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1.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672046

RESUMO

Substituted N-phenyl cinnamamide derivatives were designed and synthesized to confirm activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway by the electronic effect on beta-position of Michael acceptor according to introducing the R1 and R2 group. Compounds were screened using the Nrf2/antioxidant response element (ARE)-driven luciferase reporter assay. Compound 1g showed desirable luciferase activity in HepG2 cells without cell toxicity. mRNA and protein expression of Nrf2/ARE target genes such as NAD(P)H quinone oxidoreductase 1, hemeoxygenase-1, and glutamate-cysteine ligase catalytic subunit (GCLC) were upregulated by compound 1g in a concentration-dependent manner. Treatment with 1g resulted in increased endogenous antioxidant glutathione, showing strong correlation with enhanced GCLC expression for synthesis of glutathione. In addition, tert-butyl hydroperoxide (t-BHP)-generated reactive oxygen species were significantly removed by 1g, and the results of a cell survival assay in a t-BHP-induced oxidative cell injury model showed a cytoprotective effect of 1g in a concentration dependent manner. In conclusion, the novel compound 1g can be utilized as an Nrf2/ARE activator in antioxidative therapy.


Assuntos
Cinamatos/farmacologia , Citoproteção/efeitos dos fármacos , Glutationa/biossíntese , Hepatócitos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Elementos de Resposta Antioxidante/genética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Morte Celular/efeitos dos fármacos , Cinamatos/química , Glutationa/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Luciferases/metabolismo , Fator 2 Relacionado a NF-E2/agonistas , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido
2.
Phytomedicine ; 83: 153490, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33601255

RESUMO

BACKGROUND: Rosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation. PURPOSE AND STUDY DESIGN: The present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aß1-42-induced mouse model of AD. METHODS: BALB/c mice were divided into ten groups. Half were injected with Aß1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis. RESULTS: The results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aß1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid. CONCLUSION: Our findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aß1-42-induced neurotoxicity in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cinamatos/farmacologia , Cognição/efeitos dos fármacos , Depsídeos/farmacologia , Hipocampo/efeitos dos fármacos , Triterpenos/farmacologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Rosmarinus/química
3.
Int J Biol Macromol ; 173: 99-108, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460660

RESUMO

The present investigation reports an in-vitro study using combination of laccase and an enhancer capable of inhibiting the growth of pathogenic microorganisms, preventing biofilm formation, and whitening teeth. Laccase-cinnamic acid system remarkably inhibited the growth of Aggregatibacter actinomycetemcomitans, Candida albicans, S. aureus, and Streptococcus mutans whilst showed no significant effects on Gram-negative bacteria. Data presented that cinnamic acid (10 mM) with laccase (0.125 U ml-1) led to a maximum decrease of about 90%, in S. mutans biofilm formation. The confocal laser scanning microscopy showed considerable detachment of S. mutans cells from glass substratum. The combined laccase-cinnamic acid system could remove teeth discoloration caused by coffee. SEM of the teeth surface exhibited no damages such as surface cracking or fracture. Liquid chromatography-tandem mass spectrometry (LC-MS) and cyclic voltammetry (CV) studies showed that laccase can catalyze the one-electron oxidation of cinnamic acid to the respective radical. This radical can then undergo several fates, including recombination with another radical to form a dimeric species, dismutation of the radical back to cinnamic acid or decarboxylation to give various reduced oxygen species. Therefore, the redox potential values of phenolic monomers/oligomers are related with their biological activities.


Assuntos
Aggregatibacter actinomycetemcomitans/efeitos dos fármacos , Antibacterianos/farmacologia , Cinamatos/farmacologia , Proteínas Fúngicas/farmacologia , Lacase/farmacologia , Aggregatibacter actinomycetemcomitans/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Ácidos Cafeicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Catecóis/farmacologia , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Proteínas Fúngicas/isolamento & purificação , Ácido Gálico/farmacologia , Hidroquinonas/farmacologia , Lacase/isolamento & purificação , Lactobacillus/efeitos dos fármacos , Lactobacillus/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Oxirredução , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/crescimento & desenvolvimento , Clareadores Dentários/farmacologia
4.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498178

RESUMO

The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.


