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1.
Int J Nanomedicine ; 15: 5239-5252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801689

RESUMO

Introduction: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. Methods: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. Results: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. Conclusion: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.


Assuntos
Compostos de Bifenilo/farmacologia , Reestenose Coronária/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Lignanas/farmacologia , Nanopartículas/química , Intervenção Coronária Percutânea/efeitos adversos , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/metabolismo , Modelos Animais de Doenças , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanopartículas/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Dióxido de Silício/química
2.
Chem Biol Interact ; 328: 109190, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652078

RESUMO

BACKGROUND: Doxorubicin (DOX) administration decreases cardiac soluble guanylate cyclase (sGC) activity. We hypothesized that bypassing impaired NO-sGC-cGMP pathway resulting from the activation of oxidized and heme-free soluble guanylate cyclase (sGC) could be a therapeutic target for DOX-mediated cardiomyopathy (DOX-CM). The present study investigated the therapeutic roles and mechanism of BAY60-2770, an activator of oxidized sGC, in alleviating DOX-CM. METHODS: H9c2 cardiomyocytes were pretreated with BAY60-2770 followed by DOX. Cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. To determine the role BAY60-2770 in mitochondrial ROS generation and mitochondrial membrane potential, we examined mitoSOX RED and TMRE fluorescence under DOX exposure. As animal experiments, rats were orally administered with 5 mg/kg of BAY60-2770 at 1 h prior to every DOX treatment and then assessed by echocardiography and apoptotic marker and autophagy. RESULTS: BAY60-2770 ameliorated cell viability and DOX-induced oxidative stress in H9c2 cells, which was mediated by PKG activation. Mitochondrial ROS and TMRE fluorescence were attenuated by BAY60-2770 in DOX-treated H9c2 cells. DOX-induced caspase-3 activation decreased after pretreatment with BAY60-2770 in vivo and in vitro. Echocardiography showed that BAY60-2770 significantly improved DOX-induced myocardial dysfunction. Autophagosome was increased by BAY60-2770 in vivo. CONCLUSIONS: BAY60-2770 appears to mitigate DOX-induced mitochondrial ROS, membrane potential loss, autophagy, and subsequent apoptosis, leading to protection of myocardial injury and dysfunction. These novel results highlighted the therapeutic potential of BAY60-2770 in preventing DOX-CM.


Assuntos
Autofagia/efeitos dos fármacos , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Cardiotoxicidade/patologia , Doxorrubicina/efeitos adversos , Hidrocarbonetos Fluorados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
3.
Life Sci ; 255: 117846, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32470451

RESUMO

AIMS: Compared to normal cells, tumor cells maintain higher concentrations of reactive oxygen species (ROS) to support proliferation, invasion, and metastasis. Chemotherapeutic drugs often induce tumor cell apoptosis by increasing intracellular ROS concentrations to highly toxic levels. ABT737, which inhibits the apoptosis regulator B cell lymphoma 2 (Bcl2), increases the sensitivity of ovarian cancer cells to chemotherapeutic drugs by regulating the glucose metabolism, but the underlying mechanisms remain unclear. Therefore, we aimed to determine whether ABT737 promoted H2O2-induced tumor cell apoptosis by reversing glycolysis in ovarian cancer cells. MAIN METHODS: SKOV3 ovarian cancer cells were treated with H2O2, ABT737, or both. Cell viability was compared using methyl thiazolyl tetrazolium (MTT), and flow cytometry was used to detect differences in apoptosis, ROS, and mitochondrial membrane potential. The relative expression levels of proteins associated with apoptosis and the glucose metabolism were measured using immunoblotting. Finally, glucose uptake and lactate secretion were measured using kits and compared. KEY FINDINGS: ABT737 downregulated proteins associated with glucose uptake (GLUT1) and glycolysis (LHDA, PKM2 and HK2) via the Sirt3-HIF1α axis, reducing glucose uptake and lactate secretion in SKOV3 cells. This reversed glycolysis in the tumor cells, and promoted H2O2-induced apoptosis. SIGNIFICANCE: The Bcl2 inhibitor ABT737 enhanced the anti-tumor effect of oxidative stress by reversing the Warburg effect in ovarian cancer cells, providing powerful theoretical support for further clinical applications of Bcl2 inhibitors.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Piperazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo
4.
Toxicol Appl Pharmacol ; 398: 115028, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360636

RESUMO

NADPH oxidase (NOX) has been identified as a crucial contender of oxidative damage in Alzheimer's disease (AD). However, the capability of diapocynin, a NOX inhibitor, to offer neuroprotection in AD models is still a matter of debate. Hence, the current work is dedicated to investigate the influence of diapocynin on cognitive impairment prompted by ovariectomy combined with D-galactose injection in rats (an AD animal model), and to elucidate the signaling mechanisms regulating diapocynin-induced effects. Female rats were exposed to ovariectomy or sham operation. Ovariectomized rats were injected intraperitoneally with D-galactose (150 mg/kg/day) for 70 days and, on day 43, they were orally treated with diapocynin (10 mg/kg/day) for 28 days. Diapocynin amended cognitive functions as confirmed using novel object recognition and Morris water maze tests along with histopathological improvement. It caused a prominent decrement in ß-secretase, p-tau, and amyloid ß, contrary to α-secretase elevation in hippocampus and hampered neuroinflammation and oxidative stress, manifested by declined levels of NOX1, tumor necrosis factor-α, and nuclear factor-kappa B p65. In addition, diapocynin augmented synaptophysin, brain-derived neurotrophic factor, and phospho-cAMP response element binding protein and enhanced protein expression of phosphorylated forms of phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3ß (GSK-3ß), protein kinase B (Akt), extracellular signal-regulated kinase (ERK) 1/2, ERK kinase kinase (Raf-1), and ERK kinase (MEK) 1/2, while inhibiting those of c-Jun and c-Jun N-terminal kinase (JNK). In conclusion, diapocynin attenuated memory impairment and AD-like anomalies via activating Raf-1/MEK/ERK and PI3K/Akt/GSK-3ß, while inhibiting JNK/c-Jun signaling cascades.


Assuntos
Acetofenonas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Compostos de Bifenilo/farmacologia , Cognição/efeitos dos fármacos , Galactose/metabolismo , Nootrópicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Ratos Wistar
5.
PLoS One ; 15(5): e0229630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401759

RESUMO

Chromoblastomycosis (CBM) is a chronic subcutaneous mycosis caused by traumatic implantation of many species of black fungi. Due to the refractoriness of some cases and common recurrence of CBM, a more effective and less time-consuming treatment is mandatory. The aim of this study was to identify compounds with in vitro antifungal activity in the Pathogen Box® compound collection against different CBM agents. Synergism of these compounds with drugs currently used to treat CBM was also assessed. An initial screening of the drugs present in this collection at 1 µM was performed with a Fonsecaea pedrosoi clinical strain according to the EUCAST protocol. The compounds with activity against this fungus were also tested against other seven etiologic agents of CBM (Cladophialophora carrionii, Phialophora verrucosa, Exophiala jeanselmei, Exophiala dermatitidis, Fonsecaea monophora, Fonsecaea nubica, and Rhinocladiella similis) at concentrations ranging from 0.039 to 10 µM. The analysis of potential synergism of these compounds with itraconazole and terbinafine was performed by the checkerboard method. Eight compounds inhibited more than 60% of the F. pedrosoi growth: difenoconazole, bitertanol, iodoquinol, azoxystrobin, MMV688179, MMV021013, trifloxystrobin, and auranofin. Iodoquinol produced the lowest MIC values (1.25-2.5 µM) and MMV688179 showed MICs that were higher than all compounds tested (5 - >10 µM). When auranofin and itraconazole were tested in combination, a synergistic interaction (FICI = 0.37) was observed against the C. carrionii isolate. Toxicity analysis revealed that MMV021013 showed high selectivity indices (SI ≥ 10) against the fungi tested. In summary, auranofin, iodoquinol, and MMV021013 were identified as promising compounds to be tested in CBM models of infection.


Assuntos
Antifúngicos/farmacologia , Cromoblastomicose/tratamento farmacológico , Sinergismo Farmacológico , Fungos/patogenicidade , Acetatos/farmacologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/patogenicidade , Auranofina/farmacologia , Compostos de Bifenilo/farmacologia , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Dioxolanos/farmacologia , Exophiala/efeitos dos fármacos , Exophiala/patogenicidade , Fungos/efeitos dos fármacos , Humanos , Iminas/farmacologia , Iodoquinol/farmacologia , Pirimidinas/farmacologia , Estrobilurinas/farmacologia , Triazóis/farmacologia
6.
Invest Ophthalmol Vis Sci ; 61(4): 48, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32347916

RESUMO

Purpose: We characterized the effects of Honokiol (HNK) on Aspergillus fumigatus-caused keratomycosis and the underlying mechanisms. HNK is known to have anti-inflammatory and antifungal properties, but the influence on fungal keratitis (FK) remains unknown. Methods: In ex vivo, minimum inhibitory concentration and Cell Count Kit-8 assay were carried out spectrophotometrically to provide preferred concentration applied in vivo. Time kill assay pointed that HNK was fungicidal and fungistatic chronologically. Adherence assay, crystal violet staining, and membrane permeability assay tested HNK effects on different fungal stages. In vivo, clinical scores reflected the improvement degree of keratitis outcome. Myeloperoxidase (MPO) assay, flow cytometry (FCM), and immunohistofluorescence staining (IFS) were done to evaluate neutrophil infiltration. Plate count detected HNK fungicidal potentiality. RT-PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) verified the anti-inflammatory activity of HNK collaboratively. Results: In vitro, MIC90 HNK was 8 µg/mL (no cytotoxicity), and Minimal Fungicidal Concentration (MFC) was 12 µg/mL for A. fumigatus. HNK played the fungistatic and fungicidal roles at 6 and 24 hours, respectively, inhibiting adherence at the beginning, diminishing biofilms formation, and increasing membrane permeability all the time. In vivo, HNK improved C57BL/6 mice outcome by reducing disease severity (clinical scores), neutrophil infiltration (MPO, FCM, and IFS), and fungal loading (plate count). RT-PCR, Western blot, and ELISA revealed that HNK downregulated mRNA and protein expression levels of Toll-like receptor-2 (TLR-2), high mobility group box 1 (HMGB1), IL-1ß, and TNF-α. Conclusions: Our study suggested HNK played antifungal and anti-inflammatory roles on keratomycosis by reducing survival of fungi, infiltration of leucocytes, and expression of HMGB1, TLR-2, and proinflammatory cytokines, providing a potential treatment for FK.


Assuntos
Anti-Infecciosos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/isolamento & purificação , Compostos de Bifenilo/farmacologia , Infecções Oculares Fúngicas/tratamento farmacológico , Lignanas/farmacologia , Animais , Aspergilose/diagnóstico , Western Blotting , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Infecções Oculares Fúngicas/microbiologia , Feminino , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor 2 Toll-Like/efeitos dos fármacos , Resultado do Tratamento
7.
Mol Pharmacol ; 97(5): 336-350, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32111699

RESUMO

Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in preclinical and clinical studies. Their therapeutic window is narrow, however, and clinical application will likely only occur if greater discrimination in activity is achieved. Toward that end, we compared the modulatory activity of two PAMs recently considered as clinical candidates, LY451395 (mibampator) and PF-04958242/BIIB104, on recombinant and native AMPA receptors (AMPARs). We found that the principle molecular determinant that shaped modulatory activity of both PAMs on deactivation (recombinant) and decay (synaptic) of AMPARs was the auxiliary protein incorporated into the receptor complexes. AMPARs containing the stargazin/γ2 transmembrane AMPAR regulatory protein (TARP) were slowed to a >10-fold degree by both PAMs as compared with those incorporating γ8 TARP. Neither subunit composition nor flip/flop splice variation had substantive effect. Similarly, stargazin/γ2-containing mossy fiber EPSCs in cerebellar granule neurons were slowed to a ∼5-fold greater degree than EPSCs in hippocampal CA1 pyramidal cell neurons, which express the γ8 TARP. LY451395 exhibited greater efficacy than BIIB104 at both synapses. These studies provide insight into the receptor constituents that determine efficacy of sulfonamide PAMs. We conclude that compounds that discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/γ2 efficacy such as BIIB104, could act as viable procognitive therapeutics. SIGNIFICANCE STATEMENT: Positive allosteric modulators (PAMs) of AMPA receptors enhance cognitive function in a variety of preclinical models. A clearer understanding of the critical determinants of PAM activity could yield critical insight into pathways to maximize their therapeutic index. Here we show that auxiliary proteins for AMPARs play a major, but thus far underappreciated, role in shaping recombinant and neuronal AMPAR modulation by two clinical candidate PAMs. These data will inform both clinical outcomes as well as future rational development of new modulators.


Assuntos
Proteínas de Membrana/metabolismo , Receptores de AMPA/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Compostos de Bifenilo/farmacologia , Cerebelo/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Células HEK293 , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Multimerização Proteica/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Resultado do Tratamento , Triazóis/farmacologia
8.
Genes Dev ; 34(7-8): 489-494, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139422

RESUMO

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.


Assuntos
Compostos de Bifenilo/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/fisiologia , Nitrofenóis/farmacologia , Regeneração/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Piperazinas/farmacologia
9.
Asian Pac J Cancer Prev ; 21(3): 675-681, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212793

RESUMO

BACKGROUND: Despite the dramatic efficacy of ABT-737, a large percentage of cancer cells ultimately become resistance to this drug. Evidences show that over-expression of Mcl-1 is linked to ABT-737 resistance in NSCLC cells. The aim of this study was to investigate the effect of miRNA-101 on Mcl-1 expression and sensitivity of the A549 NSCLC cells to ABT-737. METHODS: After miRNA-101 transfection, the Mcl-1 mRNA expression levels were quantified by RT-qPCR. Trypan blue staining was used to explore the effect of miRNA-101 on cell growth. The cytotoxic effects of miRNA-101 and ABT-737, alone and in combination, were measured using MTT assay. The effect of drugs combination was determined using the method of Chou-Talalay. Cell death was assessed using cell death detection ELISA assay kit. RESULTS: Results showed that miRNA-101 markedly suppressed the expression of Mcl-1 mRNA in a time dependent manner, which led to A549 cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to blank control). Pretreatment with miRNA-101 synergistically decreased the cell survival rate and lowered the IC50 value of ABT-737. Furthermore, miRNA-101 dramatically enhanced the apoptotic effect of ABT-737. Negative control miRNA had no remarkable effect on cellular parameters. CONCLUSIONS: Our findings propose that suppression of Mcl-1 by miRNA-101 can effectively inhibit the cell growth and sensitize A549 cells to ABT-737. Therefore, miRNA-101 can be considered as a potential therapeutic target in patients with non-small cell lung cancer.
.


Assuntos
Compostos de Bifenilo/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Terapia Genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Piperazinas/farmacologia
10.
Transfusion ; 60(4): 806-814, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32159862

RESUMO

BACKGROUND: During platelet storage, there are extensive changes in cytoskeleton and phosphatidylserine exposure. The intrinsic mitochondrial pathway of apoptosis, activated in stored platelets, is a major mediator these changes. Cofilin-1 is an effector of actin reorganization. We examined the effect of cofilin-1 deficiency on cytoskeleton and phosphatidylserine exposure during storage and following activation of apoptosis. METHODS AND RESULTS: We assessed actin filaments by Alexa-647-phalloidin and phosphatidylserine exposure by fluorescein isothiocyanate-lactadherin by fluorescence microscopy. In fresh platelets, actin filaments are distributed in the subcortical region, and they do not express phosphatidylserine in the outer surface. In stored platelets, there is retraction of actin filaments from the subcortical region with increased phosphatidylserine expression. These changes are seen in 20% of platelets of 6 days old and increases further with storage. Treatment with ABT-737, which activates the mitochondrial apoptosis, induces similar cytoskeletal changes in actin filaments with increased phosphatidylserine. Cofilin-1 is activated in stored platelets as well as in ABT-737 treated platelets by dephosphorylation. In cofilin-1 deficient murine platelets actin filaments are abnormal and ABT-737 induces less phosphatidylserine. Despite these changes in vitro, platelet survival of cofilin-1 deficient platelets in mice was not significantly different from their wild-type controls. CONCLUSION: These results show that cofilin-1 plays a role in apoptosis-induced actin rearrangement and phosphatidylserine exposure during storage. Despite the defects in platelet cytoskeleton and phosphatidylserine exposure in cofilin-1-deficient platelets, the in vivo life span of platelets is similar to littermate controls, indicating multiple redundant pathways for the clearance of platelets in vivo.


Assuntos
Actinas/metabolismo , Plaquetas/citologia , Cofilina 1/fisiologia , Actinas/efeitos dos fármacos , Animais , Apoptose , Compostos de Bifenilo/farmacologia , Preservação de Sangue , Cofilina 1/deficiência , Citoesqueleto/metabolismo , Humanos , Camundongos , Nitrofenóis/farmacologia , Fosfatidilserinas/metabolismo , Piperazinas/farmacologia , Sulfonamidas/farmacologia
11.
Toxicol Appl Pharmacol ; 391: 114913, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32032644

RESUMO

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-ß1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-ß/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-ß/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Compostos de Bifenilo/farmacologia , Bleomicina , Líquido da Lavagem Broncoalveolar , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Receptores de Hialuronatos , Interleucina-6 , Lignanas/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Transcrição STAT3/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos
12.
Environ Toxicol ; 35(7): 758-767, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32061152

RESUMO

Increased deposition of silica dust in pulmonary interstitial tissues leads to silicosis, in which autophagy plays a defensive role in silica dust-associated stress response and cell death. Our previous studies revealed that silica dust exposure contributed to autophagy in pulmonary macrophages in vivo, while the specific regulatory mechanism is still unclear. This study aimed to figure out the regulatory mechanism as well as the role of autophagy in the pathogenesis of experimental silicosis. We used 3-methyladenine (3-MA) and ABT-737 to suppress the expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and B cell leukemia/lymphoma 2 (Bcl-2), two critical initiators of autophagy, and detected and evaluated the autophagy in NR8383 cells with or without silica dust exposure. We found that exposure of silica dust increased autophagy in NR8383 cells and elevated the expression of Beclin1 and PIK3C3, but it reduced the expression of Bcl-2. The relationship among Beclin1, PIK3C3, and Bcl-2 were then investigated using immunoprecipitation analysis, and we found that suppression of PIK3C3 and/or Bcl-2 using 3-MA and/or ABT-737 could alter the autophagy induced by silica dust in NR8383 cells, and the complexes of Beclin1/PIK3C3 and Beclin1/Bcl-2 were both downregulated, which may be that inhibition of PIK3C3 and Bcl-2 altered the affinity of Beclin1 with PIK3C3 and Bcl-2 and lead to the silence of PIK3C3 signaling. These findings indicate that silica dust exposure induces autophagy via changing the connectivity of Beclin1 from Bcl-2 to PIK3C3.


Assuntos
Poluentes Atmosféricos/toxicidade , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Dióxido de Silício/toxicidade , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular , Poeira/análise , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Nitrofenóis/farmacologia , Piperazinas/farmacologia , Ratos , Transdução de Sinais , Silicose/metabolismo , Silicose/patologia , Sulfonamidas/farmacologia
13.
Cancer Res ; 80(8): 1748-1761, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32054768

RESUMO

Adipocytes are critical for ovarian cancer cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells cocultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in ovarian cancer cells cocultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with ovarian cancer metastasis, and reduced clonogenic cancer cell survival. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated knockout of FABP4 in high-grade serous ovarian cancer cells reduced metastatic tumor burden in mice. Consequently, a small-molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells toward carboplatin both in vitro and in vivo. Taken together, these results show that targeting FABP4 in ovarian cancer cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of ovarian cancer metastasis. SIGNIFICANCE: Ovarian cancer metastatic progression can be restricted by targeting a critical regulator of lipid responses, FABP4.


Assuntos
Adipócitos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias Ovarianas/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/análise , Animais , Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Carboplatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Cocultura , Metilação de DNA , Regulação para Baixo , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metabolismo dos Lipídeos , Lipidômica , Espectrometria de Massas , Metabolômica/métodos , Camundongos , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Omento/citologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Análise Serial de Proteínas , Proteômica/métodos , Pirazóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Regulação para Cima
14.
Cancer Res ; 80(7): 1498-1511, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041837

RESUMO

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/antagonistas & inibidores
15.
PLoS One ; 15(1): e0227979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995599

RESUMO

Techno-biofunctional characteristics of nanoemulsion and (nano)emulgel loaded with mangostin extracts were elucidated. Crude mangostins from mangosteen peels recovered by virgin coconut oil (VCO), mixed VCO and propylene glycol (PG), and pure PG were used. The extracts were loaded in the dispersed phase in the presence of mixed surfactants (Tween20/Span20) with a varying hydrophilic-lipophilic balance (HLB) from 10.2 to 15.1. Results showed that globular and uniformly distributed droplets of the nanoemulsion were observed. The small particle sizes (typically 18-62 nm) with the zeta potential of -39 to -54.5 mV were obtained when mixed emulsifiers with HLB values of 12.6 and 15.1 were employed. With HLB values of 12.6 and 15.1, nanoemulsions loaded with mangostin extracts prepared with mixed VCO-PG and pure PG-based extracts showed approximately a 2 to 3-fold lower droplet size diameter when compared with the VCO-based extract. For the stability test, all nanoemulsions were stable over three freeze-thaw cycles with some changes in pH, zeta potential, and droplet size. The DPPH● scavenging activity, H2O2 scavenging activity, reducing power and antibacterial activities (E. coli and S. aureus) of the nanoemulsions were greater than their corresponding bulk extracts. Nanoemulgels produced by embedding the nanoemulsions in a hydrogel matrix was homogeneous and creamy yellow-white in appearance. The nanoemulgels had a higher mangostin release (87-92%) than their normal emulgels (74-78%). Therefore, this study presented the feasibility of nanoemulsions and nanoemulgels loaded with mangostin extracts as a promising delivery system for bioactive polyphenol in food supplements, pharmaceuticals and cosmetics.


Assuntos
Antibacterianos/química , Nanopartículas/química , Extratos Vegetais/farmacologia , Xantonas/química , Antibacterianos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Óleo de Coco/química , Emulsões/química , Emulsões/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Depuradores de Radicais Livres/química , Peróxido de Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Picratos/química , Picratos/farmacologia , Extratos Vegetais/química , Propilenoglicol/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Xantonas/farmacologia
16.
Chem Biodivers ; 17(2): e1900609, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916412

RESUMO

The fruit of Crataegus dahurica Koehne was used to treat the disease of infantile indigestion and dyspepsia as an ethnic medicine and food. As a continuous work on finding the active constituents from the edible herbs, four new biphenyl derivatives (1-4), together with two known compounds (5 and 6), were obtained from the petroleum ether fraction of the fruits of C. dahurica. Their structures were determined by the extensive 1D and 2D NMR spectra and HR-MS spectrometry. Furthermore, the anti-inflammatory activities of all the isolated compounds were investigated, in which compound 4 showed moderately inhibitory effects on NO production in RAW264.7 cells without inducing cytotoxicity.


Assuntos
Anti-Inflamatórios/química , Crataegus/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/isolamento & purificação , Compostos de Bifenilo/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Crataegus/metabolismo , Frutas/química , Frutas/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismo , Células RAW 264.7
17.
AAPS PharmSciTech ; 21(2): 62, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925586

RESUMO

The study mainly aimed to improve the solubility of honokiol (HK) by preparing honokiol nanosuspensions (HNS). In this study, HNS were obtained using Kolliphor®P407 (P407) as a stabilizer through melting method combined with high pressure homogenization (HPH). The crystalline state of HNS was confirmed through differential scanning calorimetry (DSC) and X-ray Diffraction (XRD). In vitro, the dissolution rate of HNS was significantly improved than that of pure HK. In vivo, higher anti-inflammatory activity was achieved after free HK had been made into HNS. There was no significant difference between the degree of edema (DE) of HNS group and that of aspirin group. Consequently, melting method combined with HPH was a potent technique to prepare HNS. Furthermore, nanosuspension was a valid formulation that could be utilized to enhance the anti-inflammatory effect of HK.


Assuntos
Anti-Inflamatórios/farmacologia , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Animais , Compostos de Bifenilo/química , Feminino , Lignanas/química , Masculino , Camundongos , Nanopartículas/química , Solubilidade , Suspensões
18.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906391

RESUMO

Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Lignanas/química , Plantas/química , Podofilotoxina/química , Antivirais/química , Benzodioxóis/química , Benzodioxóis/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Desenvolvimento de Medicamentos , Furanos/química , Furanos/farmacologia , Lignanas/farmacologia , Masoprocol/análogos & derivados , Masoprocol/química , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Podofilotoxina/farmacologia , Podofilotoxina/uso terapêutico
19.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936371

RESUMO

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-ß1/Smad signaling pathway.


Assuntos
Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Sirtuína 3/genética , Fator de Crescimento Transformador beta1/genética , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose/genética , Fibrose/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Nefropatias/genética , Nefropatias/patologia , Lignanas/farmacologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética
20.
Food Microbiol ; 88: 103411, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31997759

RESUMO

Fungal pathogens lead to severe quality deterioration and yield loss, making it urgent to explore efficient measures to control fungal diseases at the preharvest and postharvest stages of plants. Therefore, studies on natural substances targeting alternative antimicrobial targets have become hot spots of research. Here, we show that honokiol, a polyphenolic compound obtained from Magnolia officinalis, significantly suppressed mycelial growth and reduced virulence of B. cinerea on harvested fruit by inducing autophagic activities and apoptosis. Moreover, honokiol was capable of abolishing the mitochondrial membrane potential and inducing the accumulation of reactive oxygen species. Some key genes involved in pathogenicity on fruit were also found significantly down-regulated. In summary, honokiol was effective as an alternative agent targeting autophagic and apoptotic machineries to control the incidence of gray mold, which may further enrich the toolkit of crop managers for fighting postharvest diseases caused by this and similar fungi.


Assuntos
Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Botrytis/efeitos dos fármacos , Botrytis/patogenicidade , Lignanas/farmacologia , Botrytis/crescimento & desenvolvimento , Regulação para Baixo , Frutas/microbiologia , Genes Fúngicos , Magnolia/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Virulência
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