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1.
Int J Gen Med ; 17: 2433-2443, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38826510

RESUMO

Introduction: Chondrocyte degeneration and senescence are characteristics of osteoarthritis (OA) and other joint degenerative diseases, and ferroptosis has been observed to regulate the development of OA. However, the role of the N6-methyladenosine (m6A) modification in OA ferroptosis remains unclear. Methods: This study performed series of assays to investigate the function of the m6A reader IGF2BP1 in OA ferroptosis, including m6A quantitative analysis, Iron (Fe2+) release analysis, Malondialdehyde (MDA) measurement, lipid peroxidation (ROS) detection and Glutathione (GSH) measurement. The molecular interaction and mechanism analysis was performed by Luciferase reporter assay, mRNA stability analysis and RNA immunoprecipitation (RIP) assay. Results: These results indicate that IGF2BP1 is upregulated in IL-1ß-induced chondrocytes. Functionally, IGF2BP1 silencing represses ferroptosis, including iron (Fe2+) accumulation, malondialdehyde, and reactive oxygen species (ROS). Mechanistically, among the potential downstream targets, matrix metalloproteinase-3 (MMP3) was observed to harbor a significant m6A modified site in the 3'-UTR. IGF2BP1 combines with MMP3 through the binding of m6A sites, thereby enhancing MMP3 mRNA stability. Discussion: In conclusion, our findings revealed the functions and mechanisms of m6A regulator IGF2BP1 in OA chondrocyte's ferroptosis, providing a novel target for OA treatment.

2.
BMJ ; 385: e077890, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38897625

RESUMO

OBJECTIVE: To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma. DESIGN: Phase 3, open label, multicentre, randomised trial. SETTING: Four hospitals located in China between September 2019 and August 2022. PARTICIPANTS: Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma. INTERVENTIONS: Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m2 on day 1), cisplatin (60 mg/m2 on day 1), and capecitabine (1000 mg/m2 twice on days 1-14) or gemcitabine (1 g/m2 on days 1 and 8) and cisplatin (80 mg/m2 on day 1). MAIN OUTCOME MEASURES: Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population. RESULTS: The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) v 13/40 (33%); P=0.02), neutropenia (6/41 (15%) v 16/40 (40%); P=0.01), and anaemia (1/41 (2%) v 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up. CONCLUSION: The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027112.


Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Cisplatino , Desoxicitidina , Gencitabina , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Recidiva Local de Neoplasia , Paclitaxel , Humanos , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Cisplatino/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Capecitabina/administração & dosagem , Adulto , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Paclitaxel/efeitos adversos , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Albuminas/uso terapêutico , Idoso , Intervalo Livre de Progressão , China , Metástase Neoplásica
3.
Artigo em Inglês | MEDLINE | ID: mdl-38727689

RESUMO

BACKGROUND: The long-term prognosis of colon cancer patients remains little changed with relatively high mortality and morbidity. Since the most widely used prognostic parameter TNM staging system is less satisfactory in predicting prognosis in early-stage cancers, numerous clinicopathological factors, including tumor necrosis, have been proposed for prognosis stratification, but substantial evidences are still lacking for early-stage colon cancer. MATERIALS AND METHODS: In the retrospective study, a total of eligible 173 stage I-II colon cancer patients, who received tumor radical resection and lymphadenectomy in the local hospital between January 1, 2010, and December 31, 2018, were enrolled for analyzing the prognostic role of tumor necrosis. The primary endpoints included 5-year overall survival (OS) and progression-free survival (PFS). RESULTS: The median follow-up of enrolled early-stage colon cancer patients was 58.3 months. The 2-year and 5-year OS rates were 88.3% and 68.2%, respectively, and the 2-year and 5-year PFS rates were 85.6% and 62.7%, respectively. Seventy-eight patients (45.1%) were diagnosed with tumor necrosis by pathological examination. Demographic analysis revealed a significant association of tumor necrosis with larger tumor size and a marginal association with vascular invasion. Kaplan-Meier survival curves demonstrated that tumor necrosis was associated with worse OS (log-rank P = 0.003) and PFS (log-rank P = 0.002). The independent unfavorable prognostic effect of tumor necrosis was further validated in univariate and multivariate Cox regression analysis (hazard ratio = 1.91 (1.52-2.40), P = 0.004). CONCLUSIONS: The current study confirmed the independent prognostic role of tumor necrosis from pathological review in early-stage colon cancer patients. This pathological criterion promises to help in identifying high-risk subgroup from early-stage colon cancer patients, who may benefit from strict follow-up and adjuvant therapy.

4.
Phytochemistry ; 220: 114015, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38364884

RESUMO

Eight structurally diverse components, including six undescribed ones, (±)-daphuarin A (1a/1b), daphuarin B (2), daphuarin D-E (4-6), together with a pair of new natural products (±)-daphuarin C (3a/3b) were isolated from the herb of Daphne bholua Buch.-Ham. ex D. Don. Their planar structures were elucidated by extensive spectroscopic analyses. The configurations were established with the assistance of quantum chemical calculations, together with the Custom DP4+ method. The inhibitory potentials of all isolates against acetylcholinesterase were evaluated.


Assuntos
Daphne , Daphne/química , Daphne/metabolismo , Estrutura Molecular , Acetilcolinesterase/metabolismo
5.
Nat Commun ; 15(1): 1029, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38310101

RESUMO

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.


Assuntos
Anticorpos Monoclonais Humanizados , Quimioterapia de Indução , Neoplasias Nasofaríngeas , Piridinas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Quimioterapia de Indução/efeitos adversos , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Quimiorradioterapia/efeitos adversos
6.
Sci Rep ; 14(1): 1768, 2024 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-38242940

RESUMO

To assess the efficacy and safety of the combination of immune checkpoint inhibitors (ICIs) and target therapy (anti-angiogenesis or EGFR inhibitors) as a second-line or subsequent treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC), we conducted a retrospective study. In this study, previously treated R/M NPC patients were administered one of the following treatment: ICIs combined with target therapy and chemotherapy (ITC), ICIs combined with target therapy alone (IT), ICIs combined with chemotherapy (IC), or chemotherapy alone (C). The primary endpoint under consideration was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety measures. A total of 226 patients participated in this study, with 70 receiving the ITC regimen, 48 receiving IT, 48 treated with IC, and 60 undergoing C alone. The median PFS for the four cohorts was 20.67, 13.63, 12.47, and 7.93 months respectively. Notably, ITC regimen yielded the most favorable PFS among these cohorts. The ITC cohort exhibited a comparable tumor response and safety profile to the IT and IC cohorts (p > 0.05), but superior tumor response compared to the C cohort (p < 0.05). The ITC regimen also conferred a significant improvement in OS when comparing to C alone (HR 0.336, 95%CI 0.123-0.915, p = 0.033). The IT and IC regimens achieved a nearly identical PFS (HR 0.955, 95%CI 0.515-1.77, p = 0.884), although the IT regimen was associated with a lower occurrence of SAEs in contrast to the IC regimen (p < 0.05). In addition, the IT regimen demonstrated superior PFS (HR 0.583, 95%CI 0.345-0.985, p = 0.044) and fewer SAEs when compared to C alone (p < 0.05). These findings collectively support the notion that the combination of ICIs, target and chemotherapy exhibits robust antitumor activity in previously treated R/M NPC patients, without a significant increase in adverse events.


Assuntos
Neoplasias Nasofaríngeas , Recidiva Local de Neoplasia , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Irinotecano , Imunoterapia , Neoplasias Nasofaríngeas/tratamento farmacológico
7.
Phytochemistry ; 216: 113892, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37813132

RESUMO

Three undescribed compounds elephantopuscabers A-C, along with one previously reported compound spirowallichiione, were isolated from Elephantopus scaber L. Their structures were determined via extensive NMR spectroscopic analysis, quantum chemical calculations, and single-crystal X-ray diffraction crystallography. A plausible biosynthetic pathway for spirowallichiione was proposed. All the isolated compounds were tested for their acetylcholinesterase inhibitory activities. Among them, elephantopuscaber B and C displayed promising inhibitory activities against AChE, and the binding sites were predicted by molecular docking.


Assuntos
Terpenos , Triterpenos , Terpenos/farmacologia , Acetilcolinesterase , Simulação de Acoplamento Molecular , Estrutura Molecular
8.
Animals (Basel) ; 13(20)2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37893999

RESUMO

This experiment was conducted to investigate the effects of noni fruit extract (NFE) on growth performance, ruminal and colonic fermentation, nutrient digestion, and subacute rumen acidosis (SARA) of cashmere goats with the high-concentrate diet. Twenty-four cashmere kids (17.9 ± 1.45 kg of BW ± SD) were randomly assigned to three treatments: low-concentrate diet, high-concentrate (HC) diet, or HC diet supplemented with NFE at 1 g per kg DM (0.1%). The results showed that although the HC diet improved the average daily gain (ADG) and feed conversion rate (FCR), it was accompanied by SARA with a decreased pH and an increased lactic acid of both rumen and colon, and decreased digestibility of neutral detergent fiber (NDF)and acid detergent fiber (ADF). The supplementation of 0.10% NFE in the HC diet could not only effectively alleviate SARA symptoms and colon fermentation disorders, such as reversing the decrease of pH and alleviating the increase of lactic acid in rumen and colon, but also mitigate the decline of fiber digestibility caused by long-term feeding in the HC diet, and increase the digestibility of crude protein(CP) and dry matter (DM), which improved the ADG and FCR of cashmere kids. Thus, NFE provides new strategies for alleviating SARA and promoting cashmere goat growth.

9.
Cell Mol Biol (Noisy-le-grand) ; 69(8): 179-184, 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37715399

RESUMO

As a chronic inflammatory autoimmune disease, rheumatoid arthritis (RA) causes significant destruction to joints and cartilage. So far, from RA patients, the synovial cells and subsynovial tissues reflected the positive expression of IL-18, IL-1ß, Caspase-1 and NLRP3, with the synovial tissues of those patients also expressing the zinc finger protein A20 at a significantly lower level compared with osteoarthritis (OA) ones. Thus, the inhibition of the NLRP3/caspase-1 signaling pathway can effectively down-regulate the expression of IL-1ß, but when NLRP3 inflammasomes are activated, they can also shear GSDMD and induce pyroptosis. These suggest that the Gasdermin family of proteins, downstream of the NLRP3 inflammasome, could be involved in pyroptosis. Previous studies have shown that A20 contributes largely as an anti-inflammatory factor in many inflammatory diseases, but it remains unclear whether zinc finger protein A20, as an inhibitor of NLRP3 inflammasomes, can play a protective role against RA by inhibiting NLRP3 inflammasome-mediated pyroptosis. Therefore, this study aimed to verify the effects of zinc finger protein A20 on NLRP3/ Caspase-1-mediated pyroptosis in rheumatoid arthritis synovial fibroblasts (HFLS-RA) cells through cell experiments and clinical bidirectional verification, aim to understand the regulatory mechanism of A20 on RA. The results of clinical trials showed that NLRP3, Caspase-1, IL-1ß and IL-18 were positively scattered in RA synovial cells and subsynovial tissue. The expression level of the zinc finger protein A20 in RA synovial tissues was significantly lower than that in OA synovial tissue and was negative, while zinc finger protein A20 was strongly positive in OA synovial tissue. In addition, HFLS-RA cells with siRNA-interfering zinc finger protein A20 were constructed at the cellular level, with the results also confirming that zinc finger protein A20 can play a protective role against RA by inhibiting NLRP3 inflammasome-mediated pyroptosis. In conclusion, this study is of great significance for understanding the role of the NLRP3-caspase-1-IL-1ß/ pyroptosis signaling pathway in the occurrence and development of RA. It is expected that the results will provide a theoretical basis for the immune regulation of innate immunity in the occurrence and development of RA, while providing a new therapeutic target for the clinical treatment of RA.


Assuntos
Artrite Reumatoide , Osteoartrite , Humanos , Caspase 1 , Piroptose , Inflamassomos , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Transdução de Sinais
10.
Fitoterapia ; 171: 105668, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37683876

RESUMO

The fungus Nectria sp. MHHJ-3 was isolated from Illigera rhodantha. A molecular networking-guided the secondary metabolites investigation of Nectria sp. MHHJ-3 led to the isolation of ten metabolites (1-10), including two new naphthalenone derivatives, nectrianaphthalenones A (1) and B (2), and two new steroids, nectriasteroids A (3) and B (4). Their structures were elucidated by extensive spectroscopic analysis including the HRESIMS, 1D/2D NMR and electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for 1-2 was proposed. Compounds 1 and 2 exhibited moderate acetylcholinesterase (AChE) inhibitory activities. Compounds 3 and 4 showed significant cytotoxic activity against selected tumor cells. Particularly, compound 3 exhibited the strongest activity against A549 cells with an IC50 value of 13.73 ± 0.03 µM, which was at the same grade with that of positive control cisplatin.


Assuntos
Antineoplásicos , Nectria , Estrutura Molecular , Nectria/química , Acetilcolinesterase , Fungos , Antineoplásicos/farmacologia
11.
Crit Rev Oncol Hematol ; 190: 104113, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37633346

RESUMO

We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) patients who progressed to previous anti-PD1 therapy. Enrolled patients were divided into a combination group and a chemotherapy only group. A total of 145 patients were enrolled. The median progress-free survival (mPFS) was 7.9 months and 4.4 months, respectively for the two groups. The combination group exhibited significantly longer PFS (HR=0.363, p < 0.001), and better disease control ratio (DCR, p = 0.022) compared with the chemotherapy group. Among the combination group, longer PFS was found in those patients who received different PD1 inhibitor from prior therapy, reached object response rate (ORR) from prior anti-PD1 therapy, and EBV DNA ≤ 1500 copy/ml before therapy, comparing to the corresponding other patients. R/M NPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR agents.


Assuntos
Imunoterapia , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Neoplasias Nasofaríngeas/tratamento farmacológico
12.
Phytochemistry ; 209: 113614, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36804187

RESUMO

Fractionation motivated by biological activity screening and NMR characteristic signals analysis led to the isolation of seventeen diarylpentanoids from the whole plant of Daphne bholua Buch.-Ham. ex D. Don, among which nine compounds were undescribed. Their structures and stereochemistry were determined by comprehensive spectroscopic data, J-based configurational analysis, and quantum chemical calculations. The inhibitory potentials of all isolates against acetylcholinesterase were evaluated in vitro and in silico.


Assuntos
Daphne , Daphne/química , Daphne/metabolismo , Estrutura Molecular , Acetilcolinesterase/metabolismo , Espectroscopia de Ressonância Magnética
13.
Bioorg Chem ; 129: 106208, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36272251

RESUMO

The genus Daphne is a treasure-house of secondary metabolites with various biological effects, which inspired Daphne bholua being fully investigated phytochemically and biologically for the first time. Here, seven undescribed guaiane-type sesquiterpenoids (1-7) along with thirteen known analogues (8-20) were targeted and isolated from D. bholua using molecular networking. Their chemical structure and configurations were established via NMR spectroscopy analysis, NMR and ECD calculations, Snatzke's method, along with single-crystal X-ray diffraction technique. Moreover, two pairs of sesquiterpene isomers, either with prominent biological properties or with unprecedented skeleton, were revised by means of computer-assisted structure elucidation, chemical shift calculator using deep learning, etc. The inhibitory potentials of all isolates against acetylcholinesterase were evaluated in vitro and in silico.


Assuntos
Inibidores da Colinesterase , Daphne , Sesquiterpenos de Guaiano , Acetilcolinesterase/química , Daphne/química , Estrutura Molecular , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/isolamento & purificação , Sesquiterpenos de Guaiano/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Inibidores da Colinesterase/farmacologia
14.
Fitoterapia ; 161: 105250, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35798062

RESUMO

Three undescribed acylated sucroses (1-3), one undescribed butenolide analog (4) along with three known compounds (5-7) were isolated from the aqueous EtOH extract of the dried leaves of Tripterygium wilfordii. Their structures were elucidated on the basis of spectroscopic analyses, electron circular dichroism (ECD) techniques, and saccharide hydrolysis. All the isolated compounds were tested for their anti-tyrosinase effects. Among them, 6 exhibited similar inhibitory effects on tyrosinase with IC50 values of 0.073 mM comparing to arbutin. Additionally, the possible mechanism of the interaction between 6 and the active site of tyrosinase was explored by molecular docking.


Assuntos
Monofenol Mono-Oxigenase , Tripterygium , 4-Butirolactona/análogos & derivados , Simulação de Acoplamento Molecular , Estrutura Molecular , Tripterygium/química
15.
Pol J Pathol ; 73(1): 21-26, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35848477

RESUMO

In this study, the immunohistochemical EnVision method was applied to detect CD3, CD4 and CD8 in synovial tissues of 40 patients with rheumatoid arthritis (RA) and 10 patients with osteoarthritis (OA). In 92.5% (37/40) RA cases, lymphocytes were focally aggregated, and even germinal centers appeared, forming lymphoid follicle-like structures. The expression of CD3, CD4, and CD8 were high in synovial tissue of RA group, but low in OA group. The number of CD3, CD4+, and CD8+ lymphocytes in OA group were significantly lower than that in RA group (p < 0.05); CD4+lymphocytes in RA accounted for the majority, and mostly were focally distributed. The number of CD8+lymphocytes in the synovial tissue were small, and were mostly scattered. The number of CD4+lymphocytes were significantly higher than CD8+lymphocytes (p<0.05). Compared with the OA group, the number of CD4+T and CD8+T lymphocytes in RA group were higher, and the ratio of CD4/CD8 was higher in RA group (p < 0.05). In conclusion, the CD3, CD4 and CD8 with high level may promote the occurrence and development of RA. The ratio of CD4+/CD8+ may be used as a reference index for the diagnosis and prognosis of RA.


Assuntos
Artrite Reumatoide , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Humanos , Membrana Sinovial/química , Membrana Sinovial/metabolismo
16.
Phytochemistry ; 187: 112769, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33887559

RESUMO

Quassinoids, originating from the oxidative degradation of tetracyclic tirucallane triterpene, are a diverse class of secondary metabolites identifying from nature mostly in Simaroubaceae family. The crucial pharmacological activities and structural complexity of quassinoids have long fascinated scientists due to their medicinal uses, infamous toxicity, and unique biosynthesis. In the past few decades, 482 quassinoids, assigned to 6 skeletons, have been isolated and identified from plants. The names, classes, molecular formula, and plant sources of these secondary metabolites are collated here. This review will be a detailed update of the naturally occurring quassinoids reported from the plant kingdom, providing an in-depth discussion of their diversity, antitumor activities, structure-activity relationship.


Assuntos
Quassinas , Simaroubaceae , Extratos Vegetais , Plantas , Quassinas/farmacologia , Relação Estrutura-Atividade
17.
Bioorg Chem ; 105: 104438, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33171406

RESUMO

Six undescribed lanostane triterpenoids (1-6), together with three known compounds (7-9) were isolated from Inonotus obliquus. Compounds 3-5 are the rare natural compounds featuring a 4,5-seco-lanostane core with a 5,7,9-trien-21,24-cyclopentane moiety. The structure elucidation of the compounds was conducted by spectroscopic techniques and the ECD method. The absolute configuration of compound 1 was confirmed by single-crystal X-ray diffraction analysis. All isolated compounds were assayed for their neuroprotective activity against H2O2-induced cell injury using human neuroblastoma SH-SY5Y cells. Compound 9 exhibited the most potent neuroprotective activity and the flow cytometry analysis indicated that 9 could protect SH-SY5Y cells from oxidative damage by inhibiting cell apoptosis.


Assuntos
Antineoplásicos/química , Misturas Complexas/química , Inonotus/química , Lanosterol/química , Neuroblastoma/tratamento farmacológico , Fármacos Neuroprotetores/química , Triterpenos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida , Misturas Complexas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Peróxido de Hidrogênio/metabolismo , Conformação Molecular , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/farmacologia
18.
Bioorg Chem ; 104: 104314, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33011538

RESUMO

Small molecule accurate recognition technology (SMART) is an emerging method for the rapid structural prediction of major constituents from crude extracts and fractions. In the present study, a targeted isolation of an Elephantopus scaber extract by SMART resulted in the obtention of 15 new (1-15) and five known germacranolide sesquiterpenes (16-20). Their structures were assigned by extensively analyzing HRESIMS, NMR, X-ray crystallographic analyses, modified Mosher's method results, and quantum chemical calculate electronic circular dichroism (ECD) spectra. All germacranolide sesquiterpenes were screened to determine their inhibitory effects with two hepatoma cell lines (HepG2 and Hep3B), and compounds 14, 16, 18, 19 and 20 showed significant cytotoxic activities against the HepG2 (IC50, 3.3-9.9 µM) and Hep3B (IC50, 4.5-8.6 µM) cell lines. Further study suggested that 18 can induce the apoptosis of hepatoma cells via mitochondrial dysfunction.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Sesquiterpenos de Germacrano/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/isolamento & purificação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Relação Estrutura-Atividade
19.
Phytochemistry ; 178: 112479, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32768717

RESUMO

Seven undescribed germacranolides, named as scabertopinolide A-G were obtained from whole herbs of Elephantopus scaber L. The determination of their structures was conducted via comprehensive spectroscopic analyses combined with experimental electronic circular dichroism (ECD) spectroscopic data and quantum mechanical ECD calculations. The absolute configuration of scabertopinolide A was determined by X-ray crystallography data analysis. The cytotoxicity of all compounds was evaluated against three human cancer cell lines HepG2, Hep3B (human hepatocellular carcinoma cell lines), and MCF-7 (human breast adenocarcinoma cell line). Scabertopinolide G exhibited the most significant cytotoxic activities against the three cancer cell lines with IC50 values between 7.0 and 10.3 µM. Furthermore, flow cytometry analysis has suggested that scabertopinolide G may cause death of cancer cells through apoptosis induction.


Assuntos
Antineoplásicos Fitogênicos , Antineoplásicos , Asteraceae , Neoplasias Hepáticas , Linhagem Celular Tumoral , Humanos , Sesquiterpenos de Germacrano
20.
PLoS One ; 15(6): e0234062, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497093

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal and malignant tumours worldwide. New therapeutic targets for HCC are urgently needed. CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes have been noted to be associated with cancer-targeted therapies. Therefore, we intended to explore the effects of the CYCLOPS gene RBM17 on HCC oncogenesis to determine if it could be further used for targeted therapy. METHODS: We collected data on 12 types of cancer from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) queries for comparison with adjacent non-tumour tissues. RBM17 expression levels, clinicopathological factors and survival times were analysed. RNAseq data were downloaded from the Encyclopaedia of DNA Elements database for molecular mechanism exploration. Two representative HCC cell models were built to observe the proliferation capacity of HCC cells when RBM17 expression was inhibited by shRBM17. Cell cycle progression and apoptosis were also examined to investigate the pathogenesis of RBM17. RESULTS: Based on 6,136 clinical samples, RBM17 was markedly overexpressed in most cancers, especially HCC. Moreover, data from 442 patients revealed that high RBM17 expression levels were related to a worse prognosis. Overexpression of RBM17 was related to the iCluster1 molecular subgroup, TNM stage, and histologic grade. Pathway analysis of RNAseq data suggested that RBM17 was involved in mitosis. Further investigation revealed that the proliferation rates of HepG2 (P = 0.003) and SMMC-7721 (P = 0.030) cells were significantly reduced when RBM17 was knocked down. In addition, RBM17 knockdown also arrested the progression of the cell cycle, causing cells to halt at the G2/M phase. Increased apoptosis rates were also found in vitro. CONCLUSION: These results suggest that RBM17 is a potential therapeutic target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/genética , Variações do Número de Cópias de DNA , Neoplasias Hepáticas/genética , Fatores de Processamento de RNA/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Prognóstico , Fatores de Processamento de RNA/deficiência
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