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1.
Chem Biol Interact ; 348: 109634, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506768

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide as antipyretic analgesics and agents for rheumatoid arthritis and osteoarthritis, but known to cause damage to the gastrointestinal mucosae as their serious adverse effects. Few studies showed the impairment of intestinal epithelial barrier function (EBF) by high concentrations (0.5-1 mM) of NSAIDs, but the underlying mechanism is not fully understood. This study is aimed at clarifying effects at a low concentration (50 µM) of three NSAIDs, loxoprofen (Lox), ibuprofen and indomethacin, on intestinal EBF using human intestinal epithelial-like Caco-2 cells. Among those NSAIDs, Lox increased the transepithelial electric resistance (TER) value, decreased the paracellular Lucifer yellow CH (LYCH) permeability, and upregulated claudin (CLDN)-1, -3 and -5, indicating that low doses of Lox enhanced EBF through increasing expression of CLDNs. Lox is known to be metabolized to a pharmacologically active metabolite, (2S,1'R,2'S)-loxoprofen alcohol (Lox-RS), by carbonyl reductase 1 (CBR1), which is highly expressed in human intestine. CBR1 was expressed in the Caco-2 cells, and the pretreatment with a CBR1 inhibitor suppressed both the Lox-evoked CLDN upregulation and EBF enhancement. In addition, the treatment of the cells with Lox-RS resulted in higher TER value and lower LYCH permeability than those with Lox. Thus, Lox-RS synthesized by CBR1 may greatly contribute to the improving efficacy of Lox on the barrier function. Since EBF is decreased in inflammatory bowel disease, we finally examined the effect of Lox on EBF using the Caco-2/THP-1 co-culture system, which is used as an in vitro inflammatory bowel disease model. Lox significantly recovered EBF which was impaired by inflammatory cytokines secreted from THP-1 macrophages. These in vitro observations suggest that Lox enhances intestinal EBF, for which the metabolism of Lox to Lox-RS by CBR1 has an important role.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Carbonil Redutase (NADPH)/metabolismo , Diferenciação Celular/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fenilpropionatos/farmacologia , Anti-Inflamatórios não Esteroides/metabolismo , Células CACO-2 , Citocinas/metabolismo , Humanos , Mucosa Intestinal/citologia , Fenilpropionatos/metabolismo
2.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443414

RESUMO

Natural antioxidants, especially those of plant origins, have shown a plethora of biological activities with substantial economic value, as they can be extracted from agro-wastes and/or under exploited plant species. The perennial hydrophyte, Potamogeton perfoliatus, has been used traditionally to treat several health disorders; however, little is known about its biological and its medicinal effects. Here, we used an integrated in vitro and in vivo framework to examine the potential effect of P. perfoliatus on oxidative stress, nociception, inflammatory models, and brewer's yeast-induced pyrexia in mice. Our results suggested a consistent in vitro inhibition of three enzymes, namely 5-lipoxygenase, cyclooxygenases 1 and 2 (COX-1 and COX-2), as well as a potent antioxidant effect. These results were confirmed in vivo where the studied extract attenuated carrageenan-induced paw edema, carrageenan-induced leukocyte migration into the peritoneal cavity by 25, 44 and 64% at 200, 400 and 600 mg/kg, p.o., respectively. Moreover, the extract decreased acetic acid-induced vascular permeability by 45% at 600 mg/kg, p.o., and chemical hyperalgesia in mice by 86% by 400 mg/kg, p.o., in acetic acid-induced writhing assay. The extract (400 mg/kg) showed a longer response latency at the 3 h time point (2.5 fold of the control) similar to the nalbuphine, the standard opioid analgesic. Additionally, pronounced antipyretic effects were observed at 600 mg/kg, comparable to paracetamol. Using LC-MS/MS, we identified 15 secondary metabolites that most likely contributed to the obtained biological activities. Altogether, our findings indicate that P. perfoliatus has anti-inflammatory, antioxidant, analgesic and antipyretic effects, thus supporting its traditional use and promoting its valorization as a potential candidate in treating oxidative stress-associated diseases.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antipiréticos/farmacologia , Extratos Vegetais/farmacologia , Potamogetonaceae/química , Ácido Acético , Animais , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Movimento Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Edema/patologia , Febre/patologia , Glucosídeos Iridoides/farmacologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Cavidade Peritoneal/patologia , Fenilpropionatos/farmacologia , Compostos Fitoquímicos/análise , Ratos , Saccharomyces cerevisiae
3.
Nutrients ; 13(8)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34444688

