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BACKGROUND: Panax ginseng C. A. Mey is a precious medicinal resource that could be used to treat a variety of diseases. Saponins are the most important bioactive components of, and rare ginsenosides (Rg3, Rh2, Rk1 and Rg5, etc.) refer to the chemical structure changes of primary ginsenosides through dehydration and desugarization reactions, to obtain triterpenoids that are easier to be absorbed by the human body and have higher activity. PURPOSE: At present, the research of P. ginseng. is widely focused on anticancer related aspects, and there are few studies on the antibacterial and skin protection effects of rare ginsenosides. This review summarizes the rare ginsenosides related to bacterial inhibition and skin protection and provides a new direction for P. ginseng research. METHODS: PubMed and Web of Science were searched for English-language studies on P. ginseng published between January 2002 and March 2024. Selected manuscripts were evaluated manually for additional relevant references. This review includes basic scientific articles and related studies such as prospective and retrospective cohort studies. CONCLUSION: This paper summarizes the latest research progress of several rare ginsenosides, discusses the antibacterial effect of rare ginsenosides, and finds that ginsenosides can effectively protect the skin and promote wound healing during use, so as to play an efficient antibacterial effect, and further explore the other medicinal value of ginseng. It is expected that this review will provide a wider understanding and new ideas for further research and development of P. ginseng drugs.
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Understanding of how different grasslands types respond to climate change and human activities across different spatial and temporal dimensions is crucial for devising effective strategies to prevent grasslands degradation. In this study, we developed a novel vulnerability assessment model for grasslands that intricately evaluates the combined impact of climate change and human activities. We then applied this model to analyze the vulnerability and driving mechanism of four representative Chinese grasslands to climate change and human activities. Our findings indicate that the vulnerability of the four grasslands would show a pattern of higher in the west and lower in the east under the influence of climate change alone. However, when human activities are factored in, the vulnerability across the four grasslands tends to homogenize, with human activities notably reducing the vulnerability of alpine grasslands in the west and, conversely, increasing the vulnerability of grasslands in the east. Furthermore, our study reveals distinct major environmental drivers of grasslands vulnerability across different regions. The two western alpine grasslands exhibit higher vulnerability to annual mean temperature and isothermality compared to the eastern temperate grasslands, while their vulnerability to precipitation of the coldest quarter is lower than that of the eastern temperate grasslands. These findings are helpful for understanding the multifaceted causes and mechanisms of grasslands degradation, providing a scientific foundation for the sustainable management and conservation of grassland resources.
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USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14âE16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12â20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.
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Neural networks are frequently employed to model species distribution through backpropagation methods, known as backpropagation neural networks (BPNN). However, the complex structure of BPNN introduces parameter settings challenges, such as the determination of connection weights, which can affect the accuracy of model simulation. In this paper, we integrated the Grey Wolf Optimizer (GWO) algorithm, renowned for its excellent global search capacity and rapid convergence, to enhance the performance of BPNN. Then we obtained a novel hybrid algorithm, the Grey Wolf Optimizer algorithm optimized backpropagation neural networks algorithm (GNNA), designed for predicting species' potential distribution. We also compared the GNNA with four prevalent species distribution models (SDMs), namely the generalized boosting model (GBM), generalized linear model (GLM), maximum entropy (MaxEnt), and random forest (RF). These models were evaluated using three evaluation metrics: the area under the receiver operating characteristic curve, Cohen's kappa, and the true skill statistic, across 23 varied species. Additionally, we examined the predictive accuracy concerning spatial distribution. The results showed that the predictive performance of GNNA was significantly improved compared to BPNN, was significantly better than that of GLM and GBM, and was even comparable to that of MaxEnt and RF in predicting species distributions with small sample sizes. Furthermore, the GNNA demonstrates exceptional powers in forecasting the potential non-native distribution of invasive plant species.
