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BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a complex neuroinflammatory disease characterized by severe disability. In this study, we investigated the relationship between cerebrospinal fluid (CSF)/serum albumin quotient (Qalb) and platelet to lymphocyte ratio (PLR) in assessing disease severity. METHOD: A retrospective analysis of 72 NMOSD patients and 72 healthy controls was conducted, and patients were divided into two groups based on their Expanded Disability Status Scale (EDSS) scores. RESULTS: NMOSD patients had significantly higher levels of serum PLR, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and C-reactive protein (CRP) compared to healthy controls (all P<0.01). Patients in the EDSS≥4 group exhibited significantly elevated levels of Qalb, QIgG, QIgA, QIgM, and PLR (P=0.000, P<0.0001, P=0.0019, P=0.0001, respectively). Spearman's correlation test revealed significant positive associations between Qalb, QIgG, QIgA, QIgM, PLR, and EDSS score. Specifically, Qalb (r=0.571; P<0.001), QIgG (r=0.551; P<0.001), QIgA (r=0.519; P<0.001), and QIgM (r=0.541; P<0.001) demonstrated significant positive correlations with EDSS score, while PLR exhibited a moderate positive correlation (r=0.545; P<0.001) with EDSS score and a mild positive association (r=0.387; P<0.001) with Qalb. The increase of Qalb was positively correlated with the increased EDSS score (r=0.528, P=0.001), as well as the increase of QIgG (r=0.509, P=0.001), and the increase of QIgA (r=0.4989, P=0.03). ROC analysis indicated that Qalb, QIgG, QIgA, QIgM, and PLR levels could effectively serve as indicators of NMOSD severity (all P<0.0001). Multivariate analysis confirmed the independent significance of Qalb and PLR in assessing disease severity (P=0.000). CONCLUSION: These findings provide valuable insights into the risk and pathogenesis of NMOSD and highlight the potential of Qalb and PLR as independent markers for disease severity assessment in NMOSD patients.
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Neuromielite Óptica , Humanos , Barreira Hematoencefálica/metabolismo , Estudos Retrospectivos , Biomarcadores/metabolismo , Linfócitos/patologiaRESUMO
CONTEXT: Lappaol F (LAF), a natural lignan from Arctium lappa Linné (Asteraceae), inhibits tumor cell growth in vitro and in vivo. The underlying mechanism involves the suppression of the Yes-associated protein. However, the specific role of LAF in cell cycle regulation remains unknown. OBJECTIVE: This study determined the molecular mechanism by which LAF regulates cell cycle progression. MATERIALS AND METHODS: Various colon cancer cell lines (SW480, HCT15, and HCT116) were treated with LAF (25, 50, and 75 µmol/L) for 48 h. The effects of LAF on cell proliferation and cell cycle were determined using sulforhodamine B and flow cytometry assays. Differentially expressed proteins (DEPs) were identified using quantitative proteomics. Bioinformatic analysis of DEPs was conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Expression levels of DEPs in the cell cycle pathway were analyzed using RT-qPCR and western blotting. RESULTS: LAF suppressed the proliferation of SW480, HCT15, and HCT116 cells (IC50 47.1, 51.4, and 32.8 µmol/L, respectively) and induced cell cycle arrest at the S phase. A total of 6331 proteins were identified and quantified, of which 127 were differentially expressed between the LAF-treated and untreated groups. GO and KEGG enrichment analyses revealed that DEPs mainly participated in the cell cycle. CDKN1C/p57 showed the most significant differential expression, with the highest fold-change (3.155-fold). Knockdown of CDKN1C/p57 attenuated the S phase cell cycle arrest and proliferation inhibition induced by LAF. CONCLUSION: LAF exerts antitumor effects via S phase arrest by activating CDKN1C/p57 in colorectal cancer cells.
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Benzofuranos , Neoplasias Colorretais , Humanos , Linhagem Celular Tumoral , Ciclo Celular , Benzofuranos/farmacologia , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Inibidor de Quinase Dependente de Ciclina p57/farmacologiaRESUMO
OBJECTIVE: To compare the clearance rate of high-risk human papillomavirus (HR-HPV) in patients with a high-grade squamous intraepithelial lesion (HSIL) 12 months after focused ultrasound (FUS) or loop electrosurgical excision procedure (LEEP), and analyze the influencing factors. METHODS: A retrospective cohort was established in HSIL patients with HR-HPV infection treated with FUS or LEEP from 2015 to 2019. The cohort consisted of 321 patients under 30 years of age, of which 119 patients received FUS and 202 patients received LEEP. The Cox regression model was used to identify the influencing factors for HR-HPV clearance. Kaplan-Meier method was applied to estimate the efficacy of FUS and LEEP in HR-HPV clearance, and the log-rank test was used to compare the efficacy difference between FUS and LEEP. RESULTS: Multivariate Cox regression analysis showed that both FUS and LEEP were independent influencing factors for HR-HPV clearance. HR-HPV cleared faster in the FUS group than in the LEEP group [the median time to HR-HPV clearance: 6 months in the FUS group (95% CI: 5.492-6.508) and 6 months in the LEEP group (95% CI: 5.734-6.266), p = 0.021]. The HR-HPV clearance rates at 6 and 12 months were 54.6% and 94.1% respectively in the FUS group, and 50.5% and 79. 2%, respectively in the LEEP group (p = 0.001 at 6 months, p = 0.000 at 12 months). CONCLUSIONS: For HPV-positive HSIL patients under 30, FUS had a better HR-HPV clearance effect than LEEP 1 year after treatment. FUS may be a viable modality for the treatment of young HSIL patients.
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Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Eletrocirurgia/métodos , Feminino , Humanos , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/cirurgia , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVES: Immune dysregulation plays a key role in major depressive disorder (MDD). However, little is known about the complicated involvement of various interleukins in MDD. This study was performed to investigate the correlation between plasma interleukin-8 (IL-8) levels and treatment outcome of paroxetine (a selective serotonin reuptake inhibitor) in patients with MDD. METHODS: A total of 115 hospitalized patients (36 males and 79 females), aged from 18 to 72 years, were enrolled. Plasma levels of IL-8 were measured before treatment initiation (baseline) and at 8 weeks after oral paroxetine treatment. Efficacy of paroxetine was evaluated by use of the Hamilton Depression Rating Scale (HAMD-17). Baseline IL-8 levels were compared between responders and non-responders to paroxetine treatment. RESULTS: Plasma IL-8 levels decreased significantly after an 8-week antidepressant treatment in responders, in association with a dramatic decrease in HAMD-17 scores. In non-responders, plasma IL-8 levels did not change significantly at 8 weeks after antidepressant treatment. Baseline plasma IL-8 levels were found to be significantly lower in responders than in non-responders, showing a correlation between IL-8 and antidepressant response to paroxetine. CONCLUSIONS: These results indicate that plasma IL-8 levels were related to treatment outcome of paroxetine, and therefore suggest that IL-8 could be a promising predicator of treatment response in individual patients with MDD.
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Transtorno Depressivo Maior , Paroxetina , Masculino , Feminino , Humanos , Paroxetina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Interleucina-8 , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Antidepressivos/uso terapêutico , Resultado do TratamentoRESUMO
CONTEXT: Lappaol F (LAF), a natural lignan from Arctium lappa Linné (Asteraceae), inhibits tumour cell growth by inducing cell cycle arrest. However, its underlying anticancer mechanism remains unclear. OBJECTIVE: The effects of LAF on the Hippo-Yes-associated protein (YAP) signalling pathway, which plays an important role in cancer progression, were explored in this study. MATERIALS AND METHODS: Cervical (HeLa), colorectal (SW480), breast (MDA-MB-231) and prostate (PC3) cancer cell lines were treated with LAF at different concentrations and different durations. BALB/c nude mice bearing colon xenografts were intravenously injected with vehicle, LAF (10 or 20 mg/kg) or paclitaxel (10 mg/kg) for 15 days. The expression and nuclear localisation of YAP were analysed using transcriptome sequencing, quantitative PCR, western blotting and immunofluorescence. RESULTS: LAF suppressed the proliferation of HeLa, MDA-MB-231, SW480 and PC3 cells (IC50 values of 41.5, 26.0, 45.3 and 42.9 µmol/L, respectively, at 72 h), and this was accompanied by significant downregulation in the expression of YAP and its downstream target genes at both the mRNA and protein levels. The expression of 14-3-3σ, a protein that causes YAP cytoplasmic retention and degradation, was remarkably increased, resulting in a decrease in YAP nuclear localisation. Knockdown of 14-3-3σ with small interfering RNA partially blocked LAF-induced YAP inhibition and anti-proliferation effects. In colon xenografts, treatment with LAF led to reduced YAP expression, increased tumour cell apoptosis and tumour growth inhibition. CONCLUSION: LAF was shown to be an inhibitor of YAP. It exerts anticancer activity by inhibiting YAP at the transcriptional and post-translational levels.
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4-Butirolactona/análogos & derivados , Antineoplásicos Fitogênicos/farmacologia , Benzofuranos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Transcrição Gênica/efeitos dos fármacos , 4-Butirolactona/farmacologia , Animais , Proteínas de Ciclo Celular/biossíntese , Relação Dose-Resposta a Droga , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Processamento de Proteína Pós-Traducional/fisiologia , Fatores de Transcrição/biossíntese , Transcrição Gênica/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Pancreatic cancer (PC) is one of the most lethal gastrointestinal malignancies. The PTEN/AKT signalling pathway is closely related to the tumourigenesis and progression of PC. The downstream effectors, FOXO3a, PLZF and VEGF, are reported to be involved in angiogenesis, lymph node metastasis and poor survival in PC. By using tissue microarrays and immunohistochemistry, we found, that PTEN, FOXO3a and PLZF expression was significantly decreased in PC specimens compared with that in chronic pancreatitis (CP) specimens, while VEGF expression was significantly increased. Furthermore, the expression of PTEN was positively correlated with that of FOXO3a and PLZF but negatively correlated with that of VEGF. Our results suggest that the PTEN/FOXO3a/PLZF signalling pathway may negatively regulate VEGF expression in PC. Through clinical analysis of 69 PC patients, PTEN, FOXO3a and PLZF expression was found to be significantly decreased in specimens from PC patients with lymph node metastasis and poor prognosis, while VEGF expression was significantly increased. Taken together, these reaults suggest that the PTEN/FOXO3a/PLZF signalling pathway may be capable of inhibiting growth and metastasis in PC by regulating VEGF-mediated angiogenesis, which requires further in vivo and in vitro studies and can potentially be a therapeutic target for PC.
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Proteína Forkhead Box O3/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Pinocembrin is one of the most abundant flavonoids in propolis, and it may also be widely found in a variety of plants. In addition to natural extraction, pinocembrin can be obtained by biosynthesis. Biosynthesis efficiency can be improved by a metabolic engineering strategy and a two-phase pH fermentation strategy. Pinocembrin poses an interest for its remarkable pharmacological activities, such as neuroprotection, anti-oxidation, and anti-inflammation. Studies have shown that pinocembrin works excellently in treating ischemic stroke. Pinocembrin can reduce nerve damage in the ischemic area and reduce mitochondrial dysfunction and the degree of oxidative stress. Given its significant efficacy in cerebral ischemia, pinocembrin has been approved by China Food and Drug Administration (CFDA) as a new treatment drug for ischemic stroke and is currently in progress in phase II clinical trials. Research has shown that pinocembrin can be absorbed rapidly in the body and easily cross the blood-brain barrier. In addition, the absorption/elimination process of pinocembrin occurs rapidly and shows no serious accumulation in the body. Pinocembrin has also been found to play a role in Parkinson's disease, Alzheimer's disease, and specific solid tumors, but its mechanisms of action require in-depth studies. In this review, we summarized the latest 10 years of studies on the biosynthesis, pharmacological activities, and pharmacokinetics of pinocembrin, focusing on its effects on certain diseases, aiming to explore its targets, explaining possible mechanisms of action, and finding potential therapeutic applications.
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Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Flavanonas/biossíntese , Flavanonas/farmacologia , Animais , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Vias Biossintéticas , Avaliação Pré-Clínica de Medicamentos , Fermentação , Flavanonas/química , Flavanonas/farmacocinética , Humanos , Relação Estrutura-AtividadeRESUMO
Cajanolactone A (CLA) is a stilbenoid discovered by us from Cajanus cajan (L.) Millsp. In our study, CLA was found to promote osteoblast differentiation in human bone marrow mesenchymal stem cells (hBMSCs), as judged by increased cellular alkaline phosphatase activity and extracellular calcium deposits, and elevated protein expression of Runx2, collagen-1, bone morphogenetic protein-2, and osteopontin. Mechanistic studies revealed that hBMSCs undergoing osteoblast differentiation expressed upregulated mRNA levels of Wnt3a, Wnt10b, LRP5/6, Frizzled 4, ß-catenin, Runx2, and Osterix from the early stage of differentiation, indicating the role of activated Wnt/ß-catenin signaling pathway in osteoblast differentiation. Addition of CLA to the differentiation medium further increased the mRNA level of Wnt3a, Wnt10b, Frizzled 4, LRP5, and ß-catenin, inferring that CLA worked by stimulating Wnt/LRP5/ß-catenin signaling. Wnt inhibitor dickkopf-1 antagonized CLA-promoted osteoblastogenesis, indicating that CLA did not target the downstream of canonical Wnt signaling pathway. Treatment with CLA caused no changes in mRNA expression level, as well as protein secretion of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), indicating that CLA did not affect the OPG/RANKL axis. Our results showed that CLA, which promoted osteoblast differentiation in hBMSCs, through activating Wnt/LRP5/ß-catenin signaling transduction, is a promising anti-osteoporotic drug candidate.
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Cajanus/química , Lactonas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Humanos , Lactonas/química , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Estrutura Molecular , Osteoblastos/citologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
CONTEXT: The leaves of Cajanus cajan (L.) Millsp. (Fabaceae) have diverse bioactivities, but little safety data are reported. OBJECTIVE: This study examines the toxicological profiles of C. cajan leaf extracts. MATERIALS AND METHODS: The leaves were extracted by water or 90% ethanol to obtain water or ethanol extract (WEC or EEC). EEC was suspended in water and successively fractionated into dichloroform and n-butanol extracts (DEC and BEC). Marker compounds of the extracts were monitored by high-performance liquid chromatography (HPLC). Kunming mice were administered with a single maximum acceptable oral dose (15.0 g/kg for WEC, EEC and BEC and 11.3 g/kg for DEC) to determine death rate or maximal tolerated doses (MTDs). In sub-chronic toxicity investigation, Sprague-Dawley rats were orally given WEC or EEC at 1.5, 3.0 or 6.0 g/kg doses for four weeks and observed for two weeks after dosing to determine toxicological symptoms, histopathology, biochemistry and haematology. RESULTS: Flavonoids and stilbenes in the extracts were assayed. In acute toxicity test, no mortality and noted alterations in weight and behavioural abnormality were observed, and the maximum oral doses were estimated as MTDs. In sub-chronic toxicity study, no mortality and significant variances in haematological and biochemical parameters or organ histopathology were observed, but increased kidney weight in 3.0 g/kg WEC- or 3.0 and 6.0 g/kg EEC-treated female rats, and reduced testes and epididymis weight in EEC-treated male rats were recorded. These changes returned to the level of control after recovery period. CONCLUSION: Acute and sub-chronic toxicity of Cajanus cajan leaf extracts was not observed.
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Cajanus/toxicidade , Extratos Vegetais/toxicidade , Folhas de Planta/toxicidade , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Cajanus/química , Relação Dose-Resposta a Droga , Feminino , Masculino , Dose Máxima Tolerável , Camundongos , Modelos Animais , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos Sprague-Dawley , Medição de Risco , Solventes/química , Fatores de TempoRESUMO
Fragment-based quantum chemistry methods are either based on the many-body expansion or the inclusion-exclusion principle. To compare the applicability of these two categories of methods, we have systematically evaluated the performance of the generalized energy based fragmentation (GEBF) method (J. Phys. Chem. A, 2007, 111, 2193) and the electrostatically embedded many-body (EE-MB) method (J. Chem. Theory Comput., 2007, 3, 46) for medium-sized water clusters (H2O)n (n = 10, 20, 30). Our calculations demonstrate that the GEBF method provides uniformly accurate ground-state energies for 10 low-energy isomers of three water clusters under study at a series of theory levels, while the EE-MB method (with one water molecule as a fragment and without using the cutoff distance) shows a poor convergence for (H2O)20 and (H2O)30 when the basis set contains diffuse functions. Our analysis shows that the neglect of the basis set superposition error for each subsystem has little effect on the accuracy of the GEBF method, but leads to much less accurate results for the EE-MB method. The accuracy of the EE-MB method can be dramatically improved by using an appropriate cutoff distance and using two water molecules as a fragment. For (H2O)30, the average deviation of the EE-MB method truncated up to the three-body level calculated using this strategy (relative to the conventional energies) is about 0.003 hartree at the M06-2X/6-311++G** level, while the deviation of the GEBF method with a similar computational cost is less than 0.001 hartree. The GEBF method is demonstrated to be applicable for electronic structure calculations of water clusters at any basis set.
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A new natural halogen-containing stilbene derivative was isolated from the leaves of Cajanus cajan (L.) Millsp. and identified as 3-O-(3-chloro-2-hydroxyl-propanyl)-longistylin A by comprehensive spectroscopic and chemical analysis, and named cajanstilbene H (1). It is the first halogen-containing stilbene derivative found from plants. In human mesenchymal stem cells (hMSC) from bone marrow, 1 did not promote cell proliferation, but distinctly enhanced osteogenic differentiation of hMSC in time- and dose-dependent manners. In six human cancer cell lines, 1 showed a moderate inhibitory effect on cell proliferation, with IC50 values of 21.42-25.85 µmol·L(-1).
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Diferenciação Celular/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Cajanus/química , Halogênios/administração & dosagem , Halogênios/química , Humanos , Extratos Vegetais/química , Folhas de Planta/química , Estilbenos/administração & dosagem , Estilbenos/químicaRESUMO
Marsdeniae tenacissimae Caulis (MTC) is a Chinese herbal medicine used mainly for treatment of cancer, whose pharmacologically active constituents responsible for its in vivo activity and clinical efficacy have not been clearly elucidated. In this study, total aglycones of MTC (ETA) showed the ability to sensitize KB-3-1, HeLa, HepG2 and K562 cells to paclitaxel treatment. More inspiringly, ETA markedly enhanced the antitumor activity of paclitaxel in nude mice bearing HeLa or KB-3-1 xenografts. Compared to treatment with paclitaxel alone, treatment with combination of paclitaxel and ETA achieved significant reduction in volume and weight of HeLa tumors (p<0.05), and remarkable inhibition to the growth of KB-3-1 tumors (p<10â»6). ETA was characterized by the presence of a group of tenacigenin B ester derivatives, among which four reference compounds, 11α-O-tigloyl-12ß-O-acetyltenacigenin B, 11α,12ß-di-O-tigloyltenacigenin B, 11α-O-2-methylbutanoyl-12ß-O-tigloyltenacigenin B, and 11α-O-(2-methylbutanoyl)-12ß-O-benzoyltenacigenin B, accounted for 42.14% of the total peak area of 19 detectable components assayed by HPLC. Our study has identified ETA as a promising sensitizer for cancer chemotherapy.
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Antineoplásicos Fitogênicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Marsdenia/química , Paclitaxel/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Purpose: To verify whether there is lower incidence of adverse pregnancy outcomes after high-intensity focused ultrasound (HIFU) treatment than loop electrosurgical excision procedure (LEEP) in young women of childbearing age. Patients and Methods: This retrospective cohort study enrolled 46 patients treated with HIFU and 46 patients treated with LEEP. To compare the differences between the two groups, Fisher's exact test or the Kruskal-Wallis (K-W/H) test was used in the univariate analysis, while the logistic regression method was applied for further verification. Results: Basic characteristics showed no differences between the two groups (P > 0.05) except for parity (P < 0.001). Preterm birth rates were 6.52% and 0.00% in patients with cervical high-grade squamous intraepithelial lesions (HSIL) treated with LEEP and HIFU, respectively. The incidence rates of premature rupture of membranes (PROM) were respectively 15.22% and 21.74% in the two groups. There was no significant difference in pregnancy outcomes between the two groups (P > 0.05). Conclusion: This study is the first to compare the pregnancy outcomes of patients with cervical HSIL who treated with LEEP and HIFU procedures. Both HIFU treatment and LEEP are available options for patients of reproductive age with cervical HSIL. Therefore, it is necessary to conduct prospective single-center or multicenter randomized controlled studies.
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BACKGROUND: Ischemic stroke refers to a disorder in the blood supply to a local area of brain tissue for various reasons and is characterized by high morbidity, mortality, and disability. Early reperfusion of brain tissue at risk of injury is crucial for the treatment of acute ischemic stroke. The purpose of this study was to evaluate comfort levels in managing acute stroke patients with hypoxemia who required endotracheal intubation after multidisciplinary in situ simulation training and to shorten the door-to-image time. METHODS: This quality improvement project utilized a comprehensive multidisciplinary in situ simulation exercise. A total of 53 participants completed the two-day in situ simulation training. The main outcome was the self-reported comfort levels of participants in managing acute stroke patients with hypoxemia requiring endotracheal intubation before and after simulation training. A 5-point Likert scale was used to measure participant comfort. A paired-sample t-test was used to compare the mean self-reported comfort scores of participants, as well as the endotracheal intubation time and door-to-image time on the first and second days of in situ simulation training. The door-to-image time before and after the training was also recorded. RESULTS: The findings indicated that in situ simulation training could enhance participant comfort when managing acute stroke patients with hypoxemia who required endotracheal intubation and shorten door-to-image time. For the emergency management of hypoxemia or tracheal intubation, the mean post-training self-reported comfort score was significantly higher than the mean pre-training comfort score (hypoxemia: 4.53±0.64 vs. 3.62±0.69, t= -11.046, P<0.001; tracheal intubation: 3.98±0.72 vs. 3.43±0.72, t= -6.940, P<0.001). We also observed a decrease in the tracheal intubation and door-to-image time and a decreasing trend in the door-to-image time, which continued after the training. CONCLUSION: Our study demonstrates that the implementation of in situ simulation training in a clinical environment with a multidisciplinary approach may improve the ability and confidence of stroke team members, optimize the first-aid process, and effectively shorten the door-to-image time of stroke patients with emergency complications.
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INTRODUCTION: The relationship between depression and gut microbiota remains unclear, but an important role of gut microbiota has been verified. The relationship between gut microbiota and antibiotic resistance genes (ARGs) may be a potential new explanatory pathway. METHODS: We collected samples from 63 depressed patients and 30 healthy controls for metagenomic sequencing. The two groups' microbiota characteristics, functional characteristics, and ARG differences were analyzed. RESULTS: We obtained 30 differential KEGG orthologs (KOs) and their producers in 5 genera and 7 species by HUMAnN3. We found 6 KOs from Weissella_cibaria and Lactobacillus_plantaru are potentially coring functional mechanism of gut microbiota. Different metabolites including sphingolipids, pyrans, prenol lipids, and isoflavonoids also showed significance between MDD and HC. We detected 48 significantly different ARGs: 5 ARGs up-regulated and 43 ARGs down-regulated in MDD compared to HC. Based on Cox model results, Three ARGs significantly affected drug efficacy (ARG29, ARG105, and ARG111). Eggerthella, Weissella, and Lactobacillus were correlated with different core ARGs, which indicated different mechanisms in affecting MDD. LIMITATIONS: The present study needs to be replicated in different ethnic groups. At the same time, a larger Chinese cohort study and detailed experimental verification are also the key to further discussion. CONCLUSION: Our findings suggest that ARGs play a role in the interplay between major depressive disorder and gut microbiota. The role of ARGs should be taken into account when understanding the relationship between depression and gut microbiota.