RESUMO

Propolis is produced by honeybees from materials collected from plants they visit. It is a resinous material having mixtures of wax and bee enzymes. Propolis is also known as bee glue and used by bees as a building material in their hives, for blocking holes and cracks, repairing the combs and strengthening their thin borders. It has been extensively used since ancient times for different purposes in traditional human healthcare practices. The quality and composition of propolis depend on its geographic location, climatic zone and local flora. The New Zealand and Brazilian green propolis are the two main kinds that have been extensively studied in recent years. Their bioactive components have been found to possess a variety of therapeutic potentials. It was found that Brazilian green propolis improves the cognitive functions of mild cognitive impairments in patients living at high altitude and protects them from neurodegenerative damage through its antioxidant properties. It possesses artepillin C (ARC) as the key component, also known to possess anticancer potential. The New Zealand propolis contains caffeic acid phenethyl ester (CAPE) as the main bioactive with multiple therapeutic potentials. Our lab performed in vitro and in vivo assays on the extracts prepared from New Zealand and Brazilian propolis and their active ingredients. We provided experimental evidence that these extracts possess anticancer, antistress and hypoxia-modulating activities. Furthermore, their conjugation with γCD proved to be more effective. In the present review, we portray the experimental evidence showing that propolis has the potential to be a candidate drug for different ailments and improve the quality of life.


Assuntos
Ansiolíticos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Própole/farmacologia , Animais , Brasil , Ácidos Cafeicos/farmacologia , Humanos , Nova Zelândia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Fenilpropionatos/farmacologia
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361067

RESUMO

Carotenoids and phenylpropanoids play a dual role of limiting and countering photooxidative stress. We hypothesize that their "antioxidant" function is prominent in plants exposed to summer drought, when climatic conditions exacerbate the light stress. To test this, we conducted a field study on Phillyrea latifolia, a Mediterranean evergreen shrub, carrying out daily physiological and biochemical analyses in spring and summer. We also investigated the functional role of the major phenylpropanoids in different leaf tissues. Summer leaves underwent the most severe drought stress concomitantly with a reduction in radiation use efficiency upon being exposed to intense photooxidative stress, particularly during the central hours of the day. In parallel, a significant daily variation in both carotenoids and phenylpropanoids was observed. Our data suggest that the morning-to-midday increase in zeaxanthin derived from the hydroxylation of ß-carotene to sustain non-photochemical quenching and limit lipid peroxidation in thylakoid membranes. We observed substantial spring-to-summer and morning-to-midday increases in quercetin and luteolin derivatives, mostly in the leaf mesophyll. These findings highlight their importance as antioxidants, countering the drought-induced photooxidative stress. We concluded that seasonal and daily changes in photosynthetic and non-photosynthetic pigments may allow P. latifolia leaves to avoid irreversible photodamage and to cope successfully with the Mediterranean harsh climate.


Assuntos
Antioxidantes/farmacologia , Oleaceae/efeitos dos fármacos , Fenilpropionatos/farmacologia , Folhas de Planta/efeitos dos fármacos , Protetores contra Radiação/farmacologia , Estações do Ano , Estresse Fisiológico , Carotenoides/farmacologia , Secas , Luz , Peroxidação de Lipídeos , Oleaceae/crescimento & desenvolvimento , Oleaceae/efeitos da radiação , Estresse Oxidativo , Fotossíntese , Pigmentação , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/efeitos da radiação
5.
Life Sci ; 283: 119759, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34171381

