"title":"Effect of hypoxia on chemosensitivity to 5-fluorouracil in SH-SY5Y neuroblastoma cells","authors":"H. R. Warren, M. Hejmadi","doi":"10.1093/BIOHORIZONS/HZW005","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW005","url":null,"abstract":"Resistance to chemotherapy is a major obstacle in clinical oncology. Hypoxia is a hallmark of solid tumours as a result of poorly structured tumour neovasculature and is known to be a key contributor to cancer malignancy and reduced drug effectiveness. Hypoxia-inducible factor-1 (HIF-1) mediates the hypoxic response, bringing about adaptive responses to the change in microenvironment. This study investigated the effect of 24 h hypoxia on the sensitivity of SH-SY5Y neuroblastoma cells to 5-fluorouracil (5-FU). Cytotoxicity, apoptosis and membrane integrity cell-based assays were carried out to observe changes in cell viability alongside apoptotic and necrotic cell death to determine the molecular mechanisms underlying reduced drug sensitivity. Hypoxic cells showed no change in cell viability to 5-FU in comparison to normoxic controls, suggesting that hypoxia conferred reduced drug sensitivity. As a measure of apoptosis, caspase-3/7 levels were significantly higher in hypoxic cells treated with increasing 5-FU concentrations. However, this was associated with less cell necrosis, suggesting that despite increased hypoxia-induced apoptosis, a significant decrease in uncontrolled cell death accounted for the change in viability observed. This finding also implies that alternative cell survival mechanisms could also be activated.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01DOI: 10.1093/BIOHORIZONS/HZW008
K. Sales, Laurie Kerr, J. Gardner
The niches of epiphytes are widely studied and have been shown to be complex involving interspecific competition, succession and predation. This study is unique in that it applies the niche concept to moss and lichen distributions within Killarney National Park, Kerry, Ireland. We studied 75 trees between three pristine ancient woodlands and measured a range of physical and biological factors to ascertain influences on epiphyte cover. The species of tree was found as the principal determinant in community structure as it bioengineers conditions such as light, temperature and humidity that the epiphytes are reliant upon. Furthermore, the bark character and trunk circumference were important. Zonation of the epiphytes was apparent with both aspect and height on the trunk. Typically, moss dominated over lichen within a niche that was relatively sheltered. Lichen tolerated drier and lighter niches often being further up the trunk on sun facing aspects. Ultimately, there was succession up the tree mediated through competition. This study highlights the complexity and interrelatedness between biotic and abiotic factors in a relatively unstudied geographical and biological area. Understanding agents behind a population's distribution enables manipulation for conservation or sustainable exploitation.
{"title":"Factors influencing epiphytic moss and lichen distribution within Killarney National Park","authors":"K. Sales, Laurie Kerr, J. Gardner","doi":"10.1093/BIOHORIZONS/HZW008","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZW008","url":null,"abstract":"The niches of epiphytes are widely studied and have been shown to be complex involving interspecific competition, succession and predation. This study is unique in that it applies the niche concept to moss and lichen distributions within Killarney National Park, Kerry, Ireland. We studied 75 trees between three pristine ancient woodlands and measured a range of physical and biological factors to ascertain influences on epiphyte cover. The species of tree was found as the principal determinant in community structure as it bioengineers conditions such as light, temperature and humidity that the epiphytes are reliant upon. Furthermore, the bark character and trunk circumference were important. Zonation of the epiphytes was apparent with both aspect and height on the trunk. Typically, moss dominated over lichen within a niche that was relatively sheltered. Lichen tolerated drier and lighter niches often being further up the trunk on sun facing aspects. Ultimately, there was succession up the tree mediated through competition. This study highlights the complexity and interrelatedness between biotic and abiotic factors in a relatively unstudied geographical and biological area. Understanding agents behind a population's distribution enables manipulation for conservation or sustainable exploitation.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZW008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-01-01DOI: 10.1093/BIOHORIZONS/HZV004
R. Langley
{"title":"Aspergillus nidulans Upf1: putative role of conserved active sites in ribosome recycling and 3′ end mRNA tagging","authors":"R. Langley","doi":"10.1093/BIOHORIZONS/HZV004","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZV004","url":null,"abstract":"","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"8 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZV004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-01-01DOI: 10.1093/BIOHORIZONS/HZV005
H. Paine
Neurodegenerative disorders such as Huntington’s, Alzheimer’s, Parkinson’s and prion diseases are progressive and without a cure. A common finding is one of misfolded protein aggregates, conventionally believed to underlie pathogenesis via a toxic gain of function. Recently, a potential contribution of loss of normal protein function has come under the spotlight. With a focus on huntingtin, the protein involved in Huntington’s disease, this review examines the evidence for the conventional ‘gain of function’ model, before considering the hypothesis that a loss of function contributes to pathogenesis. In support of a primarily toxic gain of function are findings that huntingtin aggregates are neurotoxic in vitro. Additionally, aggregates of mutant huntingtin proteins have been detected prior to neuropathological changes, supporting a causal role. However, a dissociation between the neurons containing mutant huntingtin aggregates and those that are most vulnerable in Huntington’s disease indicates the possibility of a contribution from a loss of protein function. Evidence suggests a neuroprotective role for huntingtin; loss of its functions could feasibly lead to neurodegeneration. An exclusive role of loss of function is contradicted by the finding that genetic ablation of huntingtin protein does not cause Huntington’s disease, but a contribution from loss of function is supported by similarities between neuropathological and behavioural phenotypes in animal models of Huntington’s Disease and those produced by loss of the normal functions of huntingtin. Perhaps, therefore, both loss and gain of function are necessary processes in Huntington’s pathogenesis, with neither one sufficient to cause the disease alone. Review of the current evidence fails to elucidate an exact role for loss of function in Huntington’s disease pathogenesis. More information is required on the extent to which depletion of the normal protein causes, rather than accompanies, disease. In the meantime, attempts at drug discovery should be mindful of the possibility of a contribution from loss of function when designing treatments and interpreting trial results.
{"title":"Does loss of the normal protein function contribute to the pathogenesis of Huntington's disease?","authors":"H. Paine","doi":"10.1093/BIOHORIZONS/HZV005","DOIUrl":"https://doi.org/10.1093/BIOHORIZONS/HZV005","url":null,"abstract":"Neurodegenerative disorders such as Huntington’s, Alzheimer’s, Parkinson’s and prion diseases are progressive and without a cure. A common finding is one of misfolded protein aggregates, conventionally believed to underlie pathogenesis via a toxic gain of function. Recently, a potential contribution of loss of normal protein function has come under the spotlight. With a focus on huntingtin, the protein involved in Huntington’s disease, this review examines the evidence for the conventional ‘gain of function’ model, before considering the hypothesis that a loss of function contributes to pathogenesis. In support of a primarily toxic gain of function are findings that huntingtin aggregates are neurotoxic in vitro. Additionally, aggregates of mutant huntingtin proteins have been detected prior to neuropathological changes, supporting a causal role. However, a dissociation between the neurons containing mutant huntingtin aggregates and those that are most vulnerable in Huntington’s disease indicates the possibility of a contribution from a loss of protein function. Evidence suggests a neuroprotective role for huntingtin; loss of its functions could feasibly lead to neurodegeneration. An exclusive role of loss of function is contradicted by the finding that genetic ablation of huntingtin protein does not cause Huntington’s disease, but a contribution from loss of function is supported by similarities between neuropathological and behavioural phenotypes in animal models of Huntington’s Disease and those produced by loss of the normal functions of huntingtin. Perhaps, therefore, both loss and gain of function are necessary processes in Huntington’s pathogenesis, with neither one sufficient to cause the disease alone. Review of the current evidence fails to elucidate an exact role for loss of function in Huntington’s disease pathogenesis. More information is required on the extent to which depletion of the normal protein causes, rather than accompanies, disease. In the meantime, attempts at drug discovery should be mindful of the possibility of a contribution from loss of function when designing treatments and interpreting trial results.","PeriodicalId":52095,"journal":{"name":"Bioscience Horizons","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/BIOHORIZONS/HZV005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"60765505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-01-01DOI: 10.1093/BIOHORIZONS/HZV001
Jiawen Liu, D. Yellon, S. Davidson
Reductions in cardiac infarct size can be achieved in ischaemic preconditioning, a procedure which subjects the heart to intermittent, non-lethal cycles of ischaemia and reperfusion. Similar cardioprotection can be induced upon preconditioning distal tissues such as the upper limb, and this procedure is called remote ischaemic preconditioning. Nano-sized, cell-derived vesicles known as exosomes have been shown previously to be capable of inducing cardioprotection when administered acutely, and we hypothesized that exosomes produced after remote ischaemic preconditioning (RIPC) enhances the observed cardioprotection. We also investigated whether exosomes can confer cardioprotection 24 h later. We isolated exosomes from the plasma of three healthy male volunteers before and after they underwent four cycles of 5 min upper limb ischaemia and 5 min reperfusion, and then administered the exosomes to primary rat ventricular cardiomyocytes isolated from male Sprague Dawley rats. Cardiomyocytes were subjected to 2.5 h of simulated ischaemia and 1 h simulated reperfusion. We assessed cardiomyocyte viability with propidium iodide staining and observed significant reductions in cardiomyocyte death when control exosomes were administered either 30 min or 24 h before hypoxia. Exosomes obtained after RIPC induced a similar degree of cardioprotection at both time points. As miRNA-144/451 have been proposed to mediate RIPC, we investigated whether introducing antagomiRs of miRNA-144/451 with the exosomes would attenuate cardioprotection after 24 h. No significant differences in cardioprotection were observed, suggesting that miRNA-144/451 may not be directly involved in this model. Our findings suggest that regardless of their origin from control or RIPC hearts, exosomes per se can be used to induce cardioprotection either acutely or after 24 h.
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