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1.
Molecules ; 29(11)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38893358

RESUMO

Pseudoginsenoside DQ (PDQ), an ocotillol-type ginsenoside, is synthesized with protopanaxadiol through oxidative cyclization. PDQ exhibits good anti-arrhythmia activity. However, the inhibitory effect of PDQ on the cytochrome 450 (CYP450) enzymes and major drug transporters is still unclear. Inhibition of CYP450 and drug transporters may affect the efficacy of the drugs being used together with PDQ. These potential drug-drug interactions (DDIs) are essential for the clinical usage of drugs. In this study, we investigated the inhibitory effect of PDQ on seven CYP450 enzymes and seven drug transporters with in vitro models. PDQ has a significant inhibitory effect on CYP2C19 and P-glycoprotein (P-gp) with a half-inhibitory concentration (IC50) of 0.698 and 0.41 µM, respectively. The inhibition of CYP3A4 and breast cancer-resistant protein (BCRP) is less potent, with IC50 equal to 2.02-6.79 and 1.08 µM, respectively.


Assuntos
Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Ginsenosídeos , Humanos , Ginsenosídeos/farmacologia , Ginsenosídeos/química , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores
2.
Phytomedicine ; 124: 155292, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38190784

RESUMO

BACKGROUND: (-)-Syringaresinol (SYR), a natural lignan with significant antioxidant and anti-inflammatory activities, possesses various pharmacological benefits including cardio-protective, antibacterial, anticancer, and anti-aging effects. It was shown that the effectiveness of (+)-syringaresinol diglucoside on the ulcerative colitis (UC) was attributed to the active metabolite (+)-syringaresinol (the enantiomor of SYR). However, the efficacy of SYR against UC remains unclear, and the associated molecular mechanism has not been revealed yet PURPOSE: This study aimed to assess the protective effect of SYR in UC and its underlying mechanism STUDY DESIGN AND METHODS: We examined SYR's protective impact on the intestinal epithelial barrier and its ability to inhibit inflammatory responses in both a lipopolysaccharide (LPS)-induced Caco-2 cell model and a dextran sodium sulfate (DSS)-induced UC mouse model. We also explored the potential signaling pathways regulated by SYR using transcriptome analysis and western blot assay RESULTS: In Caco-2 cells, SYR significantly increased trans-epithelial electrical resistance, reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ), and cyclooxygenase-2 (COX-2) levels, and enhanced cellular tight junction protein expression and distribution. In mice with UC, oral treatment with SYR (10, 20, 40 mg·kg-1) dose-dependently increased body weight, colon length, and expression of tight junction proteins, decreased disease activity index score, spleen coefficient, cytokine serum levels, bacterial translocation, and intestinal damage, and also preserved the ultrastructure of colonic mucosal cells. Transcriptomics indicated that the anti-UC effect of SYR is mediated via the PI3K-Akt/MAPK/Wnt signaling pathway. CONCLUSION: In summary, SYR effectively mitigated the development of UC by enhancing the intestinal epithelial barrier function and attenuating the inflammatory response. The plant-derived product SYR might be a potentially effective therapeutical agent against UC.


Assuntos
Colite Ulcerativa , Colite , Furanos , Lignanas , Humanos , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Células CACO-2 , Fosfatidilinositol 3-Quinases/metabolismo , Colo/patologia , Lignanas/farmacologia , Lignanas/uso terapêutico , Mucosa Intestinal/metabolismo , Modelos Animais de Doenças , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente
3.
Int J Mol Sci ; 25(2)2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38255909