RESUMO

AIMS: Skin cancer is the most widespread cancer worldwide, mainly caused by exposure to ultraviolet radiation (UV) in sunlight. Utilizing topical preventive agents in routinely daily used cosmetics may prevent UV-related skin damages and skin cancers. γ-Oryzanol (GO) is a natural component derived from rice bran oil, with potential antioxidant and skin anti-aging properties. MAIN METHODS: We biologically thorough studied the antioxidant and anticancer effects of GO in vitro to found the effective signaling pathways, then evaluated the sun protection factor of prepared formulation, and finally investigated the long-term preventive effects of GO-loaded nanoethosomes (GO-NEs) against UVB-induced skin cancer in mice. KEY FINDINGS: GO-NEs could effectively prevent UVB-induced skin cancer. SIGNIFICANCE: Our results suggest that GO-NEs could be utilized as an innovative ingredient in cosmetics.


Assuntos
Nanoestruturas , Fenilpropionatos , Neoplasias Cutâneas/prevenção & controle , Protetores Solares , Raios Ultravioleta/efeitos adversos , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Protetores Solares/química , Protetores Solares/farmacologia
6.
BMC Cancer ; 21(1): 481, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931028

RESUMO

BACKGROUND: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms. METHODS: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells. RESULTS: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment. CONCLUSIONS: Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Ácido Dicloroacético/farmacologia , Compostos de Mostarda/farmacologia , Fenilpropionatos/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo
7.
Eur J Med Chem ; 220: 113498, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933756

RESUMO

Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 µM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Cinamatos/farmacologia , Inibidores da Protease de HIV/farmacologia , Fenilpropionatos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Amidas/síntese química , Amidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Cinamatos/síntese química , Cinamatos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Protease de HIV/metabolismo , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Transcriptase Reversa do HIV/antagonistas & inibidores , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Fenilpropionatos/síntese química , Fenilpropionatos/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
8.
Nature ; 593(7857): 125-129, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33854236

RESUMO

Antibiotics that target Gram-negative bacteria in new ways are needed to resolve the antimicrobial resistance crisis1-3. Gram-negative bacteria are protected by an additional outer membrane, rendering proteins on the cell surface attractive drug targets4,5. The natural compound darobactin targets the bacterial insertase BamA6-the central unit of the essential BAM complex, which facilitates the folding and insertion of outer membrane proteins7-13. BamA lacks a typical catalytic centre, and it is not obvious how a small molecule such as darobactin might inhibit its function. Here we resolve the mode of action of darobactin at the atomic level using a combination of cryo-electron microscopy, X-ray crystallography, native mass spectrometry, in vivo experiments and molecular dynamics simulations. Two cyclizations pre-organize the darobactin peptide in a rigid ß-strand conformation. This creates a mimic of the recognition signal of native substrates with a superior ability to bind to the lateral gate of BamA. Upon binding, darobactin replaces a lipid molecule from the lateral gate to use the membrane environment as an extended binding pocket. Because the interaction between darobactin and BamA is largely mediated by backbone contacts, it is particularly robust against potential resistance mutations. Our results identify the lateral gate as a functional hotspot in BamA and will allow the rational design of antibiotics that target this bacterial Achilles heel.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Desenho de Fármacos , Escherichia coli/citologia , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Espectrometria de Massas , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína
9.
Eur J Pharmacol ; 899: 174032, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33753107

RESUMO

Diabetic retinopathy is a serious complication of diabetes, marked by retinal vascular damage, inflammation, and angiogenesis. This study's objective was to assess the potential benefits of saroglitazar, a peroxisome proliferator-activated receptor-alpha/gamma (PPAR-α/γ) agonist in diabetic retinopathy. Diabetic retinopathy was induced by streptozotocin in Sprague Dawley rats. The effect of saroglitazar was also assessed in the oxygen-induced retinopathy model in newborn rats and VEGF-induced angiogenesis in the chick chorioallantoic membrane (CAM) assay. Treatment of saroglitazar (1 and 4 mg/kg, oral) for 12 weeks significantly ameliorated retinal vascular leakage and leukostasis in the diabetic rats. Saroglitazar decreased oxidative stress, VEGF receptor signalling, NF-κBp65, and ICAM-1 in the retina of diabetic rats. The beneficial effects of saroglitazar (1 and 4 mg/kg, oral) were also observed on the neovascularization in oxygen-induced retinopathy in newborn rats. Saroglitazar also reduced VEGF-induced angiogenesis in CAM assay. This study reveals that saroglitazar has the potential to prevent the progression of retinopathy in diabetic patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Retinopatia Diabética/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/farmacologia , Pirróis/farmacologia , Retina/efeitos dos fármacos , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Embrião de Galinha , Diabetes Mellitus Experimental/induzido quimicamente , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Feminino , Hiperóxia/complicações , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Retina/metabolismo , Retina/patologia , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais , Estreptozocina , Fator de Transcrição RelA/metabolismo
10.
Life Sci ; 271: 119191, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33571514