Assuntos
Hiperalgesia/metabolismo , Células do Corno Posterior/metabolismo , Receptor PAR-2/metabolismo , Anilidas/farmacologia , Animais , Carragenina/farmacologia , Carragenina/toxicidade , Cinamatos/farmacologia , Potenciais Pós-Sinápticos Excitadores , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Potenciais Pós-Sinápticos em Miniatura , Nociceptividade , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/fisiologia , Ratos , Ratos Wistar , Estaurosporina/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
5.
Nat Commun ; 12(1): 280, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436582

RESUMO

Developing effective drugs for Alzheimer's disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, we report an efficient, network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of AD with human iPSC-derived cerebral organoids (iCOs), including CRISPR-Cas9-edited isogenic lines. We use 1300 organoids from 11 participants to build a high-content screening (HCS) system and test blood-brain barrier-permeable FDA-approved drugs. Our study provides a strategy for precision medicine through the convergence of mathematical modeling and a miniature pathological brain model using iCOs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Encéfalo/patologia , Avaliação Pré-Clínica de Medicamentos , Redes Reguladoras de Genes , Organoides/patologia , Doença de Alzheimer/genética , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Redes Reguladoras de Genes/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Modelos Biológicos , Reprodutibilidade dos Testes , Fatores de Risco
6.
Anticancer Res ; 41(2): 747-756, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517279

RESUMO

BACKGROUND/AIM: Lapathoside A, a phenylpropanoid ester, was isolated from the roots of buckwheat by searching for bioactive compounds against human pancreatic cancer cells. MATERIALS AND METHODS: Buckwheat root extracts, prepared by 70% ethanol, were separated into n-hexane, methylene chloride, ethyl acetate, n-butanol, and water fraction by solvent partitioning. Seven fractions were obtained from the ethyl acetate fraction by liquid chromatography, and fraction No. 6 contained lapathoside A. The effects of lapathoside A on Panc-1 and SNU-213 human pancreatic cancer cell lines were examined. RESULTS: The structure of lapathoside A was determined by liquid chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, and nuclear magnetic resonance analysis. Next, we investigated whether lapathoside A has anticancer activity in human pancreatic cancer cell lines (PANC-1 and SNU-213). After treatment with 25 µM lapathoside A, viability of PANC-1 and SNU-213 cells decreased to about 40 and 27%, respectively. In addition, lapathoside A treatment also increased apoptosis while affecting the expression levels of apoptotic proteins. CONCLUSION: The effect of lapathoside A on apoptosis was confirmed in pancreatic cancer cell lines, supporting the application of lapathoside A in the treatment of pancreatic cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Cinamatos/farmacologia , Fagopyrum , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos Fitogênicos/isolamento & purificação , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Cinamatos/isolamento & purificação , Fagopyrum/química , Humanos , Neoplasias Pancreáticas/patologia , Transdução de Sinais
7.
Phytomedicine ; 80: 153382, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113506

RESUMO

BACKGROUND: Although gastroprotective drugs have been used for peptic ulcer disease prevention and treatment, side effects have been observed. Finding a safe and effective treatment strategy is important. PURPOSE: Edible Trichodesma khasianum (T. khasianum) Clarke leaves are considered to protect against peptic ulcers. However, scientific evidence of this effect of T. khasianum Clarke leaves remains limited. STUDY DESIGN/METHODS: In this study, we aimed to evaluate the effect of T. khasianum Clarke leaves on ethanol-induced gastric injury and gut microbiota using RAW 264.7 cells, RGM-1 cells, and BALB/c mice, respectively. RESULT: The rosmarinic acid was identified as the major component of T. khasianum Clarke leaves extracted by 80% ethanol (80EETC). The results showed that 80EETC suppressed inflammatory mediator protein levels in LPS-induced RAW 264.7 cells. Additionally, heat shock protein expression, antiapoptotic ability, and wound healing migration capability were increased by 80EETC pretreatment in RGM-1 cells with the ethanol-induced injury. Remarkably, pretreatment with 80EETC (150 mg/kg b.w.) promoted gastric mucosal healing by decreasing oxidative stress, inflammatory response, proapoptotic protein expression, and gastric mucosa damage in ethanol-induced gastric injury in mice. Crucially, no liver or kidney toxicities were observed by 80EETC oral gavage. Moreover, 80EETC increased gut microbiota diversity and short-chain fatty acid production. CONCLUSION: Our results illustrated the remarkable gastroprotective effect by 80EETC treatment in vitro and in vivo. These findings are the first to demonstrate the powerful protective effect of T. khasianum Clarke leaves against gastric mucosal injury development.


