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Chromatin-bound oxidized α-synuclein causes strand breaks in neuronal genomes in in vitro models of Parkinson’s disease
Full text linkAlpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD
Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016
Full text linkBackground Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI).Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate.Background Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI).Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate
Water quality effects of intermittent water supply in Arraiján, Panama
Full text linkIntermittent drinking water supply is common in low- and middle-income countries throughout the world and can cause waterquality to degrade in the distribution system.In this study,we characterized waterquality in one study zone with continuous supply and three zoneswith intermittentsupply in the drinking waterdistribution network in Arraija!n,Panama.Low orzero pressuresoccurred in allzones,and negative pressuresoccurred in the continuouszone and two ofthe intermittentzones.Despite hydraulic conditions that created risks for backflow and contaminant intrusion, only four of 423 (0.9%) grab samplescollected atrandom timeswere positive fortotalcoliform bacteria and only one waspositive for E.coli.Only nine of 496 (1.8%) samples had turbidity >1.0 NTU and all samples had !0.2 mg/L free chlorine residual.In contrast,water quality was often degraded during the first-flush period (when supply first returned after an outage).Still, routine and first-flush water quality under intermittent supply was much better in Arraija!n than that reported in a previous study conducted in India.Better waterquality in Arraija!n could be due to betterwaterquality leaving the treatmentplant,shortersupply outages,highersupply pressures,a more consistentand higherchlorine residual,and fewercontaminant sourcesnearpipes.The resultsillustrate thatintermittentsupply and itseffectson waterquality can vary greatly between and within distribution networks.The study also demonstrated thatmonitoring techniques designed specifically for intermittentsupply,such as continuous pressure monitoring and sampling the firstflush,can detectwaterquality threats and degradation thatwould notlikely be detected with conventionalmonitoring.Intermittent drinking water supply is common in low- and middle-income countries throughout the world and can cause waterquality to degrade in the distribution system.In this study,we characterized waterquality in one study zone with continuous supply and three zoneswith intermittentsupply in the drinking waterdistribution network in Arraija!n,Panama.Low orzero pressuresoccurred in allzones,and negative pressuresoccurred in the continuouszone and two ofthe intermittentzones.Despite hydraulic conditions that created risks for backflow and contaminant intrusion, only four of 423 (0.9%) grab samplescollected atrandom timeswere positive fortotalcoliform bacteria and only one waspositive for E.coli.Only nine of 496 (1.8%) samples had turbidity >1.0 NTU and all samples had !0.2 mg/L free chlorine residual.In contrast,water quality was often degraded during the first-flush period (when supply first returned after an outage).Still, routine and first-flush water quality under intermittent supply was much better in Arraija!n than that reported in a previous study conducted in India.Better waterquality in Arraija!n could be due to betterwaterquality leaving the treatmentplant,shortersupply outages,highersupply pressures,a more consistentand higherchlorine residual,and fewercontaminant sourcesnearpipes.The resultsillustrate thatintermittentsupply and itseffectson waterquality can vary greatly between and within distribution networks.The study also demonstrated thatmonitoring techniques designed specifically for intermittentsupply,such as continuous pressure monitoring and sampling the firstflush,can detectwaterquality threats and degradation thatwould notlikely be detected with conventionalmonitoring
Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015
Full text linkBackground National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Methods We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time.Background National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Methods We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time
Imaging mass spectrometry and MS/MS molecular networking reveals chemical interactions among cuticular bacteria and pathogenic fungi associated with fungus-growing ants
Full text linkThe fungus-growing ant-microbe symbiosis is an ideal system to study chemistry-based microbial interactions due to the wealth of microbial interactions described, and the lack of information on the molecules involved therein. In this study, we employed a combination of MALDI imaging mass spectrometry (MALDI-IMS) and MS/MS molecular networking to study chemistry-based microbial interactions in this system. MALDI IMS was used to visualize the distribution of antimicrobials at the inhibition zone between bacteria associated to the ant Acromyrmex echinatior and the fungal pathogen Escovopsis sp. MS/MS molecular networking was used for the dereplication of compounds found at the inhibition zones. We identified the antibiotics actinomycins D, X2 and X0β, produced by the bacterium Streptomyces CBR38; and the macrolides elaiophylin, efomycin A and efomycin G, produced by the bacterium Streptomyces CBR53.These metabolites were found at the inhibition zones using MALDI IMS and were identified using MS/MS molecular networking. Additionally, three