RESUMO
The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Lipossomos/uso terapêutico , Ditiocarb/uso terapêutico , Dissulfiram , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Zinco , Cobre/uso terapêutico , Microambiente Tumoral , Descarboxilases de Aminoácido-L-Aromático/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Lung adenocarcinoma (LUAD) is one of the main types of lung cancer. Ophiocordyceps sinensis has many potentially useful pharmacologic features, such as lung protection, and both anti-inflammatory and antioxidant activities. AIM OF THE STUDY: This study was conducted to investigate-using bioinformatics and in vivo experimental validation-the possible role of O. sinensis against LUAD. MATERIALS AND METHODS: We obtained important targets of O. sinensis for the treatment of LUAD using network pharmacology techniques and deep mining of the TCGA database, and validated them by molecular docking techniques and in vivo experiments. RESULTS: Through bioinformatics analysis and research, we screened BRCA1 and CCNE1 as important biomarkers for LUAD and as core targets of O. sinensis against LUAD. The non-small cell lung cancer signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway are potentially important pathways of O. sinensis against LUAD. The molecular docking results showed good binding between the active components in O. sinensis and the two core targets, and the in vivo experimental validation results indicated that O. sinensis had good inhibitory effects in the Lewis lung cancer (LLC) model. CONCLUSIONS: BRCA1 and CCNE1 are crucial biomarkers for LUAD and are important targets for O. sinensis to exert anti-LUAD effects.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Cordyceps , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Biologia ComputacionalRESUMO
Cellular inflammation is the underlying cause of several diseases and development of a safe and effective anti-inflammatory drug is need-of-the hour for treatment of diseases like lung inflammation. Callicarpa integerrima Champ. is a well-known herbal medicine with hemostatic and anti-inflammatory functions. However, the exact ingredient exhibiting anti-inflammatory activity in C. integerrima Champ. is largely unknown. Here, we first isolated, purified and characterized a novel clerodane-type diterpenoid Cintelactone A (CA) from C. integerrima Champ. We demonstrated that CA could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators production both in mouse peritoneal macrophages and THP1 cells. Consistently, CA also relieved inflammation and reduced LPS-induced lung injury in mice. We systematically elucidated the mechanism of action as well. CA interacted with Arg78 of tumor necrosis factor receptor-associated factor 6 (TRAF6) by hydrogen bonding. It further promoted the K48-linked ubiquitination and proteasomal degradation of TRAF6, and suppressed the activation of NF-κB and MAPKs signaling pathways. Collectively, our study reveals that new clerodane-type diterpenoid CA suppresses LPS-induced inflammation by promoting TRAF6 degradation, suggesting that CA as the potential therapeutic candidate for the treatment of inflammation associated diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos Clerodânicos/uso terapêutico , Fator 6 Associado a Receptor de TNF/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Callicarpa , Células Cultivadas , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Diterpenos Clerodânicos/farmacologia , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Folhas de Planta , Caules de Planta , Ubiquitinação/efeitos dos fármacosRESUMO
OBJECTIVES: Two labdane diterpenoids, leojapone B and heteronone B, were isolated from Leonurus japonicus Houtt., and their biological activity were evaluated in this study. METHODS: Human and mouse cancer cells, human peripheral blood mononuclear cells (PBMCs) and mouse macrophages (RAW264.7 cells) were used to evaluate the activity of leojapone B and heteronone B, while the in vivo effects of leojapone B were further examined in Lewis Lung Cancer tumour-bearing mice. KEY FINDINGS: In vitro studies showed that leojapone B selectively inhibited the proliferation of lung cancer cells, and both leojapone B and heteronone B inhibited the production of pro-inflammatory cytokines in activated PBMCs. In tumour-bearing mice model, lung tumours were reduced in size in mice treated with intraperitoneal injections of leojapone B at 20 and 30 mg/kg for 14 days. The population ratio of CD4+ /CD8+ T cells in mouse spleens was found to be increased, while regulatory T cells were decreased after leojapone B treatment. CONCLUSIONS: The inhibitory effects of leojapone B in mouse lung tumours were demonstrated for the first time in this study. The immunomodulatory activity of heteronone B were also demonstrated. Our findings indicated that both leojapone B and heteronone B may act as active components in L. japonicus.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Diterpenos/farmacologia , Fatores Imunológicos/farmacologia , Leonurus , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Diterpenos/isolamento & purificação , Células HT29 , Células Hep G2 , Humanos , Fatores Imunológicos/isolamento & purificação , Mediadores da Inflamação/metabolismo , Leonurus/química , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Células MCF-7 , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
OBJECTIVES: Post-stroke depression (PSD) is common consequence of stroke. However, today the majority of PSD patients remains untreated or inadequately treated, especially in the developing countries. Herein, we performed a meta-analysis to evaluate efficacy and safety of hyperbaric oxygen (HBOT) therapy for PSD. PATIENTS AND METHODS: Seven electronic databases were comprehensively searched for randomized clinical trials (RCTs) from inception to May 2019. Outcome measures included response rate, depression severity, neurological deficit, physical disability and adverse events. RESULTS: A total of 27 RCTs involving 2250 participants were identified. Patients in HBOT group had a higher response rate than patients in control group (response rate: 69.4% vs 51.2%, odds ratio [OR]â¯=â¯2.51, 95% confidence interval [CI] [1.83-3.43], Pâ¯=â¯0.000). HBOT significantly reduced Hamilton Depression (HAMD) -17 item scores (weighted mean difference [WMD] â¯=â¯-4.33, 95% CI [-4.82 to -3.84], Pâ¯=â¯0.000), HAMD-24 item scores (WMDâ¯=â¯-4.31, 95% CI [-5.01 to -3.62], Pâ¯=â¯0.000), National Institute of Health Stroke Scale (NIHSS) scores (WMDâ¯=â¯-2.77, 95% CI [-3.57 to -1.98], Pâ¯=â¯0.000), Chinese Stroke Scale (CSS) scores (WMDâ¯=â¯-3.75, 95% CI [-5.12 to -2.38], Pâ¯=â¯0.000) and Modified Scandinavian Stroke Scale (MASSS) scores (WMDâ¯=â¯-3.66, 95% CI [-6.26 to -1.06], Pâ¯=â¯0.000). HBOT also improved Barthel Index (WMDâ¯=â¯10.68, 95% CI [7.98-13.37], Pâ¯=â¯0.000). In subgroup analysis, Group A of studies with hemorrhage patients accounting for less than 20% achieved more reduction of HAMD 17-item score (WMDâ¯=â¯-4.47, 95% CI [-5.17 to -3.77], Pâ¯=â¯0.000) than Group B of studies with hemorrhage patients no less than 20% (WMDâ¯=â¯-3.73, 95% CI [-4.20 to -3.26], Pâ¯=â¯0.000). In addition, patents with HBOT along with antidepressants treatment achieve superior results than patients with antidepressants monotherapy. Patients with HBOT monotherapy achieve a slightly higher response rate than patients with antidepressants monotherapy (ORâ¯=â¯1.29, 95% CI [1.04-1.60], Pâ¯=â¯0.000). Besides, HBOT group reported less adverse events (9.6%vs16.6%, Pâ¯<â¯0.05). The most frequent side-effect of HBOT is ear pain (26 cases). CONCLUSION: Based on our pooled analysis, HBOT is effective and safe therapeutic approach for PSD. However, results should be cautiously interpreted due to a relatively poor methodological quality.