RESUMO

AIMS: Insulin resistance (IR) has become one of the major causative factors for the pathogenesis of various metabolic and neurometabolic diseases. The sedentary lifestyle in association with the consumption of protein-deficient and high-calorie diet results in IR development. This study was aimed to evaluate the neuroprotective effects of Saroglitazar (SGZ), a dual peroxisome-proliferator activated receptor (PPAR-α/γ) in a high fat-low protein diet (HFLPD) fed mouse model of MetS and associated cognitive deficits. METHODS: Adult male C57BL/6J mice were fed with HFLPD plus 15% oral fructose solution for 16 weeks. Starting at the 13th week, SGZ (5 & 10 mg/kg; p.o.) was administered along with HFLPD for four weeks, i.e., the 12th to 16th week of the study groups. Various physiological, serum metabolic, neurobehavioral, neuroinflammatory, and oxidative stress parameters were assessed. The brain histopathology and mRNA expression of diverse genes in specific brain regions were also estimated. RESULTS: The treatment with SGZ at both doses have significantly reversed various HFLPD-induced metabolic and cognitive alterations by improving the glucose and lipid profile in the periphery in addition to the enhanced cerebral glucose homeostasis, BBB integrity, reduced oxidative stress, and neuroinflammation. Furthermore, the SGZ improved locomotion and memory retention while reducing the HFLPD-induced anxiety-like behaviors in the mice. CONCLUSIONS: SGZ treatment showed significant metabo-neuroprotective effects in mice fed with HFLPD, possibly through peripherally mediated activation of PPAR-α/γ and insulin downstream signaling in the cortex and hippocampus.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Dieta com Restrição de Proteínas/efeitos adversos , Doenças Metabólicas/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/uso terapêutico , Pirróis/uso terapêutico , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , PPAR gama/metabolismo , Fenilpropionatos/farmacologia , Pirróis/farmacologia
11.
Neurochem Res ; 46(3): 675-685, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33471295

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder disease, disturbing people's normal life. Syringin was mentioned to antagonize Amyloid-ß (Aß)-induced neurotoxicity. However, the action mechanism is still not fully elucidated. This study aimed to explore a molecular mechanism of syringin in defending Aß-induced neurotoxicity. SK-N-SH and SK-N-BE cells were treated with amyloid ß-protein fragment 25-35 (Aß25-35) to induce cell neurotoxicity. The injury effects were distinguished by assessing cell viability and cell apoptosis using cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The expression of Cleaved-caspase3 (Cleaved-casp3), B cell lymphoma/leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax) and BH3 interacting domain death agonist (BID) at the protein level was determined by western blot. The expression of miR-124-3p and BID was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-124-3p and BID was predicted by the online database starBase and confirmed by dual-luciferase reporter assay plus RNA pull-down assay. Aß25-35 treatment inhibited cell viability and induced cell apoptosis, while the addition of syringin recovered cell viability and suppressed cell apoptosis. MiR-124-3p was significantly downregulated in Aß25-35-treated SK-N-SH and SK-N-BE cells, and BID was upregulated. Nevertheless, the addition of syringin reversed their expression. BID was a target of miR-124-3p, and its downregulation partly prevented Aß25-35-induced injuries. Syringin protected against Aß25-35-induced neurotoxicity by enhancing miR-124-3p expression and weakening BID expression, and syringin strengthened the expression of miR-124-3p to diminish BID level. Syringin ameliorated Aß25-35-induced neurotoxicity in SK-N-SH and SK-N-BE cells by regulating miR-124-3p/BID pathway, which could be a novel theoretical basis for syringin to treat AD.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Glucosídeos/farmacologia , MicroRNAs/metabolismo , Fragmentos de Peptídeos/toxicidade , Fenilpropionatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Humanos , Regulação para Cima
12.
Commun Biol ; 4(1): 53, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420329