shearinines D, F, and J produced by the fungal pathogen Escovopsis TZ49 were detected. This is the first report of elaiophylins, actinomycin X0β and shearinines in the fungus-growing ant symbiotic system. These results suggest a secondary prophylactic use of these antibiotics by A. echinatior because of their permanent production by the bacteria.The fungus-growing ant-microbe symbiosis is an ideal system to study chemistry-based microbial interactions due to the wealth of microbial interactions described, and the lack of information on the molecules involved therein. In this study, we employed a combination of MALDI imaging mass spectrometry (MALDI-IMS) and MS/MS molecular networking to study chemistry-based microbial interactions in this system. MALDI IMS was used to visualize the distribution of antimicrobials at the inhibition zone between bacteria associated to the ant Acromyrmex echinatior and the fungal pathogen Escovopsis sp. MS/MS molecular networking was used for the dereplication of compounds found at the inhibition zones. We identified the antibiotics actinomycins D, X2 and X0β, produced by the bacterium Streptomyces CBR38; and the macrolides elaiophylin, efomycin A and efomycin G, produced by the bacterium Streptomyces CBR53.These metabolites were found at the inhibition zones using MALDI IMS and were identified using MS/MS molecular networking. Additionally, three shearinines D, F, and J produced by the fungal pathogen Escovopsis TZ49 were detected. This is the first report of elaiophylins, actinomycin X0β and shearinines in the fungus-growing ant symbiotic system. These results suggest a secondary prophylactic use of these antibiotics by A. echinatior because of their permanent production by the bacteria
Discovery and Synthesis of Caracolamide A, an Ion Channel Modulating Dichlorovinylidene Containing Phenethylamide from a Panamanian Marine Cyanobacterium cf. Symploca Species
Full text linkA recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent targetdirected isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gemdichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a threestep synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 μM).A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent targetdirected isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gemdichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a threestep synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 μM)
Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016
Full text linkBackground The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030.Methods We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0–100, with 0 as the 2·5th percentile estimated between 1990 and 2030, and 100 as the 97·5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country-specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment.Background The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030.Methods We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0–100, with 0 as the 2·5th percentile estimated between 1990 and 2030, and 100 as the 97·5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country-specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment
Are pulmonary fibrosis and Alzheimer's disease linked? Shared dysregulation of two miRNA species and downstream pathways accompany both disorders
Full text linkAs neuroscientists, we were intrigued when Huang et al. (1) reported that miR101 can attenuate pulmonary fibrosis (PF)2 through suppression of Wnt family member 5A (WNT5A). Accumulating evidence suggests that prima facie unrelated disorders in multiple fields of medicine share fundamental molecular pathways. For example, PF associates with cognitive impairment (2). It is reasonable to presume that such links would be due to hypoxia and general inflammation, but could there be a deeper connection? Both miR101 and miR27b expression levels were significantly reduced in more severe PF cases (1). These same miRNA are implicated and reduced (3, 4) in Alzheimer's disease (AD). Interestingly, while miR101 levels are reduced in late-stage AD brain samples, an miRNA associated with AD and Parkinson's disease, miR153, is not (5). Notably, miR27b regulates peroxisome proliferator–activated receptor γ (PPARγ), and PPARγ disruption is implicated in both AD and PF (3). Wnt signaling disruption is a well-known molecular feature of AD (6). That two miRNA species are both down-regulated and pathways they regulate are linked to specific pulmonary and neurological disorders is noteworthy. If we want to take a broader view of connection or divergence of progressive disorders, we also can consider that miRNAs usually have multiple mRNA targets. In addition to regulating Wnt signaling, miR101 regulates levels of the Aβ-precursor protein (APP) and, by extension, its neurotoxic processing product, Aβ (4). APP, as such, has not been directly implicated in PF, but it would not be unreasonable to propose that disruption of miR101 would impact several vital signaling and expression pathways. Disruption of a fundamental, multiorgan-wide pathway such as Wnt or PPARγ signaling could be a broad precursor to multiple disorders, with specificity to be determined by other interactions. This suggests the potential for developing a therapeutic strategy to utilize common dysregulation of specific miRNAs for disparate diseases.As neuroscientists, we were intrigued when Huang et al. (1) reported that miR101 can attenuate pulmonary fibrosis (PF)2 through suppression of Wnt family member 5A (WNT5A). Accumulating evidence suggests that prima facie unrelated disorders