RESUMEN

Anaplastic thyroid cancer (ATC), an aggressive malignancy with virtually 100% disease-specific mortality, has long posed a formidable challenge in oncology due to its resistance to conventional treatments and the severe side effects associated with current regimens such as doxorubicin chemotherapy. Consequently, there was urgent need to identify novel candidate compounds that could provide innovative therapeutic strategies for ATC. Ophiopogonin D' (OPD'), a triterpenoid saponin extracted, yet its roles in ATC has not been reported. Our data demonstrated that OPD' potently inhibited proliferation and metastasis of ATC cells, promoting cell cycle arrest and apoptosis. Remarkably, OPD' impeded growth and metastasis of ATC in vitro and in vivo, displaying an encouraging safety profile. Regulator of G-protein signalling 4 (RGS4) expression was significantly up-regulated in ATC compared to normal tissues, and this upregulation was suppressed by OPD' treatment. Mechanistically, we elucidated that the transcription factor JUN bound to the RGS4 promoter, driving its transactivation. However, OPD' interacted with JUN, attenuating its transcriptional activity and thereby disrupting RGS4 overexpression. In summary, our research revealed that OPD' bound with JUN, which in turn resulted in the suppression of transcriptional activation of RGS4, thereby eliciting cell cycle arrest and apoptosis in ATC cells. These findings could offer promise in the development of high-quality candidate compounds for treatment in ATC.

Asunto(s)

Apoptosis , Proliferación Celular , Proteínas RGS , Saponinas , Transducción de Señal , Espirostanos , Carcinoma Anaplásico de Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Saponinas/farmacología , Proteínas RGS/metabolismo , Proteínas RGS/genética , Proliferación Celular/efectos de los fármacos , Animales , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Espirostanos/farmacología , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratones Desnudos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Metástasis de la Neoplasia

RESUMEN

The plant genus Tacca comprises twenty species including Tacca plantaginea, essentially distributed in the Indo-China region. Medicinal preparations from the rhizomes are used traditionally to treat gastrointestinal ailments, stomach aches and inflammatory disorders. A variety of bioactive molecules have been isolated from T. plantaginea, including potent anticancer steroids such as the taccanolides which interfere with microtubules dynamic. Other efficient anticancer natural products have been isolated from the plant, in particular a series of diosgenin/yamogenin-type sapogenins including taccaoside (monodesmosidic) and taccaoside A (bidesmosidic). Taccaoside A displays marked anticancer properties through two complementary mechanisms: a direct action on cancer stem cells via HRas and Pi3K/Akt signaling and an indirect immunomodulatory action via activation of cytotoxic T cells. A similar mechanism of action has been invoked with a total saponin extract from Schizocapsa plantaginea Hance (synonym to T. plantaginea) and the saponin SSPH 1. This saponin reduced tumor growth in mice through stimulation of cytotoxic T lymphocytes. Other bioactive products have been isolated from T. plantaginea, including withanolide-type steroids (plantagiolides, chantriolides), diarylheptanoids (plantagineosides) and different saponins (diosbulbisides, lieguonins). The discussion centers around the mechanism of action of spirostanol saponins, with the objective to promote their study as immuno-active anticancer agents.

Asunto(s)

Antineoplásicos Fitogénicos , Saponinas , Espirostanos , Saponinas/farmacología , Saponinas/aislamiento & purificación , Saponinas/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Humanos , Espirostanos/farmacología , Espirostanos/química , Espirostanos/aislamiento & purificación , Animales , Dioscoreaceae/química , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Estructura Molecular

RESUMEN

BACKGROUND: Acute lung injury (ALI) is characterized by acute pulmonary inflammatory infiltration. Alveolar epithelial cells (AECs) release numerous pro-inflammatory cytokines, which result in the pathological changes seen in ALI. Ophiopogonin D (OD), extracted from the roots of Ophiopogon japonicus (Thunb.) Ker Gawl. (Liliaceae), reduces inflammation; however, the efficacy of OD in ALI has not been reported and the underlying molecular mechanisms remain unclear. PURPOSE: This study investigated the anti-inflammatory effects of OD, as well as the underlying mechanisms, in AECs and a mouse ALI model. METHODS: Lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were used to stimulate macrophages and A549 cells, and a mouse ALI model was established by intratracheal LPS administration. The anti-inflammatory effects and mechanisms of OD in the TNF-α-induced in vitro inflammation model was evaluated using real-time quantitative polymerase chain reaction qPCR), enzyme-linked immunosorbent assay (ELISA), western blotting, nuclear and cytoplasmic protein extraction, and immunofluorescence. The in vivo anti-inflammatory activity of OD was evaluated using hematoxylin and eosin staining, qPCR, ELISA, and western blotting. RESULTS: The bronchoalveolar lavage fluid and lung tissue of LPS-induced ALI mice exhibited increased TNF-α expression. TNF-α induced a significantly greater pro-inflammatory effect in AECs than LPS. OD reduced inflammation and mitogen-activated protein kinase (MAPK) and transcription factor p65 phosphorylation in vivo and in vitro and promoted signal transducer and activator of transcription 3 (STAT3) phosphorylation and A20 expression, thereby inducing apoptosis signal-regulating kinase 1 (ASK1) proteasomal degradation. CONCLUSION: OD exerts an anti-inflammatory effect by promoting STAT3-dependent A20 expression and ASK1 degradation. OD may therefore have therapeutic value in treating ALI and other TNF-α-related inflammatory diseases.

Asunto(s)

Lesión Pulmonar Aguda , Antiinflamatorios , Lipopolisacáridos , Factor de Transcripción STAT3 , Saponinas , Espirostanos , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Animales , Saponinas/farmacología , Espirostanos/farmacología , Ratones , Factor de Transcripción STAT3/metabolismo , Humanos , Antiinflamatorios/farmacología , Masculino , MAP Quinasa Quinasa Quinasa 5/metabolismo , Células A549 , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Células RAW 264.7 , Ratones Endogámicos C57BL , Ophiopogon/química , Inflamación/tratamiento farmacológico , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Transducción de Señal/efectos de los fármacos , Raíces de Plantas/química

RESUMEN

Four undescribed spirostan glycosides, (25S)-5α-spirostan- 12-one-2α,3ß-diol-3-O-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (1), (25S)-5α-spirostan-12-one-2α,3ß-diol-3-O-ß-D-galatopyranosyl-(1→2)-ß-D-glucopyranosyl- (1→4)-ß-D-galactopyranoside (2), (25S)-5α-spirostan-12-one-2α,3ß-diol-3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→3)]-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (3), and hecogenin 3-O-ß-D-glucopyranosyl-(1→3)-[ß-D-xylopyranosyl-(1→2)]-ß-D-glucopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-ß-D-galactopyranoside (4), together with eleven known compounds (5-15) were isolated from the branches and leaves of Tribulus terrestris. Their chemical structures were established through spectroscopic methods, including HR-ESI-MS, 1D-, and 2D-NMR spectra. Preliminary biological evaluation on NO production inhibitory activity in LPS activated RAW 264.7 cells showed that compounds 1-3, 5, and 6 had significant inhibitory effects with IC50 values ranging from 2.4 to 18.3 µM, compared to that of the positive control compound, dexamethazone (IC50 13.6 µM).

Asunto(s)

Glicósidos , Lipopolisacáridos , Óxido Nítrico , Hojas de la Planta , Espirostanos , Tribulus , Ratones , Animales , Células RAW 264.7 , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Tribulus/química , Hojas de la Planta/química , Glicósidos/química , Glicósidos/farmacología , Glicósidos/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Espirostanos/química , Espirostanos/aislamiento & purificación , Espirostanos/farmacología , Tallos de la Planta/química , Relación Estructura-Actividad

RESUMEN

ETHNOPHARMACOLOGY RELEVANCE: Rohdea pachynema F.T.Wang & Tang (R. pachynema), is a traditional folk medicine used for the treatment of stomach pain, stomach ulcers, bruises, and skin infections in China. Some of the diseases may relate to microbial infections in traditional applications. However few reports on its antimicrobial properties and bioactive components. AIM OF THE STUDY: To identify its bioactive constituents against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and in vivo, and its mechanism. MATERIALS AND METHODS: The anti-MRSA ingredient 6α-O-[ß-D-xylopyranosyl-(1 â†’ 3)-ß-D-quinovopyranosyl]-(25S)-5α-spirostan-3ß-ol (XQS) was obtained from R. pachynema by phytochemical isolation. Subsequently, XQS underwent screening using the broth microdilution method and growth inhibition curves to assess its antibacterial activity. The mechanism of XQS was evaluated by multigeneration induction, biofilm resistance assay, scanning electron microscopy, transmission electron microscopy, and metabolomics. Additionally, a mouse skin infection model was established in vivo. RESULTS: 26 compounds were identified from the R. pachynema, in which anti-MRSA spirostane saponin (XQS) was reported for the first time with a minimum inhibitory concentration (MIC) of 8 µg/mL. XQS might bind to peptidoglycan (PGN) of the cell wall, phosphatidylglycerol (PG), and phosphatidylethanolamine (PE) of the cell membrane, then destroying the cell wall and the cell membrane, resulting in reduced membrane fluidity and membrane depolarization. Furthermore, XQS affected MRSA lipid metabolism, amino acid metabolism, and ABC transporters by metabolomics analysis, which targeted cell walls and membranes causing less susceptibility to drug resistance. Furthermore, XQS (8 mg/kg) recovered skin wounds in mice infected by MRSA effectively, superior to vancomycin (8 mg/kg). CONCLUSIONS: XQS showed anti-MRSA bioactivity in vitro and in vivo, and its mechanism association with cell walls and membranes was reported for the first, which supported the traditional uses of R. pachynema and explained its sensitivity to MRSA.

Asunto(s)

Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Saponinas , Animales , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Ratones , Saponinas/farmacología , Saponinas/aislamiento & purificación , Espirostanos/farmacología , Espirostanos/aislamiento & purificación , Biopelículas/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Femenino , Peces , Masculino

RESUMEN

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.

Asunto(s)

Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Melanthiaceae , Rizoma , Saponinas , Espirostanos , Humanos , Saponinas/aislamiento & purificación , Saponinas/farmacología , Saponinas/química , Rizoma/química , Melanthiaceae/química , Espirostanos/química , Espirostanos/aislamiento & purificación , Espirostanos/farmacología , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Conformación Molecular , Relación Dosis-Respuesta a Droga

RESUMEN

ABSTRACT: Sepsis-induced myocardial dysfunction commonly occurs in individuals with sepsis and is a severe complication with high morbidity and mortality rates. This study aimed to investigate the effects and potential mechanisms of the natural steroidal sapogenin ruscogenin (RUS) against lipopolysaccharide (LPS)-induced myocardial injury in septic mice. We found that RUS effectively alleviated myocardial pathological damage, normalized cardiac function, and increased survival in septic mice. RNA sequencing demonstrated that RUS administration significantly inhibited the activation of the NOD-like receptor signaling pathway in the myocardial tissues of septic mice. Subsequent experiments further confirmed that RUS suppressed myocardial inflammation and pyroptosis during sepsis. In addition, cultured HL-1 cardiomyocytes were challenged with LPS, and we observed that RUS could protect these cells against LPS-induced cytotoxicity by suppressing inflammation and pyroptosis. Notably, both the in vivo and in vitro findings indicated that RUS inhibited NOD-like receptor protein-3 (NLRP3) upregulation in cardiomyocytes stimulated with LPS. As expected, knockdown of NLRP3 blocked the LPS-induced activation of inflammation and pyroptosis in HL-1 cells. Furthermore, the cardioprotective effects of RUS on HL-1 cells under LPS stimulation were abolished by the novel NLRP3 agonist BMS-986299. Taken together, our results suggest that RUS can alleviate myocardial injury during sepsis, at least in part by suppressing NLRP3-mediated inflammation and pyroptosis, highlighting the potential of this molecule as a promising candidate for sepsis-induced myocardial dysfunction therapy.

Asunto(s)

Antiinflamatorios , Modelos Animales de Enfermedad , Lipopolisacáridos , Ratones Endogámicos C57BL , Miocitos Cardíacos , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Sepsis , Transducción de Señal , Espirostanos , Animales , Lipopolisacáridos/toxicidad , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Espirostanos/farmacología , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Piroptosis/efectos de los fármacos , Masculino , Transducción de Señal/efectos de los fármacos , Línea Celular , Antiinflamatorios/farmacología , Ratones , Cardiomiopatías/prevención & control , Cardiomiopatías/patología , Cardiomiopatías/metabolismo , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/inducido químicamente , Mediadores de Inflamación/metabolismo

RESUMEN

Bulbs of Lilium brownii, commonly known as "Bai-he" in China, serve both edible and medicinal purposes in clinical practice. In this study, two new isospirostanol-type saponins were isolated from L. brownii, and their structures were identified by spectroscopic method, and absolute configurations were elucidated by comprehensive analysis of spectral data obtained from combined acid hydrolysis. Two compounds were finally identified as 3-O-[α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside]-(22R,25R)-5α-spirosolane-3ß-ol (1) and 3-O-{α-L-rhamnopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→4)]-ß-D-glucopyranoside}-(22R,25R)-5α-spirosolane-3ß-ol (2), respectively. Further, we found that compound 2 significantly suppressed the proliferation of SMMC-7721 and HepG2 cells with IC50 values of 26.3±1.08 µM and 30.9±1.59 µM, whereas compound 1 didn't inhibit both of the two hepatocellular carcinoma. Subsequently, compound 2 effectively decreased the levels of interleukin-1ß and tumor necrosis factor-α and the expression of Bcl-2, and increased the expression of Bax and Caspase-3 proteins. Which indicated that the anti-hepatocellular carcinoma effect of compound 2 involves reducing the level of inflammation and inducing apoptosis.

Asunto(s)

Apoptosis , Proliferación Celular , Lilium , Neoplasias Hepáticas , Raíces de Plantas , Saponinas , Humanos , Saponinas/farmacología , Saponinas/química , Saponinas/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Lilium/química , Raíces de Plantas/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Espirostanos/farmacología , Espirostanos/química , Espirostanos/aislamiento & purificación , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Interleucina-1beta/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Células Hep G2 , Estructura Molecular , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Conformación Molecular

RESUMEN

The spirostanol saponin gitonin was efficiently synthesized in 12 steps (longest linear sequence) in 18.5% overall yield from the commercially available isopropyl ß-D-1-thiogalactopyranoside (IPTG) and tigogenin. A cascade two-step glycosylation and Schmidt's inverse procedure significantly facilitated the synthesis of gitonin and its derivatives. The cytotoxic activities of gitonin and its structural analogues were evaluated against A549, HepG2, and MCF-7, and most of them exhibited moderate to excellent inhibitory activity. Our study demonstrates that the removal of the ß-D-galactopyranosyl residue (attached at C-2 of the glucose unit) from gitonin would not decrease the inhibition activities; however, further cleavage of sugar units could seriously reduce the activities. A bioassay on these cancer cell lines also suggested that the presence of 2α-hydroxy on the aglycone weakened the cytotoxicity of the designed saponin.

Asunto(s)

Antineoplásicos , Saponinas , Espirostanos , Saponinas/química , Estructura Molecular , Glicósidos Digitálicos , Antineoplásicos/farmacología , Espirostanos/farmacología , Línea Celular Tumoral

RESUMEN

Ornithogalum thyrsoides Jacq belongs to the Asparagaceae family and is cultivated for ornamental purposes. The authors have previously reported several cholestane- and spirostan-type steroidal glycosides from O. thyrsoides. Conventional TLC analysis of the methanolic bulb extract of O. thyrsoides suggested the presence of unprecedented compounds; therefore, a detailed phytochemical investigation of the extract was performed and 35 steroidal glycosides (1-35), including 21 previously undescribed ones (1-21) were collected. The structures of 1-21 were determined mainly by analyses of their 1H and 13C NMR spectra with the aid of two-dimensional NMR spectroscopy. The isolated compounds were classified into three distinct groups: furostan-type (1, 2, 8-12, and 22), spirostan-type (3-7 and 23-26), and cholestane-type (13-21 and 27-35). Although the C/D-ring junction of the steroidal skeleton is typically trans-oriented, except for some cardiotonic and pregnane-type steroidal derivatives, 7 possess a cis C/D-ring junction. This is the first reported instance of such a configuration in spirostan-type steroidal derivatives, marking it as a finding of significant interest. Compounds 1-35 were evaluated for cytotoxicity against HL-60 human promyelocytic leukemia cells and SBC-3 human small-cell lung cancer cells. Compounds 3-6, 9, 17-21, 23-25, and 30-35 demonstrated cytotoxicity in a dose-dependent manner with IC50 values ranging from 0.000086 to 18 µM and from 0.00014 to 37 µM toward HL-60 and SBC-3 cells, respectively. Compound 19, which is obtained in a good yield and shows relatively potent cytotoxicity among the undescribed compounds, induces apoptosis in HL-60 cells, accompanied by arresting the cell cycle of HL-60 cells at the G2/M phase. In contrast, 19 causes oxidative stress-associated necrosis in SBC-3 cells. The cytotoxic mechanism of 19 is different between HL-60 and SBC-3 cells.

Asunto(s)

Colestanos , Leucemia , Neoplasias Pulmonares , Ornithogalum , Espirostanos , Humanos , Células HL-60 , Ornithogalum/química , Glicósidos/química , Colestanos/química , Esteroides/farmacología , Esteroides/química , Extractos Vegetales/farmacología

RESUMEN

Aspidiatas C and D (1 and 2), two new spirostanol saponins, were isolated along with two known compounds, (25 R*)-spirost-5-en-3ß-yl α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-ß-D-glucopyranoside (3), (25 R*)-spirost-5-en-3ß-yl α-L-rhamnopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranoside (4) from the whole plant of Aspidistra triradiata collected in Vietnam. The chemical structures were determined by HRESIMS, 1D- and 2D-NMR analysis, and comparison with published data. Compound 3 exhibited potent cytotoxicity against MCF7, HepG2, SK-LU-1, and HT-29 human cancer cell lines with IC50 values ranging from 0.19 to 0.65 µM. Compounds 1, 2, and 4 displayed moderate cytotoxic effects with IC50 values ranging from 12.32 to 82.27 µM. Compounds 1-4 were isolated from the genus Aspidistra for the first time.

Asunto(s)

Antineoplásicos , Saponinas , Espirostanos , Humanos , Saponinas/farmacología , Saponinas/química , Antineoplásicos/química , Células HT29 , Vietnam

RESUMEN

The rhizome of Rohdea chinensis (Baker) N.Tanaka (RRc) is a famous folk medicine for the treatment of carbuncles and pharyngitis. Steroidal saponins (SSs) were considered to be the most abundant active constituents in RRc. However, to date, the in-depth study of SSs is still lacking. This study was aimed to investigate the SSs profiles of RRc extract by HPLC-ESI-QTOF-MS/MS. Analysis was performed on an Agilent poroshell 120 EC-C18 column (2.1 mm × 100 mm, i.d., 2.7 µm) with 0.1% formic acid aqueous solution and acetonitrile as the mobile phase under gradient conditions. The results showed that 32 SSs including 20 furospirostanol, 11 spirostanol and 1 pseudo-spirostanol saponins were identified, 5 of which were reported in this plant for the first time. This is the first report on the analysis of SSs in RRc. This novel analysis method may stimulate further research regarding the identification of SSs in other plant species.

