Inhalation of panaxadiol alleviates lung inflammation via inhibiting TNFA/TNFAR and IL7/IL7R signalling [Human]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226900 | GEO | 2024/02/02
REPOSITORIES: GEO
Similar Datasets
Project description:Background: There are no highly effective medications for treating pneumonia. Ginseng and its derivatives have anti-inflammatory properties, but their unstable physicochemical and metabolic properties prevent them from being used to treat pneumonia. The aforementioned issues may be resolved by inhalation, but the precise mechanism of action must be investigated. Methods: In order to study the effects and mechanisms of PD inhalation drug delivery, models of LPS-induced murine holistic pneumonia, isolated macrophage inflammation, and epithelial cell co-culture are utilized. For the evaluation of efficacy, pathology and molecular assays have been utilized. Mechanisms of action and targets were screened and validated by molecular means using transcriptome sequencing. Efficacy and mechanism of action were ultimately validated using human BALF cell models. Also studied were pharmacokinetic parameters of inhaled PD. Results: Inhalation of PD dose-dependently reduced LPS-induced lung inflammation in mice, including inflammatory cell infiltration, lung histopathology, and inflammatory factor expression. Oral PD had the same anti-inflammatory effect as inhalation, but inhalation was more effective at the same dose. It could be a result of its increased bioavailability and improved pharmacokinetic parameters. Using transcriptome analysis and validation of macrophage and epithelial cell experiments, we discovered that PD may inhibit TNFA/TFNAR and IL7/IL7R signaling to inhibit macrophage inflammatory factor-induced epithelial cell apoptosis and promote value-added initiation. Human alveolar lavage cell experimentation confirmed this result. Conclusion: PD inhalation alleviates lung inflammation and pathology by inhibiting TNFA/TFNAR and IL7/IL7R signaling. PD may be a novel drug for the clinical treatment of lung inflammation.
2024-02-02 | GSE227089 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-02-02 | GSE227090 | GEO
Project description:Lymph node (LN) development depends on prenatal interactions occurring between LN inducer and LN organizer cells. We have distinguished defects in LN formation due to failure in embryonic development (aly/aly) from defects in postnatal maturation (Il2rgamma(-/-)Rag2(-/-)). Both mutant strains form normal primordial LNs with differing fate. In aly/aly mice, the LN primordium dissipates irreversibly late in gestation; in contrast, Il2rgamma(-/-)Rag2(-/-) LN anlage persists for a week after birth but disperses subsequently, a process reversible by neonatal transfer of WT IL7r(+) TCR(+) T or natural killer (NK) cells, suggesting a role for IL7/IL7r interactions. Thus, we reveal a unique stage of postnatal LN development during which mature lymphocytes and IL7/IL7r interactions may play an important role.
| S-EPMC1569185 | biostudies-literature
Project description:Bronchoalveolar lavage is commonly performed to examine inflammation and responsible pathogens in lung diseases, and its findings may be used to assess the immune profile of the lung tumor microenvironment (TME). To investigate whether analyses of bronchoalveolar lavage fluid (BALF) can help identify non-small cell lung cancer (NSCLC) patients who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis were compared regarding therapeutic effect in 12 patients. Compared to non-responders, responders showed significantly higher CXCL9 levels and greater diversity in the lung microbiome profile in BALF, and greater frequency of CD56+ subset in blood T cells, whereas no significant difference was found in PD-L1 expression of tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to nivolumab, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 and the microbiome in the lung TME might be associated with each other, and their balance could contribute to nivolumab sensitivity in NSCLC patients. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.
2022-04-07 | GSE193049 | GEO
Project description:Pharmacokinetic/pharmacodynamic (PK/PD) studies are an essential component of pre-clinical drug discovery. Current best approaches for PK/PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PK/PD studies using transplanted human kidney organoids. We performed PK studies with GFB-887, an investigational new drug now in Phase 2 trials. Orally dosed GFB-887 to athymic rats that had undergone organoid transplantation resulted in measurable drug exposure in human transplanted organoids. Importantly, we established the efficacy of orally dosed GFB-887 in PD studies, where quantitative analysis showed significant protection of kidney filter cells in human organoids and endogenous rat host kidneys. This widely applicable approach demonstrates, for the first time, feasibility of using transplanted human organoids in PK/PD studies, empowering organoids to revolutionize drug discovery.
2022-06-14 | GSE165104 | GEO
Project description:Zhu2015 - Combined gemcitabine and birinapant
in pancreatic cancer cells - basic PD model
Mathematical model to illustrate the
effectiveness of combination chemotherapy involving gemcitabine and
birinapant against pancreatic cancer.
This model is described in the article:
Mechanism-based mathematical
modeling of combined gemcitabine and birinapant in pancreatic
cancer cells.
Zhu X, Straubinger RM, Jusko
WJ.
J Pharmacokinet Pharmacodyn 2015 Oct;
42(5): 477-496
Abstract:
Combination chemotherapy is standard treatment for
pancreatic cancer. However, current drugs lack efficacy for
most patients, and selection and evaluation of new combination
regimens is empirical and time-consuming. The efficacy of
gemcitabine, a standard-of-care agent, combined with
birinapant, a pro-apoptotic antagonist of Inhibitor of
Apoptosis Proteins (IAPs), was investigated in pancreatic
cancer cells. PANC-1 cells were treated with vehicle,
gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and
combinations of the two drugs. Temporal changes in cell
numbers, cell cycle distribution, and apoptosis were measured.