Assuntos
Boraginaceae/química , Cinamatos/farmacologia , Depsídeos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Cinamatos/análise , Depsídeos/análise , Etanol/toxicidade , Ácidos Graxos Voláteis/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Úlcera Péptica/prevenção & controle , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Células RAW 264.7
8.
Cell Death Dis ; 11(12): 1069, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318479

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder and frequently exacerbates in postmenopausal women. In NAFLD, the endoplasmic reticulum (ER) plays an important role in lipid metabolism, in which salubrinal is a selective inhibitor of eIF2α de-phosphorylation in response to ER stress. To determine the potential mechanism of obesity-induced NAFLD, we employed salubrinal and evaluated the effect of ER stress and autophagy on lipid metabolism. Ninety-five female C57BL/6 mice were randomly divided into five groups: standard chow diet, high-fat (HF) diet, HF with salubrinal, HF with ovariectomy, and HF with ovariectomy and salubrinal. All mice except for SC were given HF diet. After the 8-week obesity induction, salubrinal was subcutaneously injected for the next 8 weeks. The expression of ER stress and autophagy markers was evaluated in vivo and in vitro. Compared to the normal mice, the serum lipid level and adipose tissue were increased in obese mice, while salubrinal attenuated obesity by blocking lipid disorder. Also, the histological severity of hepatic steatosis and fibrosis in the liver and lipidosis was suppressed in response to salubrinal. Furthermore, salubrinal inhibited ER stress by increasing the expression of p-eIF2α and ATF4 with a decrease in the level of CHOP. It promoted autophagy by increasing LC3II/I and inhibiting p62. Correlation analysis indicated that lipogenesis in the development of NAFLD was associated with ER stress. Collectively, we demonstrated that eIF2α played a key role in obesity-induced NAFLD, and salubrinal alleviated hepatic steatosis and lipid metabolism by altering ER stress and autophagy through eIF2α signaling.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Fator de Iniciação 2 em Eucariotos/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Transdução de Sinais , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adiposidade/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Cinamatos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipidoses/complicações , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Tioureia/análogos & derivados , Tioureia/farmacologia
9.
Am J Chin Med ; 48(6): 1353-1368, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33016104

RESUMO

Diabetes mellitus is a chronic endocrine disease result from absolute or relative insulin secretion deficiency, insulin resistance, or both, and has become a major and growing public healthy menace worldwide. Currently, clinical antidiabetic drugs still have some limitations in efficacy and safety such as gastrointestinal side effects, hypoglycemia, or weight gain. Rosmarinus officinalis is an aromatic evergreen shrub used as a food additive and medicine, which has been extensively used to treat hyperglycemia, atherosclerosis, hypertension, and diabetic wounds. A great deal of pharmacological research showed that rosemary extract and its phenolic constituents, especially carnosic acid, rosmarinic acid, and carnosol, could significantly improve diabetes mellitus by regulating glucose metabolism, lipid metabolism, anti-inflammation, and anti-oxidation, exhibiting extremely high research value. Therefore, this review summarizes the pharmacological effects and underlying mechanisms of rosemary extract and its primary phenolic constituents on diabetes and relative complications both in vitro and in vivo studies from 2000 to 2020, to provide some scientific evidence and research ideas for its clinical application.


Assuntos
Abietanos/farmacologia , Abietanos/uso terapêutico , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Fenóis/farmacologia , Fenóis/uso terapêutico , Fitoterapia , Extratos Vegetais/química , Rosmarinus/química , Abietanos/isolamento & purificação , Animais , Anti-Inflamatórios , Antioxidantes , Cinamatos/isolamento & purificação , Depsídeos/isolamento & purificação , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação
10.
J Oleo Sci ; 69(11): 1487-1495, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33055443

RESUMO

Photoaged skin is characterized by the appearance of pigmented spots such as solar lentigos, deep wrinkles and sags, and progresses due to chronic sun exposure. Among the wavelengths of sunlight, UVA is responsible for the appearance of wrinkles and sags that originate from structural alterations in the dermis of photoaged skin such as the depletion of collagen fibers. Thus, improving and restoring collagen fibers is an effective approach to reduce skin photoaging and maintain a youthful appearance. This study was conducted to evaluate the potential of an extract of Ocimum basilicum (OC), which contains rosmarinic acid (RA), as an anti-photoaging material focusing on the capacity to restore collagen fibers that are disrupted due to intracellular oxidative stress. In spite of their relatively low capacities for chemical scavenging of reactive oxygen species (ROS), both OC and RA showed efficient removal of biological oxidative stress by reducing levels of intracellular ROS and carbonylated proteins (CPs) in fibroblasts following exposure to single or repetitive UVA irradiations. Fibroblasts irradiated with repetitive UVA as a model for chronic sun-exposed cells showed significant increases in matrix metalloproteinase-1 and decreases in type I collagen synthesis and formed reduced numbers of collagen fibers. Since both OC and RA restored the adverse phenomena caused by repetitive UVA irradiation, we conclude that OC containing RA is an effective anti-photoaging material.


Assuntos
Cinamatos/farmacologia , Colágeno/metabolismo , Colágeno/efeitos da radiação , Depsídeos/farmacologia , Derme/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Ocimum basilicum/química , Extratos Vegetais/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Células Cultivadas , Cinamatos/isolamento & purificação , Depsídeos/isolamento & purificação , Fibroblastos/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento da Pele/patologia
11.
PLoS One ; 15(9): e0236081, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960890

RESUMO

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of ß cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of ß cells. The purpose of this study was to assess whether an analogue of FR258900 can influence ß cell function. BF142 (Meso-Dimethyl 2,3-bis[(E)-3-(4-acetoxyphenyl)prop-2-enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence ß cell function and can support the insulin producing ability of ß cells.


Assuntos
Cinamatos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutaratos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Ácido Succínico/farmacologia , Animais , Linhagem Celular Tumoral , Cinamatos/química , Inibidores Enzimáticos/química , Glucose/metabolismo , Glutaratos/química , Glicogênio Fosforilase/metabolismo , Glicólise/efeitos dos fármacos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Metilação , Camundongos , Ácido Succínico/química
12.
PLoS One ; 15(9): e0239019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941497

RESUMO

The melanosome is a specialized membrane-bound organelle that is involved in melanin synthesis, storage, and transportation. In contrast to melanosome biogenesis, the processes underlying melanosome degradation remain largely unknown. Autophagy is a process that promotes degradation of intracellular components' cooperative process between autophagosomes and lysosomes, and its role for process of melanosome degradation remains unclear. Here, we assessed the regulation of autophagy and its contributions to depigmentation associated with Melasolv (3,4,5-trimethoxycinnamate thymol ester). B16F1 cells-treated with Melasolv suppressed the α-MSH-stimulated increase of melanin content and resulted in the activation of autophagy. However, introduction of bafilomycin A1 strongly suppressed melanosome degradation in Melasolv-treated cells. Furthermore, inhibition of autophagy by ATG5 resulted in significant suppression of Melasolv-mediated depigmentation in α-MSH-treated cells. Taken together, our results suggest that treatment with Melasolv inhibits skin pigmentation by promoting melanosome degradation via autophagy activation.


Assuntos
Cinamatos/farmacologia , Melanossomas/efeitos dos fármacos , Melanossomas/metabolismo , Animais , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/metabolismo , Macrolídeos/farmacologia , Melaninas/metabolismo , Melanócitos/metabolismo , Camundongos , Pigmentação/efeitos dos fármacos , Transtornos da Pigmentação/metabolismo , Pigmentação da Pele/efeitos dos fármacos , alfa-MSH/efeitos dos fármacos , alfa-MSH/metabolismo
13.
Sci Adv ; 6(35): eaba7910, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923629

RESUMO

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antivirais/farmacologia , Cinamatos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , ortoaminobenzoatos/farmacologia , Células A549 , Animais , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Cães , Células HEK293 , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/patologia , Ligação Proteica/genética , Transporte Proteico/efeitos dos fármacos , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/patologia
14.
J Toxicol Sci ; 45(7): 373-390, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612006

RESUMO

DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 µM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Dietilexilftalato/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/tratamento farmacológico , Inflamassomos/metabolismo , Fitoterapia , Animais , Boraginaceae , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Dietilexilftalato/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Disruptores Endócrinos/toxicidade , Hipotireoidismo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Ratos Sprague-Dawley , Células Epiteliais da Tireoide/efeitos dos fármacos
15.
Acta Cir Bras ; 35(3): e202000304, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32692796

RESUMO

PURPOSE: To investigate the protective effect of rosmarinic acid (RA) in ovarian ischemia/reperfusion injury using biochemical, histopathological, and immunohistochemical methods. METHODS: Wistar female rats (n = 32) were randomly divided into four groups: control, ischemia, ischemia-reperfusion, and ischemia-reperfusion with RA. Rosmarinic acid was given at a dose of 50 mg/kg by oral gavage three hours after reperfusion. Malondialdehyde (MDA) levels and glutathione peroxidase (GSH-Px) activities were determined in the ovary tissue homogenates for each rat. RESULTS: In the ischemia-reperfusion with RA group, the epithelial cells are regularly regulated at the periphery, and the degenerative changes in preantral and antral follicle cells are reduced. Follicle cells and cells in the corpus luteum showed a decrease in vascular endothelial growth factor (VEGF) expression, while VEGF demonstrated a positive reaction in vascular endothelial cells and stromal cells. The TNF-α expression due to the decreased degenerative effect and inflammation was positive in the macrophage cells. The expression of caspase-3 as an apoptosis change was negative in antral follicle cells and granular cells around the antral follicle. CONCLUSION: Different doses of RA may be useful in preventing ischemic damage after vascularization, inflammation, and apoptotic development after ischemia/reperfusion.


Assuntos
Cinamatos , Depsídeos , Doenças Ovarianas , Traumatismo por Reperfusão , Fator A de Crescimento do Endotélio Vascular , Animais , Antioxidantes , Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Células Endoteliais , Feminino , Inflamação , Malondialdeído , Doenças Ovarianas/tratamento farmacológico , Ratos , Ratos Wistar , Anormalidade Torcional/tratamento farmacológico
16.
Acta Cir Bras ; 35(4): e202000406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578724

RESUMO

PURPOSE: To investigate the role of Rosmarinic acid (RA) in the prevention of traumatic brain injury and the immunohistochemical analysis of IBA-1 and GFAP expressions. METHODS: Healthy male rats were randomly divided into 3 groups consisting of 10 rats. Groups were as follows; control group, traumatic brain injury (TBI) group, and TBI+RA group. After traumatic brain injury, blood samples were taken from the animals and analyzed with various biochemical markers. And then IBA-1 and GFAP expressions were evaluated immunohistochemically. RESULTS: Significant results were obtained in all biochemical parameters between groups. Immunohistochemical sections showed IBA-1 not only in microglia and macrophage activity but also in degenerative neurons in blood vessel endothelial cells. However, GFAP reaction and post-traumatic rosmarinic acid administration showed positive expression in astrocytes with regular structure around the blood vessel. CONCLUSION: Rosmarinic acid in blood vessel endothelial cells showed that preserving the integrity of astrocytic structure in the blood brain barrier may be an important antioxidant.


Assuntos
Lesões Encefálicas Traumáticas/prevenção & controle , Proteínas de Ligação ao Cálcio/análise , Cinamatos/farmacologia , Craniotomia/métodos , Depsídeos/farmacologia , Proteína Glial Fibrilar Ácida/análise , Proteínas dos Microfilamentos/análise , Fármacos Neuroprotetores/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/cirurgia , Glutationa Peroxidase/análise , Imuno-Histoquímica , Masculino , Malondialdeído/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes
17.
Int J Food Microbiol ; 328: 108664, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32474229

