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Regulation of microtubule dynamics is required to properly control various steps of neurodevelopment. In this study, we identified granule cell antiserum-positive 14 (Gcap14) as a microtubule plus-end-tracking protein and as a regulator of microtubule dynamics during neurodevelopment. Gcap14 knockout mice exhibited impaired cortical lamination. Gcap14 deficiency resulted in defective neuronal migration. Moreover, nuclear distribution element nudE-like 1 (Ndel1), an interacting partner of Gcap14, effectively corrected the downregulation of microtubule dynamics and the defects in neuronal migration caused by Gcap14 deficiency. Finally, we found that the Gcap14-Ndel1 complex participates in the functional link between microtubule and actin filament, thereby regulating their crosstalks in the growth cones of cortical neurons. Taken together, we propose that the Gcap14-Ndel1 complex is fundamental for cytoskeletal remodeling during neurodevelopmental processes such as neuronal processes elongation and neuronal migration.
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Actinas , Proteínas Associadas aos Microtúbulos , Neurônios , Animais , Camundongos , Actinas/metabolismo , Movimento Celular/fisiologia , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Neuritos/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.
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Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , Aterosclerose/metabolismo , Inflamação , Proteína Quinase 7 Ativada por Mitógeno/genética , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
The Streptomyces strain G222, isolated from a Vietnamese marine sediment, was confidently identified by 16S rRNA gene sequencing. Its AcOEt crude extract was successfully analyzed using non-targeted LC-MS/MS analysis, and molecular networking, leading to a putative annotation of its chemical diversity thanks to spectral libraries from GNPS and in silico metabolite structure prediction obtained from SIRIUS combined with the bioinformatics tool conCISE (Consensus Annotation Propagation of in silico Elucidations). This dereplication strategy allowed the identification of an interesting cluster of a series of putative cyclic and linear lipopeptides of the lichenysin and surfactin families. Lichenysins (3-7) were isolated from the sub-fraction, which showed significant anti-biofilm activity against Pseudomonas aeruginosa MUC-N1. Their structures were confirmed by detailed 1D and 2D NMR spectroscopy (COSY, HSQC, HMBC, TOCSY, ROESY) recorded in CD3OH, and their absolute configurations were determined using the modified Marfey's method. The isolated lichenysins showed anti-biofilm activity at a minimum concentration of 100 µM. When evaluated for antibacterial activity against a panel of Gram-positive and Gram-negative strains, two isolated lichenysins exhibited selective activity against the MRSA strain without affecting its growth curve and without membranotropic activity. This study highlights the power of the MS/MS spectral similarity strategy using computational methods to obtain a cross-validation of the annotated molecules from the complex metabolic profile of a marine sediment-derived Streptomyces extract. This work provides the first report from a Streptomyces strain of combined cyclic and linear lichenysins and surfactins, known to be characteristic compounds of the genus Bacillus.
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Sedimentos Geológicos , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida , RNA Ribossômico 16S , VietnãRESUMO
Prevalence of mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are increasing at alarming rates in our societies. Growing evidence points toward major sex differences in these conditions, and high rates of treatment resistance support the need to consider novel biological mechanisms outside of neuronal function to gain mechanistic insights that could lead to innovative therapies. Blood-brain barrier alterations have been reported in MDD, BD and SZ. Here, we provide an overview of sex-specific immune, endocrine, vascular and transcriptional-mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders. We also identify pitfalls in current literature and highlight promising vascular biomarkers. Better understanding of how these adaptations can contribute to mental health status is essential not only in the context of MDD, BD and SZ but also cardiovascular diseases and stroke which are associated with higher prevalence of these conditions.
