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BACKGROUND: Recent evidences highlight the potential impact of outdoor Light at Night (LAN) on executive function. However, few studies have investigated the association between outdoor LAN exposure and executive function. METHODS: We employed data from 48,502 Chinese children aged 5-12 years in a cross-sectional study conducted in Guangdong province during 2020-2021, to examine the association between outdoor LAN and executive function assessed using the validated parent-completed Behavior Rating Inventory of Executive Function. We assessed children's outdoor LAN exposure using the night-time satellite images based on the residential addresses. We used generalized linear mixed models to estimate the association between outdoor LAN exposure and executive function scores and executive dysfunction. RESULTS: After adjusting for potential covariates, higher quintiles of outdoor LAN exposure were associated with poorer executive function. Compared to the lowest quintile (Q1), all higher quintiles of exposure showed a significant increased global executive composite (GEC) score with ß (95% confidence intervals, CI) of 0.58 (0.28, 0.88) in Q2, 0.59 (0.28, 0.9) in Q3, 0.85 (0.54, 1.16) in Q4, and 0.76 (0.43, 1.09) in Q5. Higher quintiles of exposure were also associated with higher risks for GEC dysfunction with odd ratios (ORs) (95% CI) of 1.34 (1.18, 1.52) in Q2, 1.40 (1.24, 1.59) in Q3, 1.40 (1.23, 1.59) in Q4, and 1.39 (1.22, 1.58) in Q5. And stronger associations were observed in children aged 10-12 years. CONCLUSIONS: Our study suggested that high outdoor LAN exposure was associated with poor executive function in children. These findings suggested that future studies should determine whether interventions to reduce outdoor LAN exposure can have a positive effect on executive function.
Assuntos
Função Executiva , Humanos , Criança , Masculino , Feminino , Estudos Transversais , Pré-Escolar , China , Exposição Ambiental , Luz , Iluminação/efeitos adversos , População do Leste AsiáticoRESUMO
Continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants urges the development of new vaccines. We assessed the safety and immunogenicity of SYS6006.32, a bivalent vaccine (XBB.1.5/BQ.1), in healthy adults who had received SARS-CoV-2 primary vaccination. In a randomised, double-blinded, active-controlled trial, 200 participants were randomised to receive one dose of SYS6006.32 (N = 100) or a prototype-based, monovalent control vaccine SYS6006 (N = 100). Adverse events (AEs) were collected through the study. Immunogenicity was assessed by live-virus neutralising antibody (Nab) and pseudovirus Nab. 61 (61.0 %) and 60 (60.0 %) participants reported AE in the SYS6006.32 and SYS6006 groups, respectively. Most AEs were grade 1 or 2. Pain and fever were the most common injection-site and systemic AEs, respectively. No serious AEs were observed. SYS6006.32 heterologous boosting induced robust Nab responses against BA.5, XBB.1.5 and EG.5 with live-virus Nab geometric mean titres (GMTs) increased by 17.1-, 34.0-, and 48.0-fold, and pseudovirus Nab GMTs increased by 12.2-, 32.0-, and 35.1-fold, respectively, 14 days after vaccination. SYS6006.32 demonstrated a superior immunogenicity to SYS6006. SYS6006.32 also induced robust pseudovirus Nab responses against XBB.1.16, XBB.2.3, and BA.2.86, with GMTs 3- to 6-fold higher than those induced by SYS6006. In conclusion, SYS6006.32 showed good safety profile and superior immunogenicity to the monovalent vaccine SYS6006.