RESUMO

The purpose of this study was to explore the therapeutic effect of the oral administration of pseudo-ginsenoside RT4 (RT4) on ulcerative colitis (UC), and to determine the rate of absorption and distribution of RT4 in mice with UC. Balb/c mice were induced using dextran sulfate sodium salts (DSS) to establish the UC model, and 10, 20, or 40 mg/kg of RT4 was subsequently administered via gavage. The clinical symptoms, inflammatory response, intestinal barrier, content of total short-chain fatty acids (SCFAs), and gut microbiota were investigated. Caco-2 cells were induced to establish the epithelial barrier damage model using LPS, and an intervention was performed using 4, 8, and 16 µg/mL of RT4. The inflammatory factors, transient electrical resistance (TEER), and tight-junction protein expression were determined. Finally, pharmacokinetic and tissue distribution studies following the intragastric administration of RT4 in UC mice were performed. According to the results in mice, RT4 decreased the disease activity index (DAI) score, restored the colon length, reduced the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), and boosted the levels of immunosuppressive cytokine IL-10, increased the content of SCFAs, improved the colonic histopathology, maintained the ultrastructure of colonic mucosal epithelial cells, and corrected disturbances in the intestinal microbiota. Based on the results in caco-2 cells, RT4 reduced the levels of TNF-α, IL-6, and IL-1ß; protected integrity of monolayers; and increased tight-junction protein expression. Additionally, the main pharmacokinetic parameters (Cmax, Tmax, t1/2, Vd, CL, AUC) were obtained, the absolute bioavailability was calculated as 18.90% ± 2.70%, and the main distribution tissues were the small intestine and colon. In conclusion, RT4, with the features of slow elimination and directional distribution, could alleviate UC by inhibiting inflammatory factors, repairing the intestinal mucosal barrier, boosting the dominant intestinal microflora, and modulating the expression of SCFAs.


Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Ginsenosídeos , Animais , Camundongos , Humanos , Distribuição Tecidual , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Células CACO-2 , Interleucina-6 , Fator de Necrose Tumoral alfa , Citocinas , Interleucina-1beta , Camundongos Endogâmicos BALB C
4.
Sci Rep ; 13(1): 19107, 2023 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-37925591

RESUMO

TGFB1, which encodes TGF-ß1, a potent cytokine regulating varies cellular processes including immune responses. TGF-ß1 plays context-dependent roles in cancers and is increasingly recognized as a therapeutic target to enhance immunotherapy responses. We comprehensively evaluated expression of TGFB1 and its clinical and biological effects across hematological malignancies. TGFB1 expression was first explored using data from the GTEx, CCLE, and TCGA databases. The expression and clinical significances of TGFB1 in hematological malignancies were analyzed using Hemap and our In Silico curated datasets. We also analyzed the relationship between TGFB1 with immune scores and immune cell infiltrations in Hemap. We further assessed the value of TGFB1 in predicting immunotherapy response using TIDE and real-world immunotherapy datasets. TGFB1 showed a hematologic-tissue-specific expression pattern both across normal tissues and cancer types. TGFB1 expression were broadly dysregulated in blood cancers and generally associated with adverse prognosis. TGFB1 expression were associated with distinct TME properties among different blood cancer types. In addition, TGFB1 expression was found to be a useful marker in predicting immunotherapy responses. Our results suggest that TGFB1 is broadly dysregulated in hematological malignancies. TGFB1 might regulate the immune microenvironment in a cancer-type-specific manner, which could be applied in the development of new targeted drugs for immunotherapy.


Assuntos
Neoplasias Hematológicas , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Citocinas , Prognóstico , Neoplasias Hematológicas/genética , Microambiente Tumoral/genética , Imunoterapia
5.
Nanoscale ; 15(17): 7894-7908, 2023 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-37060139

RESUMO

Periodontitis is an inflammatory disease, mainly caused by the formation of a subgingival plaque biofilm. In recent years, growing attention has been paid to immunotherapy in the treatment of periodontitis, and the importance of communal intervention associated with macrophage polarization was emphasized. Herein, resveratrol (RES) and 20(S)-protopanaxadiol (PPD) were successfully self-assembled into RES@PPD nanoparticles (NPs) by the phenolic resin reaction. RES@PPD NPs have good stability and biocompatibility. The combined application of PPD and RES enhances the anti-inflammatory and antioxidant properties of nanocomposites, remarkably reduces the level of reactive oxygen species, and finally realizes the coordinated regulation of host immunity in periodontitis. The detailed mechanism is as follows: RES@PPD NPs inhibit M1 polarization of macrophages, promote M2 polarization by scavenging ROS, and then inhibit the NF-κB signalling pathway to regulate host immunity. In the animal model of periodontitis, RES@PPD NPs can remarkably decrease the level of pro-inflammatory cytokines, up-regulate the anti-inflammatory cytokines, and exhibit a profound therapeutic effect on local inflammation. Therefore, RES@PPD NPs are effective in antioxidation and anti-inflammation, thus providing a promising candidate drug for the treatment of periodontitis.


Assuntos
Nanopartículas , Periodontite , Animais , Resveratrol/farmacologia , Macrófagos/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fenótipo , Citocinas/metabolismo , Periodontite/tratamento farmacológico
6.
Molecules ; 28(4)2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36838515

RESUMO

BACKGROUND: Saussurea pulchella (SP) is a traditional medicinal plant that is widely used in folk medicine because of its diverse biological activities, particularly its anti-inflammatory effects. However, the alleviation effect of SP on ulcerative colitis (UC) has not yet been realized. PURPOSE: To investigate the chemical composition and therapeutic effect of SP extract against UC. METHODS: First, qualitative and quantitative analysis of SP 75% ethanol extract was performed by UPLC-Q/TOF-MS. Second, a dextran sodium sulfate (DSS) model of UC mice was developed to study the effects of SP on the symptoms, inflammatory factors, oxidative stress indexes and colon histopathology. Third, an integration of network pharmacology with metabolomics was performed to investigate the key metabolites, biological targets and metabolisms closely related to the effect of SP. RESULTS: From the SP ethanol extract, 149 compounds were identified qualitatively and 20 were determined quantitatively. The SP could dose-dependently decrease the DAI score, spleen coefficient and the levels of TNF-α, IL-6, iNOS, MPO and MDA; increase the colon length, GSH level and SOD activity; and protect the intestinal barrier in the UC mice. Moreover, 10 metabolite biomarkers,18 targets and 5 metabolisms were found to play crucial roles in the treatment of UC with SP. CONCLUSIONS: SP 75% ethanol extract could effectively alleviate the progression of UC and, therefore, could be classified as a novel natural treatment for UC.


Assuntos
Colite Ulcerativa , Saussurea , Fator de Necrose Tumoral alfa , Animais , Camundongos , Colite Ulcerativa/tratamento farmacológico , Colo/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Saussurea/química , Fator de Necrose Tumoral alfa/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Compostos Fitoquímicos/química
7.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675303

RESUMO

Stroke, one of the leading causes of disability and death worldwide, is a severe neurological disease that threatens human life. Protopanaxatriol (PPT), panaxatriol-type saponin aglycone, is a rare saponin that exists in Panax ginseng and Panax Noto-ginseng. In this study, we established an oxygen-glucose deprivation (OGD)-PC12 cell model and middle cerebral artery occlusion/reperfusion (MCAO/R) model to evaluate the neuroprotective effects of PPT in vitro and in vivo. In addition, metabolomics analysis was performed on rat plasma and brain tissue samples to find relevant biomarkers and metabolic pathways. The results showed that PPT could significantly regulate the levels of LDH, MDA, SOD, TNF-α and IL-6 factors in OGD-PC12 cells in vitro. PPT can reduce the neurological deficit score and infarct volume of brain tissue in rats, restore the integrity of the blood-brain barrier, reduce pathological damage, and regulate TNF-α, IL-1ß, IL-6, MDA, and SOD factors. In addition, the results of metabolomics found that PPT can regulate 19 biomarkers involving five metabolic pathways, including amino acid metabolism, arachidonic acid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism. Thus, it could be inferred that PPT might serve as a novel natural agent for MCAO/R treatment.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Saponinas , Ratos , Humanos , Animais , Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fator de Necrose Tumoral alfa , Interleucina-6 , Infarto da Artéria Cerebral Média/patologia , Glucose , Traumatismo por Reperfusão/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Superóxido Dismutase
8.
Cancer Med ; 12(2): 2046-2057, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35801342

RESUMO

BACKGROUND: Enhancer RNAs (eRNAs), the transcriptional products of active enhancers, are of great significance in the initial progression of cancers. However, the biological function and bioinformatics profiles of eRNA in gastric cancer remains largely enigmatic. METHODS: Firstly, STAD were clustered into three subtypes with the data of eRNA expression from TCeA. Then we explored the difference of the tumor immune microenvironment, transcription levels, and transcription regulation among the three clusters. Finally, samples collected from 12 patients diagnosed with STAD were used to conduct qRT-PCR, verifying the conclusion based on network database. RESULTS: The three clusters were detected to have different tumor microenvironments: Cluster A has an immune "cold" microenvironment. While cluster B features as more infiltration of immune cells, accompanied with higher expression of immune checkpoints such as PDCD1, LAG3, and TIGIT. Besides, Cluster C shows a higher stromal feature with B lineage, neutrophils, and fibroblasts. Further analyses indicated that CpG island methylation level of Cluster B is different from the other two clusters. Meanwhile, Cluster A and B showed significant enrichment of TP53 and KRAS mutation respectively while Cluster C has higher tumor mutation burden (TMB) and microsatellite instability (MSI). With the elaboration of transcriptional regulation of epigenetic clustering, we detected that Cluster A enriched in epithelial phenotype pathways. Cluster B enriched in cell-cell adhesion. Cluster C enriched in fibroblast proliferation. The clinical cohort show that Cluster B patients have lower interstitial cell characteristics and CAF infiltration. CONCLUSION: We identified three unique epigenetic clusters of STAD through the differential activation of super-enhancers, and identified Cluster B with a higher immune infiltrating and a better prognosis, which provides a novel understanding of eRNAs and potential clinical applicability of eRNA-based molecular subtypes in gastric cancer.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , RNA , Prognóstico , Adesão Celular , Análise por Conglomerados , Microambiente Tumoral/genética
9.
Molecules ; 27(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36500439

RESUMO

Ulcerative colitis (UC) is a chronic, nonspecific inflammation of the bowel that mainly affects the mucosa and submucosa of the rectum and colon. Ginsenosides are the main active ingredients in ginseng and show many therapeutic effects in anti-inflammatory diseases, cancer, and nervous system regulation. Protopanaxatriol saponin (PTS) is an important part of saponins, and there is no research on its pharmacological effects on colitis. In this study, a model of ulcerative colitis in mice was induced by having mice freely drink 3.5% dextran sodium sulfate (DSS) solution, and UPLC-Q-TOF-MS-based metabolomics methods were applied to explore the therapeutic effect and protective mechanism of PTS for treating UC. The results showed that PTS could significantly prevent colon shortening and pathological damage and alleviate abnormal changes in UC mouse physiological and biochemical parameters. Moreover, PTS intervention regulated proinflammatory cytokines such as TNF-α, IL-6, and IL-1 in serum, and MPO and NO in colon. Interestingly, PTS could significantly inhibit UC mouse metabolic dysfunction by reversing abnormal changes in 29 metabolites and regulating eleven metabolic pathways. PTS has potential application in the treatment of UC and could alleviate UC in mice by affecting riboflavin metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, retinol metabolism, and steroid hormone biosynthesis and by regulating pentose and glucuronate conversion, linoleic acid metabolism, phenylalanine metabolism, ether lipid metabolism, sphingolipid metabolism, and tyrosine metabolism, which points at a direction for further research and for the development of PTS as a novel natural agent.