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Transtorno Depressivo Maior , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/microbiologia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Resistência Microbiana a Medicamentos/genética , Estudos de Casos e ControlesRESUMO
Under nitrogen deficient conditions, the Aurantiochytrium limacinum strain BL10 greatly increases the production of docosahexaenoic acid (DHA) and n-6 docosapentaenoic acid. Researchers have yet to elucidate the mechanism by which BL10 promotes the activity of polyunsaturated fatty acid synthase (Pfa), which plays a key role in the synthesis of polyunsaturated fatty acid (PUFA). Analysis in the current study revealed that in nitrogen-depleted environments, BL10 boosts the transcription and synthesis of proteins by facilitating the expression of pfa genes via transcriptional regulation. It was also determined that BL10 adjusts the lengths of the 5'- and 3'-untranslated regions (suggesting post-transcriptional regulation) and modifies the ratio of two Pfa1 isoforms to favor PUFA production via post-translational regulation (ubiquitination). These findings clarify the exceptional DHA production of BL10 and provide additional insights into the regulatory mechanisms of PUFA biosynthesis in Aurantiochytrium.
Assuntos
Ácido Graxo Sintases , Ácidos Graxos Insaturados , Nitrogênio , Estramenópilas , Nitrogênio/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos Insaturados/biossíntese , Ácidos Graxos Insaturados/metabolismo , Estramenópilas/genética , Estramenópilas/enzimologia , Processamento de Proteína Pós-Traducional , Transcrição Gênica , Ácidos Docosa-Hexaenoicos/biossíntese , Ácidos Docosa-Hexaenoicos/metabolismoRESUMO
For most frequent respiratory viruses, there is an urgent need for a universal influenza vaccine to provide cross-protection against intra- and heterosubtypes. We previously developed an Escherichia coli fusion protein expressed extracellular domain of matrix 2 (M2e) and nucleoprotein, named NM2e, and then combined it with an aluminum adjuvant, forming a universal vaccine. Although NM2e has demonstrated a protective effect against the influenza virus in mice to some extent, further improvement is still needed for the induction of immune responses ensuring adequate cross-protection against influenza. Herein, we fabricated a cationic solid lipid nanoadjuvant using poly(lactic acid) (PLA) and dimethyl-dioctadecyl-ammonium bromide (DDAB) and loaded NM2e to generate an NM2e@DDAB/PLA nanovaccine (Nv). In vitro experiments suggested that bone marrow-derived dendritic cells incubated with Nv exhibited â¼4-fold higher antigen (Ag) uptake than NM2e at 16 h along with efficient activation by NM2e@DDAB/PLA Nv. In vivo experiments revealed that Ag of the Nv group stayed in lymph nodes (LNs) for more than 14 days after initial immunization and DCs in LNs were evidently activated and matured. Furthermore, the Nv primed T and B cells for robust humoral and cellular immune responses after immunization. It also induced a ratio of IgG2a/IgG1 higher than that of NM2e to a considerable extent. Moreover, NM2e@DDAB/PLA Nv quickly restored body weight and improved survival of homo- and heterosubtype influenza challenged mice, and the cross-protection efficiency was over 90%. Collectively, our study demonstrated that NM2e@DDAB/PLA Nv could offer notable protection against homo- and heterosubtype influenza virus challenges, offering the potential for the development of a universal influenza vaccine.