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Algoritmos , Redes Neurais de Computação , Curva ROCRESUMO
To explore the formation mechanism of the ozone ï¼O3ï¼ and emission reduction strategy in a northwestern cityï¼ an extensive field campaign was conducted in summertime in 2021 in Yining Cityï¼ in which the 0-D box model incorporating the latest explicit chemical mechanism ï¼MCMv3.3.1ï¼ was applied for the first time to quantify the O3-NOx-VOCs sensitivity and formulate a precise O3 control strategy in this city. The results showed thatï¼ â the three indicators ï¼»i.e.ï¼ O3 formation potential ï¼OFPï¼ï¼ ·OH reaction rate ï¼k·OHï¼ï¼ and relative incremental reactivity ï¼RIRï¼ï¼½ jointly indicated that alkenesï¼ oxygenated volatile organic compounds ï¼OVOCsï¼ï¼ and aromatics were the highest contributors among anthropogenic volatile organic compounds ï¼AVOCï¼ to O3 formationï¼ and the contribution of biogenic volatile organic compounds ï¼BVOCï¼ also could not be ignored. Additionallyï¼ the results based on RIR calculation implied that that the acetaldehydeï¼ ethyleneï¼ and propylene were the most sensitive individual VOCs species in Yining City. â¡ The in-situ photochemical O3 variations were primarily influenced by the local photochemical production and export process horizontally to downwind areas or vertically to the upper layerï¼ and the reaction pathways of HO2·+ NO and ·OH + NO2 contributed the most to the gross Ox photochemical production ï¼60%ï¼ and photochemical destruction production ï¼53%ï¼ï¼ respectively. Henceï¼ the reduction in local emissions for O3 precursors was more essential to alleviate O3 pollution in this city. ⢠The outcome based on RIRï¼NOxï¼ / RIRï¼AVOCï¼ and EKMA jointly suggested that the photochemical regime in this city can be considered a transitional regime that was also nearly a VOCs-limited regime. Detailed mechanism modeling based on multiple scenarios further suggested that the NOx and VOCs synergic emission reduction strategies was helpful to alleviate O3 pollution. These results are useful to provide policy-related guidance for other cities facing similar O3 pollution in northwest China.
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How to effectively obtain species-related low-dimensional data from massive environmental variables has become an urgent problem for species distribution models (SDMs). In this study, we will explore whether dimensionality reduction on environmental variables can improve the predictive performance of SDMs. We first used two linear (i.e., principal component analysis (PCA) and independent components analysis) and two nonlinear (i.e., kernel principal component analysis (KPCA) and uniform manifold approximation and projection) dimensionality reduction techniques (DRTs) to reduce the dimensionality of high-dimensional environmental data. Then, we established five SDMs based on the environmental variables of dimensionality reduction for 23 real plant species and nine virtual species, and compared the predictive performance of those with the SDMs based on the selected environmental variables through Pearson's correlation coefficient (PCC). In addition, we studied the effects of DRTs, model complexity, and sample size on the predictive performance of SDMs. The predictive performance of SDMs under DRTs other than KPCA is better than using PCC. And the predictive performance of SDMs using linear DRTs is better than using nonlinear DRTs. In addition, using DRTs to deal with environmental variables has no less impact on the predictive performance of SDMs than model complexity and sample size. When the model complexity is at the complex level, PCA can improve the predictive performance of SDMs the most by 2.55% compared with PCC. At the middle level of sample size, the PCA improved the predictive performance of SDMs by 2.68% compared with the PCC. Our study demonstrates that DRTs have a significant effect on the predictive performance of SDMs. Specifically, linear DRTs, especially PCA, are more effective at improving model predictive performance under relatively complex model complexity or large sample sizes.