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Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , Vacinas de mRNA , COVID-19/prevenção & controle , Anticorpos Bloqueadores , China , Imunogenicidade da Vacina , Anticorpos Antivirais , Anticorpos Neutralizantes , Método Duplo-CegoRESUMO
Vaccination plays a key role in preventing morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the safety and immunogenicity of a SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine SYS6006. In the two randomized, observer-blinded, placebo-controlled phase 1 trials, 40 adult participants aged 18-59 years and 40 elderly participants aged 60 years or more were randomized to receive two doses of SYS6006 or placebo (saline). Adverse events (AEs) were collected through 30 days post the second vaccination. Immunogenicity was assessed by live-virus neutralizing antibody (Nab), spike protein (S1) binding antibody (S1-IgG), and cellular immunity. The result showed that 7/15, 9/15 and 4/10 adult participants, and 9/15, 8/15 and 4/10 elderly participants reported at least one AE in the 20-µg, 30-µg and placebo groups, respectively. Most AEs were grade 1. Injection-site pain was the most common AE. Two adults and one elder reported fever. No vaccination-related serious AE was reported. SYS6006 elicited wild-type Nab response with a peak geometric mean titer of 232.1 and 130.6 (adults), and 48.7 and 66.7 (elders), in the 20-µg and 30-µg groups, respectively. SYS6006 induced moderate-to-robust Nab response against Delta, and slight Nab response against Omicron BA.2 and BA.5. Robust IgG response against wild type and BA.2 was observed. Cellular immune response was induced. In conclusion, two-dose primary vaccination with SYS6006 demonstrated good safety and immunogenicity during a follow-up period of 51 days in immunologically naive population aged 18 years or more. (Trial registry: Chictr.org.cn ChiCTR2200059103 and ChiCTR2200059104).
Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Idoso , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , China , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Método Duplo-Cego , Imunogenicidade da Vacina , Imunoglobulina G , Vacinas de mRNA , RNA Mensageiro , SARS-CoV-2 , Vacinação , Adolescente , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Rabies, caused by the rabies virus (RABV), is the most fatal zoonotic disease. It is a neglected tropical disease which remains a major public health problem, causing approximately 59,000 deaths worldwide annually. Despite the existence of effective vaccines, the high incidence of human rabies is mainly linked to tedious vaccine immunisation procedures and the overall high cost of post-exposure prophylaxis. Therefore, it is necessary to develop an effective vaccine that has a simple procedure and is affordable to prevent rabies infection in humans. RABV belongs to the genus Lyssavirus and family Rhabdoviridae. Previous phylogenetic analyses have identified seven major clades of RABV in China (China I-VII), confirmed by analysing nucleotide sequences from both the G and N proteins. This study evaluated the immunogenicity and protective capacity of SYS6008, an mRNA rabies vaccine expressing rabies virus glycoprotein, in mice and cynomolgus macaques. We demonstrated that SYS6008 induced sufficient levels of rabies neutralising antibody (RVNA) in mice. In addition, SYS6008 elicited strong and durable RVNA responses in vaccinated cynomolgus macaques. In the pre-exposure prophylaxis murine model, one or two injections of SYS6008 at 1/10 or 1/30 of dosage provided protection against a challenge with a 30-fold LD50 of rabies virus (China I and II clades). We also demonstrated that in the post-exposure prophylaxis murine model, which was exposed to lethal rabies virus (China I-VII clades) before vaccination, one or two injections of SYS6008 at both 1/10 and 1/30 dosages provided better protection against rabies virus challenge than the immunization by five injections of commercial vaccines at the same dosage. In addition, we proved that SYS6008-induced RVNAs could neutralise RABV from the China I-VII clades. Finally, 1/10 of the dosage of SYS6008 was able to stimulate significant RABV-G specificity in the T cell response. Furthermore, we found that SYS6008 induced high cellular immunity, including RABV-G-specific T cell responses and memory B cells. Our results imply that the SYS6008 rabies vaccine, with a much simpler vaccination procedure, better immunogenicity, and enhanced protective capacity, could be a candidate vaccine for post-exposure prophylaxis of rabies infections.
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Vacina Antirrábica , Vírus da Raiva , Raiva , Humanos , Animais , Camundongos , Raiva/prevenção & controle , Vacina Antirrábica/genética , Vírus da Raiva/genética , Profilaxia Pós-Exposição/métodos , Modelos Animais de Doenças , Filogenia , Anticorpos Antivirais , MacacaRESUMO
The spike protein of SARS-CoV-2 can recognize the ACE2 membrane protein on the host cell and plays a key role in the membrane fusion process between the virus envelope and the host cell membrane. However, to date, the mechanism for the spike protein recognizing host cells and initiating membrane fusion remains unknown. In this study, based on the general assumption that all three S1/S2 junctions of the spike protein are cleaved, structures with different forms of S1 subunit stripping and S2' site cleavage were constructed. Then, the minimum requirement for the release of the fusion peptide was studied by all-atom structure-based MD simulations. The results from simulations showed that stripping an S1 subunit from the A-, B- or C-chain of the spike protein and cleaving the specific S2' site on the B-chain (C-chain or A-chain) may result in the release of the fusion peptide, suggesting that the requirement for the release of FP may be more relaxed than previously expected.
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Particulate matter (PM) exposure is associated to the adverse change in blood lipids. Vitamin D is beneficial to lipid metabolism, but whether vitamin D levels modifies the impact of air pollutants on lipids is unclear. The purpose of the study was to investigate if vitamin D modifies the associations of PM and serum lipids in young healthy people. From December 2017 to January 2018, a panel study with five once weekly follow-ups was conducted on 88 healthy adults aged 21.09 (1.08) (mean (SD)) years on average in Guangzhou, China. We measured serum lipids, serum 25-hydroxyvitamin D (25(OH)D) concentrations (440 blood samples in total), mass concentrations of particulate matter with diameters ≤2.5 µm (PM2.5), ≤1.0 µm (PM1.0), and ≤0.5 µm (PM0.5), and number concentrations of particulate matter with diameters ≤0.2 µm (PN0.2) and ≤0.1 µm (PN0.1) at each follow-up. Linear mixed-effect models were applied to assess the interaction of vitamin D and size-fractionated PM short-term exposure on four lipid metrics. We found the interactions between 25(OH)D and size-fractionated PM exposure on blood lipids in different lags (lag 3 days and 4 days). An interquartile range increase in PM2.5, PM1.0, PM0.5 were significantly associated with increments of 12.30%, 12.99%, and 13.66% in triglycerides (TGs) at lag 4 days at vitamin D levels <15 ng/mL group, respectively. Similar results were found for PN0.2, PN0.1 and low-density lipoprotein cholesterol (LDL-C). All the associations between size-fractionated PM and blood lipids were found null statistically significant in vitamin D levels ≥15 ng/mL group.
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Poluentes Atmosféricos , Poluição do Ar , Humanos , Adulto , Material Particulado/análise , Poluentes Atmosféricos/análise , Vitamina D , Vitaminas , China , Lipídeos , Exposição Ambiental , Poluição do Ar/análiseRESUMO
Diabetes is often associated with vitamin A disorders. All-trans retinoic acid (ATRA) is the main active constituent of vitamin A. We aimed to investigate whether ATRA influences diabetic progression and its mechanisms using both Goto-Kazizazi (GK) rats and INS-1 cells. Rat experiments demonstrated that ATRA treatment worsened diabetes symptoms, as evidenced by an increase in fasting blood glucose (FBG) levels and impairment of glucose homeostasis. Importantly, ATRA impaired glucose-stimulated insulin secretion (GSIS) and increased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) and uncoupling protein 2 (UCP2) in the rat pancreas. Data from INS-1 cells also showed that ATRA upregulated SREBP-1c and UCP2 expression and impaired GSIS at 23 mM glucose. Srebp-1c or Ucp2 silencing attenuated GSIS impairment by reversing the ATRA-induced increase in UCP2 expression and decrease in ATP content. ATRA and the retinoid X receptor (RXR) agonists 9-cis RA and LG100268 induced the gene expression of Srebp-1c, which was almost completely abolished by the RXR antagonist HX531. RXRα-LBD luciferase reporter plasmid experiments also demonstrated that ATRA concentration-dependently activated RXRα, the EC50 of which was 1.37 µM, which was lower than the ATRA concentration in the pancreas of GK rats treated with a high dose of ATRA (approximately 3 µM), inferring that ATRA can upregulate Srebp-1c expression in the pancreas by activating RXR. In conclusion, ATRA impaired GSIS partly by activating the RXR/SREBP-1c/UCP2 pathway, thus worsening diabetic symptoms. The results highlight the roles of ATRA in diabetic progression and establish new strategies for diabetes treatment.
Assuntos
Glucose , Vitamina A , Animais , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ratos , Receptores X de Retinoides/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Tretinoína/farmacologia , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo , Vitamina A/metabolismoRESUMO
Neuroinflammation plays an important role in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease. HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) is a tumor suppressor. Recent evidence suggests that HACE1 may be involved in oxidative stress responses. Due to the critical role of ROS in neuroinflammation, we speculated that HACE1 might participate in neuroinflammation and related neurodegenerative diseases, such as PD. In this study, we investigated the role of HACE1 in neuroinflammation of PD models. We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit. Furthermore, we showed that HACE1 exerted vital neuronal protection through increasing Rac1 activity and stability in LPS-treated SH-SY5Y cells, as HACE1 knockdown leading to lower tolerance to LPS challenge. In MPTP-induced acute PD mouse model, HACE1 knockdown exacerbated motor deficits by activating Rac1. Finally, mutant α-synuclein (A53T)-overexpressing mice, a chronic PD mouse model, exhibited age-dependent reduction of HACE1 levels in the midbrain and striatum, implicating that HACE1 participated in PD pathological progression. This study for the first time demonstrates that HACE1 is a negative regulator of neuroinflammation and involved in the PD pathogenesis by regulating Rac1 activity. The data support HACE1 as a potential target for PD and other neurodegenerative diseases.
Assuntos
Transtornos Parkinsonianos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Imunofluorescência , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/metabolismo , Teste de Desempenho do Rota-Rod , UbiquitinaçãoRESUMO
Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes. However, research on the role of Marco in regulating neuroinflammation has reported conflicting results. In the present study, we examined the role Marco played in triggering neuroinflammation and its underlying mechanisms. The results demonstrated that silencing the Marco gene resulted in a significantly reduced neuroinflammatory response and vice versa. α-Syn stimulation in Marco overexpressing cells induced a pronounced inflammatory response, suggesting that Marco alone could trigger an inflammatory response. We also found that TLR2 significantly promoted Marco-mediated neuroinflammation, indicating TLR2 was an important co-receptor of Marco. Knocking down the TLR2 gene in microglia and mouse substantia nigra resulted in decreased expression of Marco. Subsequent mechanistic studies showed that deleting the SRCR domain of Marco resulted in disruption of the inflammatory response and the interaction between TLR2 and Marco. This suggested that TLR2 binds directly to the SRCR domain of Marco and regulates Marco-mediated neuroinflammation. In summary, this investigation revealed that TLR2 could potentiate Marco-mediated neuroinflammation by interacting with the SRCR domain of Marco, providing a new target for inhibiting neuroinflammation in neurodegenerative diseases.
Assuntos
Doenças Neuroinflamatórias/metabolismo , Receptores Imunológicos/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Linhagem Celular , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia , Óxido Nítrico/metabolismo , Polissacarídeos/farmacologia , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Interferência de RNA , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/química , Proteínas Recombinantes/metabolismo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , alfa-Sinucleína/farmacologiaRESUMO
Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are co-located at blood-brain barrier (BBB) cells, preventing their substrates from entering brain. Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain. In the current study, we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation (BDL). The function of BCRP, P-gp and BBB integrity was assessed using distribution of prazosin, rhodamine 123 and fluorescein, respectively. We showed that BDL significantly decreased BCRP function, but increased P-gp function without affecting BBB integrity. Furthermore, we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus. In human cerebral microvascular endothelial cells, NH4Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein, but upregulated P-gp function and expression of membrane P-gp protein. The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein, while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein. Silencing ezrin impaired membrane location of P-gp, whereas silencing radixin impaired membrane location of BCRP protein. BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain. We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp, attributing to the altered expression of membrane radixin and ezrin protein, respectively, due to hyperbilirubinemia and hyperammonemia.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Ductos Biliares/metabolismo , Encéfalo/metabolismo , Proteínas do Citoesqueleto/biossíntese , Proteínas de Membrana/biossíntese , Proteínas dos Microfilamentos/biossíntese , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Membrana Celular/metabolismo , Proteínas do Citoesqueleto/genética , Expressão Gênica , Ligadura/efeitos adversos , Masculino , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Fármacos Anti-HIV/toxicidade , Encéfalo/efeitos dos fármacos , Zidovudina/toxicidade , Animais , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Ductos Biliares/patologia , Barreira Hematoencefálica/metabolismo , Encéfalo/patologia , Linhagem Celular , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Cães , Humanos , Células Madin Darby de Rim Canino , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Zidovudina/farmacocinéticaRESUMO
Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ. Here we found that FLZ markedly improved the function of dopaminergic neurons in primary mesencephalic neuron/glia cultures. Further investigation demonstrated that astroglia were required for FLZ to function as a neurotrophic regulator, as FLZ failed to show neurotrophic effects in the absence of astroglia. We clarified that GDNF was responsible for the neurotrophic effects of FLZ since FLZ selectively stimulated GDNF production, which was confirmed by the finding that the neurotrophic effect of FLZ was attenuated by GDNF-neutralizing antibody. Mechanistic study demonstrated that GDNF induction by FLZ was CREB-dependent and that PI3K/Akt was the main pathway regulating CREB activity, which was confirmed by in vivo studies. We also validated that the induction of GDNF by FLZ contributed to PD treatment in vivo. In conclusion, the present data provided evidence that FLZ had robust neurotrophic effects on dopaminergic neurons through sustained induction of GDNF in astroglia by activating the PI3K/Akt/CREB pathway.
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Astrócitos/metabolismo , Neurônios Dopaminérgicos/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Acrilamidas/efeitos adversos , Acrilamidas/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Benzenoacetamidas/farmacologia , Ácidos Cafeicos/efeitos adversos , Ácidos Cafeicos/farmacologia , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Mesencéfalo/citologia , Neuroglia/metabolismo , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/metabolismo , Fenóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Four new species of Gesneriaceae from Yunnan, southwest China, are described and illustrated. They are Petrocosmea rhombifolia, Petrocosmea tsaii, Didymocarpus brevipedunculatus, and Henckelia xinpingensis. Diagnostic characters between the new species and their morphologically close relatives are provided. Their distribution, ecology, phenology, and conservation status are also described.
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MicroRNAs (miRNAs) regulate the development and growth cycle of hair follicles (HFs). The molecular mechanism by which miRNAs determine the development of HFs in the sheep foetus remains elusive. In this study, the expression profiles of miRNAs at 11 development periods (45, 55, 65, 75, 85, 95, 105, 115, 125, 135 and 145 d) in sheep foetus skin were analysed by high-throughput sequencing and bioinformatics analysis. A total of 72 conserved miRNAs, 44 novel miRNAs and 32 known miRNAs were significantly differentially expressed. qRT-PCR results for 18 miRNAs were consistent with the sequencing data. 85 d of foetal development was the starting point for secondary hair follicle (SF) development according to tissue morphology and cluster analysis. In SF development, the prolactin signalling pathway and platelet activation played important roles, and 10 miRNAs were potential candidate miRNAs in SF initiation.
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Desenvolvimento Fetal/genética , Perfilação da Expressão Gênica , Folículo Piloso/crescimento & desenvolvimento , MicroRNAs/genética , Ovinos/embriologia , Animais , Biologia Computacional , Regulação para Baixo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Ativação Plaquetária , Prolactina/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , Transdução de Sinais , Regulação para Cima , LãRESUMO
Cinnamic acid and its analogues (pyragrel and ozagrel) undergo chain-shortened (ß-oxidative) and reductive metabolism on acyl side chain. In this study, we characterized the ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues using primary rat hepatocytes, hepatic mitochondrial, and microsomal systems. A compartmental model including parent compounds and metabolites was developed to characterize in vivo ß-oxidative and reductive metabolism following an intravenous dose of parent compounds to rats. The fitted total in vivo clearance values were further compared with the in vitro values predicted by the well-stirred model. We showed that hepatic microsomal CYP450s did not catalyze ß-oxidative or reductive metabolism of the three compounds. Similar to ß-oxidation of fatty acids, ß-oxidative metabolism on their acyl side chain occurred mainly in mitochondria, which was highly dependent on ATP, CoA and NAD+. Fatty acids and NADH inhibited the ß-oxidative metabolism. Reductive metabolism occurred in both mitochondria and microsomes. Reduction in mitochondria was ATP-, CoA-, and NAD(P)H-dependent and reversible, which was suppressed by enoyl reductase inhibitor triclosan. Reduction in microsomes was ATP-, CoA-, and NADPH-dependent but little affected by triclosan. Both plasma concentrations of ß-oxidative metabolites and reductive metabolites were successfully fitted using the compartmental model. The estimated total in vivo clearance values were consistent with those predicted from hepatocytes and organelles, implicating significance of in vitro kinetics. These findings demonstrate the roles of hepatic mitochondria and microsomes in ß-oxidative and reductive metabolism on acyl side chain of cinnamic acid and its analogues along with their metabolic characteristics.
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Cinamatos/metabolismo , Metacrilatos/metabolismo , Pirazinas/metabolismo , Animais , Cinamatos/química , Cinamatos/farmacocinética , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Masculino , Metacrilatos/química , Metacrilatos/farmacocinética , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Estrutura Molecular , NAD/metabolismo , Oxirredução/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacocinética , Ratos Sprague-Dawley , Triclosan/farmacologiaRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. Although the exact causes of AD have not yet been fully elucidated, cholinergic dysfunction, mitochondrial damage, oxidative stress and neuroinflammation have been recognized as influential factors. Current drugs that are designed to address only a single target are unable to mitigate or prevent the progression of this complicated disease, so new disease-modifying drugs are urgently needed. Chinese herbs with thousand years of effective usage might be a good source for potential drugs. Gardenia jasminoides J. Ellis (Fructus Gardenia) is a common traditional Chinese medicine with tranquilizing effects, which is an important component of widely-used traditional Chinese medicine for dementia. GJ-4 is crocin richments extracted from Gardenia jasminoides J. Ellis. In our study, we attempted to observe the effects of GJ-4 on learning and memory injury induced by amyloid-[Formula: see text] 25-35 (A[Formula: see text] injection in mice. Treatment with GJ-4 dose-dependently enhanced the memory and cognition ability of A[Formula: see text]-injected mice. Preliminary mechanistic studies revealed the protective effect of GJ-4 was related to its protection of neurons and cholinergic dysfunction. The mechanistic results also indicated that GJ-4 could enhance antioxidant capacity and attenuate neuroinflammation. Our results implied that GJ-4 might be a promising drug to improve cognitive and memory impairment, with multiple targets.
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Peptídeos beta-Amiloides/efeitos adversos , Antioxidantes , Carotenoides/farmacologia , Carotenoides/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/prevenção & controle , Gardenia/química , Fragmentos de Peptídeos/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Carotenoides/isolamento & purificação , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Frutas/química , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Extratos Vegetais/isolamento & purificaçãoRESUMO
Sanggenon X, an unusual tri-O-bridged Diels-Alder adduct, was isolated from Cortex Mori Radicis. Its structure was established by spectroscopic analysis, including NMR and HR-MS (High Resolution Mass Spectrometry). Sanggenon X contained three O-bridged rings, where the oxygenated bridgeheads were all quaternary carbons. Chemical methylation was carried out to deduce the linkages of the three O-bridges. The absolute configuration was determined by calculating the ECD (Electronic Circular Dichroism) using the TDDFT (Time-Dependent Density Functional Theory) method. Sanggenon X showed significant antioxidant activity against Fe2+-Cys-induced lipid peroxidation in rat liver microsomes, and was as effective as the positive control, curcumin.