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Transtorno Bipolar , Transtorno Depressivo Maior , Barreira Hematoencefálica/patologia , Feminino , Humanos , Masculino , Saúde Mental , Caracteres SexuaisRESUMO
The natural antimicrobial peptide Polybia-MP1 is a promising candidate for developing new treatment therapy for infection and cancer. It showed broad-spectrum antimicrobial and anticancer activity with high safety on healthy cells. However, previous sequence modification usually resulted in at least one of two consequences: a notable increase in hemolytic activity or a considerable decrease in activity against Gram-negative bacteria and cancer cells. Herein, a new approach was applied by replacing the amino acid Glutamine at position 12 with Lysine and generating the MP1-Q12K analog. Our preliminary data suggested an enhancement in antibacterial and antifungal activity, whereas the anticancer and hemolytic activity of the two peptides were comparable. Moreover, MP1-Q12K was found to be less self-assembly than Polybia-MP1, which further supports the enhancement of antimicrobial properties. Hence, this study provides new information regarding the structure-activity relationships of Polybia-MP1 and support for the development of potent, selective antimicrobial peptides.
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Anti-Infecciosos , Peptídeos Antimicrobianos , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Glutamina/farmacologia , Lisina/farmacologia , Testes de Sensibilidade Microbiana , Venenos de Vespas/químicaRESUMO
Chemical study on marine sponge-derivated fungus Aspergillus nidulans resulted in the isolation of seven depsidones (1-7) and two macrocyclic peptides (8 and 9). Their chemical structures were elucidated by extensive analyses of HRESIMS and NMR spectral data, as well as comparison with the literature. Compoundâ 1 was an undescribed depsidone. All compounds exhibited significant antimicrobial activity (MICs: 2-128â µg/mL) towards at least one of seven microbial strains, including Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, and Candida albicans. Of these, chlorinated depsidones (1-3, and 5) displayed potential antimicrobial activity. Nidulin (2) possessed good activity against tested strains except for S. enterica with MIC values in range of 2-16â µg/mL. Interestingly, undescribed depsidone 1 was selectively bioactive on the Gram-positive bacteria (MICs: 2-4â µg/mL) and yeast (MIC: 8â µg/mL) but inactivity on the Gram-negative bacteria (MICs: >256â µg/mL). Macrocyclic peptides, 8 and 9, displayed modest activity against E. faecalis strain with MIC values of 32 and 128â µg/mL, respectively.
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Anti-Infecciosos , Aspergillus nidulans , Poríferos , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Infecciosos/química , Testes de Sensibilidade Microbiana , Peptídeos/farmacologiaRESUMO
BACKGROUND: Prolactin (PRL) is one of the most diverse pituitary hormones and is known to modulate normal neuronal function and neurodegenerative conditions. Many studies have described the influence that PRL has on the central nervous system and addressed its contribution to neurodegeneration, but little is known about the mechanisms responsible for the effects of PRL on neurodegenerative disorders, especially on Alzheimer's disease (AD) and Parkinson's disease (PD). SUMMARY: We review and summarize the existing literature and current understanding of the roles of PRL on various PRL aspects of AD and PD. KEY MESSAGES: In general, PRL is viewed as a promising molecule for the treatment of AD and PD. Modulation of PRL functions and targeting of immune mechanisms are needed to devise preventive or therapeutic strategies.
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Doença de Alzheimer , Doença de Parkinson , Humanos , Neurônios , ProlactinaRESUMO
Studies on bacterial plant diseases have thus far been focused on the single bacterial species causing the disease, with very little attention given to the many other microorganisms present in the microbiome. This study intends to use pathobiome analysis of the rice foot rot disease, caused by Dickeya zeae, as a case study to investigate the effects of this bacterial pathogen to the total resident microbiome and to highlight possible interactions between the pathogen and the members of the community involved in the disease process. The microbiome of asymptomatic and the pathobiome of foot-rot symptomatic field-grown rice plants over two growing periods and belonging to two rice cultivars were determined via 16S rRNA gene amplicon sequencing. Results showed that the presence of D. zeae is associated with an alteration of the resident bacterial community in terms of species composition, abundance and richness, leading to the formation of microbial consortia linked to the disease state. Several bacterial species were significantly co-presented with the pathogen in the two growing periods suggesting that they could be involved in the disease process. Besides, culture-dependent isolation and in planta inoculation studies of a bacterial member of the pathobiome, identified as positive correlated with the pathogen in our in silico analysis, indicated that it benefits from the presence of D. zeae. A similar microbiome/pathobiome experiment was also performed in a symptomatically different rice disease evidencing that not all plant diseases have the same consequence/relationship with the plant microbiome. This study moves away from a pathogen-focused stance and goes towards a more ecological perception considering the effect of the entire microbial community which could be involved in the pathogenesis, persistence, transmission and evolution of plant pathogens.