A basic pharmacodynamic (PD) model based on cell numbers, and a
mechanism-based PD model integrating all measurements, were
developed. The basic PD model indicated that synergistic
effects occurred in both cell proliferation and death
processes. The mechanism-based model captured key features of
drug action: temporary cell cycle arrest in S phase induced by
gemcitabine alone, apoptosis induced by birinapant alone, and
prolonged cell cycle arrest and enhanced apoptosis induced by
the combination. A drug interaction term Ψ was employed in
the models to signify interactions of the combination when data
were limited. When more experimental information was utilized,
Ψ values approaching 1 indicated that specific mechanisms
of interactions were captured better. PD modeling identified
the potential benefit of combining gemcitabine and birinapant,
and characterized the key interaction pathways. An optimal
treatment schedule of pretreatment with gemcitabine for 24-48 h
was suggested based on model predictions and was verified
experimentally. This approach provides a generalizable modeling
platform for exploring combinations of cytostatic and cytotoxic
agents in cancer cell culture studies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000668.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000668 | BioModels
Project description:Zhu2015 - combined gemcitabine and birinapant
in pancreatic cancer cells - mechanistic PD model
Mechanistic mathematical model to
illustrate the effectiveness of combination chemotherapy involving
gemcitabine and birinapant against pancreatic cancer.
This model is described in the article:
Mechanism-based mathematical
modeling of combined gemcitabine and birinapant in pancreatic
cancer cells.
Zhu X, Straubinger RM, Jusko
WJ.
J Pharmacokinet Pharmacodyn 2015 Oct;
42(5): 477-496
Abstract:
Combination chemotherapy is standard treatment for
pancreatic cancer. However, current drugs lack efficacy for
most patients, and selection and evaluation of new combination
regimens is empirical and time-consuming. The efficacy of
gemcitabine, a standard-of-care agent, combined with
birinapant, a pro-apoptotic antagonist of Inhibitor of
Apoptosis Proteins (IAPs), was investigated in pancreatic
cancer cells. PANC-1 cells were treated with vehicle,
gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and
combinations of the two drugs. Temporal changes in cell
numbers, cell cycle distribution, and apoptosis were measured.
A basic pharmacodynamic (PD) model based on cell numbers, and a
mechanism-based PD model integrating all measurements, were
developed. The basic PD model indicated that synergistic
effects occurred in both cell proliferation and death
processes. The mechanism-based model captured key features of
drug action: temporary cell cycle arrest in S phase induced by
gemcitabine alone, apoptosis induced by birinapant alone, and
prolonged cell cycle arrest and enhanced apoptosis induced by
the combination. A drug interaction term Ψ was employed in
the models to signify interactions of the combination when data
were limited. When more experimental information was utilized,
Ψ values approaching 1 indicated that specific mechanisms
of interactions were captured better. PD modeling identified
the potential benefit of combining gemcitabine and birinapant,
and characterized the key interaction pathways. An optimal
treatment schedule of pretreatment with gemcitabine for 24-48 h
was suggested based on model predictions and was verified
experimentally. This approach provides a generalizable modeling
platform for exploring combinations of cytostatic and cytotoxic
agents in cancer cell culture studies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000669.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000669 | BioModels
Project description:Rosuvastatin is a quite known lipid-lowering agent generally used for hypercholesterolemia treatment and coronary artery diseases prevention. There is substantial inter-individual variability in the absorption of statins usually caused by genetic polymorphisms leading to variation in the corresponding pharmacokinetic parameters, which may affect drug therapy safety and efficacy. Therefore, the investigation of metabolic markers associated with rosuvastatin inter-individual variability is exceedingly relevant for drug therapy optimization and minimizing side effects. This work describes the application of pharmacometabolomics strategies using liquid chromatography coupled to mass spectrometry to investigate endogenous plasma metabolites capable of predicting pharmacokinetic parameters in predose samples. First, a targeted method for the determination of plasma concentration levels of rosuvastatin was validated and applied to obtain the pharmacokinetic parameters from the 40 enrolled individuals, then predose samples were analyzed using the metabolomics approach to search for associations between endogenous metabolites and the corresponding pharmacokinetic parameters. Data processing using machine learning revealed some candidates including sterols and bile acids, carboxylated metabolites as well as lipids suggesting the approach herein described as promising for personalized drug therapy.
2021-10-29 | MTBLS3128 | MetaboLights
Project description:Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA’s biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated antiinflammatory markers (e.g. IL10), and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA.
2015-05-22 | GSE68527 | GEO
Project description:Gene Expression Profiling of a Mouse Xenograft Model of â??Triple-Negativeâ?? Breast Cancer Brain Metastases With and Without Vorinostat Treatment. Purpose: As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer. Experimental Design: The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo. Results: Following systemic administration, uptake of [14C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231-BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle-treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52. Conclusions: We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. Experiment Overall Design: We performed gene expression profiling on metastases from vehicle- or vorinostat-treated mice to determine if alterations in gene expression were observable that were consistent with the phenotypes observed. Brain metastases from five vehicle-treated mice and six 150 mg/kg vorinostat-treated mice were procured by laser capture microdissection. RNA was extracted from the captured tumor cells from each brain and two rounds of linear amplification was done. The amplified RNA from each mouse was processed separately through microarray hybridization and analysis.
2009-10-27 | E-GEOD-18544 | biostudies-arrayexpress