RESUMO

The G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A-/-) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A-/- mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A-/- mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A-/- mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/ß-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/ß-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A-/- mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.


Assuntos
Reabsorção Óssea/prevenção & controle , Hipuratos/farmacologia , Osteogênese/efeitos dos fármacos , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Microbioma Gastrointestinal , Hipuratos/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenilpropionatos/uso terapêutico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Via de Sinalização Wnt
13.
J Ethnopharmacol ; 271: 113849, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485983

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. AIM OF THE STUDY: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. MATERIALS AND METHODS: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. RESULTS: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. CONCLUSIONS: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Descoberta de Drogas/métodos , Medicamentos de Ervas Chinesas/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanoconjugados/química , Saussurea/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Celecoxib/efeitos adversos , Linhagem Celular , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Glucosídeos/efeitos adversos , Glucosídeos/farmacologia , Articulações/diagnóstico por imagem , Articulações/patologia , Ligantes , Simulação de Acoplamento Molecular , Células Musculares/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Componentes Aéreos da Planta/química , Ratos Sprague-Dawley , Escopoletina/efeitos adversos , Escopoletina/farmacologia , Remodelação Ventricular/efeitos dos fármacos
14.
J Ethnopharmacol ; 270: 113740, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33388429

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia pachystachya Trécul (Urticaceae) is a medicinal plant popularly known as 'embaúba'. In Brazil, the leaves of this species are used for the treatment of various kidney and cardiovascular diseases. However, there are no detailed studies on the renal and cardiovascular activities of this species. No studies on the anatomy or the quality control of this herbal drug is available thus far. AIM: This study was aimed to investigate the ethnopharmacological properties of the leaves of C. pachystachya. MATERIAL AND METHODS: The leaves of C. pachystachya were analyzed by light and scanning electron microscopy for pharmacobotanical and anatomical characterization. The ethanol-soluble fraction of C. pachystachya leaf extract (ESCP) was characterized by high-performance liquid chromatograph equipped with diode array detector and mass spectrometry (HPLC-DAD-MS). The acute oral toxicity of ESCP on female Wistar rats was assessed. The acute and prolonged diuresis and antioxidant effects of ESCP (30, 100, and 300 mg/kg) were evaluated in male Wistar rats. In addition, the hypotensive effects of the ESCP as well as the vasodilatory activity in isolated and perfused mesenteric vascular beds were investigated. RESULTS: The anatomical markers obtained in this study can help in the identification of C. pachystachya, as well as to distinguish it from the other 'embaúbas'. The metabolites found in the ESCP were phenolic compounds, mainly C- and O-glycosylated flavonoids. The ESCP did not exhibit any toxic effects at a dose of 2000 mg/kg. Significant diuretic activities were observed at the doses of 30, 100, and 300 mg/kg. In addition, a significant modulating activity of the tissue redox state was observed after prolonged treatment. On the other hand, no hypotensive or vasodilator activity was observed. CONCLUSION: The key findings of the present study can contribute to the taxonomy, species identification and quality control of C. pachystachya. Chemical studies have shown the presence of glycosylated flavonoids, phenylpropanoid derivative and proanthocyanidins. The pharmacological studies showed significant diuretic and antioxidant effects of C. pachystachya leaf extract, indicating a possible validation of its popular medicinal use.