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Compared to other techniques, RNA sequencing (RNA-Seq) has the advantage of having details of the expression abundance of all transcripts in a single run. In this study, we used RNA-Seq to monitor the maturity and dynamic characteristics of in vitro hepatocyte cultures. Hepatocytes, including mature hepatocytes and small hepatocytes, were analyzed in vitro using RNA-Seq and quantitative polymerase chain reaction (qPCR). The results demonstrated that the gene expression profiles measured by RNA-Seq showed a similar trend to the expression profiles measured by qPCR, and can be used to infer the success of in vitro hepatocyte cultures. The results of the differential analysis, which compared mature hepatocytes against small hepatocytes, revealed 836 downregulated and 137 upregulated genes. In addition, the success of the hepatocyte cultures could be explained by the gene list screened from the adopted gene enrichment test. In summary, we demonstrated that RNA-Seq could become an effective method for monitoring the whole transcriptome of hepatocyte cultures and provide a more comprehensive list of factors related to the differentiation of small hepatocytes into mature hepatocytes. This monitoring system not only shows high potential in medical applications but may also be a novel method for the clinical diagnosis of liver-related diseases.
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Hepatócitos , Transcriptoma , Ratos , Animais , RNA-Seq , Hepatócitos/metabolismo , Análise de Sequência de RNA , Células Cultivadas , FígadoRESUMO
Climate change increases the extinction risk of species, and studying the impact of climate change on endangered species is of great significance to biodiversity conservation. In this study, the endangered plant Meconopsis punicea Maxim (M. punicea) was selected as the research object. Four species distribution models (SDMs): the generalized linear model, the generalized boosted regression tree model, random forest and flexible discriminant analysis were applied to predict the potential distribution of M. punicea under current and future climates scenarios. Among them, two emission scenarios of sharing socio-economic pathways (SSPs; i.e., SSP2-4.5 and SSP5-8.5) and two global circulation models (GCMs) were considered for future climate conditions. Our results showed that temperature seasonality, mean temperature of coldest quarter, precipitation seasonality and precipitation of warmest quarter were the most important factors shaping the potential distribution of M. punicea. The prediction of the four SDMs consistently indicated that the current potential distribution area of M. punicea is concentrated between 29.02° N-39.06° N and 91.40° E-105.89° E. Under future climate change, the potential distribution of M. punicea will expand from the southeast to the northwest, and the expansion area under SSP5-8.5 would be wider than that under SSP2-4.5. In addition, there were significant differences in the potential distribution of M. punicea predicted by different SDMs, with slight differences caused by GCMs and emission scenarios. Our study suggests using agreement results from different SDMs as the basis for developing conservation strategies to improve reliability.
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The adult cortex has long been regarded as non-neurogenic. Whether injury can induce neurogenesis in the adult cortex is still controversial. Here, we report that focal ischemia stimulates a transient wave of local neurogenesis. Using 5'-bromo-2'-deoxyuridine labeling, we demonstrated a rapid generation of doublecortin-positive neuroblasts that died quickly in mouse cerebral cortex following ischemia. Nestin-CreER-based cell ablation and fate mapping showed a small contribution of neuroblasts by subventricular zone neural stem cells. Using a mini-photothrombotic ischemia mouse model and retrovirus expressing green fluorescent protein labeling, we observed maturation of locally generated new neurons. Furthermore, fate tracing analyses using PDGFRα-, GFAP-, and Sox2-CreER mice showed a transient wave of neuroblast generation in mild ischemic cortex and identified that Sox2-positive astrocytes were the major neurogenic cells in adult cortex. In addition, a similar upregulation of Sox2 and appearance of neuroblasts were observed in the focal ischemic cortex of Macaca mulatta. Our findings demonstrated a transient neurogenic response of Sox2-positive astrocytes in ischemic cortex, which suggests the possibility of inducing neuronal regeneration by amplifying this intrinsic response in the future.