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Microbiota , Oryza , Dickeya , Enterobacteriaceae/genética , Microbiota/genética , Oryza/microbiologia , Doenças das Plantas/microbiologia , RNA Ribossômico 16S/genéticaRESUMO
Data from the Voyager probes have provided us with the first measurement of cosmic ray intensities at MeV energies, an energy range that had previously not been explored. Simple extrapolations of models that fit data at GeV energies, e.g., from AMS-02, however, fail to reproduce the Voyager data in that the predicted intensities are too high. Oftentimes, this discrepancy is addressed by adding a break to the source spectrum or the diffusion coefficient in an ad hoc fashion, with a convincing physical explanation yet to be provided. Here, we argue that the discrete nature of cosmic ray sources, which is usually ignored, is instead a more likely explanation. We model the distribution of intensities expected from a statistical model of discrete sources and show that its expectation value is not representative but has a spectral shape different from that for a typical configuration of sources. The Voyager proton and electron data are however compatible with the median of the intensity distribution.
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BACKGROUND/AIMS: The prevalence of acute lower gastrointestinal bleeding (ALGIB) has progressively increased worldwide but there are few studies in Asian populations. This study aimed to develop and validate a scoring system to predict severe ALGIB in Vietnamese. METHODS: Risk factors for severe ALGIB were identified by multiple logistic regression analysis using data from a retrospective cohort of 357 patients admitted to a tertiary hospital. These factors were weighted to develop the severe acute lower gastrointestinal bleeding (SALGIB) score to predict severe ALGIB. The performance of SALGIB was validated in a prospective cohort of 324 patients admitted to 6 other hospitals using area under the receiver operating characteristics curve (AUC) analysis. RESULTS: There were four factors at admission independently associated with severe ALGIB in the derivation cohort: heart rate ≥ 100/min, systolic blood pressure < 100 mmHg, hematocrit < 35%, and platelets ≤ 150 × 103/µL. The SALGIB score determined severe ALGIB with AUC values of 0.91 and 0.86 in the derivation and validation cohorts, respectively. A SALGIB score < 2 associated with low risk of severe ALGIB in both cohorts (3.7% and 1.2%; respectively). CONCLUSIONS: The SALGIB score has good performance in discriminating risk of severe ALGIB in Vietnamese.
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Povo Asiático/estatística & dados numéricos , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etnologia , Medição de Risco/normas , Avaliação de Sintomas/normas , Doença Aguda , Idoso , Área Sob a Curva , Pressão Sanguínea , Feminino , Hemorragia Gastrointestinal/etiologia , Frequência Cardíaca , Hematócrito , Humanos , Modelos Logísticos , Trato Gastrointestinal Inferior , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos , Vietnã/etnologiaRESUMO
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Insuficiência Cardíaca/genética , Ventrículos do Coração/embriologia , Proteína Homeobox Nkx-2.5/metabolismo , Miocárdio Ventricular não Compactado Isolado/genética , Morfogênese/genética , Animais , Modelos Animais de Doenças , Feminino , Fibrose , Perfilação da Expressão Gênica , Ventrículos do Coração/patologia , Proteína Homeobox Nkx-2.5/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Miocárdio Ventricular não Compactado Isolado/complicações , Miocárdio Ventricular não Compactado Isolado/diagnóstico , Miocárdio Ventricular não Compactado Isolado/patologia , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Ramos Subendocárdicos/patologia , Deleção de Sequência , Índice de Gravidade de Doença , Regulação para CimaRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1007502.].