Assuntos
Colite Ulcerativa , Colite , Saponinas , Camundongos , Animais , Sulfato de Dextrana/efeitos adversos , Saponinas/metabolismo , Modelos Animais de Doenças , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/metabolismo , Colite/tratamento farmacológico , Inflamação/tratamento farmacológico , Camundongos Endogâmicos C57BL
10.
Int J Mol Sci ; 23(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36292949

RESUMO

Gastric ulcer (GU) is a peptic disease with high morbidity and mortality rates affecting approximately 4% of the population throughout the world. Current therapies for GU are limited by the high relapse incidence and side effects. Therefore, novel effective antiulcer drugs are urgently needed. Ginsenosides have shown good anti-GU effects, and the major intestinal bacterial metabolite of ginsenosides, protopanaxatriol (PPT), is believed to be the active component. In this study, we evaluated the anti-GU effect of PPT in rats in an acetic acid-induced GU model. High (H-PPT) and medium (M-PPT) doses of PPT (20.0 and 10.0 mg/mg/day) significantly reduced the ulcer area and the ET-1, IL-6, EGF, SOD, MDA and TNF-α levels in serum were regulated by PPT in a dose-dependent manner. We also investigated the mechanisms of anti-GU activity of PPT based on metabolomics coupled with network pharmacology strategy. The result was that 16 biomarkers, 3 targets and 3 metabolomic pathways were identified as playing a vital role in the treatment of GU with PPT and were further validated by molecular docking. In this study, we have demonstrated that the integrated analysis of metabolomics and network pharmacology is an effective strategy for deciphering the complicated mechanisms of natural compounds.


Assuntos
Ginsenosídeos , Úlcera Gástrica , Ratos , Animais , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo , Ácido Acético/toxicidade , Ginsenosídeos/uso terapêutico , Fator de Necrose Tumoral alfa , Simulação de Acoplamento Molecular , Interleucina-6/efeitos adversos , Fator de Crescimento Epidérmico/efeitos adversos , Farmacologia em Rede , Metabolômica , Biomarcadores , Superóxido Dismutase
11.
Biosci Rep ; 42(5)2022 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-35506368

RESUMO

The objective of our study was to measure DLEU7-AS1 expression in de novo acute myeloid leukemia (AML) whilst also analyzing its clinical relevance. We used gene expression data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Cancer Cell Line Encyclopedia (CCLE) and Genotype-Tissue Expression project (GTEx) to assess the expression profile of DLEU7-AS1 in pan-cancers, cancer cell lines and normal tissues. Reverse transcription-quantitative PCR was used to measure DLEU7-AS1 expression in bone marrow from 30 normal individuals and 110 patients with de novo AML. DLEU7-AS1 expression was found to be markedly reduced in the AML samples of the TCGA pan-cancer datasets. In our PCR validation, DLEU7-AS1 expression was significantly decreased in the AML samples compared with that in controls (P<0.001). Low DLEU7-AS1 expression (DLEU7-AS1low) correlated positively with lower blood platelet counts (P=0.029). In addition, low DLEU7-AS1 expression was more frequently observed in the intermediate (58%; 44/76) and favorable karyotypes (65%; 15/23) compared with that in the poor karyotype (10%; 1/10; P=0.005). In particular, patients with high expression levels of DLEU7-AS1 (DLEU7-AS1high) showed lower complete remission rates (P=0.002) than patients with DLEU7-AS1low. Survival analysis revealed that patients with DLEU7-AS1low had longer overall survival (OS) than patients with DLEU7-AS1high (P<0.05). Multivariate Cox analysis demonstrated that in patients with non-acute promyelocytic leukemia (non-M3) who were ≤60 years old, DLEU7-AS1 expression was an independent prognostic factor for OS. Furthermore, we found distinct correlations among the expression of DLEU7-AS1, infiltration by immune cells and immune checkpoint genes in AML.


