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1.
Life Sci ; 261: 118433, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950572

RESUMO

AIMS: Sinomenine (SIN) is clinically used as an anti-rheumatic drug. However, the metabolic and pharmacological mechanisms of SIN combined with its metabolites are unclear. This study aims to explore the cyclic metabolic mechanism of SIN, the anti-inflammation effects of SIN and its major metabolites (N-demethylsinomenine (DS) and sinomenine-N-oxide (SNO)), and the oxidation property of SNO. MATERIALS AND METHODS: SIN was administrated to rats via gavage. Qishe pills (a SIN-containing drug) were orally administrated to humans. The bio-samples were collected to identify SIN's metabolites. Enzymatic and non-enzymatic incubations were used to reveal SIN's metabolic mechanism. Impacts of SIN, SNO and DS on the inflammation-related cytokine's levels and nuclear translocation of NF-κB were evaluated in LPS-induced Raw264.7 cells. ROS induced by SNO (10 µM) was also assessed. KEY FINDINGS: CYP3A4 and ROS predominantly mediated the formation of SNO, and CYP3A4 and CYP2C19 primarily mediated the formation of DS. Noteworthily, SNO underwent N-oxide reduction both enzymatically, by xanthine oxidase (XOD), and non-enzymatically, by ferrous ion and heme moiety. The levels of IL-6 and TNF-α and nuclear translocation of NF-κB were ameliorated after pretreatment of SIN in LPS-induced Raw264.7 cells, while limited attenuations were observed after pretreatment of DS (SNO) even at 200 µM. In contrast, SNO induced ROS production. SIGNIFICANCE: This study elucidated that SIN underwent both enzymatic and non-enzymatic cyclic metabolism and worked as the predominant anti-inflammation compound, while SNO induced ROS production, suggesting more studies of SIN combined with SNO and DS are necessary in case of DDI and potential toxicities.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Morfinanos/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Morfinanos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
2.
EBioMedicine ; 59: 102969, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32853989

RESUMO

Coronavirus disease-2019 (COVID-19) is associated with severe inflammation in mainly the lung, and kidney. Reports suggest a beneficial effect of the use of heparin/low molecular weight heparin (LMWH) on mortality in COVID-19. In part, this beneficial effect could be explained by the anticoagulant properties of heparin/LMWH. Here, we summarise potential beneficial, non-anticoagulant mechanisms underlying treatment of COVID-19 patients with heparin/LMWH, which include: (i) Inhibition of heparanase activity, responsible for endothelial leakage; (ii) Neutralisation of chemokines, and cytokines; (iii) Interference with leukocyte trafficking; (iv) Reducing viral cellular entry, and (v) Neutralisation of extracellular cytotoxic histones. Considering the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of heparin/LMWH in COVID-19 patients. In addition, identification of specific heparin-derived sequences that are functional in targeting non-anticoagulant mechanisms may have even higher therapeutic potential for COVID-19 patients, and patients suffering from other inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Heparina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Glucuronidase/antagonistas & inibidores , Glucuronidase/metabolismo , Heparina/metabolismo , Heparina/farmacologia , Heparina de Baixo Peso Molecular/metabolismo , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Histonas/sangue , Histonas/metabolismo , Humanos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Internalização do Vírus/efeitos dos fármacos
3.
Mol Immunol ; 126: 40-45, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32750537

RESUMO

Oxidative stress-related injury is a negative state caused by the imbalance between oxidation and antioxidant effects in the internal environment of the body. Oxidative stress has been confirmed to be an important factor in aging and a variety of diseases and the inhibition of inappropriate oxidative stress responses are important for maintaining normal physiological functions. Recently, considerable attention has been focused on specialized pro-resolving mediators(SPMs). SPMs are endogenous mediators derived from polyunsaturated fatty acids, which have multiple protective effects such as anti-inflammation, pro-resolution, and promoting tissue damage repair, etc. Moreover, the role of SPMs on oxidative stress has been extensively researched and provides a possible treatment method. In the current study, we review the positive role of SPMs in oxidative stress-related disease and outline the possible involved mechanism, thus providing the theoretical support for a better understanding of the roles of SPMs in oxidative stress and the theoretical basis for finding targets for the oxidative stress-related diseases.