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Three new lavandulylated flavonoids, (2S,2''S)-6-lavandulyl-7,4'-dimethoxy-5,2'-dihydroxylflavanone (1), (2S,2''S)-6-lavandulyl-5,7,2',4'-tetrahydroxylflavanone (2), and (2''S)-5'-lavandulyl-2'-methoxy-2,4,4',6'-tetrahydroxylchalcone (3), along with seven known compounds 4-10 were isolated from culture broth of Streptomyces sp. G248. Their structures were established by spectroscopic data analysis, including 1D and 2D nuclear magnetic resonance (NMR), and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configurations of 1-3 were resolved by comparison of their experimental and calculated electronic circular dichroism spectra. Compounds 1-3 exhibited remarkable antimicrobial activity. Whereas, two known compounds 4 and 5 exhibited inhibitory activity against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) values of 6.0 µg/mL and 11.1 µg/mL, respectively.
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Antibióticos Antituberculose/farmacologia , Flavonoides/farmacologia , Poríferos/microbiologia , Streptomyces/química , Animais , Antibióticos Antituberculose/química , Antibióticos Antituberculose/isolamento & purificação , Linhagem Celular Tumoral , Dicroísmo Circular , Flavonoides/química , Flavonoides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , VietnãRESUMO
The preservation of perishable food via refrigeration in the supply chain is essential to extend shelf life and provide consumers with safe food. However, electricity consumed in refrigeration processes has an economical and an environmental impact. This study focuses on the cold chain of cooked ham, including transport, cold room in supermarket, display cabinet, transport by consumer, and domestic refrigerator, and aims to predict the risk for human health associated with Listeria monocytogenes, the amount of food wasted due to the growth of spoilage bacteria, and the electrical consumption to maintain product temperature through the cold chain. A set of eight intervention actions were tested to evaluate their impact on the three criteria. Results show that the modification of the thermostat of the domestic refrigerator has a high impact on food safety and food waste and a limited impact on the electrical consumption. Inversely, the modification of the airflow rate in the display cabinet has a high impact on electrical consumption and a limited impact on food safety and food waste. A cost-benefit analysis approach and two multicriteria decision analysis methods were used to rank the intervention actions. These three methodologies show that setting the thermostat of the domestic refrigerator to 4 °C presents the best compromise between the three criteria. The impact of decisionmaker preferences (criteria weight) and limitations of these three approaches are discussed. The approaches proposed by this study may be useful in decision making to evaluate global impact of intervention actions in issues involving conflicting outputs.
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Medição de Risco , Economia , Alimentos , Inocuidade dos Alimentos , Humanos , Fundos de SeguroRESUMO
Marine microorganisms are an invaluable source of novel active secondary metabolites possessing various biological activities. In this study, the extraction and isolation of the marine sediment Penicillium species collected in Vietnam yielded ten secondary metabolites, including sporogen AO-1 (1), 3-indolecarbaldehyde (2), 2-[(5-methyl-1,4-dioxan-2-yl)methoxy]ethanol (3), 2-[(2R-hydroxypropanoyl)amino]benzamide (4), 4-hydroxybenzandehyde (5), chrysogine (6), 3-acetyl-4-hydroxycinnoline (7), acid 1H-indole-3-acetic (8), cyclo (Tyr-Trp) (9), and 2',3'-dihydrosorbicillin (10). Their structures were identified by the analysis of 1D and 2D NMR data. Among the isolated compounds, 2-[(5-methyl-1,4-dioxan-2-yl)methoxy]ethanol (3) showed a strong inhibitory effect against Enterococcus faecalis with a minimum inhibitory concentration value of 32 µg/mL. Both 2-[(2R-hydroxypropanoyl)amino]benzamide (4) and 4-hydroxybenzandehyde (5) selectively inhibited E. coli with minimum inhibitory concentration values of 16 and 8 µg/mL, respectively. 2',3'-Dihydrosorbicillin (10) potentially inhibited α-glucosidase activity at a concentration of 2.0 mM (66.31%).
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Antibacterianos , Organismos Aquáticos , Enterococcus faecalis/crescimento & desenvolvimento , Penicillium , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Organismos Aquáticos/química , Organismos Aquáticos/metabolismo , Estrutura Molecular , Penicillium/química , Penicillium/metabolismo , VietnãRESUMO
Heavy metal and metalloid contamination and related risks for the environment and human health are matters of increasing concern. This study assessed metal and metalloid concentrations in soil, surface water, and locally grown vegetable to assess exposure and related risks for the environment and human health in the northeastern rural area of Hanoi. Concentrations of metals and metalloids in soils exceeded regulatory thresholds in some locations (e.g., Me Linh and Gia Lam districts). The carcinogenic elements As and Cr were identified as a major concern with concentrations up to 693 µg g-1 and 147 µg g-1, respectively. Industrial point sources or groundwater irrigation practices in the intensive organic farming areas were identified as potential factors contributing to the accumulation of carcinogenic metals and metalloids in topsoil layers. Metal and metalloid concentrations detected in water and vegetables were below the regulatory threshold levels (WHO guideline and maximum allowable limits). While contamination was not observed at a large geographical scale, local soil contamination in specific areas of agricultural importance could pose high ecological and human health-related risks with unclear long-term impacts. The highly carcinogenic soil contamination detected in this study may be a factor adding to the increased cancer incidence rate in Hanoi area, as the total carcinogenic risk calculated for Hanoi area exceeds the cancer likelihood threshold by a factor of 25. Further research is needed to examine potential links, and the involvement of both stakeholders and policy makers is needed to adequately evaluate the risks for Hanoi area and coordinate future remediation plans if risks are justified.
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Monitoramento Ambiental/métodos , Poluição Ambiental/análise , Metaloides/análise , Metais Pesados/análise , Agricultura , Ecologia , Humanos , Medição de Risco , Solo/química , Poluentes do Solo/análise , Verduras/química , Vietnã , Água/análiseRESUMO
BACKGROUND: The current literature discourages the use of acid suppressive therapy (AST) for stress ulcer prophylaxis (SUP) in noncritically ill patients. However, several sources indicate that the majority of noncritically ill patients are given AST for SUP while there may only be a small proportion of high-risk patients who need SUP therapy. There is a new scoring system to aid practitioners in stratifying the risk of stress ulcer-related gastrointestinal bleeding in noncritically ill patients developed by Herzig et al and appropriately prescribe AST for SUP in this population. OBJECTIVE: Our primary objective was to determine the current usage of AST in noncritically ill patients at a tertiary teaching hospital and use the new scoring system to identify non-intensive care unit patients who were inappropriately given AST. METHODS: We retrospectively determined the percentage of noncritically ill patients who were given AST on medical floors between January 2010 and December 2012. After identifying these patients, we randomly selected a sample and retrospectively collected data from their medical record to determine the gastrointestinal bleeding risk score to determine if the patient was appropriately given AST. RESULTS: Of the 42 600 admissions, 22 949 (53.7%) noncritically ill patients were given AST. A total of 442 patients were randomly selected for data collection and 156 patients were excluded. Gastrointestinal bleeding risk score was calculated in 286 patients. This new risk stratification tool identified 253 (88.5%) patients to have a low (≤7) and low-medium risk score (8-9). CONCLUSIONS: A large percentage of noncritically ill patients were given AST during their hospital stay; 88.5% of these medications were given inappropriately to patients who were at extremely low risk of gastrointestinal bleeding. Using the above information and the AST prescribing patterns at our institution, we estimate a potential inpatient medication cost savings of $114 622 for the study period.
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Úlcera Péptica/prevenção & controle , Adulto , Idoso , Redução de Custos , Custos de Medicamentos , Feminino , Hemorragia Gastrointestinal/economia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/prevenção & controle , Antagonistas dos Receptores H2 da Histamina/economia , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Hospitalização , Hospitais de Ensino , Humanos , Pacientes Internados , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/economia , Úlcera Péptica/etiologia , Inibidores da Bomba de Prótons/economia , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Risco , Estresse Fisiológico , Estresse Psicológico/complicações , Centros de Atenção Terciária , ÚlceraRESUMO
Exposure to n-hexane and its metabolite 2,5-hexandione (HD) is a well-known cause of neurotoxicity, particularly in the peripheral nervous system. To date, few studies have focused on the neurotoxic effects of HD on cognitive impairment. Exposure to HD and diabetes mellitus can exacerbate neurotoxicity. There are links among HD, diabetes mellitus, and cognitive impairment; however, the specific mechanisms underlying them remain unclear. Therefore, we aimed to elucidate the neurotoxic effects of HD on cognitive impairment in ob/ob (C57BL/6-Lepem1Shwl/Korl) mice. We found that HD induced cognitive impairment by altering the expression of genes (FN1, AGT, ACTA2, MYH11, MKI67, MET, CTGF, and CD44), miRNAs (mmu-miR15a-5p, mmu-miR-17-5p, and mmu-miR-29a-3p), transcription factors (transcription factor AP-2 alpha [TFAP2A], serum response factor [Srf], and paired box gene 4 [PAX4]), and signaling pathways (ERK/CERB, PI3K/AKT, GSK-3ß/p-tau/amyloid-ß), as well as by causing neuroinflammation (TREM1/DAP12/NF-κB), oxidative stress, and apoptosis. The prevalent use of n-hexane in various industrial applications (for instance, shoe manufacturing, printing inks, paints, and varnishes) suggests that individuals with elevated body weight and glucose levels and those employed in high-risk workplaces have greater probability of cognitive impairment. Therefore, implementing screening strategies for HD-induced cognitive dysfunction is crucial. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00228-1.
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BACKGROUND: Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease. METHODS: We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation. RESULTS: Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied. CONCLUSIONS: GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.
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Condrócitos/citologia , Códon sem Sentido , Proteínas Nucleares/genética , Osteocondrodisplasias/genética , Animais , Diferenciação Celular , Proliferação de Células , Proteínas do Citoesqueleto , Retículo Endoplasmático/ultraestrutura , Genes Recessivos , Glicosilação , Complexo de Golgi/ultraestrutura , Humanos , Camundongos , Camundongos Mutantes , Proteínas Nucleares/deficiência , Fenótipo , Polimorfismo de Nucleotídeo Único , Processamento de Proteína Pós-Traducional/fisiologia , Análise de Sequência de DNARESUMO
Cognitive impairment and organic solvent exposure have been becoming public health concerns due to an increasingly aging population, increased life expectancy, urbanization, and industrialization. Converging evidence indicates the link between 1,2-diacetylbenzene (DAB), prolactin (PRL), risperidone, and cognitive impairment. However, these relationships remain unclear. We investigated the therapeutic properties of risperidone in DAB-induced cognitive impairment using both in vivo and in silico methods. Risperidone alleviated DAB-induced cognitive impairment in hippocampal mice, possibly by inhibiting GSK-3ß, ß-amyloid, CDK5, BACE, and tau hyperphosphorylation. Risperidone also attenuated the activation of TREM-1/DAP12/NLRP3/caspase-1/IL-1ß, and TLR4/NF-κB pathways caused by DAB. Furthermore, risperidone inhibited DAB-induced oxidative stress, advanced glycation end products, and proinflammatory cytokines, as well as increased the expression of Nrf2, IL-10, Stat3, MDM2, and catalase activity. On the other hand, risperidone activated the expression of IRS1, PI3K, AKT, BDNF, Drd2, Scna5, and Trt as well as reduced the Bax/Bcl2 ratio and Caspase-3 levels. In silico analyses identified the prolactin signaling pathway, miR-155-5p, miR-34a-5p, and CEBPB as the main molecular mechanisms involved in the pathophysiology of DAB-induced cognitive impairment and targeted by risperidone. Our results suggest that risperidone could be used to treat cognitive impairment caused by organic solvents, especially DAB.