Assuntos
Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cecropia (Planta)/química , Diuréticos/farmacologia , Diuréticos/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Pressão Arterial/efeitos dos fármacos , Brasil , Feminino , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Masculino , Oxirredução/efeitos dos fármacos , Fenilpropionatos/farmacologia , Fenilpropionatos/uso terapêutico , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Folhas de Planta/química , Folhas de Planta/citologia , Plantas Medicinais/química , Proantocianidinas/farmacologia , Proantocianidinas/uso terapêutico , Ratos Wistar , Urina/química , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
15.
Nat Prod Res ; 35(12): 2028-2036, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31496280

RESUMO

One new naturally occurring quinone, 3',4'-dihydroxy-1,2,6-trimethoxy-[1,1'-biphenyl]-4(1H)-one (1), one new diarylpropane, emarginone A (2), and one new neolignan, emarginone B (3), along with eighteen known compounds have been isolated from the chemical investigation of the EtOAc-soluble fraction of the Vaccinium emarginatum whole plant methanolic extract. The new structures were elucidated by combined analysis of spectroscopic analytical methods and comparison with the literature data obtained from known analogues. In addition, the cytotoxicity of compounds 2, 4, and 14-20 against Du145 and PC-3 prostate cancer cell lines using MTT cell proliferation assay was evaluated. Compounds 2 and 19 showed most potent cytotoxicity against Du145 with IC50 values of 7.53 and 6.63 µg/mL, respectively. Furthermore, compounds 2, 17, and 19 also exhibited significant cytotoxicity against PC-3 with IC50 values ranging from 3.44-6.64 µg/mL.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Vaccinium/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Estrutura Molecular , Células PC-3 , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Extratos Vegetais/química , Neoplasias da Próstata/patologia , Quinonas/química , Quinonas/farmacologia
16.
J Pharmacol Exp Ther ; 376(1): 51-63, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33115824

RESUMO

Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine-induced AHR in naïve mice and suppressed both AHR and airway inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate, or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, pharmacokinetics/pharmacodynamics, formulation, and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe, and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation, and abrogating some features of airway remodeling. SIGNIFICANCE STATEMENT: Calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) reduce airway smooth muscle hyperresponsiveness, reverse airway inflammation as efficiently as topical corticosteroids, and suppress airway remodeling in asthma surrogates. CaSR NAMs, which were initially developed for oral therapy of osteoporosis proved inefficacious for this indication despite being safe and well tolerated. Here we show that structurally unrelated CaSR NAMs are suitable for inhaled delivery and represent a one-stop, steroid-free approach to asthma control and prophylaxis.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Indanos/uso terapêutico , Naftalenos/uso terapêutico , Fenilpropionatos/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores de Detecção de Cálcio/agonistas , Regulação Alostérica , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Reposicionamento de Medicamentos , Células HEK293 , Humanos , Indanos/efeitos adversos , Indanos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacologia , Receptores de Detecção de Cálcio/metabolismo
17.
Mol Cell Endocrinol ; 520: 111095, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33253762

RESUMO

The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue. METHODS: Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + Î³Oz (HSF + Î³Oz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis. RESULTS: Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression. CONCLUSION: Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.


Assuntos
Tecido Adiposo/metabolismo , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Fenilpropionatos/farmacologia , SARS-CoV-2/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/virologia , Animais , COVID-19/metabolismo , COVID-19/patologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Inflamação/virologia , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar
18.
Environ Toxicol ; 36(3): 433-444, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33146439

RESUMO

Asthma is an allergic chronic inflammatory disease of the pulmonary airways, characterized by the infiltration of white blood cells and release of inflammatory cytokines of complex pathways linked to its pathogenesis. Syringin extracted from various medicinal plants has been used extensively for the treatment of inflammatory diseases. Hence, this study was conducted to further explore the protective effects of the syringin in ovalbumin (OVA) induced-asthma mice model. OVA-sensitized BALB mice were treated intraperitonealy with three doses (25, 50 and 100 mg/kg) of the syringin which was validated by the alteration in the immunoglobulin E (IgE) levels, cytokines levels, histopathological evaluation inflammatory cell count, lung weight, nitrite (NO) levels, oxidative stress biomarkers and gene markers. The treatment of syringin intensely reduced the increased IgE, inflammatory cytokines, WBC count and restored the antioxidant stress markers OVA stimulated animals. In addition, a significant reduction in inflammation and mucus production was evidenced in histopathological analysis which was further validated by suppression NF-κB pathway activation by syringin. These results suggest that syringin may improve asthma symptoms in OVA-induced mice by modulating NF-κB pathway activation.


Assuntos
Antiasmáticos/farmacologia , Glucosídeos/farmacologia , Fenilpropionatos/farmacologia , Animais , Asma/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Pulmão/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ovalbumina/efeitos adversos , Pneumonia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
19.
Exp Mol Pathol ; 118: 104576, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33197425

RESUMO

In this study, we investigated the clinical value of CC chemokine ligand 2 (CCL2) and CC chemokine ligand 3 (CCL3) in osteoarthritis (OA). A prospective analysis was performed on 126 patients with rheumatoid arthritis of the knee (observation group (OG)) who admitted to Qilu hospital from August 2016 to August 2018 and 135 healthy controls (control group (CG)) who underwent physical examinations during the same period. The concentrations of CCL2 and CCL3 in peripheral blood were compared between the two groups, and the predictive value of the two on the occurrence, efficacy and prognosis of recurrence of OA were analyzed. In addition, an OA rat model was established to detect the relative protein levels of CCL2 and CCL3 in rat knee joint tissues. There were no statistically significant differences between the two groups in baseline data such as age, body mass index (BMI), gender, smoking, drinking, educational level, family medical history and living environment (P > 0.05). CCL2 and CCL3 increased in peripheral blood of patients in the OG (P < 0.05), both of which were positively correlated with rheumatoid factor (RF) (P < 0.001). CCL2 and CCL3 were of good predictive value for the occurrence, efficacy and prognosis of recurrence of OA (P < 0.001). The relative protein levels of CCL2 and CCL3 in bone and joint tissues of OA rats were significantly higher than those of normal rats (P < 0.001). CCL2 and CCL3 are elevated in peripheral blood of OA patients, which have good predictive value for the occurrence, efficacy and prognosis of recurrence of OA, indicating their potential roles as excellent markers for diagnosis and treatment of OA in the future.


Assuntos
Artrite Experimental/metabolismo , Biomarcadores/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoartrite/metabolismo , Fenilpropionatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Prognóstico , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença
20.
Int Immunopharmacol ; 90: 107268, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33316740

RESUMO

Inflammation plays an important role in the pathogenesis of cerebral ischemia. Syringin (SYR) is an active substance isolated from Acanthopanax senticosus plants, and possesses anti-inflammatory and neuroprotective properties. However, its effects on cerebral ischemic injury, as well as the underlying molecular events, are still unclear. The purpose of this study was to investigate the effect of SYR in a rat model of cerebral ischemia and address the related molecular mechanism. A middle cerebral artery occlusion/reperfusion model (MCAO) was used to simulate ischemic injury. SYR treatment clearly reduced the infarct volume, decreased cerebral water content, improved the neurological score, and attenuated neuronal death. Moreover, SYR decreased the expression of NF-κB, IL-1ß, IL-6, TNF-α, and MPO, promoted FOXO3a phosphorylation and cytoplasmic retention, and inhibited the nuclear translocation of NF-κB. FOXO3a knockdown by RNA interference significantly prevented SYR-induced inhibition of NF-κB-mediated inflammation. Confocal microscopy revealed that SYR reduced NF-κB translocation to the nucleus, and FOXO3a silencing reversed this effect. Finally, immunofluorescence and CO-IP experiments showed that SYR promoted the interaction between FOXO3a and NF-κB. In conclusion, SYR exerted a protective effect against brain I/R injury by reducing the inflammation accompanying cerebral ischemia. This effect was mediated by the FOXO3a /NF-κB pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Proteína Forkhead Box O3/efeitos dos fármacos , Glucosídeos/farmacologia , NF-kappa B/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fenilpropionatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Água Corporal/metabolismo , Isquemia Encefálica/genética , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/patologia , Fosforilação , Ratos , Ratos Sprague-Dawley
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