RESUMO

To control Pseudomonas and Shewanella as important psychrotrophic spoilage bacteria in fish meat, we used ethanolic extracts of oregano (Origanum vulgare subsp. vulgare) and nettle (Urtica dioica), with phytochemical characterisation of the extracts and their bioactive compounds. Liquid chromatography coupled with photodiode array detection and electrospray ionisation-mass spectrometry was used for qualitative compositional determination of the extracts. Four main compounds were identified in the oregano extract, with rosmarinic acid the most abundant, followed by three glycosylated phenolics, one of which is reported for the first time in O. vulgare: 4'-O-ß-d-glucopyranosyl-3',4'-dihydroxybenzyl-4-hydroxybenzoate. Six main compounds were identified in the nettle extract, as caffeoylmalic acid and five flavonoid glycosides. These oregano and nettle ethanolic extracts showed in-vitro antimicrobial activities against selected Pseudomonas and Shewanella strains in broth and fish meat homogenate when evaluated at two inoculum concentrations. The antimicrobial activities were more pronounced for the nettle extract at the lower inoculum concentration, and for both the Shewanella strains. Growth inhibition in the fish meat homogenate was evaluated at 3.13 mg/mL and 1.56 mg/mL at 5 °C. Again, the nettle extract showed greater antimicrobial activity, which was seen as the lowest maximum growth rate, followed by the oregano extract, which was inhibitory only at 3.13 mg/mL. Finally, the extracts were applied to fish meat that was then stored at 5 °C for 9 days. Evaluation here was for the counts of the mesophilic, psychrotrophic, Pseudomonas and H2S producers. These confirmed the better antimicrobial effects of the nettle extract, especially against the H2S-producing bacteria, which included Shewanella. Both of the extracts were rich in glycosides of flavonoids and phenolic acids. The enzymatic activities of the Pseudomonas and Shewanella spoilage bacteria and their actions on the phenolic glycosides from natural sources will be further investigated.


Assuntos
Doenças dos Peixes/tratamento farmacológico , Origanum/química , Extratos Vegetais/farmacologia , Pseudomonas/efeitos dos fármacos , Shewanella/efeitos dos fármacos , Urtica dioica/química , Animais , Ácidos Cafeicos/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Peixes/microbiologia , Flavonoides , Microbiologia de Alimentos , Hidroxibenzoatos/farmacologia , Malatos/farmacologia , Fenóis/química , Alimentos Marinhos/microbiologia , Espectrometria de Massas por Ionização por Electrospray
18.
J Stroke Cerebrovasc Dis ; 29(8): 104818, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32439352

RESUMO

BACKGROUND: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear. METHODS: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO. RESULTS: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice. CONCLUSION: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Cinamatos/farmacologia , Depsídeos/farmacologia , Suplementos Nutricionais , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Aldeídos/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Camundongos Endogâmicos C57BL
19.
J Steroid Biochem Mol Biol ; 202: 105697, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461092

RESUMO

Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cinamatos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cinamatos/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Nus , Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/farmacologia
20.
Biochem Pharmacol ; 177: 113984, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32311348

RESUMO

Pluripotent stem cells are have therapeutic applications in regenerative medicine and drug discovery. However, the differentiation of stem cells in vitro hinders their large-scale production and clinical applications. The maintenance of cell pluripotency relies on a complex network of transcription factors; of these, octamer-binding transcription factor-4 (Oct4) plays a key role. This study aimed to construct an Oct4 gene promoter-driven firefly luciferase reporter and screen small-molecule compounds could maintain cell self-renewal and pluripotency. The results showed that ethyl-p-methoxycinnamate (EPMC) enhance the promoter activity of the Oct4 gene, increased the expression of Oct4 at both mRNA and protein levels, and significantly promoted the colony formation of P19 cells. These findings suggesting that EPMC could reinforce the self-renewal capacity of P19 cells. The pluripotency markers Oct4, SRY-related high-mobility-group-box protein-2, and Nanog were expressed at higher levels in EPMC-induced colonies. EPMC could promote teratoma formation and differentiation potential of P19 cells in vivo. It also enhanced self-renewal and pluripotency of human umbilical cord mesenchymal stem cells and mouse embryonic stem cells. Moreover, it significantly activated the nuclear factor kappa B (NF-κB) signaling pathway via the myeloid differentiation factor 88-dependent pathway. The expression level of Oct4 decreased after blocking the NF-κB signaling pathway, suggesting that EPMC promoted the expression of Oct4 partially through the NF-κB signaling pathway. This study indicated that EPMC could maintain self-renewal and pluripotency of stem cells.


Assuntos
Autorrenovação Celular/efeitos dos fármacos , Cinamatos/farmacologia , NF-kappa B/genética , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco Pluripotentes/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/agonistas , NF-kappa B/metabolismo , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/agonistas , Fator 3 de Transcrição de Octâmero/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais/genética
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