Assuntos
Anti-Inflamatórios/metabolismo , Ácidos Graxos Insaturados/metabolismo , Inflamação/imunologia , Estresse Oxidativo/imunologia , Animais , Anti-Inflamatórios/imunologia , Modelos Animais de Doenças , Ácidos Graxos Insaturados/imunologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
4.
ACS Chem Neurosci ; 11(15): 2137-2144, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32639711

RESUMO

Now, it has been evidenced that Covid19 (SARS-CoV-2) infects the brain tissues. Along with this, a challenge has been raised for research professionals to find effective drugs for its treatment since the recent spread of this virus from Wuhan, China. Targeting the treatment of brain infection, it has also been a challenge that the clinical drug should have good CNS penetration ability to cross the blood-brain barrier.


Assuntos
Betacoronavirus , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Antivirais/administração & dosagem , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/virologia , Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Metilprednisolona/administração & dosagem , Metilprednisolona/metabolismo , Pandemias , Resultado do Tratamento
5.
Life Sci ; 256: 117908, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512011

RESUMO

BACKGROUND: Excessive alcohol intake contributes to severe liver damage involving oxidative stress and inflammatory responses, which make them promising therapeutic targets. Previous studies have demonstrated that empagliflozin (EMPA) showed cardiovascular, renal, and cerebral benefits potentially mediated through its antioxidant and anti-inflammatory actions. AIMS: This experiment aimed to evaluate the hepatoprotective effect of EMPA on alcoholic liver disease (ALD) and the possible underlying mechanisms. MATERIALS AND METHODS: Serum biochemical parameters and the liver contents of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Real-time qPCR was conducted to determine the gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (Hmox-1). In addition, ELISA was performed to measure tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, Nrf-2, and PPAR-γ. Nuclear factor-kappa B (NF-κB) was detected by immunohistochemical staining using an anti-NF-κB p65 antibody. KEY FINDINGS: Our results revealed that the serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were significantly reduced by EMPA. EMPA also decreased the content of MDA and NO and increased the activities of SOD and GSH in liver homogenates. Moreover, EMPA inhibited the release of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, via the downregulation of NF-κB. These changes were associated with an improvement in histopathological deterioration. The protective effect of EMPA against oxidative stress and inflammation was associated with the upregulation of PPAR-γ, Nrf-2, and their target gene Hmox-1. SIGNIFICANCE: EMPA showed protective activities against ethanol-induced liver injury by suppressing inflammation and oxidative stress via modulation of the NF-κB/Nrf-2/PPAR-γ axis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glucosídeos/farmacologia , NF-kappa B/metabolismo , PPAR gama/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Compostos Benzidrílicos/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Descoberta de Drogas , Etanol/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Interleucinas/metabolismo , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/genética , Superóxido Dismutase/metabolismo
6.
J Food Sci ; 85(7): 1983-1987, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32572984

RESUMO

Because omega-3 fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their metabolites are known to possess anti-inflammatory and health-promoting functions in human and experimental animals, their intake is assumed to be beneficial for maintaining our health. We previously identified a cytochrome P450-metabolite of EPA, 5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE), as a novel bioactive lipid, which inhibits vascular hyperpermeability in inflammation. Because blue back fishes including sardine, mackerel, and horse mackerel are reported to contain high concentrations of omega-3 fatty acids, we investigated which tissue of blue back fish is suitable as a source of 5,6-DiHETE. We measured the concentration of 5,6-DiHETE as well as major fatty acids in muscle, bone, heart, liver, and intestine of blue back fishes. Arachidonic acid was detected richer in intestines than other tissues of blue back fishes. The concentrations were between 4.45 and 5.62 µg/g tissue weight. EPA and DHA are also detected richer in intestines of blue back fishes. The concentrations were between 75.95 and 358.04 µg/g, and 203.09 and 464.88 µg/g, respectively. Especially, mackerel intestine contained the highest levels of both EPA and DHA. 5,6-DiHETE was present in greater amount in livers and intestines of blue back fishes. The livers contained 118.98 to 476.11 ng/g, whereas intestines contained 156.14 to 970.22 ng/g of 5,6-DiHETE. Of interest, sardine intestine contained much higher level of 5,6-DiHETE than the other fish tissues. These results suggest that visceral organs of blue back fishes, remarkably sardine intestine, can be a good source of 5,6-DiHETE. PRACTICAL APPLICATION: A novel anti-inflammatory lipid, 5,6-DiHETE, was detected in each tissues of blue back fishes. Especially their intestines contain the highest concentration of this lipid.