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By rational altering the structure of CN auxiliary ligand, Near-infrared (NIR) phosphorescent cyclometalated platinum (II) and iridium (III) complexes with metformin (Met) have been successfully obtained and characterized. The dissociation of Met in aqueous solution can be accelerated by addition of Glutathione (GSH) and alleviated by drop of histidine, accompanied with a significant decay change of deep red phosphorescence. Besides, Pt3 and Ir1 with moiety of btpq mainly selectively targeted and located in Mitochondrial, while Pt1 of ppy and Pt2 with thpy mainly accumulated in endoplasmic reticulum. Moreover, Pt1-3 and Ir1 with metformin moiety all exert a significant enhanced anticancer activity, among them, Pt3 displays ca.66-fold, ca.147-fold and ca.588-fold higher cytotoxicity than cisplatin, Met-free analogue Pt3a and Met. Their relative anticancer mechanism was further investigated, both Pt2 and Pt3 could form covalent interaction with bovine serum albumin (BSA) and effectively induce reactive oxygen species (ROS) generation, arrest of cell cycle, loss of Mitochondrial membrane potential (MMP), display effective anti-metastasis activity and eventually induce apoptosis of cancer cell.
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Antineoplásicos , Complexos de Coordenação , Metformina , Irídio/química , Platina/farmacologia , Metformina/farmacologia , Medicina de Precisão , Antineoplásicos/química , Apoptose , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Linhagem Celular TumoralRESUMO
BACKGROUND: Gentiana plants, which have great medicinal and ornamental value, are widely distributed in diverse habitats and have complex taxonomy. Here 40 Gentiana chloroplast genomes were used for comparative genomic analysis and divergence time estimation. METHODS: The complete chloroplast genome of G. rhodantha was sequenced, assembled, and annotated. Comparative genomic and phylogenetic analysis were provided for variation analysis of Gentiana. RESULTS: Gentiana species satisfy the characteristics of intra-Sect conservation and inter-Sect variation in chloroplast genome structure and IR boundaries. All Gentiana Sects can be clustered into a single one and separated from each other; however, Ser. Apteroideae and Ser. Confertifoliae in Sect. Monopodiae are more closely related to Sect. Frigida and Sect. Cruciata, respectively. Gentiana has experienced two large gene loss events; the first, the collective loss of the rps16 gene at genus formation and the second, the collective loss of the ndh gene when Ser. Ornatae and Ser. Verticillatae completed their differentiation. Comparative genomic analysis support that Sect. Stenogyne and Sect. Otophora became the independent genera Metagentiana and Kuepferia. Seven divergence hotspot regions were screened based on Pi values, and could serve as DNA-specific barcodes for Gentiana. CONCLUSIONS: This study provides a further theoretical basis for taxonomic analysis, genetic diversity, evolutionary mechanism and molecular identification in Gentiana.
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Genoma de Cloroplastos , Gentiana , Sequência de Bases , Genoma de Cloroplastos/genética , Genômica , Gentiana/genética , FilogeniaRESUMO
N6-methyladenosine (m6A) is the most abundant methylation modification on mRNA in mammals. Fat mass and obesity-related protein (FTO) is the main RNA m6A demethylase. FTO is involved in the occurrence and maintenance of neuropathic pain (NP). NP often induces mental disorders. We found that NP downregulated the expression of FTO in the anterior cingulate cortex (ACC), inhibited the expression of matrix metalloproteinase-9 (MMP-9) in the ACC, maladjusted the brain-derived neurotrophic factor precursor (proBDNF) and mature brain-derived neurotrophic factor (mBDNF) levels in the ACC, and induced anxiety- and depression-like behaviors in mice. Blocking the downregulation of FTO in the ACC induced by peripheral nerve injury could reverse the anxiety- and depression-like behaviors of mice. Contrarily, downregulation of simulated FTO induced anxiety- and depression-like behaviors in mice. After peripheral nerve injury, the binding of FTO to MMP-9 mRNA decreased and the enrichment of m6A on MMP-9 mRNA increased. In conclusion, downregulation of FTO in ACC by regulating MMP-9 mRNA methylation level contributes to the occurrence of anxiety- and depression-like behaviors in NP mice.
