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1.
Anticancer Res ; 40(9): 4947-4960, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878783

RESUMO

BACKGROUND/AIM: This study aimed to investigate the anticancer effects and potential mechanisms of sclareol in a human small cell lung carcinoma (SCLC) cell line. MATERIALS AND METHODS: Cell viability was determined by the MTT assay. Cell cycle, apoptosis and caspase activity were evaluated by flow cytometry. Cell cycle and DNA damage related protein expression was determined by western blotting. In vivo evaluation of sclareol was carried out in xenografted tumor mice models. RESULTS: Sclareol significantly reduced cell viability, induced G1 phase arrest and subsequently triggered apoptosis in H1688 cells. In addition, this sclareol-induced growth arrest was associated with DNA damage as indicated by phosphorylation of H2AX, activation of ATR and Chk1. Moreover, in vivo evaluation of sclareol showed that it could inhibit tumor weight and volume in a H1688 xenograft model. CONCLUSION: Sclareol might be a novel and effective therapeutic agent for the treatment of SCLC patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Diterpenos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Diterpenos/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Biochem Biophys Res Commun ; 530(1): 4-9, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32828312

RESUMO

COVID-19 has become one of the worst epidemic in the world, currently already more than four million people have been infected, which probably co-exist with human beings, and has a significant impact on the global economy and political order. In the process of fighting against the epidemic in China, the clinical value of a variety of herbal medicines has been recognized and written into the clinical application guide. However, their effective molecular mechanism and potential targets are still not clear. Pathology and pharmacology research will gradually attract attention in the post-epidemic outbreak term. Here, we constructed a COVID-19 protein microarray of potential therapy targets, which contains the main drug targets to the SARS-CoV-2 virus and the anti-virus, anti-inflammatory cellar targets of the host. Series of quality controls test has been carried out, which showed that it could be applied for drug target screening of bio-active natural products. The establishment of this microarray will provide a useful tool for the study of the molecular pharmacology of natural products.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Pneumonia Viral/tratamento farmacológico , Proteínas/metabolismo , Proteínas Virais/metabolismo , Betacoronavirus/metabolismo , Produtos Biológicos/farmacologia , Ácido Clorogênico/farmacologia , Infecções por Coronavirus/metabolismo , Diterpenos/farmacologia , Descoberta de Drogas , Glucosídeos/farmacologia , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Pandemias , Pneumonia Viral/metabolismo , Análise Serial de Proteínas , Estilbenos/farmacologia
3.
Medicine (Baltimore) ; 99(29): e21223, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702892

RESUMO

Lefamulin is a novel pleuromutilin antibiotic with potent in vitro activity against key community-acquired bacterial pneumonia (CABP) pathogens. However, the clinical efficacy and safety of lefamulin for treating CABP remains unclear.An integrated analysis of 2 phase III trials investigating the clinical efficacy and safety of lefamulin vs moxifloxacin in the treatment of CABP was conducted.A total of 1289 patients (lefamulin group: 646 and moxifloxacin group: 643) were included in this analysis. The early clinical response rate was 89.3% and 90.5% among lefamulin and moxifloxacin group, respectively. Lefamulin was noninferior to moxifloxacin (89.3% vs 90.5%, RR: 0.99, 95% CI: 0.95-1.02, I = 0%). In terms of clinical response at test of cure, no significant difference was observed between the lefamulin and moxifloxacin groups (for modified intention to treat population, RR: 0.98, 95% CI: 0.94-1.02, I = 0%; for clinically evaluable population, RR: 0.96, 95% CI: 0.93-1.00, I = 0%). In the subgroup analysis, the early clinical response rate at early clinical assessment and clinical response rate at test of cure of lefamulin was similar to that of moxifloxacin across different subgpopulations and all baseline CABP pathogens. Lefamulin was associated with a similar risk of adverse events as moxifloxacin.Clinical efficacy and tolerability for lefamulin in the treatment of CABP were similar to those for moxifloxacin.


Assuntos
Antibacterianos/uso terapêutico , Diterpenos/uso terapêutico , Moxifloxacina/uso terapêutico , Pneumonia Bacteriana/diagnóstico , Compostos Policíclicos/uso terapêutico , Tioglicolatos/uso terapêutico , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/mortalidade , Diterpenos/administração & dosagem , Diterpenos/farmacologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacologia , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificação , Taiwan , Tioglicolatos/administração & dosagem , Tioglicolatos/farmacologia , Resultado do Tratamento
4.
J Cancer Res Clin Oncol ; 146(10): 2559-2574, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32681294

RESUMO

PURPOSE: Canonical Wnt/ ß-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study. METHODS: Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (ß-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data. RESULTS: We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progression-free (PFS) and overall survival (OS). CONCLUSION: According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Caderinas/biossíntese , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi/farmacologia , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Indóis/farmacologia , Maleimidas/farmacologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/patologia , Fenantrenos/farmacologia , beta Catenina/biossíntese , beta Catenina/metabolismo
5.
PLoS One ; 15(6): e0220350, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544163

RESUMO

Mycoplasma hyopneumoniae is the major pathogenic microorganism causing enzootic pneumonia in pigs. With increasing resistance of M. hyopneumoniae to conventional antibiotics, treatment is becoming complicated. Herein, we investigated the mutant selection window (MSW) of doxycycline, tylosin, danofloxacin, tiamulin, and valnemulin for treating the M. hyopneumoniae type strain (ATCC 25934) to determine the likelihood of promoting resistance with continued use of these antibiotics. Minimum inhibitory concentration (MIC) values against M. hyopneumoniae were determined for each antimicrobial agent based on microdilution broth and agar dilution methods (bacterial numbers ranged from 105 colony-forming units (CFU)/mL to 109 CFU/mL). The minimal concentration inhibiting colony formation by 99% (MIC99) and the mutant prevention concentration (MPC) were determined by the agar dilution method with three inoculum sizes. Antimicrobial killing was determined based on MIC99 and MPC values for all five agents. MIC values ranged from 0.001 to 0.25 µg/mL based on the microdilution broth method, and from 0.008 to 1.0 µg/mL based on the agar dilution method. MPC values ranged from 0.0016 to 10.24 µg/mL. MPC/MIC99 values were ordered tylosin > doxycycline > danofloxacin > tiamulin > valnemulin. MPC achieved better bactericidal action than MIC99. Based on pharmacodynamic analyses, danofloxacin, tylosin, and doxycycline are more likely to select resistant mutants than tiamulin and valnemulin.


Assuntos
Antibacterianos/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Mutação , Mycoplasma hyopneumoniae/efeitos dos fármacos , Mycoplasma hyopneumoniae/genética , Diterpenos/farmacologia , Doxiciclina/farmacologia , Fluoroquinolonas/farmacologia , Cinética , Testes de Sensibilidade Microbiana , Mycoplasma hyopneumoniae/fisiologia , Tilosina/farmacologia
6.
Toxicol Appl Pharmacol ; 401: 115109, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32544403

RESUMO

Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and ß-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and ß-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV + CDDP combination both resulted in significant reductions in mTOR, ß-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed ß-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa.


Assuntos
Quinase 6 Dependente de Ciclina/metabolismo , Diterpenos/uso terapêutico , MicroRNAs/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/antagonistas & inibidores , Plantas Medicinais , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , beta Catenina/antagonistas & inibidores
7.
Life Sci ; 255: 117842, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: covidwho-403331

RESUMO

The outbreak of COVID-19 caused by 2019-nCov/SARS-CoV-2 has become a pandemic with an urgent need for understanding the mechanisms and identifying a treatment. Viral infections including SARS-CoV are associated with increased levels of reactive oxygen species, disturbances of Ca++ caused by unfolded protein response (UPR) mediated by endoplasmic reticulum (ER) stress and is due to the exploitation of virus's own protein i.e., viroporins into the host cells. Several clinical trials are on-going including testing Remdesivir (anti-viral), Chloroquine and Hydroxychloroquine derivatives (anti-malarial drugs) etc. Unfortunately, each drug has specific limitations. Herein, we review the viral protein involvement to activate ER stress transducers (IRE-1, PERK, ATF-6) and their downstream signals; and evaluate combination therapies for COVID-19 mediated ER stress alterations. Melatonin is an immunoregulator, anti-pyretic, antioxidant, anti-inflammatory and ER stress modulator during viral infections. It enhances protective mechanisms for respiratory tract disorders. Andrographolide, isolated from Andrographis paniculata, has versatile biological activities including immunomodulation and determining SARS-CoV-2 binding site. Considering the properties of both compounds in terms of anti-inflammatory, antioxidant, anti-pyrogenic, anti-viral and ER stress modulation and computational approaches revealing andrographolide docks with the SARS-CoV2 binding site, we predict that this combination therapy may have potential utility against COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Diterpenos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Melatonina/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Fator 6 Ativador da Transcrição/metabolismo , Antivirais/farmacologia , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Humanos , Terapia de Alvo Molecular , Pandemias , Proteínas Serina-Treonina Quinases/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/metabolismo
8.
Life Sci ; 255: 117842, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454157

RESUMO

The outbreak of COVID-19 caused by 2019-nCov/SARS-CoV-2 has become a pandemic with an urgent need for understanding the mechanisms and identifying a treatment. Viral infections including SARS-CoV are associated with increased levels of reactive oxygen species, disturbances of Ca++ caused by unfolded protein response (UPR) mediated by endoplasmic reticulum (ER) stress and is due to the exploitation of virus's own protein i.e., viroporins into the host cells. Several clinical trials are on-going including testing Remdesivir (anti-viral), Chloroquine and Hydroxychloroquine derivatives (anti-malarial drugs) etc. Unfortunately, each drug has specific limitations. Herein, we review the viral protein involvement to activate ER stress transducers (IRE-1, PERK, ATF-6) and their downstream signals; and evaluate combination therapies for COVID-19 mediated ER stress alterations. Melatonin is an immunoregulator, anti-pyretic, antioxidant, anti-inflammatory and ER stress modulator during viral infections. It enhances protective mechanisms for respiratory tract disorders. Andrographolide, isolated from Andrographis paniculata, has versatile biological activities including immunomodulation and determining SARS-CoV-2 binding site. Considering the properties of both compounds in terms of anti-inflammatory, antioxidant, anti-pyrogenic, anti-viral and ER stress modulation and computational approaches revealing andrographolide docks with the SARS-CoV2 binding site, we predict that this combination therapy may have potential utility against COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Diterpenos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Melatonina/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Fator 6 Ativador da Transcrição/metabolismo , Antivirais/farmacologia , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Humanos , Terapia de Alvo Molecular , Pandemias , Proteínas Serina-Treonina Quinases/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/metabolismo
9.
PLoS One ; 15(5): e0232146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413042

RESUMO

Actinic keratosis is a common skin disease that may progress to invasive squamous cell carcinoma if left untreated. Ingenol mebutate has demonstrated efficacy in field treatment of actinic keratosis. However, molecular mechanisms on ingenol mebutate response are not yet fully understood. In this study, we evaluated the gene expression profiles of actinic keratosis lesions before and after treatment with ingenol mebutate using microarray technology. Actinic keratoses on face/scalp of 15 immunocompetent patients were identified and evaluated after treatment with topical ingenol mebutate gel 0.015%, applied once daily for 3 consecutive days. Diagnostic and clearance of lesions was determined by clinical, dermoscopic, and reflectance confocal microscopy criteria. Lesional and non-lesional skin biopsies were subjected to gene expression analysis profiled by Affymetrix microarray. Differentially expressed genes were identified, and enrichment analyses were performed using STRING database. At 8 weeks post-treatment, 60% of patients responded to ingenol mebutate therapy, achieving complete clearance in 40% of cases. A total of 128 differentially expressed genes were identified following treatment, and downregulated genes (114 of 128) revealed changes in pathways important to epidermal development, keratinocyte differentiation and cornification. In responder patients, 388 downregulated genes (of 450 differentially expressed genes) were also involved in development/differentiation of the epidermis, and immune system-related pathways, such as cytokine and interleukin signaling. Cluster analysis revealed two relevant clusters showing upregulated profile patterns in pre-treatment actinic keratoses of responders, as compared to non-responders. Again, differentially expressed genes were mainly associated with cornification, keratinization and keratinocyte differentiation. Overall, the present study provides insight into the gene expression profile of actinic keratoses after treatment with ingenol mebutate, as well as identification of genetic signatures that could predict treatment response.


Assuntos
Diterpenos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ceratose Actínica/genética , Idoso , Idoso de 80 Anos ou mais , Diterpenos/uso terapêutico , Géis , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
10.
BMC Neurol ; 20(1): 173, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380977

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS. METHODS: A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change. RESULTS: Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was - 0.679% for the AP group and - 1.069% for the placebo group (mean difference: -0.39; 95% CI [- 0.836-0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200-1.777], p = 0.06). The mean EDSS change was - 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia. CONCLUSIONS: AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Diterpenos/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Idoso , Andrographis , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/diagnóstico por imagem , Progressão da Doença , Diterpenos/farmacologia , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla , Fitoterapia , Projetos Piloto , Estudos Prospectivos
11.
Mar Drugs ; 18(4)2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32331404

RESUMO

Further chemical investigation of the EtOAc extract of the soft coral Lobophytum varium resulted in the discovery of eleven new diterpenoids lobovarols F-P (1-11) of lobane- and prenyleudesmane-types, along with two known metabolites (12 and 13). The structures of the new metabolites were established by spectroscopic analyses, including 2D NMR experiments. The absolute configuration of 1 was determined using Mosher's method. The complete assignment of 1H and 13C NMR spectroscopic data of 12 and 13 and the identification of pyran-derived moieties in the prenyleudesmanes were reported for the first time. Anti-inflammatory activities of the isolated compounds in suppressing elastase release and superoxide anion generation in human neutrophils were disclosed for 1, 2, 4, 12, and 13. A stereospecific biosynthesis for lobanes and prenyleudesmanes from the related prenylgermacranes could explain the coexistence of lobanes and prenylgermacranes in L. varium.


Assuntos
Antozoários/química , Anti-Inflamatórios/isolamento & purificação , Diterpenos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Humanos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Elastase Pancreática/metabolismo , Estereoisomerismo , Superóxidos/metabolismo
12.
Life Sci ; 252: 117612, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32247004

RESUMO

AIMS: Intestinal mucositis is the most common side effect of 5-fluorouracil (5-Fu) treatment in cancer patients. Previous research suggested that andrographolide (Andro) attenuated the intestinal injury in colitis or diarrhea in mice. The present study was aimed at investigating the protective effect of Andro against 5-Fu induced intestinal mucositis and the underlying mechanism. MAIN METHODS: BALB/C mice were injected 5-Fu at a dose of 100 mg/kg for 5 days to induce intestinal mucositis. Andro at different doses (25, 50, 100 mg/kg/day) was administered. Weight loss, diarrhea score, cellular apoptosis and proliferation were evaluated. Apoptosis related proteins were detected by Western blotting. Then, NCM460 cells were used to explore the possible mechanism in vitro. The effect of Andro on the anti-tumor efficacy of 5-Fu was investigated in H22 tumor-bearing mice. KEY FINDINGS: Andro significantly ameliorated the 5-Fu induced weight loss and diarrhea. The apoptosis of intestinal cells was also attenuated by Andro treatment both in vivo and in vitro. Besides, Andro markedly down-regulated the 5-Fu-induced protein expression of caspase8/3, Bax and the phosphorylation of p38. Moreover, 5-Fu significantly reduced the viability of NCM460 cells, which was restored by the Andro pretreatment. Furthermore, asiatic acid, an agonist of p38 MAPK, reversed the anti-apoptotic effect of Andro in NCM460 cells. Andro did not weaken the anti-H22 tumor effect of 5-Fu in vivo. SIGNIFICANCE: We have demonstrated that p38 MAPK inhibition mediates anti-apoptotic effects of Andro against 5-Fu induced intestinal mucositis, suggesting that Andro may benefit the patients undergoing 5-Fu based chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Diterpenos/administração & dosagem , Fluoruracila/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosite/prevenção & controle , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Modelos Animais de Doenças , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Mucosa Intestinal/patologia , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mucosite/induzido quimicamente , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Environ Toxicol ; 35(8): 888-894, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32267089

RESUMO

Respiratory syncytial virus (RSV), a member of Paramyxoviridae family is responsible for bronchiolitis and pneumonia. The present study investigated anti-viral and anti-inflammatory activities of jatrophone against RSV-infection in pulmonary epithelial cells in vitro and in mice model in vivo. The changes in viabilities of RSV infected cells by jatrophone treatment were determined by MTT assay. The fluorescence associated with production of ROS was evaluated by fluorescence microscopy using H2DCFDA dye. The IFN-γ secreting cells were detected in mice BALF by stimulation with phorbol myristate acetate and ionomycin. The reduction of BEAS-2B cell viability by RSV was alleviated on treatment with jatrophone in dose based manner. The cytopathogenic changes by RSV infection were prevented and viral growth inhibited by jatrophone in BEAS-2B cells. Jatrophone treatment significantly alleviated RSV mediated overproduction of IL-6/-8 and suppressed ROS generation in the cells. The pulmonary viral titers were found to be markedly lower in mice treated with jatrophone relative to untreated group. The jatrophone treated mice also showed reduced IL-4/-5/-13 levels and elevated IFN-γ level in BALF relative to untreated RSV infected mice. Flow cytometry revealed elevated count of IFN-γ generating cells in RSV infected mice on treatment with jatrophone. Thus jatrophone inhibits viral growth and oxidative damage by RSV in pulmonary epithelial cells. In RSV infected mice jatrophone increased immunity for viral infection by modulating cell phenotype for promotion of anti-viral IFN-γ. Thus jatrophone acts as potential anti-viral compound and may be developed for treatment of respiratory treat infection.


Assuntos
Antivirais/farmacologia , Diterpenos/farmacologia , Interferon gama/metabolismo , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Células Dendríticas/patologia , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/patologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Carga Viral
14.
Proc Natl Acad Sci U S A ; 117(18): 9964-9972, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312817

RESUMO

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.


Assuntos
Diterpenos/farmacologia , Glioma/tratamento farmacológico , Isocitrato Desidrogenase/genética , Fator 2 Relacionado a NF-E2/genética , Fenantrenos/farmacologia , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Vias Biossintéticas/efeitos dos fármacos , Linhagem Celular Tumoral , Compostos de Epóxi/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Glutamato-Cisteína Ligase/genética , Glutationa/metabolismo , Humanos , Camundongos , Mutação/genética , Espécies Reativas de Oxigênio/metabolismo , Mutações Sintéticas Letais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Commun ; 11(1): 1830, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286350

RESUMO

A synthetic biology method based on heterologous biosynthesis coupled with genome mining is a promising approach for increasing the opportunities to rationally access natural product with novel structures and biological activities through total biosynthesis and combinatorial biosynthesis. Here, we demonstrate the advantage of the synthetic biology method to explore biological activity-related chemical space through the comprehensive heterologous biosynthesis of fungal decalin-containing diterpenoid pyrones (DDPs). Genome mining reveals putative DDP biosynthetic gene clusters distributed in five fungal genera. In addition, we design extended DDP pathways by combinatorial biosynthesis. In total, ten DDP pathways, including five native pathways, four extended pathways and one shunt pathway, are heterologously reconstituted in a genetically tractable heterologous host, Aspergillus oryzae, resulting in the production of 22 DDPs, including 15 new analogues. We also demonstrate the advantage of expanding the diversity of DDPs to probe various bioactive molecules through a wide range of biological evaluations.


Assuntos
Diterpenos/farmacologia , Fungos/química , Naftalenos/farmacologia , Pironas/farmacologia , Biologia Sintética , Peptídeos beta-Amiloides/metabolismo , Animais , Fármacos Anti-HIV/farmacologia , Aspergillus/química , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Drosophila/efeitos dos fármacos , Fungos/genética , Genoma Fúngico , HIV-1/efeitos dos fármacos , Humanos , Células MCF-7 , Naftalenos/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Agregados Proteicos , Pironas/química , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Estereoisomerismo
16.
Am J Pathol ; 190(7): 1505-1512, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275905

RESUMO

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among the working-age population. Diabetic patients often experience functional deficits in dark adaptation, contrast sensitivity, and color perception before any microvascular pathologies on the fundus become detectable. Previous studies showed that the regeneration of 11-cis-retinal and visual pigment is impaired in a type 1 diabetes animal model, which negatively affects visual function at the early stage of DR. Here, Akita mice, type 1 diabetic model, were treated with the visual pigment chromophore, 9-cis-retinal. This treatment rescued a- and b-wave amplitudes of scotopic electroretinography responses, compared with vehicle-treated Akita mice. In addition, the administration of 9-cis-retinal alleviated oxidative stress significantly as shown by reduced 3-nitrotyrosine levels in the retina of Akita mice. Furthermore, the 9-cis-retinal treatment decreased retinal apoptosis as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and DNA fragment enzyme-linked immunosorbent assay. Overall, these findings showed that 9-cis-retinal administration restored visual pigment formation and decreased oxidative stress and retinal degeneration, which resulted in improved visual function in diabetic mice, suggesting that chromophore deficiency plays a causative role in visual defects in early DR.


Assuntos
Retinopatia Diabética/fisiopatologia , Diterpenos/farmacologia , Retina/efeitos dos fármacos , Retinaldeído/farmacologia , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Estresse Oxidativo/efeitos dos fármacos , Retina/fisiopatologia
17.
Bol. latinoam. Caribe plantas med. aromát ; 19(2): 236-246, mar. 2020. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-1104216

RESUMO

Chloroform extract (CE) and fractions obtained from Aldama arenaria roots were evaluated for their in vitro antiproliferative activity against 10 human tumor cell lines [leukemia (K-562), breast (MCF-7), ovary expressing a multidrug-resistant phenotype (NCI/ADR-RES), melanoma (UACC-62), lung (NCI-H460), prostate (PC-3), colon (HT29), ovary (OVCAR-3), glioma (U251), and kidney (786-0)]. CE presented weak to moderate antiproliferative activity (mean log GI50 1.07), whereas fractions 3 and 4, enriched with pimaranetype diterpenes [ent-pimara-8(14),15-dien-19-oic acid and ent-8(14),15-pimaradien-3ß-ol], presented moderate to potent activity for most cell lines, with mean log GI50 of 0.62 and 0.59, respectively. The results showed promising in vitro antiproliferative action of the samples obtained from A. arenaria, with the best results for NCI/ADR-RES, HT29, and OVCAR-3, and TGI values ranging from 5.95 to 28.71 µg.ml -1, demonstrating that compounds of this class may be potential prototypes for the discovery of new therapeutic agents.


El extracto de cloroformo (CE) y las fracciones obtenidas de las raíces de Aldama arenaria fueron evaluadas por su actividad antiproliferativa in vitro contra 10 líneas celulares tumorales humanas [leucemia (K-562), mama (MCF-7), ovario que expresa un fenotipo resistente a múltiples fármacos (NCI/ADR-RES), melanoma (UACC-62), pulmón (NCI-H460), próstata (PC-3), colon (HT29), ovario (OVCAR-3), glioma (U251) y riñón (786-0)]. CE presentó actividad antiproliferativa débil a moderada (log GI50 promedio de 1.07), mientras que las fracciones 3 y 4, enriquecidas con diterpenos de tipo pimarane [ent-pimara-8 (14), ácido 15-dien-19-oico y ent-8 (14), 15-pimaradien-3ß-ol], presentaron actividad moderada a potente para la mayoría de las líneas celulares, con un log GI50 promedio de 0.62 y 0.59, respectivamente. Los resultados mostraron una prometedora acción antiproliferativa in vitro de las muestras obtenidas de A. arenaria, con los mejores resultados para NCI/ADR-RES, HT29 y OVCAR-3, y valores de TGI que van desde 5.95 a 28.71 µg.ml -1, lo que demuestra que los compuestos de esta clase pueden ser prototipos potenciales para el descubrimiento de nuevos agentes terapéuticos.


Assuntos
Extratos Vegetais/farmacologia , Clorofórmio , Plectranthus/química , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas In Vitro , Extratos Vegetais/química , Etnobotânica , Cuba , Diterpenos/farmacologia , Diterpenos/química
18.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 51(2): 207-212, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32220189

RESUMO

Objective: To observe the changes of cardiac function in arthritic rats and the effect of triptolide on it. Methods: Forty rats were divided in random into normal control (NC) group, model control (MC) group, leflunomide (LEF) group and triptolide (TP) group. Except for the normal group, rats in the other three groups were injected with Freund's complete adjuvant to create arthritic inflammation in the right hind paws, and the interventional drug was administered on the 12th day after the inflammation. By treating for 30 d, the cardiac function of rats was detected by left ventricular catheterization. The expressions of superoxide dismutase (SOD), malondialdehyde (MDA), reacitve oxygen species (ROS), total antioxidation (T-AOC), interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) in serum were measured by enzyme-linked immunosorbent assay. The expressions of keap-like protein 1 ( Keap1), muscular aponeurotic fibrosarcom ( maf) and nuclear factor-E2 related factor2 ( Nrf2) mRNAs in cardiac tissue were detected by real-time PCR. The expressions of Keap1, maf and Nrf2 proteins in heart tissues were detected by Western blot. Results: Comparing with the normal group, the heart rate (HR), heart index (HI), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) of the model group were significantly increased, whereas the maximum change rate of ventricular pressure rise or decline (±dp/dtmax) was significantly decreased ( P<0.01). SOD, MDA, ROS, T-AOC, and TNF-α were all increased, and IL-10 was significantly decreased ( P<0.01). The mRNA and protein expressions of Keap1, maf and Nrf2 in heart tissues were increased ( P<0.01). Comparing with the model group, HR, HI, LVSP, and LVEDP in the triptolide group were significantly decreased, whereas the ±dp/dtmax was significantly increased ( P<0.01). SOD, MDA, T-AOC, ROS, TNF-α decreased while the IL-10 increased ( P<0.05, P<0.01). The expressions of Keap1, maf and Nrf2 mRNAs and proteins in the heart tissues of the triptolide group were decreased ( P<0.01). Conclusion: Triptolide could improve cardiac function in arthritic rats, and the mechanism may related to its ability of improving the anti-oxidationin cardiomyocytes, reducing oxidative stress damage, and inhibiting abnormal immune inflammatory response.


Assuntos
Artrite/complicações , Diterpenos/farmacologia , Cardiopatias/tratamento farmacológico , Coração/efeitos dos fármacos , Imunossupressores/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Fenantrenos/farmacologia , Animais , Compostos de Epóxi/farmacologia , Cardiopatias/complicações , Proteína 1 Associada a ECH Semelhante a Kelch , Miócitos Cardíacos/fisiologia , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Ratos
19.
Environ Toxicol ; 35(6): 707-713, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32023008

RESUMO

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD-induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac-damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro-apoptotic proteins and decrease in the proteins of IGF-1R-survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Dieta Hiperlipídica/efeitos adversos , Diterpenos/farmacologia , Coração/efeitos dos fármacos , Obesidade/patologia , Andrographis/química , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Fármacos Cardiovasculares/isolamento & purificação , Diterpenos/isolamento & purificação , Masculino , Camundongos , Camundongos Obesos , Miocárdio/metabolismo , Miocárdio/patologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Transdução de Sinais
20.
Chem Biol Interact ; 319: 108984, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061742

RESUMO

OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.


Assuntos
Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Diterpenos/farmacologia , Adjuvante de Freund/farmacologia , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Catalase/metabolismo , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Glutationa/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Masculino , Metotrexato/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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