Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 956
Filtrar
1.
Eur J Med Chem ; 279: 116915, 2024 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-39366126

RESUMO

Plants are rich in steroidal and triterpenoid saponins. Diosgenin is an important sapogenin obtained from various steroidal saponins and specially from dioscin. It possesses diverse pharmacological activities as it is capable of modulating various endogenous pathways. Diosgenin is the molecule of choice for the industrial synthesis of the steroid based clinical drugs namely progesterone, testosterone, dexamethasone, dehydroepiandrosterone, vitamin D3, steroidal contraceptive pills, norethindrone, norgestrel etc. Diosgenin has been a molecule of discussion due to its high demand in industry as well as for future research applications. Present review describes its chemistry and detailed pharmacological profile.


Assuntos
Diosgenina , Sapogeninas , Diosgenina/química , Diosgenina/farmacologia , Sapogeninas/química , Sapogeninas/farmacologia , Humanos , Animais , Esteroides/química , Esteroides/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Estrutura Molecular
2.
Molecules ; 29(18)2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39339339

RESUMO

The overproduction of proinflammatory cytokines triggers a variety of diseases. Protopanaxadiol (PPD) and resveratrol are naturally found in plants such as ginseng and have potential anti-inflammatory properties, and resveratrol- and PPD-enriched rice seeds have been previously successfully generated. Herein, the synergistic anti-inflammatory activities of extracts of these enriched seeds were assessed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In comparison with treatment using extract prepared from PPD-producing transgenic rice (DJ-PPD) alone, cotreatment with DJ526 and DJ-PPD (TR_3) markedly enhanced the anti-inflammatory activities at a similar (compared to DJ526) or higher (compared to DJ-PPD) level. Cotreatment with DJ526 and DJ-PPD markedly inhibited the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Thus, DJ526 and DJ-PPD in combination suppressed the expression of phosphorylated (p)-NF-κB p65, p-p38 MAPK, and p-ERK 1/2. Cotreatment with DJ526 and DJ-PPD downregulated the expression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), LPS receptor (toll-like receptor-4, TLR-4), proinflammatory mediators (nitric oxide and PGE2), and arachidonic acid pathway critical enzyme (COX-2). These findings demonstrate the synergistic potential anti-inflammatory activities of resveratrol- and PPD-enriched rice seed extract.


Assuntos
Anti-Inflamatórios , Lipopolissacarídeos , Oryza , Extratos Vegetais , Resveratrol , Sapogeninas , Sementes , Animais , Camundongos , Oryza/química , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Sapogeninas/farmacologia , Sapogeninas/química , Sementes/química , Resveratrol/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Citocinas/metabolismo , NF-kappa B/metabolismo
3.
Bioorg Med Chem ; 112: 117901, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39232465

RESUMO

Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5-4 µg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo, following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Sapogeninas , Staphylococcus aureus , Peixe-Zebra , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Sapogeninas/farmacologia , Sapogeninas/química , Sapogeninas/síntese química , Staphylococcus aureus/efeitos dos fármacos , Animais , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química
4.
Molecules ; 29(17)2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39275122

RESUMO

The objective of this study was to enhance the membrane permeability and anticancer effectiveness of (20S)-protopanaxadiol (PPD) by introducing triphenylphosphonium into the OH group at the C-3 site. This study shows that the anti-proliferation activity of CTPPPPD, with an IC50 value of 1.65 ± 0.10 µmol/L, was 33-times better than that of PPD (with an IC50 value of 54.56 ± 4.56 µmol/L) and superior to that of cisplatin (with an IC50 value of 1.82 ± 0.25 µmol/L) against A549 cells. Biological examinations suggested that CTPPPPD treatment reduced the growth rate of A549 cells, increased the permeability of cell membranes, and changed the structure of chromosomal DNA in a concentration-dependent manner. Annexin V/PI assay and flow cytometry were employed to detect the effect of CTPPPPD on the apoptosis of A549 cells. The results showed that CTPPPPD could induce the apoptosis of A549 cells, and the apoptosis rate of A549 cells treated with 0, 1.0, 2.0, and 4.0 µM of CTPPPPD for 24 h was 0%, 4.9%, 12.7%, and 31.0%, respectively. The integration of transcriptomics and metabolomics provided a systematic and detailed perspective on the induced antitumor mechanisms. A combined analysis of DEGs and DAMs suggested that they were primarily involved in the central carbon metabolism pathway in cancer, as well as the metabolism of aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate. Central carbon metabolism in cancer-related genes, i.e., SLC16A3, FGFR3, LDHA, PGAM1, and SLC2A1, significantly reduced after treatment with CTPPPPD. In particular, the dominant mechanism responsible for total antitumor activity may be attributed to perturbations in the PI3K-AKT, MAPK, and P53 pathways. The findings derived from transcriptomics and metabolomics were empirically confirmed through q-PCR and molecular docking. Further analyses revealed that CTPPPPD could be a promising lead for the development of protopanaxadiol for non-small-cell lung cancer (NSCLC) drugs.