Assuntos
Antioxidantes/química , Medicamentos de Ervas Chinesas/química , Compostos Heterocíclicos de Anel em Ponte/química , Microssomos Hepáticos/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Dicroísmo Circular/métodos , Medicamentos de Ervas Chinesas/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Casca de Planta/química , Raízes de Plantas/química , Ratos , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Neuroinflammation triggered by activation of glial cells plays an important role in the pathophysiology of several neurodegenerative diseases including Parkinson's disease (PD). Besides microglia, astrocytes are also critical in initiating and perpetuating inflammatory process associated with PD. Heat shock protein 70 (Hsp70) is originally described as intracellular chaperone, however, recent study revealed that it had anti-inflammatory effects as well. The present study is designed to investigate whether Hsp70 mediates neuroinflammation in astrocytes. By employing α-synuclein (α-Syn) (A53T) aggregates on primary cultured astrocytes of rats, we found that astrocytes were activated and neuroinflammatory response was triggered, as indicated by over-expression of glial fibrillary acidic protein (GFAP), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), increased production of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). The data also showed that the neuroinflammatory response accompanied up-regulated Hsp70 expression. Moreover, over-expression of Hsp70 through transfection of Hsp70 cDNA plasmids could significantly reduce the production of TNF-α, IL-1ß, and the expression of GFAP, COX-2 as well as iNOS. While inhibition of Hsp70 by VER155008 exacerbated neuroinflammatory response in astrocytes challenged by α-Syn aggregates. Further mechanistic study indicated that c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) signalings were responsible for the neuroinflammation, which was also regulated by Hsp70. These findings demonstrated that Hsp70 was an important modulator in astrocytes induced inflammation, and up-regulation of Hsp70 might be a potential regulating approach for neuroinflammation-related neurodegenerative diseases, such as PD.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proteínas de Choque Térmico HSP70/biossíntese , alfa-Sinucleína/toxicidade , Animais , Células Cultivadas , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Ratos , Ratos Sprague-DawleyRESUMO
The rich diversity in medicinal plants provides an important material basic for the development of Traditional Chinese medicine in China. It is important to explore the present situation of medicinal plants within special regions in order to provide scientific instructions for their sustainable protection and exploitation and utilization. In this study, we carried out the field survey according to the guideline of national survey of Chinese material medica resources and the guideline of plant species diversity survey and estimation at county level with the line transect method. With the field surveyed data, we explored the diversity and distribution of the threatened medicinal vascular plants in Lancang. We found that there were 33 species of the threatened medicinal vascular plants in this county. These species were from 23 genera and 17 families, and were composed of one critical endangered, 10 endangered and 22 vulnerable species. They were widely distributed across the whole county and were most concentrated in the town of Nuozhadu, Fazhanhe, Nuofu and Zhutang, which were located in the southeastern, southwestern and western of Lancang, respectively. We also found that the plant species richness followed a unimodal pattern along elevation. In addition, we found that the areas of Nuozhadu Nature Reserve in Lancang only covered six threatened medicinal vascular plants, while most of the regions with high species richness were not well protected. Therefore, we proposed to make more efforts to improve the protection measurements in order to better protect and utilize the medicinal plants in Lancang.
Assuntos
Biodiversidade , Plantas Medicinais/classificação , Traqueófitas/classificação , China , Conservação dos Recursos Naturais , Medicina Tradicional ChinesaRESUMO
Microfluidic systems based on fluorescence detection have been developed and applied for many biological and chemical applications. Because of the tiny amount of sample in the system; the induced fluorescence can be weak. Therefore, most microfluidic systems deploy multiple optical components or sophisticated equipment to enhance the efficiency of fluorescence detection. However, these strategies encounter common issues of complex manufacturing processes and high costs. In this study; a miniature, cylindrical and hybrid lens made of polydimethylsiloxane (PDMS) to improve the fluorescence detection in microfluidic systems is proposed. The hybrid lens integrates a laser focusing lens and a fluorescence collecting lens to achieve dual functions and simplify optical setup. Moreover, PDMS has advantages of low-cost and straightforward fabrication compared with conventional optical components. The performance of the proposed lens is first examined with two fluorescent dyes and the results show that the lens provides satisfactory enhancement for fluorescence detection of Rhodamine 6G and Nile Red. The overall increments in collected fluorescence signal and detection sensitivity are more than 220% of those without lens, and the detection limits of Rhodamine 6G and Nile red are lowered to 0.01 µg/mL and 0.05 µg/mL, respectively. The hybrid lens is further applied to the detection of Nile red-labeled Chlorella vulgaris cells and it increases both signal intensity and detection sensitivity by more than 520%. The proposed hybrid lens also dramatically reduces the variation in detected signal caused by the deviation in incident angle of excitation light.