Assuntos
Anti-Inflamatórios/química , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/química , Peixes/metabolismo , Animais , Anti-Inflamatórios/metabolismo , Ácido Eicosapentaenoico/análise , Ácido Eicosapentaenoico/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/química , Alimentos Marinhos/análise
7.
J Dairy Sci ; 103(8): 6771-6781, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32505409

RESUMO

Hypoallergenic formulas are recommended for infants who are not breastfed and cannot tolerate cow milk formulas due to allergy. These formulas are hydrolyzed to break down larger protein chains into shorter, easy-to-digest, and potentially less allergenic proteins. Hydrolysis, however, possibly occurs at the expense of the transforming growth factor beta (TGF-ß) and anti-inflammatory activity that is inherent in regular formula. Our objective was to determine the TGF-ß and the anti-inflammatory activity of commercially available hypoallergenic and regular formulas. Human gingival fibroblasts were incubated with reconstituted formulas followed by detection of TGF-ß target genes and activation of Smad2/3 signaling. Gingival fibroblasts and the oral squamous cell carcinoma cell line HSC-2 were also exposed to formulas before adding interleukin (IL)1ß and tumor necrosis factor (TNF)α to provoke expression of pro-inflammatory cytokines. For murine bone marrow-derived macrophages, pro-inflammatory cytokine expression was stimulated with saliva. Changes in p65 nuclear translocation and phosphorylation of smad3 and p38 were analyzed by immunostaining. Our study demonstrated that regular formula, but not hypoallergenic formula, enhanced the expression of TGF-ß target genes IL11, PRG4, and NOX4 in gingival fibroblasts. Hypoallergenic formulas also failed to initiate nuclear translocation of Smad2/3 and phosphorylation of Smad3. Moreover, regular formulas were more potent than hypoallergenic formulas in reducing the expression of pro-inflammatory cytokines in gingival fibroblasts, HSC-2 epithelial cells, and murine bone marrow macrophages. Hypoallergenic and regular formulas had a similar capacity to reduce p65 nuclear translocation and phosphorylation of p38 in fibroblasts. These findings suggest that hypoallergenic formulas lack in vitro TGF-ß activity and have a lower anti-inflammatory activity compared with regular formulas.


Assuntos
Hipersensibilidade Alimentar/etiologia , Fórmulas Infantis , Fator de Crescimento Transformador beta/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Bovinos , Linhagem Celular Tumoral , Citocinas/metabolismo , Fibroblastos/metabolismo , Humanos , Lactente , Fórmulas Infantis/efeitos adversos , Fórmulas Infantis/química , Camundongos , Leite/imunologia , Leite/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
8.
Chemosphere ; 256: 127038, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32470728

RESUMO

Baicalein is a flavonoid that is widely found in plants. Studies have shown that baicalein has anti-inflammatory, anti-cancer, and liver-protective effects. However, the effects of baicalein on TAA-induced toxicity and the underlying molecular mechanisms in zebrafish larvae are still unknown. Here, we investigated the effects of baicalein on liver development and its anti-inflammatory effects in zebrafish larvae. The results showed that baicalein has significant anti-embryonic developmental toxicity and significant antioxidant and anti-inflammatory capabilities in TAA-induced zebrafish larvae and promotes liver development and cell proliferation, reduces the expression of apoptotic proteins, and induces the expression of anti-apoptotic proteins. At the molecular level of TAA-treated zebrafish larvae, there was a decrease in the relative expression levels of mRNAs of three subfamilies, P38, ERK1, and ERK2, of the MAPK-signaling pathway and of the products of peroxisome proliferator-activated receptor (PPAR)α. Compared with TAA-treated zebrafish larvae, zebrafish larvae treated with baicalein showed an increase in the relative expression levels of P38, ERK1, and ERK2 mRNAs and the downstream products of PPARα. When MAPK signal inhibitor (SB203580) was added, it was found that liver development was inhibited and baicalin had no protective effect on TAA induced hepatotoxicity in zebrafish larvae. The results showed baicalein can protect the zebrafish larvae against toxicity induced by TAA through MAPK signal pathway. Several molecular mechanisms discovered in this study may help in the development of new drugs.