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PURPOSE: To evaluate the difference of Totaled Health Risks In Vascular Events (THRIVE) in predicting adverse outcomes in acute ischemic stroke (AIS) of the anterior circulation and posterior circulation at 3-month and 1-year follow-up. METHODS: A total of 858 patients with AIS were followed up for 3 months and 1 year, and their data prospectively collected. The occurrence of death or moderate to severe disability (modified Rankin Scale ≥ 3 points) was regarded as the endpoint. MedCalc software was used to create the THRIVE receiver operating characteristic curve. The area under the curve (AUC) was calculated to compare the THRIVE scale in predicting adverse outcomes in AIS of the anterior and posterior circulation and compare the differences. RESULTS: At 3-month follow-up, the AUC of THRIVE was 0.685 (95% CI 0.644-0.724) for AIS of the anterior circulation and 0.709 (95% CI 0.647-0.765) for AIS of the posterior circulation. The area difference between them was 0.0235 (95% CI -0.0728-0.120, P = 0.6330[>0.05]). The AUC of THRIVE for AIS in the anterior circulation at 1 year was 0.701 (95% CI 0.660-0.740), and that for AIS in the posterior circulation at 1 year was 0.747 (95% CI 0.687-0.800). The area difference between them was 0.0458 (95% CI -0.0489-0.140, P = 0.3436 [>0.05]). The difference was not statistically significant. CONCLUSION: THRIVE can well predict the short-term and long-term adverse prognosis of AIS in the anterior and posterior circulation and has the same predictive effect.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Estudos de Coortes , Seguimentos , Humanos , Prognóstico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells in vitro and secrete higher levels of cytokines than single-target CAR-T cells. More importantly, in vivo experiments indicated that Tandem CAR-T cells markedly decreased tumor volume, exhibited enhanced antitumor activity, and prolonged mouse survival. Furthermore, the infiltration and persistence of T cells in the Tandem-CAR group were higher than those in the MSLN-CAR and Control-T groups but comparable to those in the FOLR1-CAR group. Collectively, this study demonstrated that Tandem CAR-T cells secreting IL-12 could enhance immunotherapeutic effects by reducing tumor antigen escape and increasing T cell functionality, which could be a promising therapeutic strategy for OV and other solid tumors.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Receptor 1 de Folato/metabolismo , Mesotelina/metabolismo , Neoplasias Ovarianas/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Citocinas/genética , Citocinas/metabolismo , Bases de Dados Genéticas , Feminino , Receptor 1 de Folato/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-12/metabolismo , Mesotelina/genética , Camundongos , Camundongos Nus , Transcriptoma , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: To evaluate the prognosis of acute cerebral infarction at 1-year follow-up in different circulation infarctions. METHODS: Clinical data of 858 consecutive patients with acute cerebral infarction were collected. Of the 858 cases, 21 (2.45%) were lost to follow-up and 837 completed follow-up and thus were enrolled in this study. At 1-year follow-up, death or moderate-to-severe dysfunction (modified Rankin Scale (mRS) ≥ 3 points) was regarded as the poor prognostic endpoint. Univariate analysis and multivariate logistic stepwise regression analysis were performed to assess the prognosis. The prediction probability of indicators was obtained for the multivariate model, and the receiver operating characteristic curve was delineated to calculate the area under the curve (AUC) to predict the fitness of the model. RESULTS: The older the age, the greater the probability of a poor prognosis. Patients with previous diabetes and cerebral infarction had a poor prognosis. The higher the National Institutes of Health Stroke Scale and mRS scores and the lower the Barthel index at admission, the worse the prognosis of the patients. The longer the hospital stay, the worse the prognosis of the patients. The prognosis of different circulation infarctions was different. The AUC of the multivariate model was AUC = 0.893, and the 95% confidence interval was 0.870-0.913, indicating a good fit. The prognosis of anterior circulation infarction (ACI) was worse than that of posterior circulation infarction (PCI) (P < 0.05). The prognosis of patients with ACI and PCI was not significantly different from that of patients with ACI or PCI alone (P > 0.05). CONCLUSIONS: Diabetes, the Barthel index at admission and previous cerebral infarction are poor prognostic factors of acute cerebral infarction. The prognosis of ACI is worse than that of PCI. Different factors affect the prognosis of different circulatory system infarctions.