in multiple fields of medicine share fundamental molecular pathways. For example, PF associates with cognitive impairment (2). It is reasonable to presume that such links would be due to hypoxia and general inflammation, but could there be a deeper connection? Both miR101 and miR27b expression levels were significantly reduced in more severe PF cases (1). These same miRNA are implicated and reduced (3, 4) in Alzheimer's disease (AD). Interestingly, while miR101 levels are reduced in late-stage AD brain samples, an miRNA associated with AD and Parkinson's disease, miR153, is not (5). Notably, miR27b regulates peroxisome proliferator–activated receptor γ (PPARγ), and PPARγ disruption is implicated in both AD and PF (3). Wnt signaling disruption is a well-known molecular feature of AD (6). That two miRNA species are both down-regulated and pathways they regulate are linked to specific pulmonary and neurological disorders is noteworthy. If we want to take a broader view of connection or divergence of progressive disorders, we also can consider that miRNAs usually have multiple mRNA targets. In addition to regulating Wnt signaling, miR101 regulates levels of the Aβ-precursor protein (APP) and, by extension, its neurotoxic processing product, Aβ (4). APP, as such, has not been directly implicated in PF, but it would not be unreasonable to propose that disruption of miR101 would impact several vital signaling and expression pathways. Disruption of a fundamental, multiorgan-wide pathway such as Wnt or PPARγ signaling could be a broad precursor to multiple disorders, with specificity to be determined by other interactions. This suggests the potential for developing a therapeutic strategy to utilize common dysregulation of specific miRNAs for disparate diseases
Volatile organic compounds associated with Plasmodium falciparum infection in vitro
Full text linkBackground: In order to identify new ways to prevent transmission of vector-borne diseases such as malaria, efforts have been made to understand how insects are attracted to humans. Vector-host interaction studies have shown that several volatile compounds play an important role in attracting mosquitoes to human targets. A headspace solid-phase micro-extraction/gas chromatography-mass spectrometry (HSPME GC-MS) analysis of the volatile organic composition of extracellular vesicles (EVs) and supernatants of ultracentrifugation (SNUs) was carried out in Plasmodium falciparum-infected cultures with high and low parasitemias.
Results: A list of 18 volatile organic compounds (VOCs) was obtained from the EVs of both infected and uninfected RBCs with 1,2,3-Propanetriol, diacetate (diacetin) increased in the infected EVs, regardless of the parasitemia of the culture. The supernatant analysis, however, gave off 56 VOCs, with pentane 2,2,4-trimethyl being present in all the SNUs of uninfected erythrocytes but absent from the parasite-infected ones. Standing out in this study was hexanal, a reported insect attractant, which was the only VOC present in all samples from SNUs from infected erythrocytes and absent from uninfected ones, suggesting that it originates during parasite infection.
Conclusions: The hexanal compound, reportedly a low-level component found in healthy human samples such as breath and plasma, had not been found in previous analyses of P. falciparum-infected patients or cultures. This compound has been reported as an Anopheles gambiae attractant in plants. While the compound could be produced during infection by the malaria parasite in human erythrocytes, the A. gambiae attraction could be used by the parasite as a strategy for transmission.Background: In order to identify new ways to prevent transmission of vector-borne diseases such as malaria, efforts have been made to understand how insects are attracted to humans. Vector-host interaction studies have shown that several volatile compounds play an important role in attracting mosquitoes to human targets. A headspace solid-phase micro-extraction/gas chromatography-mass spectrometry (HSPME GC-MS) analysis of the volatile organic composition of extracellular vesicles (EVs) and supernatants of ultracentrifugation (SNUs) was carried out in Plasmodium falciparum-infected cultures with high and low parasitemias.
Results: A list of 18 volatile organic compounds (VOCs) was obtained from the EVs of both infected and uninfected RBCs with 1,2,3-Propanetriol, diacetate (diacetin) increased in the infected EVs, regardless of the parasitemia of the culture. The supernatant analysis, however, gave off 56 VOCs, with pentane 2,2,4-trimethyl being present in all the SNUs of uninfected erythrocytes but absent from the parasite-infected ones. Standing out in this study was hexanal, a reported insect attractant, which was the only VOC present in all samples from SNUs from infected erythrocytes and absent from uninfected ones, suggesting that it originates during parasite infection.
Conclusions: The hexanal compound, reportedly a low-level component found in healthy human samples such as breath and plasma, had not been found in previous analyses of P. falciparum-infected patients or cultures. This compound has been reported as an Anopheles gambiae attractant in plants. While the compound could be produced during infection by the malaria parasite in human erythrocytes, the A. gambiae attraction could be used by the parasite as a strategy for transmission
Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer’s drug discovery
Full text linkAlzheimer’s disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD.Alzheimer’s disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD