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1.
Proc Natl Acad Sci U S A ; 119(20): e2202255119, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35544688

RESUMO

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid­functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Neoplasias , Platina , Estilbenos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Ácido Fólico/química , Humanos , Camundongos , Nanopartículas , Neoplasias/tratamento farmacológico , Platina/química , Polímeros/uso terapêutico , Estilbenos/administração & dosagem , Estilbenos/farmacologia , Microambiente Tumoral
2.
Pharm Biol ; 60(1): 394-403, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35271397

RESUMO

CONTEXT: Pterostilbene (PTE), a common polyphenol compound, exerts an anti-inflammatory effect in many diseases, including acute lung injury (ALI). OBJECTIVE: This study explores the potential mechanism of PTE pre-treatment against lipopolysaccharide (LPS)-induced ALI. MATERIALS AND METHODS: Sixty Sprague-Dawley rats were divided into control, ALI, 10 mg/kg PTE + LPS, 20 mg/kg PTE + LPS, and 40 mg/kg PTE + LPS groups. At 24 h before LPS instillation, PTE was administered orally. At 2 h before LPS instillation, PTE was again administered orally. After 24 h of LPS treatment, the rats were euthanized. The levels of inflammatory cells and inflammatory factors in the bronchoalveolar lavage fluid (BALF), the expression of nuclear receptor subfamily 4 group A member 1 (NR4A1), and the nuclear factor (NF)-κB pathway-related protein levels were detected. NR4A1 agonist was used to further investigate the mechanism of PTE pre-treatment. RESULTS: After PTE pre-treatment, the LPS induced inflammation was controlled and the survival rate was increased to 100% from 70% after LPS treatment 24 h. For lung injury score, it decreased to 1.5 from 3.5 after treating 40 mg/kg PTE. Compared with the control group, the expression of NR4A1 in the ALI group was decreased by 20-40%. However, the 40 mg/kg PTE pre-treatment increased the NR4A1 expression by 20-40% in the lung tissue. The results obtained with pre-treatment NR4A1 agonist were similar to those obtained by pre-treatment 40 mg/kg PTE. CONCLUSIONS: PTE pre-treatment might represent an appropriate therapeutic target and strategy for preventing ALI induced by LPS.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Estilbenos/farmacologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos , Masculino , Ratos , Ratos Sprague-Dawley , Estilbenos/administração & dosagem
3.
Sci Rep ; 12(1): 704, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027628

RESUMO

In this study, we examined the antileukemic effects of pterostilbene, a natural methylated polyphenol analog of resveratrol that is predominantly found in berries and nuts, using various human and murine leukemic cells, as well as bone marrow samples obtained from patients with leukemia. Pterostilbene administration significantly induced apoptosis of leukemic cells, but not of non-malignant hematopoietic stem/progenitor cells. Interestingly, pterostilbene was highly effective in inducing apoptosis of leukemic cells harboring the BCR/ABL fusion gene, including ABL tyrosine kinase inhibitor (TKI)-resistant cells with the T315I mutation. In BCR/ABL+ leukemic cells, pterostilbene decreased the BCR/ABL fusion protein levels and suppressed AKT and NF-κB activation. We further demonstrated that pterostilbene along with U0126, an inhibitor of the MEK/ERK signaling pathway, synergistically induced apoptosis of BCR/ABL+ cells. Our results further suggest that pterostilbene-promoted downregulation of BCR/ABL involves caspase activation triggered by proteasome inhibition-induced endoplasmic reticulum stress. Moreover, oral administration of pterostilbene significantly suppressed tumor growth in mice transplanted with BCR/ABL+ leukemic cells. Taken together, these results suggest that pterostilbene may hold potential for the treatment of BCR/ABL+ leukemia, in particular for those showing ABL-dependent TKI resistance.


Assuntos
Apoptose/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia/tratamento farmacológico , Leucemia/genética , Mutação/genética , Estilbenos/farmacologia , Administração Oral , Animais , Caspases/metabolismo , Estresse do Retículo Endoplasmático , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia/patologia , Camundongos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estilbenos/administração & dosagem , Células Tumorais Cultivadas
5.
N Engl J Med ; 385(24): 2219-2229, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34879448

RESUMO

BACKGROUND: Tapinarof cream is a topical aryl hydrocarbon receptor-modulating agent under investigation for the treatment of psoriasis. Tapinarof modulates the expression of interleukin-17 and the skin-barrier proteins filaggrin and loricrin. METHODS: We conducted two identical phase 3 randomized trials of tapinarof in patients with mild-to-severe plaque psoriasis. Adults with a baseline Physician's Global Assessment (PGA) score of 2 (mild) to 4 (severe) (on a scale from 0 to 4, with higher scores indicating more severe psoriasis) and a percent of total body-surface area affected of 3 to 20% were randomly assigned in a 2:1 ratio to use tapinarof 1% cream or vehicle cream once daily for 12 weeks. The primary end point, PGA response, was a PGA score of 0 (clear) or 1 (almost clear) and a decrease from baseline of at least 2 points at week 12. Secondary efficacy end points at week 12 were a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) score, a PGA score of 0 or 1, the mean change from baseline in the percent of body-surface area affected, and a reduction of at least 90% in the PASI score. Patient-reported outcomes were the mean changes from baseline to week 12 in the proportion of patients who had a decrease of at least 4 points in the Peak Pruritus Numeric Rating Scale (PP-NRS) score (range, 0 [no itch] to 10 [worst imaginable itch]), the PP-NRS total score, the Dermatology Life Quality Index total score, and the Psoriasis Symptom Diary score. RESULTS: In trials 1 and 2, a total of 692 and 674 patients, respectively, were screened, with 510 and 515 patients being enrolled. A PGA response occurred in 35.4% of the patients in the tapinarof group and in 6.0% of those in the vehicle group in trial 1 and in 40.2% and 6.3%, respectively, in trial 2 (P<0.001 for both comparisons). Results for secondary end points and patient-reported outcomes were generally in the same direction as those for the primary end point. Adverse events with tapinarof cream included folliculitis, nasopharyngitis, contact dermatitis, headache, upper respiratory tract infection, and pruritus. CONCLUSIONS: Tapinarof 1% cream once daily was superior to vehicle control in reducing the severity of plaque psoriasis over a period of 12 weeks but was associated with local adverse events and headache. Larger and longer trials are needed to evaluate the efficacy and safety of tapinarof cream as compared with existing treatments for psoriasis. (Funded by Dermavant Sciences; PSOARING 1 and 2 ClinicalTrials.gov numbers, NCT03956355 and NCT03983980, respectively.).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Psoríase/tratamento farmacológico , Resorcinóis/administração & dosagem , Estilbenos/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Dermatite de Contato/etiologia , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Psoríase/complicações , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Resorcinóis/efeitos adversos , Índice de Gravidade de Doença , Creme para a Pele/administração & dosagem , Estilbenos/efeitos adversos
6.
Nutrients ; 13(12)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34959765

RESUMO

Trans-ε-viniferin (εVin) is a resveratrol dimer exhibiting promising biological activities for human health. Its bioavailability being low, the development of encapsulation methods would be used to overcome this issue. The aim of this study was to measure the consequences of the encapsulation of εVin in multilamellar liposomes on its pharmacokinetic parameters, metabolism and tissue distribution in rats. After oral administration of εVin (20 mg/kg body weight), either as free or encapsulated forms, plasmas were sequentially collected (from 0 to 4 h) as well as liver, kidneys and adipose tissues (4 h after administration) and analyzed by LC-HRMS. The glucuronide metabolites (εVG) were also produced by hemisynthesis for their quantification in plasma and tissues. The encapsulation process did not significantly modify the pharmacokinetic parameters of εVin itself. However, a significant increase of the T1/2 was noticed for εVG after administration of the encapsulated form as compared to the free form. An accumulation of εVin and εVG in adipose tissues was noticed, and interestingly a significant increase of the latter in the mesenteric one after administration of the encapsulated form was highlighted. Since adipose tissues could represent storage depots, and encapsulation allows for prolonging the exposure time of glucuronide metabolites in the organism, this could be of interest to promote their potential biological activities.


Assuntos
Benzofuranos/administração & dosagem , Glucuronídeos/biossíntese , Estilbenos/administração & dosagem , Distribuição Tecidual/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Disponibilidade Biológica , Cápsulas , Rim/efeitos dos fármacos , Lipossomos , Fígado/efeitos dos fármacos , Ratos
7.
J Agric Food Chem ; 69(46): 13821-13830, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34752070

RESUMO

Studies have revealed that a novel anti-inflammatory mediator─maresin-1 (MaR1)─can reduce the level of inflammatory factors. There is evidence that physical exercise (PE) promotes the biosynthesis of MaR1, leading to the prevention of rheumatoid arthritis (RA). Previously, we have proven that resveratrol can mitigate the formation of RA. Pterostilbene (Pte) is an analogue of resveratrol, but it is around four times more bioavailable. Hence, we hypothesize that Pte could be more effective in preventing RA, in particular, when accompanied by moderate PE. Based on this hypothesis, we explored the preventive effect of Pte combined with PE on a bovine type II collagen (BIIC)-stimulated rat RA model and its underlying molecular mechanism. Compared with the BIIC-stimulated group, the serum content of MaR1 with continuous intervention of Pte plus PE for 8 weeks was significantly increased to 46.3 pg/mL from 7.2 pg/mL in BIIC-treated alone. Besides, the variation in the relative expression levels of p-NF-κB and p-Akt was reversed with the administration of Pte plus PE. More importantly, the in vitro results confirmed that the treatment of Pte plus MaR1 inhibited proliferation and apoptosis and promoted the autophagy of the interleukin (IL)-1ß-stimulated primary rat synovial cells through the PI3K/Akt/NF-κB signal pathway. Collectively, the oral administration of Pte plus moderate PE helped to ameliorate the pathological process of RA by correcting the PI3K/Akt/NF-κB signal pathway.


Assuntos
Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , NF-kappa B , Proteínas Proto-Oncogênicas c-akt , Estilbenos/administração & dosagem , Animais , Bovinos , Colágeno , NF-kappa B/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Condicionamento Físico Animal , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais
8.
Molecules ; 26(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34641529

RESUMO

Neurodegenerative diseases (NDDs) are one of the leading causes of death and disability in humans. From a mechanistic perspective, the complexity of pathophysiological mechanisms contributes to NDDs. Therefore, there is an urgency to provide novel multi-target agents towards the simultaneous modulation of dysregulated pathways against NDDs. Besides, their lack of effectiveness and associated side effects have contributed to the lack of conventional therapies as suitable therapeutic agents. Prevailing reports have introduced plant secondary metabolites as promising multi-target agents in combating NDDs. Polydatin is a natural phenolic compound, employing potential mechanisms in fighting NDDs. It is considered an auspicious phytochemical in modulating neuroinflammatory/apoptotic/autophagy/oxidative stress signaling mediators such as nuclear factor-κB (NF-κB), NF-E2-related factor 2 (Nrf2)/antioxidant response elements (ARE), matrix metalloproteinase (MMPs), interleukins (ILs), phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt), and the extracellular regulated kinase (ERK)/mitogen-activated protein kinase (MAPK). Accordingly, polydatin potentially counteracts Alzheimer's disease, cognition/memory dysfunction, Parkinson's disease, brain/spinal cord injuries, ischemic stroke, and miscellaneous neuronal dysfunctionalities. The present study provides all of the neuroprotective mechanisms of polydatin in various NDDs. Additionally, the novel delivery systems of polydatin are provided regarding increasing its safety, solubility, bioavailability, and efficacy, as well as developing a long-lasting therapeutic concentration of polydatin in the central nervous system, possessing fewer side effects.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glucosídeos/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estilbenos/farmacologia , Animais , Transtornos Cognitivos/tratamento farmacológico , Glucosídeos/administração & dosagem , Glucosídeos/química , Glucosídeos/uso terapêutico , Humanos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Estilbenos/administração & dosagem , Estilbenos/química , Estilbenos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico
9.
Nutrients ; 13(9)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34579124

RESUMO

This efficacy trial evaluated the effects of two polyphenolic stilbenes, resveratrol and pterostilbene, mostly found in grapes, on the brush border membrane functionality, morphology and gut microbiome. This study applied the validated Gallus gallus intra-amniotic approach to investigate the effects of stilbene administration versus the controls. Three treatment groups (5% resveratrol; 5% pterostilbene; and synergistic: 4.75% resveratrol and 0.25% pterostilbene) and three controls (18 MΩ H2O; no injection; 5% inulin) were employed. We observed beneficial morphological changes, specifically an increase in the villus length, diameter, depth of crypts and goblet cell diameter in the pterostilbene and synergistic groups, with concomitant increases in the serum iron and zinc concentrations. Further, the alterations in gene expression of the mineral metabolism proteins and pro-inflammatory cytokines indicate a potential improvement in gut health and mineral bioavailability. The cecal microbiota was analyzed using 16S rRNA sequencing. A lower α-diversity was observed in the synergistic group compared with the other treatment groups. However, beneficial compositional and functional alterations in the gut microbiome were detected. Several key microbial metabolic pathways were differentially enriched in the pterostilbene treatment group. These observations demonstrate a significant bacterial-host interaction that contributed to enhancements in intestinal functionality, morphology and physiological status. Our data demonstrate a novel understanding of the nutritional benefits of dietary stilbenes and their effects on intestinal functionality, morphology and gut microbiota in vivo.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/embriologia , Resveratrol/administração & dosagem , Estilbenos/administração & dosagem , Vitis/química , Âmnio/efeitos dos fármacos , Animais , Embrião de Galinha/efeitos dos fármacos , Galinhas , Citocinas/genética , Sinergismo Farmacológico , Frutas/química , Expressão Gênica/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/fisiologia , Microvilosidades/fisiologia , Minerais/metabolismo
10.
Biochem Pharmacol ; 192: 114717, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352281

RESUMO

Metastasis, the main cause of breast cancer-associated fatalities, relies on many regular pathways involved in normal cell physiology and metabolism, thus, making it challenging to identify disease-specific therapeutic target(s). Chemically synthesized anti-metastatic agents are preferred for their fast and robust actions. However, these agents have adverse side effects, thus, increasingly favouring the identification of phytocompounds as suitable alternatives. Resveratrol and pterostilbene have long been established as potent anti-cancer agents. Earlier studies from our laboratory documented the anti-cancer activities associated with pterostilbene-isothiocyanate (PTER-ITC), a derivative of pterostilbene. The current study focuses on evaluating the anti-metastatic property of PTER-ITC and the underlying mechanism, by employing in silico, in vitro, and in vivo approaches. The significant anti-metastatic activity of PTER-ITC was observed in vitro against breast cancer metastatic cell line (MDA-MB-231) and in vivo in the 4T1 cell-induced metastatic mice model. Epithelial-mesenchymal transition (EMT), a hallmark of metastasis regulated by the transcription factors, Snail1 and Twist, was found to be reverted in vitro by PTER-ITC treatment. PTER-ITC blocked the activation of NF-κB/p65 and its concomitant nuclear translocation, resulting in the transcriptional repression of its target genes, Snail1 and Twist. PTER-ITC prevented the formation of IKK complex, central to NF-κB activation, by binding to the NEMO-binding domain (NBD) of IKK-ß and inhibiting its interaction with NEMO (NF-κB essential modulator). According to our observations, PTER-ITC attenuated NF-κB activation selectively in cancerous cells. In conclusion, this study demonstrated that PTER-ITC is a potent anti-metastatic agent capable of targeting physiologically important pathways in a cancer-specific manner.


Assuntos
Neoplasias da Mama/metabolismo , Quinase I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isotiocianatos/administração & dosagem , Estilbenos/administração & dosagem , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Feminino , Humanos , Quinase I-kappa B/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia
11.
J Biochem Mol Toxicol ; 35(10): e22869, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34339076

RESUMO

Breast cancer is a leading cause of death. Anticancer treatment such as gold nanoparticles (AuNP) seems highly promising in this regard. Therefore, this study aimed to assess the beneficial effect of doxorubicin (Dox) and polydatin (PD) AuNP in Ehrlich ascites carcinoma (EAC) and the ability of PD-AuNP to protect the heart from Dox's deteriorating effects. EAC was induced in mice. The mice were divided into nine groups: normal, EAC, PD: received PD (20 mg/kg), Dox: received Dox (2 mg/kg), PD-AuNPH: received 10 ppm AuNP of PD, PD-AuNPL: received 5 ppm AuNP of PD, Dox-AuNP: received Dox-AuNP, PD-Dox-AuNP: received PD-Dox-AuNP, AuNP: received AuNP. On the 21st day from tumor inoculation, the mice were sacrificed and tumor and heart tissues were removed. Tumor ß-catenin/Cyclin D1 and p53 were assessed by immunohistochemistry. IL-6 was determined by enzyme-linked immunosorbent assay. PD-AuNP and Dox-AuNP showed a significant reduction in tumor volume and weight more than their free forms. Also, PD-AuNP and Dox-AuNP showed markedly less dense tumor cells. ß-catenin and Cyclin D1 were markedly decreased and p53 was highly upregulated by PD-AuNP and Dox-AuNP. Moreover, PD-AuNP and Dox-AuNP have the ability to decrease IL-6 production. PD-AuNP protected the heart from Dox-induced severe degeneration. Therefore, PD-AuNP could be a tool to decelerate the progression of breast cancer.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma de Ehrlich/tratamento farmacológico , Doxorrubicina/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Fallopia japonica/química , Glucosídeos/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Sistemas de Liberação de Fármacos por Nanopartículas/química , Compostos Fitoquímicos/administração & dosagem , Fitoterapia/métodos , Substâncias Protetoras/administração & dosagem , Estilbenos/administração & dosagem , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Coração/efeitos dos fármacos , Camundongos , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
12.
Int J Nanomedicine ; 16: 4001-4016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135585

RESUMO

BACKGROUND: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy. METHODS: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test. RESULTS: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery. CONCLUSION: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Lipossomos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Ligantes , Lipossomos/administração & dosagem , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Estilbenos/administração & dosagem , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Nanobiotechnology ; 19(1): 124, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933077

RESUMO

BACKGROUND: According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. RESULTS: In this study, the use of poly(L-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects-enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. CONCLUSIONS: We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/administração & dosagem , Estilbenos/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1 , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Polietilenoglicóis , Estilbenos/química , Microambiente Tumoral/efeitos dos fármacos
14.
Nat Commun ; 12(1): 3187, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045459

RESUMO

Failure of conventional clinical therapies such as tumor resection and chemotherapy are mainly due to the ineffective control of tumor metastasis. Metastasis consists of three steps: (i) tumor cells extravasate from the primary sites into the circulation system via epithelial-mesenchymal transition (EMT), (ii) the circulating tumor cells (CTCs) form "micro-thrombi" with platelets to evade the immune surveillance in circulation, and (iii) the CTCs colonize in the pre-metastatic niche. Here, we design a systemic metastasis-targeted nanotherapeutic (H@CaPP) composed of an anti-inflammatory agent, piceatannol, and an anti-thrombotic agent, low molecular weight heparin, to hinder the multiple steps of tumor metastasis. H@CaPP is found efficiently impeded EMT, inhibited the formation of "micro-thrombi", and prevented the development of pre-metastatic niche. When combined with surgical resection or chemotherapy, H@CaPP efficiently inhibits tumor metastasis and prolonged overall survival of tumor-bearing mice. Collectively, we provide a simple and effective systemic metastasis-targeted nanotherapeutic for combating tumor metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Portadores de Fármacos/química , Neoplasias Mamárias Experimentais/terapia , Metástase Neoplásica/terapia , Nanomedicina Teranóstica/métodos , Animais , Anti-Inflamatórios/administração & dosagem , Anticoagulantes/administração & dosagem , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante/métodos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Heparina de Baixo Peso Molecular/administração & dosagem , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Animais/cirurgia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Nanopartículas/química , Células Neoplásicas Circulantes/efeitos dos fármacos , Paclitaxel/administração & dosagem , Estudo de Prova de Conceito , Ratos , Estilbenos/administração & dosagem
15.
J Pharm Pharmacol ; 73(2): 263-271, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33793802

RESUMO

OBJECTIVES: Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination. METHODS: Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot. KEY FINDINGS: Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway. CONCLUSIONS: Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ginsenosídeos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Estilbenos/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Sinergismo Farmacológico , Ginsenosídeos/administração & dosagem , Células Hep G2 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Pharmazie ; 76(4): 155-158, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33849700

RESUMO

This study used human liver microsomes to assess pterostilbene's effect on the metabolic activity of cytochrome P450 (CYP) 1A2, CYP2C9, and CYP2D6. The metabolism of their substrates (phenacetin, tolbutamide, and dextromethorphan) was assayed by quantifying their relevant metabolites by HPLC. The IC50 value was used to express the strength of inhibition, and the value of a volume per dose index (VDI) was used to indicate the metabolic ability of the enzyme. In this study, pterostilbene inhibited CYP1A2, CYP2C9, and CYP2D6's metabolic activities in vitro. CYP2C9's activity was most significantly inhibited by pterostilbene; its IC50 value was 0.12±0.04 µM. The IC50 value of CYP1A2 and CYP2D6 was 56.3±10.4 µM and 62.33±11.4 µM, respectively. The finding that suggests that pterostilbene has the potential to interact with CYP2C9 substrates in vivo. These results warrant clinical studies to assess the in vivo significance of these interactions.


Assuntos
Inibidores do Citocromo P-450 CYP1A2/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Estilbenos/farmacologia , Citocromo P-450 CYP1A2/efeitos dos fármacos , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP1A2/administração & dosagem , Citocromo P-450 CYP2C9/efeitos dos fármacos , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estilbenos/administração & dosagem
17.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916909

RESUMO

Oxyresveratrol, a stilbene extracted from the plant Artocarpus lakoocha Roxb., has been reported to provide a considerable anti-inflammatory activity. Since the mechanisms of this therapeutic action have been poorly clarified, we investigated whether oxyresveratrol affects the release of the pro-inflammatory cytokines IL-12, IL-6, and TNF-α by human dendritic cells (DCs). We found that oxyresveratrol did not elicit per se the release of these cytokines, but inhibited their secretion induced upon DC stimulation with R848 (Resiquimod), a well-known immune cell activator engaging receptors recognizing RNA viruses. We then investigated whether the inclusion of oxyresveratrol into nanoparticles promoting its ingestion by DCs could favor its effects on cytokine release. For this purpose we synthesized and characterized poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and we assessed their effects on DCs. We found that bare PLGA nanoparticles did not affect cytokine secretion by resting DCs, but increased IL-12, IL-6, and TNF-α secretion by R848-stimulated DCs, an event known as "priming effect". We then loaded PLGA nanoparticles with oxyresveratrol and we observed that oxyresveratrol-bearing particles did not stimulate the cytokine release by resting DCs and inhibited the PLGA-dependent enhancement of IL-12, IL-6, and TNF-α secretion by R848-stimulated DCs. The results herein reported indicate that oxyresveratrol suppresses the cytokine production by activated DCs, thus representing a good anti-inflammatory and immune-suppressive agent. Moreover, its inclusion into PLGA nanoparticles mitigates the pro-inflammatory effects due to cooperation between nanoparticles and R848 in cytokine release. Therefore, oxyresveratrol can be able to contrast the synergistic effects of nanoparticles with microorganisms that could be present in the patient tissues, therefore overcoming a condition unfavorable to the use of some nanoparticles in biological systems.


Assuntos
Anti-Inflamatórios/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Imidazóis/efeitos adversos , Mediadores da Inflamação/metabolismo , Extratos Vegetais/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Estilbenos/administração & dosagem , Anti-Inflamatórios/química , Citocinas/metabolismo , Células Dendríticas/imunologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Humanos , Nanopartículas/química , Extratos Vegetais/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Estilbenos/química
18.
Food Funct ; 12(7): 3266-3279, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33877249

RESUMO

The use of phenolic compounds as a new therapeutic approach against NAFLD has emerged recently. In the present study, we aim to study the effect of pterostilbene in the prevention of liver steatosis developed as a consequence of high-fat (saturated) high-fructose feeding, by analysing the changes induced in metabolic pathways involved in triglyceride accumulation. Interestingly, a comparison with the anti-steatotic effect of its parent compound resveratrol will be made for the first time. Rats were distributed into 5 experimental groups and fed either a standard laboratory diet or a high-fat high-fructose diet supplemented with or without pterostilbene (15 or 30 mg per kg per d) or resveratrol (30 mg per kg per d) for 8 weeks. Serum triglyceride, cholesterol, NEFA and transaminase levels were quantified. Liver histological analysis was carried out by haematoxylin-eosin staining. Different pathways involved in liver triglyceride metabolism, including fatty acid synthesis, uptake and oxidation, triglyceride assembly and triglyceride release, were studied. Pterostilbene was shown to partially prevent high-fat high-fructose feeding induced liver steatosis in rats, demonstrating a dose-response pattern. In this dietary model, it acts mainly by reducing de novo lipogenesis and increasing triglyceride assembly and release. Improvement in mitochondrial functionality was also appreciated. At the same dose, the magnitude of pterostilbene and resveratrol induced effects, as well as the involved mechanisms of action, were similar.


Assuntos
Dieta Hiperlipídica , Fígado Gorduroso/metabolismo , Frutose/administração & dosagem , Resveratrol/administração & dosagem , Estilbenos/administração & dosagem , Triglicerídeos/metabolismo , Tecido Adiposo/patologia , Animais , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Fígado/química , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Wistar , Resveratrol/análise , Estilbenos/análise , Triglicerídeos/sangue
19.
Biomed Pharmacother ; 138: 111409, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33684694

RESUMO

Piceatannol (PCT), a natural polyphenolic stilbene, has pleiotropic pharmacological potentials. It possesses cytotoxic activities toward variant cancerous cells. Zein nanospheres (ZN NSs) have been introduced as ideal nanostructures due to their natural origin, safety, histocompatibility. and convenient method of formulation. The purpose of this study was to explore the impact of PCT-ZN NSs formula on pharmacotherapy potential of PCT against human breast cancer MCF-7 cells. PCT-ZN NSs were formulated and characterized selectively to particle size, zeta potential, encapsulation efficiency and diffusion of PCT. The selected formula has a particle size of 84.4 ± 2.3 nm, zeta potential value of 33.8 ± 1.2 mV and encapsulation efficiency of 89.5 ± 4.1%. PCT-ZN NSs displayed significantly lower IC50 against MCF-7 cells by about 24 folds. Further, PCT-ZN NSs formula showed higher cellular uptake as compared to free PCT. Examination of cell cycle phases displayed cells accumulation in G2-M phase and increased percentage cells in pre-G1 phase indicating an apoptosis-enhancing activity. Annexin V staining indicated augmented early and late apoptosis. PCT-ZN NSs pro-apoptotic activity was confirmed by the observed significant increased mRNA expression of CASP3, p53, and Bax as well as decreased expression of Bcl2. In addition, PCT-ZN NSs induced oxidative stress as evidenced by depletion of glutathione reductase (GR) activity, increased generation of reactive oxygen species (ROS) and accumulation of lipid peroxidation products. Conclusively, ZN nanostructures of PCT revealed superior cell death-inducing activities against MCF-7 cells in comparison with free PCT. This is mediated, at least partly, by enhanced cellular uptake, pro-apoptotic activity, and oxidative stress potential.


Assuntos
Antioxidantes/administração & dosagem , Neoplasias da Mama , Nanoestruturas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Estilbenos/administração & dosagem , Zeína/administração & dosagem , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Feminino , Humanos , Células MCF-7 , Nanoestruturas/uso terapêutico , Estresse Oxidativo/fisiologia , Estilbenos/uso terapêutico , Zeína/uso terapêutico
20.
Clin Transl Med ; 11(2): e339, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33634985

RESUMO

Inflammatory bowel disease (IBD) has emerged a global disease and the ascending incidence and prevalence is accompanied by elevated morbidity, mortality, and substantial healthcare system costs. However, the current typical one-size-fits-all therapeutic approach is suboptimal for a substantial proportion of patients due to the variability in the course of IBD and a considerable number of patients do not have positive response to the clinically approved drugs, so there is still a great, unmet demand for novel alternative therapeutic approaches. Spleen tyrosine kinase (Syk), a cytoplasmic nonreceptor protein tyrosine kinase, plays crucial roles in signal transduction and there are emerging data implicating that Syk participates in pathogenesis of several gut disorders, such as IBD. In this study, we observed the Syk expression in IBD patients and explored the effects of therapeutic Syk inhibition using small-molecule Syk inhibitor piceatannol in bone marrow-derived macrophages (BMDMs). In addition, due to the poor bioavailability and pharmacokinetics of small-molecule tyrosine kinase inhibitors and superiority of targeting nanoparticles-based drug delivery system, we herein prepared piceatannol-encapsulated poly(lactic-co-glycolic acid) nanoparticles that conjugated with chemokine C-C motif ligand 4 (P-NPs-C) and studied its therapeutic effects in vitro in BMDMs and in vivo in experimental colitis model. Our results indicated that in addition to alleviating colitis, oral administration of P-NPs-C promoted the restoration of intestinal barrier function and improved intestinal microflora dysbiosis, which represents a promising treatment for IBD.


Assuntos
Quimiocina CCL4/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Sistemas de Liberação de Fármacos por Nanopartículas/uso terapêutico , Estilbenos/uso terapêutico , Quinase Syk/antagonistas & inibidores , Animais , Células CACO-2 , Modelos Animais de Doenças , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estilbenos/administração & dosagem , Células THP-1
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