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Infarto Cerebral , Complicações do Diabetes , Doença Aguda , Fatores Etários , Idoso , Infarto Cerebral/complicações , Seguimentos , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Modelos Estatísticos , Análise Multivariada , Prognóstico , Curva ROC , Recidiva , Índice de Gravidade de DoençaRESUMO
There are increasing concerns with regard to spontaneous abortion (SAB), the loss of pregnancy without external intervention before 20 weeks of gestation, among reproductive-aged women. To date, limited evidence is available concerning the association between SAB and air pollutants, especially in developing countries. Daily baseline outpatient data for SAB from January 1, 2014, to December 31, 2018 (1826 days) were obtained in Chongqing, a metropolis of southwest China. The over-dispersed Poisson generalized additive model with control of meteorological conditions and day of week was used to estimate the short-term effects of ambient air pollution on the daily number of SAB outpatients. A total of 42,334 SAB outpatient visits for SAB were recorded. No statistically significant association was observed between SAB and CO, PM2.5, PM10, O3, and SO2. The positive association only appeared for NO2: positive associations between SAB and NO2 were observed in both single-day models (lag 0, lag 1, lag 3, and lag 4) and cumulative exposure models (lag 01, lag 03, and lag 05) and the most significant effects were observed at lag 05 (3.289%; 95% CI: 1.568%, 5.011%). Moreover, the women with higher ages (30-39 and > 39) were more sensitive than those with lower ages (18-29), and the effect estimates were more evident in cool seasons. Collectively, our results suggested that short-term NO2 exposure was associated with higher risk of SAB, especially in elder women and cool seasons, which may contribute to further understand the role of air pollution on SAB and other adverse obstetric outcomes.
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CONTEXT: Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice. OBJECTIVE: To investigate the pharmacokinetics, tissue distribution and excretion of laurolitsine. MATERIALS AND METHODS: A LC-MS/MS method was established and validated to determine laurolitsine concentrations in the biological matrix of rats (plasma, tissue homogenate, urine and faeces). 10 Sprague-Dawley (SD) rats were used for plasma exposure study: 5 rats were injected with 2.0 mg/kg of laurolitsine via the tail vein, and the other 5 rats were administered laurolitsine (10.0 mg/kg) by gavage. 25 SD rats used for tissue distribution study and 5 SD rats for urine and faeces excretion study: rats administered laurolitsine (10.0 mg/kg) by gavage. After administered, serial blood, tissue, urine and faeces were collected. Analytical quantification was performed by a previous LC-MS/MS method. The pharmacokinetics, bioavailability, tissue distribution and excretion of laurolitsine were described. RESULTS: The pharmacokinetic parameters of oral and intravenous administration with Tmax were 0.47 and 0.083 h, t1/2 were 3.73 and 1.67 h, respectively. Oral bioavailability was as low as 18.17%. Laurolitsine was found at a high concentration in the gastrointestinal tract, liver, lungs and kidneys (26 015.33, 905.12, 442.32 and 214.99 ng/g at 0.5 h, respectively) and low excretion to parent laurolitsine in urine and faeces (0.03 and 1.20% in 36 h, respectively). CONCLUSIONS: This study established a simple, rapid and accurate LC-MS/MS method to determine laurolitsine in different rat samples and successful application in a pharmacokinetic study.
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Aporfinas/farmacocinética , Cromatografia Líquida/métodos , Litsea/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Aporfinas/isolamento & purificação , Disponibilidade Biológica , Meia-Vida , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
ABSTRACT: Most cases of primary microvascular angina pectoris (PMVA) are diagnosed clinically, but the etiology and pathological mechanisms are unknown. The effect of routine clinical medications is minimal, and PMVA can progress to serious cardiovascular events. To improve the diagnosis and effective treatment of this disease, this study was designed to diagnose PMVA via cardiovascular magnetic resonance (CMR) and the coronary angiography thrombolysis in myocardial infarction (TIMI) blood flow grade, as well as to analyze vascular endothelial function to elucidate the pathogenesis of PMVA and compare the effects of routine clinical medications.The present randomized controlled trial including a parallel control group will be conducted on 63 PMVA patients in our cardiovascular department. The patients will be selected and randomly divided into the control, diltiazem, and nicorandil groups. The control group will be administered routine drug treatments (aspirin, atorvastatin, betaloc ZOK, perindopril, and isosorbidemononitrate sustained-release tablets). The diltiazem group will be additionally treated with 90âmg qd diltiazem sustained-release capsules. The nicorandil group was additionally given 5âmg tid nicorandil tablets. Coronary angiography will be performed before treatment, the severity and frequency of chest pain will be evaluated before and after 9âmonths of treatment, and homocysteine and von Willebrand factor levels will be measured. Electrocardiography, echocardiography, dynamic electrocardiography, a treadmill exercise test, and CMR will be performed. Sex, age, body mass index, complications, smoking, and family history will also be recorded. The SPSS19.0 statistical software package will be used to analyze the data. The measurements will be expressed as the meanâ±âstandard deviation. Measurement data will be compared between the groups using Student's t-test. A relative number description will be used for the counting data, and the chi-squaretest will be used to compare the groups. A multivariate logistic regression analysis will be performed A P-valueâ<â.05 will be considered significant.The direct indices (CMR and coronary angiographic TIMI blood flow grade) may improve after adding diltiazem or nicorandil during routine drug treatments (such as aspirin, statins, and nitrates) in PMVA patients, and indirect indices (homocysteine and von Willebrand factor levels) may be reduced. TRIAL REGISTRATION: Chinese Clinical Trial Registry (http://www.chictr.org.cn/showprojen.aspx?proj=41894), No. CHiCTR1900025319, Registered on August 23, 2019; pre initiation.
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Sistema Cardiovascular/diagnóstico por imagem , Angiografia Coronária , Imageamento por Ressonância Magnética , Angina Microvascular/diagnóstico , Vasodilatadores/administração & dosagem , Adolescente , Adulto , Idoso , Aspirina/administração & dosagem , Sistema Cardiovascular/efeitos dos fármacos , Diltiazem/administração & dosagem , Quimioterapia Combinada/métodos , Eletrocardiografia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Angina Microvascular/tratamento farmacológico , Pessoa de Meia-Idade , Nicorandil/administração & dosagem , Nitroglicerina/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
High-mountain areas such as the Tibeto-Himalayan region (THR) host cold-adapted biota expected to be sensitive to anthropogenic climate change. Meconopsis is a representative endangered genus confined to alpine meadow or subnival habitats in the THR. We used climate-niche factor analysis to study the vulnerability of ten Meconopsis species to climate change, comparing current climate (representative of 1960-1990) to future climate scenarios (2070: average 2061-2080). For these ten Meconopsis species, we then identified potential future climate refugia and determined optimal routes for each species to disperse to the proposed refugia. Our results indicate that for the ten Meconopsis species, the regions with low vulnerability to climate change in the THR are the central Qinghai-Tibet Plateau, the Hengduan Mountains (HDM), the eastern Himalayas, and the West Qinling Mountain (WQL), and can be considered potential future climate refugia. Under future climate change, we found for the ten Meconopsis species potential dispersal routes to three of the four identified refugia: the HDM, the eastern Himalayas, and the WQL. Our results suggest that past refugia on the THR will also be the future climate refugia for the ten Meconopsis species, and these species may potentially persist in multiple future climate refugia, likely reducing risks from climate change. Furthermore, climate change may affect the threat ranking of Red Listed Species for Meconopsis species, as Least Concern species were estimated to become more vulnerable to climate change than the only Near Threatened species.