Assuntos
Adjuvantes Imunológicos , Vacinas contra Influenza , Poliésteres , Compostos de Amônio Quaternário , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/química , Vacinas contra Influenza/administração & dosagem , Animais , Camundongos , Poliésteres/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Compostos de Amônio Quaternário/química , Feminino , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Nanopartículas/química , Proteção Cruzada/imunologia , Adjuvantes de Vacinas/química , Proteínas da Matriz Viral/imunologiaRESUMO
4-1BB (CD137, TNFRSF9) is a type I transmembrane protein which binds its natural ligand, 4-1BBL. This interaction has been exploited to improve cancer immunotherapy. With ligand binding by 4-1BB, the nuclear factor-kappa B signaling pathway is activated, which results in transcription of corresponding genes such as interleukin-2 and interferon-γ, as well as the induction of T cell proliferation and antiapoptotic signals. Moreover, monoclonal antibodies that target-4-1BB, for example, Urelumab and Utomilumab, are widely used in the treatments of B cell non-Hodgkin lymphoma, lung cancer, breast cancer, soft tissue sarcoma, and other solid tumors. Furthermore, 4-1BB as a costimulatory domain, for chimeric antigen receptor T (CAR-T) cells, improves T cell proliferation and survival as well as reduces T cell exhaustion. As such, a deeper understanding of 4-1BB will contribute to improvements in cancer immunotherapy. This review provides a comprehensive analysis of current 4-1BB studies, with a focus on the use of targeting-4-1BB antibodies and 4-1BB activation domains in CAR-T cells for the treatment of cancer.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Ligantes , Neoplasias/terapia , Imunoterapia , NF-kappa BRESUMO
Many patients with severe mental illness (SMI) relapsed and deteriorated during the COVID-19 pandemic, as they experienced medication interruption. This study aimed to investigate factors affecting medication interruption in patients with SMI during the COVID-19 pandemic. A total of 2,077 patients with SMI participated in an online survey on medication interruption during the COVID-19 outbreak. The questionnaire comprised six parts: basic demographic information, COVID-19 exposure, state of disease, medication compliance before COVID-19, medication interruption during COVID-19, and the specific impact and needs. A total of 2,017 valid questionnaires were collected. Nearly 50% of patients with SMI have been affected to varying degrees of life expectancy and treatment. Among them, 74 patients stopped taking medicines for more than 14 days without a prescription. Logistic regression analysis showed that cohabitant exposure [OR = 26.629; 95% CI (3.293-215.323), p = 0.002], medication partial compliance and non-compliance pre-COVID-19 [OR = 11.109; 95% CI (6.093-20.251), p < 0.001; OR = 20.115; 95% CI (10.490-38.571), p < 0.001], and disease status [OR = 0.326; 95% CI (0.188-0.564), p < 0.001] were related to medication interruption. More than 50% of the patients wanted help in taking medications, follow-up, and receiving more financial support and protective materials. We found that the daily lives of patients with SMI were much more susceptible to impact during the pandemic. Patients with a history of partial or non-medication compliance before COVID-19 and an unstable disease state are more easily affected by pandemics and epidemics and need extra attention should similar large-scale outbreaks occur in the future.
Assuntos
COVID-19 , Transtornos Mentais , Humanos , Pandemias , Pacientes Ambulatoriais , Transtornos Mentais/epidemiologia , Adesão à MedicaçãoRESUMO
BACKGROUND: Although the association between gut microbiota and the pathogenesis of major depressive disorder (MDD) has been well studied, it is unclear whether gut microbiota affects cognitive function in patients with MDD. In this study, we explored the association between gut microbiota and cognitive function in MDD and its possible mechanisms. METHODS: We enrolled 57 patients with MDD and 30 healthy controls (HCs) and used 16S rRNA gene sequencing analysis and shotgun metagenomic sequencing analysis to determine gut microbial composition. RESULTS: The richness and diversity of gut microbiota in patients with MDD were the same as those in HCs, but there were differences in the abundance of Bifidobacterium and Blautia. Compared with HCs, two strains (bin_32 and bin_55) were significantly increased, and one strain (bin_31) was significantly decreased in patients with MDD based on the strain-level meta-analysis. Time to complete the Stroop-C had significant negative correlations with bin_31 and bin_32. Bin_55 had significant negative correlations with time to complete the Stroop-C, time to complete the Stroop-CW, and repeated animal words in 60 s but significant positive correlations with correct answers in 120 s on the Stroop-CW. LIMITATIONS: This study only tested the cognitive function of MDD in a small sample, which may have caused some bias. CONCLUSIONS: Based on our strain-level analysis, we found that gut microbiota may be associated with the pathogenesis of MDD and may have potential effects on cognitive function.