Asunto(s)

Asparagaceae , Saponinas , Espirostanos , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masa por Ionización de Electrospray/métodos , Cromatografía Líquida de Alta Presión/métodos , Saponinas/química

RESUMEN

Osteoarthritis (OA) is a common joint degenerative disease, and chondrocyte injury is the main pathological and physiological change. Ruscogenin (Rus), a bioactive compound isolated from Radix Ophiopogon japonicus, exhibits various pharmacological effects. The aim of this research was to test the role and mechanism of Rus on OA both in vivo and in vitro. Destabilized medial meniscus (DMM)-induced OA model was established in vivo and IL-1ß-stimulated mouse chondrocytes was used to explore the role of Rus on OA in vitro. In vivo, Rus exhibited protective effects against DMM-induced OA model. Rus could inhibit MMP1 and MMP3 expression in OA mice. In vitro, IL-1ß-induced inflammation and degradation of extracellular matrix were inhibited by Rus, as confirmed by the inhibition of PGE2, NO, MMP1, and MMP3 by Rus. Also, IL-1ß-induced ferroptosis was suppressed by Rus, as confirmed by the inhibition of MDA, iron, and ROS, as well as the upregulation of GSH, GPX4, Ferritin, Nrf2, and SLC7A11 expression induced by Rus. Furthermore, the suppression of Rus on IL-1ß-induced inflammation, MMPs production, and ferroptosis were reversed when Nrf2 was knockdown. In conclusion, Rus attenuated OA progression through inhibiting chondrocyte ferroptosis via Nrf2/SLC7A11/GPX4 signaling pathway.

Asunto(s)

Ferroptosis , Osteoartritis , Espirostanos , Animales , Ratones , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Cartílago/patología , Condrocitos/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Transducción de Señal

RESUMEN

Ruscogenin (RUS), a major effective steroidal sapogenin derived from Ophiopogon japonicas, has been reported to alleviate myocardial ischemia (MI), but its cardioprotective mechanism is still not completely clear. In this study, we observed that RUS markedly reduced MI-induced myocardial injury, as evidenced by notable reductions in infarct size, improvement in biochemical markers, alleviation of cardiac pathology, amelioration of mitochondrial damage, and inhibition of myocardial apoptosis. Moreover, RUS notably suppressed oxygen-glucose deprivation (OGD)-triggered cell injury and apoptosis. Notably, RUS demonstrated a considerable decrease of the interaction between myosin IIA and F-actin, along with the restoration of mitochondrial fusion and fission balance. We further confirmed that the effects of RUS on MI were mediated by myosin IIA using siRNA and overexpression techniques. The inhibition of myosin IIA resulted in a significant improvement of mitochondrial fusion and fission imbalance, while simultaneously counteracting the beneficial effects of RUS. By contrast, overexpression of myosin IIA aggravated the imbalance between mitochondrial fusion and fission and partially weakened the protection of RUS. These findings suggest that myosin IIA is essential or even a key functional protein in the cardioprotection of RUS. Overall, our results have elucidated an undiscovered mechanism involving myosin IIA-dependent mitochondrial fusion and fission balance for treating MI. Furthermore, our study has uncovered a novel mechanism underlying the protective effects of RUS.

Asunto(s)

Isquemia Miocárdica , Miosina Tipo IIA no Muscular , Espirostanos , Humanos , Dinámicas Mitocondriales , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/genética , Espirostanos/farmacología , Espirostanos/uso terapéutico , Apoptosis/genética

RESUMEN

Alzheimer's disease (AD), a neurodegenerative disease with no cure, affects millions of people worldwide and has become one of the biggest healthcare challenges. Some investigated compounds play anti-AD roles at the cellular or the animal level, but their molecular mechanisms remain unclear. In this study, we designed a strategy combining network-based and structure-based methods together to identify targets for anti-AD sarsasapogenin derivatives (AAs). First, we collected drug-target interactions (DTIs) data from public databases, constructed a global DTI network, and generated drug-substructure associations. After network construction, network-based models were built for DTI prediction. The best bSDTNBI-FCFP_4 model was further used to predict DTIs for AAs. Second, a structure-based molecular docking method was employed for rescreening the prediction results to obtain more credible target proteins. Finally, in vitro experiments were conducted for validation of the predicted targets, and Nrf2 showed significant evidence as the target of anti-AD compound AA13. Moreover, we analyzed the potential mechanisms of AA13 for the treatment of AD. Generally, our combined strategy could be applied to other novel drugs or compounds and become a useful tool in identification of new targets and elucidation of disease mechanisms. Our model was deployed on our NetInfer web server (http://lmmd.ecust.edu.cn/netinfer/).

Asunto(s)

Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Espirostanos , Animales , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Espirostanos/química , Espirostanos/uso terapéutico

RESUMEN

The phytoconstituents of the fraction with hemostatic activity of the 70% aqueous ethanol extract of Ypsilandra thibetica Franch. were investigated. As a result, fourteen previously unreported spirostanol saponins, ypsilandrosides Z1-Z14, and nine known analogues were isolated and characterized by MS, NMR, and chemical methods. Among them, ypsilandrosides Z1-Z4 (1-4) have a rare 12-O-ß-d-glucopyranosyl group, while ypsilandrosides Z5-Z8 (5-8) possess a rare double bond between C-4 and C-5, and a hydroxyl or carbonyl located at the C-6. All isolates were further tested for their hemostatic activity. The results suggested that five spirostanol tetraglycosides show favorable inducing platelet aggregation activities. Among them, ypsilandroside G (16) displayed significant inducing platelet aggregation activity with an EC50 value of 57.17 µM. Furthermore, the preliminary structure-activity relationship of these spirostanol glycosides' hemostatic activity was discussed.

Asunto(s)

Glicósidos , Hemostáticos , Melanthiaceae , Espirostanos , Glicósidos/farmacología , Glicósidos/química , Hemostáticos/farmacología , Espectroscopía de Resonancia Magnética , Melanthiaceae/química , Espirostanos/química

RESUMEN

A four-step synthesis of five- and six-membered E/F ring spiroethers from tigogenin has been developed. An efficient strategy that features bis-Grignard reaction of dinorcholanic lactone with appropriate bis(bromomagnesio)alkanes followed by acid-mediated spirocyclization was employed to construct a new class of steroid compounds having E and F ring junction as an oxa-carbacyclic system. The synthesized carbaanalogs interact with liposomes and albumin, and also exhibit antibacterial and antifungal activity, demonstrating their pharmacological potential.

Asunto(s)

Sapogeninas , Espirostanos , Sapogeninas/farmacología , Esteroides/farmacología , Espirostanos/farmacología

RESUMEN

Lung cancer is a leading cause of tumor-associated death worldwide. Autophagy plays a key role in regulating lung cancer progression, and is a promising option for lung cancer treatment. Saponins are a group of naturally occurring plant glycosides, characterized by their strong foam-forming properties in aqueous solution, and exert various biological properties, such as anti-inflammation and anti-cancer. In the present study, we for the first time explored the effects of gitogenin (GIT), an important saponin derived from Tribulus longipetalus, on lung cancer progression both in vitro and in vivo. We found that GIT markedly reduced the proliferation and induced apoptosis in lung cancer cells through increasing the cleavage of Caspase-3 and poly (ADP-ribose) polymerases (PARPs). In addition, GIT-incubated lung cancer cells exhibited clear accumulation of autophagosome, which was essential for GIT-suppressed lung cancer. Mechanistically, GIT-induced autophagy initiation was mainly through activating AMP-activated protein kinase (AMPK) and blocking protein kinase B (AKT) signaling pathways, respectively. Moreover, the autophagic flux was disrupted in GIT-treated lung cancer cells, contributing to the accumulation of impaired autophagolysosomes. Importantly, we found that suppressing autophagy initiation could abolish GIT-induced cell death; however, autophagosomes accumulation sensitized lung cancer cells to cell death upon GIT treatment. More in vitro experiments showed that GIT led to reactive oxygen species (ROS) production in lung cancer cells, which was also involved in the modulation of apoptosis. The in vivo findings confirmed the effects of GIT against lung cancer progression with undetectable toxicity to organs. In conclusion, we provided new insights into the treatment of lung cancer, and GIT might be an effective strategy for future clinical application.

Asunto(s)

Neoplasias Pulmonares , Saponinas , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis , Autofagia , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Saponinas/farmacología , Saponinas/uso terapéutico , Espirostanos

RESUMEN

To investigate the pharmacodynamic effects of ruscogenin on acute kidney injury and the Rev-erbα/ß regulation of ferroptosis intervention mechanism. The C57BL-6 mice were induced acute kidney injury with folic acid. Plasma, urine, and kidney samples were collected after intraperitoneal injection of ruscogenin (0.01, 0.1, and 1 mg/kg). We measured mouse kidney function indicators, including creatinine (CRE), blood urea nitrogen (BUN), N-acetyl-ß-D-glucosidase (NAG), albumin, albumin and creatinine rate (ACR), renal index, and renal injury molecule-1 expression. Meanwhile, we detected the levels of ferroptosis indicators malondialdehyde (MDA), carbonylated proteins, iron ions, glutathione peroxidase 4 (GPX-4), and glutathione (GSH). The expression of solute carrier family 7 member 11 (Slc7a11), heme oxygenase-1 (HO-1), and Rev-erbα/ß were detected by the Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. Ruscogenin (1 mg/kg) significantly reduced the index of folic acid-induced acute kidney injury and alleviated acute kidney injury. In kidney tissues, ruscogenin inhibited folic acid-induced Rev-erbα/ß expression, restored HO-1 and SLC7A11 expression to normal levels, and alleviated ferroptosis. Ruscogenin ameliorates acute kidney injury via suppressing ferroptosis in kidney tissues through modulation of the Rev-erbα/ß-SLC7A11/HO-1 pathway.

Asunto(s)

Lesión Renal Aguda , Ferroptosis , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Albúminas/efectos adversos , Albúminas/metabolismo , Animales , Creatinina/efectos adversos , Creatinina/metabolismo , Ácido Fólico/efectos adversos , Ácido Fólico/metabolismo , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Espirostanos

RESUMEN

Lung cancer, one of the most often diagnosed malignancies, is the top cause of death in both men and women globally. In both developed and emerging countries, high incidences of cancer are becoming a huge health burden. Natural resources, including plants, have always been a possible source of lead compounds in the identification of optimal medications for cancer treatment, with natural resources accounting for around half of all anticancer drugs. Ruscogenin, a natural saponin, is a major component of Radix Ophiopogon japonicus with a well-established anticancer activity. In this study, the anticancer potential of ruscogenin against a B(a)P-challenged lung cancer model in mice was assessed. The mice were categorized into four groups: group I was as the control group, group II mice were challenged with B(a)P, group III rodents were treated with ruscogenin prior to challenge with B(a)P, and group IV rodents were treated with ruscogenin after B(a)P administration. Tumor incidence was calculated, and the following parameters were analyzed: body weight, lung weight, immunoglobulin (Ig) levels (IgG, IgA, and IgM), key marker enzymes, and proinflammatory cytokines in both treated and control mice. Lung tissues were analyzed via histopathological analysis. According to our results, all the markers that favor the growth of cancer were increased in the lung cancer group. After administration of ruscogenin, all the markers returned to their original levels, revealing the anticancer potential of ruscogenin.

Asunto(s)

Neoplasias Pulmonares , Ophiopogon , Espirostanos , Ratones , Femenino , Animales , Citocinas , Espirostanos/farmacología , Espirostanos/uso terapéutico , Espirostanos/análisis , Neoplasias Pulmonares/tratamiento farmacológico