Assuntos
Antineoplásicos , Apoptose , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metabolômica , Sapogeninas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Sapogeninas/farmacologia , Sapogeninas/química , Apoptose/efeitos dos fármacos , Metabolômica/métodos , Antineoplásicos/farmacologia , Antineoplásicos/química , Células A549 , Proliferação de Células/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica
5.
Cell Death Dis ; 15(8): 586, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39138191

RESUMO

Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.


Assuntos
Lisossomos , Piroptose , Carcinoma Anaplásico da Tireoide , ATPases Vacuolares Próton-Translocadoras , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Piroptose/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sapogeninas/farmacologia , Camundongos , Camundongos Nus , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Gasderminas
6.
Phytomedicine ; 134: 155978, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39186857

RESUMO

BACKGROUND: Up to 80 % of chemotherapeutic drugs induce myelosuppression in patients. Chemotherapy not only impairs of hematopoietic stem cells (HSCs) but also damages bone marrow niches (vascular and endosteal). Current treatments for myelosuppression overlook these chemotherapy-induced damages to bone marrow niches and the critical role of niche restoration on hematopoietic regeneration. Ginsenoside protopanaxatriol (PPT) protects vascular endothelium from injury, while icariin (ICA) promotes osteogenic differentiation. The combination of PPT and ICA aims to restore damaged vascular and endosteal niches, thus rejuvenating HSCs for treating myelosuppression. PURPOSE: This study aims to develop effective, bone marrow niche-directed PPT/ICA therapies for treating chemotherapy-induced myelosuppression. METHODS: 3D cell spheroids were used to investigate the effects of PPT/ICA on cell-cell interactions in vascular niches, osteogenesis, and extracellular matrix (ECM) secretion in endosteal niches. In vitro mimic niche models were designed to access the drug combination's efficacy in rejuvenating and mobilizing in HSCs within bone marrow niches. The delivery capability of PPT/ICA to key niche cell types (mesenchymal stromal cells (MSCs), endothelial cells (ECs), and osteoblasts (OBs)) via nanocarriers has been determined. DSS6 peptide-modified nanoparticles (DSS6-NPs) were prepared for specific co-delivery of PPT/ICA into key niche cell populations in vivo. RESULTS: PPT can prevent vascular niche injury by restoring vascular EC cell-cell adhesion and the intercellular interactions between ECs and MSCs in 5-fluorouracil (5-FU)-damaged cell spheroids. ICA repaired 5-FU-damaged endosteal niches by promoting osteogenesis and ECM secretion. The combination of PPT and ICA restores key HSC niche factor gene expressions, normalizing HSC differentiation and mobilization. The in vitro cellular uptake efficiency of nanocarriers in a mimic niche is positively correlated with their in vivo delivery into bone marrow niche cells. DSS6-NPs greatly enhance the delivery of PPT/ICA into MSCs and OBs within bone marrow niches. Co-loading of PPT/ICA into DSS6-NPs effectively repairs damaged bone marrow niches and promotes HSC rejuvenation in vivo. CONCLUSION: The combination of PPT and ICA effectively prevents injury to the vascular and endosteal niches, thereby promoting hematopoietic regeneration in the bone marrow. This study provides novel niche-directed PPT/ICA therapies for managing chemotherapy-induced myelosuppression.


Assuntos
Células-Tronco Hematopoéticas , Sapogeninas , Nicho de Células-Tronco , Células-Tronco Hematopoéticas/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Sapogeninas/farmacologia , Osteogênese/efeitos dos fármacos , Humanos , Animais , Esferoides Celulares/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Fluoruracila/farmacologia
7.
N Biotechnol ; 83: 219-230, 2024 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-39181198

RESUMO

Ginseng, a cornerstone of traditional herbal medicine in Asia, garnered significant attention for its therapeutic potential. Central to its pharmacological effects are ginsenosides, the primary active metabolites, many of which fall within the dammarane-type and share protopanaxadiol as a common precursor. Challenges in extracting protopanaxadiol and ginsenosides from ginseng arise due to their low concentrations in the roots. Emerging solutions involve leveraging microbial cell factories employing genetically engineered yeasts. Here, we optimized the fermentation conditions via the Design of Experiment, realizing 1.2 g/L protopanaxadiol in simple shake flask cultivations. Extrapolating the optimized setup to complex ginsenosides, like compound K, achieved 7.3-fold (0.22 g/L) titer improvements. Our adaptable fermentation conditions enable the production of high-value products, such as sustainable triterpenoids synthesis. Through synthetic biology, microbial engineering, and formulation studies, we pave the way for a scalable and sustainable production of bioactive compounds from ginseng.


Assuntos
Fermentação , Ginsenosídeos , Triterpenos , Ginsenosídeos/biossíntese , Ginsenosídeos/metabolismo , Triterpenos/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Panax/metabolismo , Panax/crescimento & desenvolvimento , Panax/química , Engenharia Metabólica , Sapogeninas
8.
Eur J Pharmacol ; 983: 176901, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39181225

RESUMO

Constant efforts have been made to move towards maintaining the positive anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. The anti-inflammatory effect of GCs is mainly attributed to the inhibition of major inflammatory pathways such as NF-κB through GR transrepression, while its side effects are mainly mediated by transactivation. Here, we investigated the selective glucocorticoid receptor modulator (SGRM)-like properties of a plant-derived compound. In this study, glucocorticoid receptor (GR)-mediated alleviation of inflammation by SP-8 was investigated by a combination of in vitro, in silico, and in vivo approaches. Molecular docking and cellular thermal shift assay suggested that SP-8 bound stably to the active site of GR via hydrogen bonding and hydrophobic interactions. SP-8 activated GR, induced GR nuclear translocation, and inhibited NF-κB pathway activation. Furthermore, SP-8 did not up-regulate the gene and protein expression of PEPCK and TAT in HepG2 cells, and it did not induce fat deposition like GC and has little effect on bone metabolism. Interestingly, SP-8 upregulated GR protein expression and did not cause GR phosphorylation at Ser211 in RAW264.7 cells. This work proved that SP-8 dissociated characteristics of transrepression and transactivation can be separated. In addition, the in vitro and in vivo anti-inflammatory effects of SP-8 were confirmed in LPS-induced RAW 264.7 cells and in a mouse model of DSS-induced ulcerative colitis, respectively. In conclusion, SP-8 might serve as a potential SGRM and might hold great potential for therapeutic use in inflammatory diseases.


Assuntos
Anti-Inflamatórios , NF-kappa B , Receptores de Glucocorticoides , Sapogeninas , Receptores de Glucocorticoides/metabolismo , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Humanos , Células RAW 264.7 , NF-kappa B/metabolismo , Sapogeninas/farmacologia , Sapogeninas/química , Células Hep G2 , Masculino , Simulação de Acoplamento Molecular , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
9.
Sci Rep ; 14(1): 19106, 2024 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-39154043

RESUMO

In current work, we studied hairy root induction in Trigonella foenum graecum, which is an important medicinal plant, and examined the impact of different elicitors on some phytochemical characteristics and metabolites production in hairy root cultures. Accordingly, some factors such as five strain types of Agrobacterium rhizogenes (1724, 15834, A4, A13 and MSU) and three different explants, namely leaf, cotyledon and hypocotyl were studied. The results showed that different A. rhizogenes strains exhibited different infection efficiency. MSU and 15834 had highest efficiency of hairy root induction than other strains. Also, hairy root induction frequency in leaf explants was higher than in other explants. Salicylic acid (SA), nitric oxide (NO), CaCl2 and penconazole (PEN) were used in elicitation process. Hairy roots were treated with SA (0.1 and 0.5 mM), NO (10 and 50 µM), CaCl2 (5 and 10 mM) and PEN (5 and 10 mg/L). Applied elicitors enhanced antioxidant enzymes activities and reduced oxidative stress markers; this observation might be ascribed to regulation of the oxidative status of the elicited cells. Significant increase of antioxidant metabolites (total phenol, flavonoid and anthocyanin) in PEN-treated hairy roots was associated to phenylalanine ammonia lyase activity, indicating an up-regulation of phenylpropanoid/flavonoid metabolism. PEN and CaCl2 treatment enhanced steroidal sapogenin in hairy root cultures. These results suggested that use of elicitors can enhance the production of secondary metabolites in transformed hairy roots. Among the elicitors applied, CaCl2 and PEN were the most effective in increasing secondary metabolite production in transformed hairy roots of T. foenum graecum.


Assuntos
Raízes de Plantas , Sapogeninas , Trigonella , Trigonella/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Sapogeninas/metabolismo , Agrobacterium/metabolismo , Agrobacterium/genética , Ácido Salicílico/metabolismo , Ácido Salicílico/farmacologia , Folhas de Planta/metabolismo , Óxido Nítrico/metabolismo , Antioxidantes/metabolismo
10.
Plant J ; 120(2): 569-577, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39180339

RESUMO

Astragaloside IV is a significant chemical component derived from the medicinal plant Astragalus membranaceus. Despite the characterization of several glycosyltransferases from A. membranaceus, the complete biosynthetic pathway of astragaloside IV has not been fully elucidated. In this study, we propose a biosynthetic pathway for astragaloside IV that involves a sequence of oxidation-reduction reactions. The biosynthesis pathway from cycloastragenol to astragaloside IV encompasses four key steps: C-3 oxidation, 6-O-glucosylation, C-3 reduction, and 3-O-xylosylation. We identified a hydroxysteroid dehydrogenase AmHSD1 from A. membranaceus. AmHSD1 catalyzes the C-3 oxidation of cycloastragenol, yielding cycloastragenol-3-one, and the C-3 reduction of cycloastragenol-3-one-6-O-glucoside, resulting in cycloastragenol-6-O-glucoside. Additionally, the glycosyltransferases AmGT8 and AmGT1, previously reported by our groups, were identified as catalyzing the 6-O-glucosylation and 3-O-xylosylation steps, respectively. Astragaloside IV was successfully synthesized in transient expression in Nicotiana benthamiana using the combination of AmHSD1, AmGT8 and AmGT1. These results support the proposed four-step biosynthetic pathway and suggest that AmHSD1 probably plays a crucial role in the biosynthesis of astragaloside IV within A. membranaceus.


Assuntos
Astragalus propinquus , Vias Biossintéticas , Glicosiltransferases , Oxirredução , Sapogeninas , Saponinas , Triterpenos , Saponinas/metabolismo , Saponinas/biossíntese , Sapogeninas/metabolismo , Astragalus propinquus/metabolismo , Astragalus propinquus/genética , Triterpenos/metabolismo , Glicosiltransferases/metabolismo , Glicosiltransferases/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Nicotiana/metabolismo , Nicotiana/genética
11.
Int J Mol Sci ; 25(14)2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-39062817

RESUMO

Depression is one of the most common psychological disorders nowadays. Studies have shown that 20(S)-protopanaxatriol (PPT) can effectively improve depressive symptoms in mice. However, its mechanism needs to be further explored. In this study, we used an integrated approach combining network pharmacology and transcriptomics to explore the potential mechanisms of PPT for depression. First, the potential targets and pathways of PPT treatment of depression were screened through network pharmacology. Secondly, the BMKCloud platform was used to obtain brain tissue transcription data of chronic unpredictable mild stress (CUMS) model mice and screen PPT-altered differential expression genes (DEGs). Gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using network pharmacology and transcriptomics. Finally, the above results were verified by molecular docking, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). In this study, we demonstrated that PPT improved depression-like behavior and brain histopathological changes in CUMS mice, downregulated nitric oxide (NO) and interleukin-6 (IL-6) levels, and elevated serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) after PPT treatment compared to the CUMS group. Eighty-seven potential targets and 350 DEGs were identified by network pharmacology and transcriptomics. Comprehensive analysis showed that transthyretin (TTR), klotho (KL), FOS, and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway were closely associated with the therapeutic effects of PPT. Molecular docking results showed that PPT had a high affinity for PI3K, AKT, TTR, KL, and FOS targets. Gene and protein level results showed that PPT could increase the expression of PI3K, phosphorylation of PI3K (p-PI3K), AKT, phosphorylation of AKT (p-AKT), TTR, and KL and inhibit the expression level of FOS in the brain tissue of depressed mice. Our data suggest that PPT may achieve the treatment of depression by inhibiting the expression of FOS, enhancing the expression of TTR and KL, and modulating the PI3K-AKT signaling pathway.


Assuntos
Depressão , Farmacologia em Rede , Sapogeninas , Transcriptoma , Animais , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Sapogeninas/farmacologia , Transcriptoma/efeitos dos fármacos , Masculino , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Perfilação da Expressão Gênica , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos
12.
J Cardiovasc Pharmacol ; 84(1): 45-57, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38922585

RESUMO

ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.


Assuntos
Aorta , Doenças da Aorta , Aterosclerose , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Pró-Proteína Convertase 9 , Receptores de LDL , Sapogeninas , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Aterosclerose/genética , Sapogeninas/farmacologia , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Humanos , Masculino , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Doenças da Aorta/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/tratamento farmacológico , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Proteólise/efeitos dos fármacos , Células Hep G2 , Inibidores de PCSK9 , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Camundongos , Dieta Hiperlipídica , Apolipoproteínas E
13.
Cell Biochem Biophys ; 82(3): 2503-2510, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38914839

RESUMO

Drug responses heterogeneity is often highlighted to justify the need for precision medicine. However, due to the highly complex nature of cell phenotypes in many diseases, one of key challenges is how to obtain the high content features in a cellular population. Here we present a single-cell vibrational phenomics approach, integrating synchrotron infrared microspectroscopy and multivariate calculation, for quantitatively evaluating the cellular responses to drug perturbation with single cell resolution. In a human hepatocellular carcinoma HepG2 cell model, the phenotypic changes induced by two types of drugs, taxol (TAX) and protopanaxadiol (PPD), were analyzed and revealed the response heterogeneity in drug concentration and chemical components. These findings not only provide a label-free strategy for determining the drug response at the single cell level, but also demonstrate the great potential of vibrational phenomics as a drug discovery platform.


Assuntos
Paclitaxel , Análise de Célula Única , Humanos , Células Hep G2 , Paclitaxel/farmacologia , Sapogeninas/farmacologia , Sapogeninas/química , Fenômica , Espectroscopia de Infravermelho com Transformada de Fourier , Vibração
14.
Nutrients ; 16(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892635

RESUMO

Dendritic cells (DCs) can initiate immune response through the presenting antigens to naïve T lymphocytes. Esculeoside A (EsA), a spirosolane glycoside, is reported as a major component in the ripe fruit of tomato. Little is known about the effect of tomato saponin on mice bone marrow-derived DCs. This study revealed that EsA and its aglycon, esculeogenin A (Esg-A), attenuated the phenotypic and functional maturation of murine DCs stimulated by lipopolysaccharide (LPS). We found that EsA/Esg-A down-regulated the expression of major histocompatibility complex type II molecules and costimulatory molecule CD86 after LPS stimulation. It was also determined that EsA-/Esg-A-treated DCs were poor stimulators of allogeneic T-cell proliferation and exhibited impaired interleukin-12 and TNF-α production. Additionally, EsA/Esg-A was able to inhibit TLR4-related and p-NFκB signaling pathways. This study shows new insights into the immunopharmacology of EsA/Esg-A, and represents a novel approach to controlling DCs for therapeutic application.


Assuntos
Células Dendríticas , Saponinas , Transdução de Sinais , Solanum lycopersicum , Receptor 4 Toll-Like , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/imunologia , Receptor 4 Toll-Like/metabolismo , Transdução de Sinais/efeitos dos fármacos , Saponinas/farmacologia , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Interleucina-12/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Frutas/química , Antígeno B7-2/metabolismo , Sapogeninas
15.
J Pharm Pharmacol ; 76(7): 884-896, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38708970

RESUMO

OBJECTIVES: Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms. METHODS: In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins. RESULTS: PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system. CONCLUSION: PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.


Assuntos
Injúria Renal Aguda , Cisplatino , Ferroptose , Sapogeninas , Cisplatino/toxicidade , Animais , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Ferroptose/efeitos dos fármacos , Camundongos , Sapogeninas/farmacologia , Humanos , Masculino , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Modelos Animais de Doenças , Linhagem Celular , Peroxidação de Lipídeos/efeitos dos fármacos , Ferro/metabolismo , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos
16.
Curr Alzheimer Res ; 21(2): 141-154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38766828

RESUMO

BACKGROUND: As individuals age, they may develop Alzheimer's disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer. OBJECTIVES: This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis. METHODS: Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed. RESULTS: Cycloastragenol significantly improved rats' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1. CONCLUSION: Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.


Assuntos
Doença de Alzheimer , Apoptose , Inflamação , Estresse Oxidativo , Ratos Sprague-Dawley , Sapogeninas , Animais , Estresse Oxidativo/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Ratos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Sapogeninas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Modelos Animais de Doenças
17.
Phytomedicine ; 129: 155699, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38733907

RESUMO

BACKGROUND: Pulmonary Fibrosis (PF) is a progressive lung disease characterized by the diffuse interstitial tissue, leading to severe breathing difficulties. The existing treatment methods are primarily aimed at slowing the progression of the disease, underscoring the urgent need to discover new drug interventions targeting novel sites. The "gut-lung axis" represents a complex bidirectional communication system where the gut microbiota not only influences lung immunity but also responds to lung-derived signals. Recent advances have uncovered that alterations in gut microbiota composition can significantly impact respiratory diseases, offering new insights into their pathogenesis and potential therapeutic approaches. METHODS: This study is based on the fundamental concepts of the lung-gut axis and our previous research, further exploring the potential mechanisms of 20(S)-Protopanaxadiol (PPD) in ginseng against PF. We utilized a bleomycin-induced mouse model of PF and employed metabolomics and 16S rRNA sequencing to investigate the pathways through which PPD regulates the pulmonary fibrosis process via the gut-lung axis. Finally, we employed strategies such as antibiotic-induced microbiota disruption and fecal microbiota transplantation (FMT) to provide a comprehensive perspective on how PPD regulates pulmonary fibrosis through gut microbiota. RESULTS: The results of the bleomycin (BLM) mouse model of PF proved that PPD can directly act on the glycolysis- related metabolic reprogramming process in lung and the AMPK/STING pathway to improve PF. Combined the analysis of gut microbiota and related metabolites, we found that PPD can regulate the process of PF through the gut-lung axis target points G6PD and SPHK1. FMT and antibiotic-induced microbiota disruption further confirmed intermediate effect of gut microbiota in PF process and the treatment of PPD. Our study suggests that PPD can alleviate the process of pulmonary fibrosis either by directly acting on the lungs or by regulating the gut microbiota. CONCLUSION: This study positions PPD as a vanguard in the therapeutic landscape for pulmonary fibrosis, offering a dual mechanism of action that encompasses both modulation of gut microbiota and direct intervention at molecular targets. These insights highlight the immense therapeutic potential of harnessing the gut-lung axis.


Assuntos
Modelos Animais de Doenças , Microbioma Gastrointestinal , Pulmão , Camundongos Endogâmicos C57BL , Panax , Fibrose Pulmonar , Sapogeninas , Animais , Sapogeninas/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Camundongos , Panax/química , Bleomicina , Transplante de Microbiota Fecal , Masculino , RNA Ribossômico 16S
18.
J Agric Food Chem ; 72(18): 10376-10390, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38661058

RESUMO

20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.