Assuntos
Flavanonas/toxicidade , Tioacetamida/toxicidade , Peixe-Zebra/fisiologia , Animais , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Flavonoides , Larva/efeitos dos fármacos , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , PPAR alfa , Substâncias Protetoras/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Nat Commun ; 11(1): 2286, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385332

RESUMO

Studies on macrophage gene expression have historically focused on events leading to RNA polymerase II recruitment and transcription initiation, whereas the contribution of post-initiation steps to macrophage activation remains poorly understood. Here, we report that widespread promoter-proximal RNA polymerase II pausing in resting macrophages is marked by co-localization of the negative elongation factor (NELF) complex and facilitated by PU.1. Upon inflammatory stimulation, over 60% of activated transcriptome is regulated by polymerase pause-release and a transient genome-wide NELF dissociation from chromatin, unexpectedly, independent of CDK9, a presumed NELF kinase. Genetic disruption of NELF in macrophages enhanced transcription of AP-1-encoding Fos and Jun and, consequently, AP-1 targets including Il10. Augmented expression of IL-10, a critical anti-inflammatory cytokine, in turn, attenuated production of pro-inflammatory mediators and, ultimately, macrophage-mediated inflammation in vivo. Together, these findings establish a previously unappreciated role of NELF in constraining transcription of inflammation inhibitors thereby enabling inflammatory macrophage activation.


Assuntos
Anti-Inflamatórios/metabolismo , Regulação da Expressão Gênica , Inflamação/genética , Macrófagos/patologia , Fatores de Transcrição/metabolismo , Animais , Cromatina/metabolismo , Interleucina-10/metabolismo , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Camundongos , Motivos de Nucleotídeos/genética , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Sítio de Iniciação de Transcrição , Transcrição Genética , Ativação Transcricional/genética
10.
Poult Sci ; 99(5): 2819-2832, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359619

RESUMO

Our patented protease A-digested crude chalaza hydrolysates (CCH) show antioxidant abilities in vitro. The prophylactic effects of CCH on cognitive dysfunction and brain oxidative damages were investigated via a D-galactose (DG)-injected mouse model in this study. Fifty-four mice were randomly divided into the following: (1) CON, 0.1 mL 0.9% saline (subcutaneous injection [SC] on the back)+distilled water (oral gavage); (2) DG, 100 mg/kg BW/day D-galactose (Bio-Serv Co., Flemington, NJ, USA) (SC on the back)+distilled water (oral gavage); (3) DG_LCH, 100 mg/kg BW/day D-galactose (SC on the back) + 50 mg CCH/kg BW/day in 0.1 ml distilled water (oral gavage); (4) DG_MCH, 100 mg/kg BW/day D-galactose (SC on the back) + 100 mg CCH/kg BW/day (oral gavage); (5) DG_HCH, 100 mg/kg BW/day D-galactose (SC on the back) + 200 mg CCH/kg BW/day (oral gavage); (6) DG_AG, 100 mg/kg BW/day D-galactose (SC on the back) + 100 mg aminoguanidine hydrochloride/kg BW/day (oral gavage). The experiment lasted for 84 D. CCH, containing antioxidant-free amino acids and anserine, restored (P < 0.05) DG-injected memory injury in the Morris water maze test and attenuated the neuronal degenerations and nucleus shrinkages in the dentate gyrus area. CCH supplementation also reduced amyloid ß-peptide protein levels and accumulation of advanced glycation end products (AGE) in the brain of DG-injected mice, whereas the brain antioxidant capacity was reversed (P < 0.05) by supplementing CCH. Furthermore, AGE receptor (RAGE), NFκb, IL-6, and TNF-α gene expressions were downregulated (P < 0.05) by supplementing CCH. Therefore, CCH show prophylactic effects on the development of oxidative stress-induced cognitive dysfunction.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Gema de Ovo/química , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Anserina/análise , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Carnosina/análise , Galinhas , Hipocampo/fisiologia , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Hidrolisados de Proteína/química
11.
J. negat. no posit. results ; 5(5): 478-490, mayo 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-194124

RESUMO

BACKGROUND: Polyphenol-rich olive extracts are non-toxic and have anti-inflammatory, neuroprotective and antiadipogenic effects in cell and animal models. OBJECTIVE: To evaluate the potential influence of olive extracts on the mechanisms of digestion and absorption of polysaccharides and fats by quantifying amylase, glucose, phospholipase, and cholesterol in the medaka fish model. MATERIAL AND METHODS: For each assay, six adult fish were placed in a tank with an extract (0.01% concentration), performing three replicates per extract. A control group with standard feeding was used. The same procedure was followed to study glucose, adding a polysaccharide-rich diet and a corresponding overfed control. The fish were maintained under these conditions for five days. Five olive extracts were used without attempting to purify the polyphenols due to possible synergistic effects. Total concentrations were between 2-116mg/g (mainly oleuropein and hydroxytyrosol). On completion, amylase, phospholipase A2, glucose and cholesterol were quantified in each group. All assays were conducted in triplicate. Enzyme activities were also studied in juveniles. Non-parametric tests were used to determine possible differences, considering p < 0.05 to denote statistical significance. RESULTS: Polyphenol extracts were not toxic at a concentration of 0.1%, ten times higher than the concentration used. An overall decrease in glucose levels was observed in fish overfed with carbohydrates with the addition of the extracts, but without returning to the levels in the control group with standard feeding (between 15-40% decrease). There was no impact on amylase in adults or juveniles, an overall but not significant decrease in cholesterol, and an overall increase in phospholipase in the juveniles. CONCLUSION: Olive extracts rich in polyphenols lower glucose levels in overfed fish


ANTECEDENTES: Los extractos de aceitunas ricos en polifenoles no son tóxicos y tienen efectos antiinflamatorios, neuroprotectores y antiadipogénicos en modelos celulares y animales. OBJETIVO: Evaluar la influencia potencial de los extractos de aceituna en los mecanismos de digestión y absorción de polisacáridos y grasas mediante la cuantificación de amilasa, glucosa, fosfolipasa y colesterol en el modelo de pez medaka. MATERIAL Y MÉTODOS: Para cada ensayo, se colocaron seis peces adultos en un tanque con un extracto (al 0,01%), realizando tres repeticiones por extracto. Se usó un grupo control con alimentación estándar. Se siguió el mismo procedimiento para estudiar la glucosa, agregando una dieta rica en polisacáridos y un control de sobrealimentados. Los peces se mantuvieron en estas condiciones durante cinco días. Se usaron cinco extractos del olivo sin intentar purificar los polifenoles debido a posibles efectos sinérgicos. Las concentraciones totales fueron entre 2-116 mg/g (principalmente oleuropeína e hidroxitirosol). Al finalizar, se cuantificaron amilasa, fosfolipasa A2, glucosa y colesterol en cada grupo. Todos los ensayos se realizaron por triplicado. Las actividades enzimáticas también se estudiaron en alevines. Se utilizaron pruebas no paramétricas para determinar posibles diferencias, considerando p <0.05 para significación estadística. RESULTADOS: Los extractos de polifenoles no fueron tóxicos a una concentración de 0.1%, diez veces mayor que la concentración utilizada. Se observó una disminución general en los niveles de glucosa en peces sobrealimentados con carbohidratos con la adición de extractos, pero sin volver a los niveles del grupo control con alimentación estándar (disminución entre 15-40%). No hubo impacto sobre la amilasa en adultos o juveniles, se observó una disminución general pero no significativa del colesterol y un aumento general de la fosfolipasa en los juveniles. CONCLUSIÓN: Los extractos de aceitunas ricos en polifenoles reducen los niveles de glucosa en peces sobrealimentados


Assuntos
Animais , Peixes/metabolismo , Polifenóis/farmacocinética , Anti-Inflamatórios/metabolismo , Glicemia/análise , Colesterol/sangue , Olea/metabolismo , Extratos Vegetais/metabolismo , Fatores de Proteção , Modelos Animais
12.
Food Chem ; 322: 126710, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32283363

RESUMO

Sourdough fermentation influences several properties of leavened baked goods also because Lactic acid bacteria (LAB) and yeasts produce bioactive peptides with a positive effect on human health. In an early study, three Lactobacilli strains (L. farciminis H3 and A11 and L. sanfranciscensis I4) possessing different proteolytic activities were used to produce sourdoughs containing peptides equipped with anti-inflammatory and/or antioxidant properties. This work was aimed to assess whether these properties could be retained after cooking. The selected LABs were used to produce breads from which low molecular weight (LMW-) peptides were extracted. The results provide solid proofs of keeping both antioxidant and anti-inflammatory activities of peptides from cooked products. Sequences of LMW-peptides either from doughs and breads were determined by mass spectrometry: differences have been noticed in amino acidic composition and in sequences, however, all the strains produce peptides equipped with antioxidant and anti-inflammatory activities.


Assuntos
Anti-Inflamatórios/análise , Antioxidantes/análise , Pão/análise , Pão/microbiologia , Lactobacillus/metabolismo , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Fermentação , Farinha/análise , Microbiologia de Alimentos , Humanos , Peptídeos/análise , Peptídeos/metabolismo , Leveduras/metabolismo
13.
Life Sci ; 253: 117673, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32311377

RESUMO

Aging effects in energy balance in all tissues and organs, including the cardiovascular. The risk of cardiovascular disease is drastically higher in postmenopausal women than in premenopausal women. Estrogen plays an important role in the cardiac function and body's metabolism. The aim of this study was to determine whether 17ß-estradiol (E2) has beneficial effects on insulin resistance and some key stages of the insulin signalling pathway in the aged hearts. Young and aged female Wistar rats were ovariectomized and were randomly divided into three groups: young (YS) and aged (AS) sham, young (YV) and aged (AV) vehicle, and young (YE2) and aged (AE2) E2 treatment groups. E2 (1 mg/kg) was administrated every four days for four weeks. Results showed that ovariectomy increased fasting blood glucose, insulin, and HOMAIR in young, while none of these parameters was affected in aged animals. On the other hand, aging itself increased these variables. Furthermore, E2 therapy alleviated these changes in both young and aged animals. Moreover, aging also decreased the p-IRS1, p-Akt level, and translocation of GLUT4 to the plasma membrane. E2 reduced the negative impact of menopause and aging on insulin sensitivity by favoring increase in the level of IL-10 and decrease in the levels of TNF-α and IL-1ß. Our results indicated that the heart response to E2 depended on age, and E2 increased insulin sensitivity in the heart of both young and aged animals by altering inflammatory conditions. Determining the exact mechanism of this action is suggested in future studies.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Insulina/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Menopausa/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar , Transdução de Sinais
14.
Life Sci ; 253: 117606, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32320707

RESUMO

BACKGROUND/AIMS: In cirrhosis, the levels of proinflammatory cytokines are high in the liver and blood. Endotoxin decreases level of consciousness in cirrhotic rats. Phosphatidylserine exists in the cell membrane structure and is essential for the survival of neurons. Phosphatidylserine receptor is found in phagocytic cells and also activates the signaling of membrane proteins in apoptotic process. Therefore this study was aimed to explore the hypothesis that hepatic encephalopathy is prevented by phosphatidylserine treatment and if so, whether this is associated with altered level of proinflammatory cytokines in the brain. METHODS: Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. The groups were treated with phosphatidylserine and saline for 4 weeks. Brain IL6, TNFα and the expression of phosphatidylserine receptor were assessed. Intraperitoneal injections of either saline or lipopolysaccharide (0.1 mg/kg) were administered to each group. Finally, animal behavior, blood ammonia and the expression of toll like receptor 4 were examined in the brain. RESULTS: Cirrhosis in rats was associated with altered expression of toll-like receptor4 in brain cortex and phosphatidylserine treatment increases toll-like receptor4 receptor expression. Phosphatidylserine had anti-inflammatory effect in healthy rats but no effect in cirrhotic rats. Chronic phosphatidylserine treatment decreased blood ammonia in BDL cirrhotic rats treated with lipopolysaccharide. CONCLUSION: The brain of cirrhotic rat is more susceptible to acute endotoxemia and chronic phosphatidylserine treatment decreases blood ammonia and encephalopathy in cirrhotic rats by encountering endotoxin. Phosphatidylserine may boost immune system against endotoxin.


Assuntos
Anti-Inflamatórios/farmacologia , Endotoxemia/tratamento farmacológico , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/prevenção & controle , Cirrose Hepática/metabolismo , Fosfatidilserinas/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Ductos Biliares/metabolismo , Encéfalo , Citocinas/metabolismo , Endotoxinas/metabolismo , Encefalopatia Hepática/complicações , Lipopolissacarídeos/metabolismo , Fígado , Cirrose Hepática Experimental , Masculino , Fagócitos/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Ratos , Ratos Wistar , Receptores de Superfície Celular/metabolismo , Receptor 4 Toll-Like/metabolismo , Resultado do Tratamento
15.
J Endocrinol ; 245(2): 291-300, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171180

RESUMO

Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.


Assuntos
Anti-Inflamatórios/metabolismo , Proteínas do Olho/metabolismo , Hiperandrogenismo/metabolismo , Fatores de Crescimento Neural/metabolismo , Síndrome do Ovário Policístico/metabolismo , Serpinas/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Di-Hidrotestosterona , Modelos Animais de Doenças , Feminino , Células da Granulosa/metabolismo , Humanos , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/complicações , Camundongos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente
16.
J Med Chem ; 63(8): 4090-4106, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202425

RESUMO

Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/metabolismo , Descoberta de Drogas/métodos , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Células 3T3 , Administração Oral , Animais , Anti-Inflamatórios/química , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Pirazóis/administração & dosagem , Pirazóis/química , Pirazóis/metabolismo , Resultado do Tratamento
17.
J Med Chem ; 63(7): 3665-3677, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32162512

RESUMO

TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here, we report (1S,3R)-3-((4-(6-methylbenzo[d]thiazol-2-yl)phenyl)carbamoyl)cyclopentane-1-carboxylic acid (C3001a), a selective activator for TREK, against other two-pore domain K+ (K2P) channels. C3001a binds to the cryptic binding site formed by P1 and TM4 in TREK-1, as suggested by computational modeling and experimental analysis. Furthermore, we identify the carboxyl group of C3001a as a structural determinant for binding to TREK-1/2 and the key residue that defines the subtype selectivity of C3001a. C3001a targets TREK channels in the peripheral nervous system to reduce the excitability of nociceptive neurons. In neuropathic pain, C3001a alleviated spontaneous pain and cold hyperalgesia. In a mouse model of acute pancreatitis, C3001a alleviated mechanical allodynia and inflammation. Together, C3001a represents a lead compound which could advance the rational design of peripherally acting analgesics targeting K2P channels without opioid-like adverse effects.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzotiazóis/uso terapêutico , Inflamação Neurogênica/tratamento farmacológico , Dor/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem/agonistas , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Sítios de Ligação , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Pancreatite/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem/química , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade
18.
Sci Rep ; 10(1): 4138, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139778

RESUMO

Diatoms are the most diverse and abundant group of phytoplankton species and represent a huge reservoir of marine natural products with possible application for human health. Several diatoms are known to have anticancer, anti-inflammatory, antioxidant and anti-microbial properties, but the compounds responsible of these activities are often still unknown. The diatom Cylindrotheca closterium showed anti-inflammatory properties inhibiting TNFα release in human monocytic leukemia cells. In this study, we present the full transcriptome of C. closterium, and used an -omic approach to identify transcripts coding enzymes that can be involved in the synthesis/degradation of anti-inflammatory compounds. This approach allowed to identify phosphatidylinositol-3-phosphatase, phosphatidylinositol 3-kinase catalytic subunit type 3, phosphatidylinositol N-acetylglucosaminyltransferase subunit A, monogalactosyldiacylglycerol synthase and violaxanthin de-epoxidase, which are known to be involved in anti-inflammatory compound metabolism. When C. closterium was cultured in silica-starvation conditions, selected as stress condition to potentially trigger the synthesis of bioactive metabolites, anti-inflammatory activity was lost and expression levels of the analyzed transcripts were reduced. These data suggested that the control culturing condition was the most active. This study used for the first time a transcriptomic-guided approach to identify enzymes involved in anti-inflammatory compound metabolism, directing future discoveries of marine natural products in microalgae.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Closterium/genética , Closterium/metabolismo , Diatomáceas/genética , Diatomáceas/metabolismo , Transcriptoma/genética , Classe III de Fosfatidilinositol 3-Quinases/genética , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo
19.
AAPS PharmSciTech ; 21(3): 97, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32128636

RESUMO

Budesonide is a glucocorticoid for the treatment of ulcerative colitis (UC). The current study aims to develop a thermosensitive in situ and adhesive gel for rectal delivery of budesonide. HPMC K4M was selected as the adhesive agent based on the adhesive force and the effect on gel performance. The formulation of gel was optimized by using the central composite design-response surface methodology (CCD-RSM); a mathematical model was successfully developed to predict desired formulations as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, and HPMC K4M and the performances of gel. Based on CCD-RSM, a thermosensitive in situ and adhesive gel consisting of 0.002% budesonide, 0.74% HPMC, 4.87% F-68, and 19.0% F-127 was developed. Furthermore, the in vivo behavior of gel was evaluated in Sprague-Dawley rats. In comparison with budesonide solution, rectal administration of budesonide gel at 0.1 mg/kg in rats showed relative bioavailability of 230% with significant increase in rectum uptake.


Assuntos
Adesivos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Adesivos/metabolismo , Administração Retal , Animais , Anti-Inflamatórios/metabolismo , Disponibilidade Biológica , Budesonida/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Géis , Masculino , Poloxâmero/administração & dosagem , Poloxâmero/metabolismo , Ratos , Ratos Sprague-Dawley , Reto/efeitos dos fármacos , Reto/metabolismo
20.
Appl Microbiol Biotechnol ; 104(7): 2777-2801, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020277

RESUMO

More than 80% of the Earth surface is consisted of hostile and harsh environments, classified as extreme from an anthropogenic perspective. Microorganisms with acclimatized nature dominate these extreme ecosystems of the biosphere. Survivals in such environments initiate an inductive force leading to the production of noteworthy metabolites having peculiar biochemistry. Recent investigations on extremophilic fungi for unprecedented bioactive compounds emphasize their remarkable potential as sources of new therapeutics. The present review covers the literature published in the last 15 years and highlights the biological activities and structure of compounds isolated from the extremophilic fungi. The compounds are grouped based on their biological functions such as cytotoxicity, lipid-lowering ability, and antimicrobial, antioxidant, nematocidal, anti-inflammatory, anti-malarial, and antifouling activities. A total of 155 compounds isolated from 25 Penicillium species, 16 Aspergillus species, and 23 other species are presented, which include 105 new and 50 known bioactive compounds. Out of these, 77 have known cytotoxic activity and 46 are antimicrobial in nature, while there are 32 other compounds with different activities including nematocidal, anti-allergic, antioxidant, and anti-inflammatory. KEY POINTS: • A broad compilation of bioactive compounds from extremophilic fungi. • Classification of bioactive compounds based on their biological functions. • Production of cytotoxic compounds is common among all kind of extremophilic fungi. • Bioactive compounds have no direct role in adaptation process of extremophiles.


Assuntos
Fatores Biológicos/metabolismo , Extremófilos/metabolismo , Fungos/metabolismo , Adaptação Fisiológica/fisiologia , Antibacterianos/metabolismo , Anti-Inflamatórios/metabolismo , Antimaláricos/metabolismo , Antinematódeos/metabolismo , Antioxidantes/metabolismo , Ecossistema
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