Assuntos
Leucemia Mieloide Aguda , RNA Longo não Codificante , Humanos , Cariótipo , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Indução de Remissão
12.
Biomed Pharmacother ; 149: 112823, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35334426

RESUMO

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease. Aiming at assessing the effect of total saponins from American ginseng on COPD, both the chemical composition and anti-COPD activity of total saponins from wild-simulated American ginseng (TSW) and field-grown American ginseng (TSF) were investigated in this study. Firstly, a HPLC-ELSD chromatographic method was established to simultaneously determine the contents of 22 saponins in TSW and TSF. Secondly, CS-induced COPD mouse model was established to evaluate the activity of TSW and TSF. The results indicated that both TSW and TSF had the protective effect against COPD by alleviating oxidative stress and inflammatory response. TSW showed a stronger effect than TSF. Thirdly, an integrated approach involving metabolomics and network pharmacology was used to construct the "biomarker-reaction-enzyme-target" correlation network aiming at further exploring the observed effects. As the results, 15 biomarkers, 9 targets and 5 pathways were identified to play vital roles in the treatment of TSW and TSF on COPD. Fourthly, based on network pharmacology and the CS-stimulated A549 cell model, ginsenoside Rgl, Rc, oleanolic acid, notoginsenoside R1, Fe, silphioside B were certified to be the material basis for the stronger effect of TSW than TSF. Finally, the molecular docking were performed to visualize the binding modes. Our findings suggested that both TSW and TSF could effectively ameliorate the progression of COPD and might be used for the treatment of COPD.


Assuntos
Fumar Cigarros , Panax , Doença Pulmonar Obstrutiva Crônica , Saponinas , Animais , Biomarcadores/metabolismo , Metabolômica/métodos , Camundongos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Panax/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Saponinas/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico
13.
Int J Mol Sci ; 23(3)2022 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-35163182

RESUMO

Aiming at assessing the therapeutic effect of ethyl rosmarinate (ER) on ulcerative colitis (UC), the following activities were performed in vitro and in vivo in the present study. Firstly, a lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation model was established to determine the level of inflammatory factors. Then, a UC mice model induced by dextran sodium sulfate (DSS) was established to further investigate the effects of ER on symptoms, inflammatory factors and colon histopathology. Finally, serum and colon metabolomics studies were performed to identify the biomarkers and metabolisms closely related to the protective effect of ER on UC. The results showed that after ER intervention, the levels of inflammatory factors (NO, TNF-α, IL-1ß and IL-6) and key enzyme (MPO) in cell supernatant, serum or colon were significantly decreased, and the disease activity index and colon tissue damage in mice were also effectively improved or restored. In addition, 28 biomarkers and 6 metabolisms were found to be re-regulated by ER in the UC model mice. Therefore, it could be concluded that ER could effectively ameliorate the progression of UC and could be used as a new natural agent for the treatment of UC.


Assuntos
Cinamatos/farmacologia , Colite Ulcerativa/tratamento farmacológico , Depsídeos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Biomarcadores/sangue , Colite Ulcerativa/metabolismo , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Ácido Rosmarínico
14.
Mol Biol Rep ; 48(3): 2639-2652, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33661439

RESUMO

Panax ginseng, an ancient herb, belonging to Chinese traditional medicine, is an important herb that has a remarkable impact on various diseases. Ginsenoside Rg3, one of the most abundant ginsenosides, exerts significant functions in the prevention of various types of cancers with few side effects. In the present review, its functional molecular mechanisms are explored, including the improvement of antioxidant and anti-inflammation properties, immune regulation, induction of tumor apoptosis, prevention of tumor invasion and metastasis, tumor proliferation and angiogenesis, and reduction of chemoresistance and radioresistance. On the other hand, metabolism, pharmacokinetics and clinical indications of Rg3 are also discussed. The biological functional role of ginsenoside Rg3 may be associated with that it is a steroid glycoside with diverse biological activities and many signaling pathway can be regulated. Many clinical trials are highly needed to confirm the functions of ginsenoside Rg3.


Assuntos
Antineoplásicos/farmacologia , Ginsenosídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Ginsenosídeos/uso terapêutico , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico
15.
Nat Prod Res ; 35(20): 3487-3493, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31951470

RESUMO

A new alkynol, platycodynol (1), identified as 2, 3, 9, 13, 14-pentahydroxy-4, 6-tetradecadiyne, along with six known compounds (2-7) were obtained from Platycodins folium for the first time. Their structures were elucidated with infrared (IR), ultraviolet (UV), 1D and 2D nuclear magnetic resonance (NMR) spectroscopic analysis as well as by high resolution electrospray ionization mass spectroscopy (HRESIMS). Platycodynol showed cytotoxicity against S180, A549 and SPC-A-1 cancer cells but no cytotoxicity against normal cells NCTC1469 and HL-7702 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method.


Assuntos
Alcinos/química , Saponinas/farmacologia , Espectroscopia de Ressonância Magnética , Saponinas/química , Saponinas/toxicidade , Espectrometria de Massas por Ionização por Electrospray
16.
Oncol Lett ; 20(6): 359, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33133259

RESUMO

Esophageal cancer (ESCA) is the eighth most common cause of cancer-associated mortality in humans. An increasing number of studies have demonstrated that microRNAs (miRs) serve important roles in mediating tumor initiation and progression. miR-454-3p has been found to be involved in the development of various human malignancies; however, little is known about the role of miR-454-3p in esophageal cancer. In the present study, the protein and gene expression levels of miR-454-3p in ESCA tissues and cells were downregulated compared with adjacent normal tissues and normal human esophageal epithelial cells. Additionally, miR-454-3p downregulation resulted in improved survival rates in patients with ESCA, and miR-454-3p overexpression significantly suppressed cell proliferation, migration and invasion and promoted apoptosis in four ESCA cell lines (EC9706, ECA109, TE-1 and TE-8). It was found that miR-454-3p overexpression inhibited the expression of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) at the protein and mRNA expression levels. Furthermore, it was demonstrated that miR-454-3p inhibited ESCA cell proliferation, migration and apoptosis by targeting IGF2BP1 via the ERK and AKT signaling pathways in a subcutaneous xenograft tumor mouse model. These results showed that miR-454-3p functioned as an important tumor suppressor in ESCA by targeting IGFBP1. Therefore, miR-454-3p may be a novel prognostic biomarker and therapeutic target for patients with ESCA.

17.
Am J Transl Res ; 12(9): 4840-4852, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042393

RESUMO

Abnormal expression of CRIP1 has been identified in numerous solid tumors. However, CRIP1 expression and its regulation are little known in acute myeloid leukemia (AML). The purpose of this study was to evaluate the expression and regulation of CRIP1 and the clinical implications of CRIP1 aberration in AML. Real-time quantitative PCR was carried out to detect the level of CRIP1 expression in 138 AML patients and 38 controls. CRIP1 methylation was detected by methylation-specific PCR and bisulfite sequencing PCR. Five public available AML datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were further analyzed. The level of CRIP1 expression was up-regulated in AML patients compared with controls (P = 0.045). CRIP1 high patients had a significantly lower complete remission (CR) rate than CRIP1 low patients (P = 0.020). CRIP1 high group had a shorter overall survival (OS) and leukemia-free survival (LFS) than CRIP1 low group in cytogenetically normal AML (CN-AML) patients (P = 0.007 and 0.012, respectively). Multivariate analysis further confirmed that high CRIP1 expression was an independent risk factor for LFS in CN-AML patients (P = 0.005). However, we found that CRIP1 expression was not associated with the status of its promoter, which was nearly fully unmethylated both in controls and AML patients. Furthermore, our results were validated using the published GEO datasets and TCGA datasets. Our findings suggest that high CRIP1 expression is independently related with unfavorable prognosis in CN-AML.

18.
Xenobiotica ; 50(11): 1323-1331, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32369406

RESUMO

The compound 20(S),25-epoxydammarane-3ß,12ß,24α-triol (24-hydroxy-panaxadiol or 24-OH-PD), isolated from the red Panax ginseng CA Meyer possesses anticancer activity. Our aim was to study the pharmacokinetic characteristics of 24-OH-PD, which is essential for pre-clinical research during the development of new drugs. In this study, a simple and sensitive ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was established and used for studying the pharmacokinetics, in vitro protein binding, tissue distribution, and elimination profiles of 24-OH-PD in rats. 24-OH-PD was characterized by linear pharmacokinetics in the dose range of 2.5-10 mg/kg and had relatively longer half-life (4.82-5.45 h) than the other ginsenosides. It had a wide tissue distribution profile in rats and was primarily distributed in the lung. Within 96 h of intravenous administration, 13.84% of 24-OH-PD was excreted out via feces and 0.02% via urine in its unchanged form. In conclusion, a simple LC-MS/MS method with high sensitivity and selectivity was established for the quantification of 24-OH-PD.


Assuntos
Antineoplásicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Animais , Antineoplásicos/metabolismo , Líquidos Corporais , Medicamentos de Ervas Chinesas/metabolismo , Panax , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
19.
Int Immunopharmacol ; 83: 106449, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278128

RESUMO

Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) is an irreversible inflammatory airways disease responsible for global health burden, involved with a complex condition of immunological change. Exacerbation-mediated neutrophilia is an important factor in the pathogenesis of cigarette smoke-induced AECOPD. Ginsenoside Rg3, a red-ginseng-derived compound, has multiple pharmacological properties such as anti-inflammatory and antitumor activities. Here, we investigated a protective role of Rg3 against AECOPD, focusing on neutrophilia. 14-week-cigarette smoke (CS) exposure and non-typeable Haemophilus inflenzae (NTHi) infection were used to establish the AECOPD murine model. Rg3 (10, 20, 40 mg/kg) was administered intragastrically from the 12th week of CS exposure before infection, and this led to improved lung function and lung morphology, and reduced neutrophilic inflammation, indicating a suppressive effect on neutrophil infiltration by Rg3. Further investigations on the mechanism of Rg3 on neutrophils were carried out using bronchial epithelial cell (BEAS-2B) and neutrophil co-culture and transepithelial migration model. Pre-treatment of neutrophils with Rg3 reduced neutrophil migration, which seemed to be the result of inhibition of phosphatidylinositol (PtdIns) 3-kinases (PI3K) activation within neutrophils. Thus, Rg3 could inhibit exacerbation-induced neutrophilia in COPD by negatively regulating PI3K activities in neutrophils. This study provides a potential natural drug against AECOPD neutrophil inflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ginsenosídeos/uso terapêutico , Infecções por Haemophilus/terapia , Haemophilus influenzae/fisiologia , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , Mucosa Respiratória/metabolismo , Animais , Células Cultivadas , Fumar Cigarros/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Doenças do Sistema Imunitário , Transtornos Leucocíticos , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Panax/imunologia , Fosfatidilinositol 3-Quinases/metabolismo
20.
Oncoimmunology ; 9(1): 1683347, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002295

RESUMO

Hematological malignancies possess a distinctive immunologic microenvironment compared with solid tumors. Here, using an established computational algorithm (CIBERSORT), we systematically analyzed the overall distribution of 22 tumor-infiltrating leukocyte (TIL) populations in more than 2000 bone marrow (BM) samples from 5 major hematological malignancies and healthy controls. Focusing on significantly altered TILs in acute myeloid leukemia (AML), we found that patients with AML exhibited increased frequencies of M2 macrophages, compared to either healthy controls or the other four malignancies. High infiltration of M2 macrophages was associated with poor outcome in AML. Further analysis revealed that CD206, a M2 marker gene, could faithfully reflect variation in M2 fractions and was more highly expressed in AML than normal controls. High CD206 expression predicted inferior overall survival (OS) and event-free survival (EFS) in two independent AML cohorts. Among 175 patients with intermediate-risk cytogenetics, the survival still differed greatly between low and high CD206 expressers (OS; P < .0001; 3-year rates, 56% v 32%; EFS; P < .001; 3-year rates, 47% v 25%). When analyzed in a meta-analysis, CD206 as a continuous variable showed superior predictive performance than classical prognosticators in AML (BAALC, ERG, EVI1, MN1, and WT1). In summary, M2 macrophages are preferentially enriched in AML. The M2 marker CD206 may serve as a new prognostic marker in AML.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Neoplasias , Biomarcadores Tumorais/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Macrófagos , Prognóstico , Microambiente Tumoral
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