Assuntos
Antidepressivos , Corticosterona , Creatina Quinase Forma BB , Depressão , Sapogeninas , Animais , Humanos , Masculino , Camundongos , Ratos , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Creatina Quinase Forma BB/metabolismo , Creatina Quinase Forma BB/genética , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Panax/química , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Ratos Sprague-Dawley , Sapogeninas/farmacologia
19.
Cell Biochem Biophys ; 82(2): 1203-1212, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38613700

RESUMO

Protopanaxadiol (PPD), which has a molecular structure similar to cholesterol, is a potent anticancer agent that has been proposed to target the lipid membrane for the pharmacological effects. However, the underlying mechanism by which PPD modulates the cell membrane leading to cancer cell death is not be fully understood. In this work, we used single cell infrared spectroscopy, scanning electron microscopy and confocal microscopy to investigate the effects of PPD on human hepatocellular carcinoma (HepG2) cells, focusing on the change in membrane structure. We found that PPD significantly reduced the number of membrane tubules over the course of treatment. Interestingly, the addition of PPD could promote the formation of lipid raft-like domains (PPD rafts) and even restore the domain disruption caused by methyl-beta-cyclodextrin depletion of membrane cholesterol. In addition, PPD pre-treatment may increase the induction effect of FasL, which impairs cell viability, although it does not appear to be beneficial for Fas clustering in the PPD rafts. Collectively, these results highlight a non-classical mechanism by which PPD induces HepG2 apoptosis by directly affecting the physical properties of the cell membrane, providing a novel insight into understanding membrane-targeted therapy.


Assuntos
Apoptose , Microdomínios da Membrana , Sapogeninas , Humanos , Apoptose/efeitos dos fármacos , Células Hep G2 , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/efeitos dos fármacos , Sapogeninas/farmacologia , Sapogeninas/química , Proteína Ligante Fas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Colesterol/metabolismo , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Receptor fas/metabolismo
20.
J Nat Med ; 78(3): 474-487, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38431911

RESUMO

Lupus nephritis (LN) is a kidney disease that occurs after systemic lupus erythematosus (SLE) affects the kidneys. Pentraxin 3 (PTX3) is highly expressed in the serum of patients with LN. Renal PTX3 deposition is directly related to clinical symptoms such as proteinuria and inflammation. The excessive proliferation of mesangial cells (MCs) is one of the representative pathological changes in the progression of LN, which is closely related to its pathogenesis. Protopanaxadiol (PPD) is the main component of ginsenoside metabolism and has not been reported in LN. The aim of this study was to investigate the relationship between PTX3 and mesangial cell proliferation and to evaluate the potential role and mechanism of PPD in improving LN. PTX3 is highly expressed in the kidneys of LN patients and LN mice and is positively correlated with renal pathological indicators, including proteinuria and PCNA. The excessive expression of PTX3 facilitated the proliferation of MCs, facilitated the activation of the MAPK/ERK1/2 signaling pathway, and increased the expression of HIF-1α. Further studies showed that PPD can effectively inhibit the abnormal proliferation of MCs with high expression of PTX3 and significantly improve LN symptoms such as proteinuria in MRL/lpr mice. The mechanism may be related to the inhibition of the PTX3/MAPK/ERK1/2 pathway. In this study, both in vitro, in vivo, and clinical sample results show that PTX3 is involved in the regulation of MCs proliferation and the early occurrence of LN. Natural active compound PPD can improve LN by regulating the PTX3/MAPK/ERK1/2 pathway.


Assuntos
Proteína C-Reativa , Nefrite Lúpica , Sistema de Sinalização das MAP Quinases , Sapogeninas , Componente Amiloide P Sérico , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/metabolismo , Animais , Sapogeninas/farmacologia , Proteína C-Reativa/metabolismo , Camundongos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Feminino , Componente Amiloide P Sérico/metabolismo , Proliferação de Células/efeitos dos fármacos , Adulto , Masculino , Camundongos Endogâmicos MRL lpr , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA