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1.
PLoS One ; 15(8): e0238148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822425

RESUMO

Root treatment with oxathiapiprolin, benthiavalicarb or their mixture Zorvec-Endavia [ZE (3+7, w/w)] was shown to provide prolonged systemic protection against foliar oomycete pathogens attacking cucumber, tomato and basil. Here we report that these fungicides can effectively protect potato plants against late blight when applied to the soil in which such potato plants are grown. In two field experiments, performed in 2019 and 2020, potato plants grown in 64 L containers were treated with a soil drench of oxathiapiprolin, benthiavalicarb or ZE at 12.5, 25 or 50 mg ai/five plants in a container. Artificial inoculations with Phytophthora infestans revealed that such treated plants were protected against late blight in a dose-dependent manner all along the season. Interestingly, oxathiapiprolin persisted in the treated soil for at least 139 days, providing systemic protection against late blight to the following potato crops grown in that treated soils. Potato plants grown in loess soil in the field were either sprayed or drenched with ZE. Plants treated via the soil were significantly better protected against late blight compared to the plants treated by a spray. The data demonstrate a new strategy for season-long protection of potato against late blight by a single soil application of ZE. The systemic nature of oxathiapiprolin and benthiavalicarb composing ZE assures the translocation to the foliage of two fungicides with different modes of action. This shall minimize the risk of developing resistance against either fungicide in the treated crops.


Assuntos
Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/farmacologia , Doenças das Plantas/prevenção & controle , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Resistência à Doença/genética , Fungicidas Industriais/farmacologia , Phytophthora infestans/efeitos dos fármacos , Phytophthora infestans/patogenicidade , Raízes de Plantas/efeitos dos fármacos , Plantas Geneticamente Modificadas/efeitos dos fármacos , Solo , Solanum tuberosum/microbiologia
2.
J Pharmacol Exp Ther ; 374(3): 469-478, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32631869

RESUMO

The complex pathophysiology of sickle cell anemia (SCA) involves intravascular hemolytic processes and recurrent vaso-occlusion, driven by chronic vascular inflammation, which result in the disease's severe clinical complications, including recurrent painful vaso-occlusive episodes. Hydroxyurea, the only drug frequently used for SCA therapy, is a cytostatic agent, although it appears to exert nitric oxide/soluble guanylyl cyclase (sGC) modulating activity. As new drugs that can complement or replace the use of hydroxyurea are sought to further reduce vaso-occlusive episode frequency in SCA, we investigated the effects of the sGC agonists BAY 60-2770 (sGC activator) and BAY 41-2272 (sGC stimulator) in the presence or absence of hydroxyurea on SCA vaso-occlusive mechanisms and cell recruitment both ex vivo and in vivo. These agents significantly reduced stimulated human SCA neutrophil adhesive properties ex vivo in association with the inhibition of surface ß2-integrin activation. A single administration of BAY 60-2770 or BAY 41-2272 decreased tumor necrosis factor cytokine-induced leukocyte recruitment in a mouse model of SCA vaso-occlusion. Importantly, the in vivo actions of both agonists were significantly potentiated by the coadministration of hydroxyurea. Erythroid cell fetal hemoglobin (HbF) elevation is also a major goal for SCA therapy. BAY 41-2272 but not BAY 60-2770 at the concentrations employed significantly induced γ-globin gene transcription in association with HbF production in cultured erythroleukemic cells. In conclusion, sGC agonist drugs could represent a promising approach as therapy for SCA, for use either as stand-alone treatments or in combination with hydroxyurea. SIGNIFICANCE STATEMENT: This preclinical study demonstrates that stimulators and activators of sGC are potent inhibitors of the adhesion and recruitment of leukocytes from humans and in mice with sickle cell anemia (SCA) and may represent a promising approach for diminishing vaso-occlusive episode frequency in SCA. Hydroxyurea, a drug already frequently used for treating SCA, was found to potentiate the beneficial effects of sGC agonists in in vivo studies, implying that these classes of compounds could be used alone or in combination therapy.


Assuntos
Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Hidroxiureia/farmacocinética , Guanilil Ciclase Solúvel/metabolismo , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Eritroides/efeitos dos fármacos , Células Eritroides/metabolismo , Hemoglobina Fetal/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirazóis/farmacologia , Piridinas/farmacologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/metabolismo , Vasodilatadores/farmacologia
3.
Chem Biol Interact ; 328: 109190, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652078

RESUMO

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


Assuntos
Autofagia/efeitos dos fármacos , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Cardiotoxicidade/patologia , Doxorrubicina/efeitos adversos , Hidrocarbonetos Fluorados/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
4.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G87-G96, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475129

RESUMO

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) plays a critical role in hepatic energy homeostasis. Liver X receptors (LXRs) are implicated in multiple physiological functions, including the inhibition of hepatocyte proliferation and regulation of fatty acid and cholesterol metabolism. We have previously reported that SULT2B1b promotes hepatocyte proliferation by inactivating LXR signaling in vivo and in vitro, leading to our hypothesis that SULT2B1b promotes fatty liver regeneration. In the present study, female C57BL/6 and S129 mice were fed a high-fat diet for 8 wk to establish a nonalcoholic fatty liver disease (NAFLD) mouse model. 70% partial hepatectomy (PH) was performed to induce liver regeneration. Our experiments revealed that the SULT2B1b overexpression significantly promotes the regeneration of hepatocytes in NAFLD C57BL/6 mice after PH, increasing liver regrowth by 11% within 1 day, and then by 21%, 33%, and 24% by 2, 3, and 5 days post-PH, respectively. Compared with the wild-type NAFLD S129 mice, SULT2B1 deletion NAFLD S129 mice presented reduced hepatocyte regeneration at postoperative day 2, as verified by decreased liver regrowth (37.4% vs. 46.1%, P < 0.05) and the results of immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. Moreover, LXRα signaling and SULT2B1b expression are highly correlated in the regeneration of NAFLD mouse liver; SULT2B1b overexpression suppresses LXRα signaling, while the LXRα-signaling agonist T0901317 blocks SULT2B1b-induced hepatocyte regeneration in NAFLD mouse liver. Thus, the upregulation of SULT2B1b may promote hepatocyte regeneration via the suppression of LXRα activation in NAFLD mice, providing a potential strategy for improving hepatic-steatosis-related liver regeneration disorders.NEW & NOTEWORTHY This study demonstrates for the first time that hydroxysteroid sulfotransferase 2B1b (SULT2B1b) overexpression promotes the regeneration of fatty liver after partial hepatectomy in mice with nonalcoholic fatty liver disease, while reducing triglyceride accumulation in the regenerative fatty liver. Liver X receptor signaling may be crucial in the SULT2B1b-mediated regeneration of fatty liver. Thus, SULT2B1b may be a potential target for treating hepatic steatosis-related liver regeneration disorders.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatectomia/métodos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos/fisiologia , Receptores X do Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sulfonamidas/farmacologia
5.
Toxicology ; 441: 152529, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32590024

RESUMO

1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid (PFESA-BP2) was first detected in 2012 in the Cape Fear River downstream of an industrial manufacturing facility. It was later detected in the finished drinking water of municipalities using the Cape Fear River for their water supply. No toxicology data exist for this contaminant despite known human exposure. To address this data gap, mice were dosed with PFESA-BP2 at 0, 0.04, 0.4, 3, and 6 mg/kg-day for 7 days by oral gavage. As an investigative study, the final dose groups evolved from an original dose of 3 mg/kg which produced liver enlargement and elevated liver enzymes. The dose range was extended to explore a no effect level. PFESA-BP2 was detected in the sera and liver of all treated mice. Treatment with PFESA-BP2 significantly increased the size of the liver for all mice at 3 and 6 mg/kg-day. At the 6 mg/kg-day dose, the liver more than doubled in size compared to the control group. Male mice treated with 3 and 6 mg/kg-day and females treated with 6 mg/kg-day demonstrated significantly elevated serum markers of liver injury including alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and liver/body weight percent. The percent of PFESA-BP2 in serum relative to the amount administered was similar in male and female mice, ranged from 9 to 13 %, and was not related to dose. The percent accumulation in the liver of the mice varied by sex (higher in males), ranged from 30 to 65 %, and correlated positively with increasing dose level.


Assuntos
Hidrocarbonetos Fluorados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Tamanho do Órgão/efeitos dos fármacos , Poluentes Químicos da Água/sangue , Poluentes Químicos da Água/farmacocinética
6.
Ecotoxicol Environ Saf ; 199: 110679, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32402896

RESUMO

Chlordane is a worldwide banned organochlorine insecticide because of its hazard to animal and human health. It is also a persistent organic pollutant, which can affect either the soil or the aquatic life. The same applies to other chlorinated cyclodiene insecticides, such as dieldrin and aldrin. In turn, organofluorine compounds have a widespread use in agriculture. Therefore, density functional calculations and docking studies showed that the bioisosteric replacement of chlorines in the above-mentioned compounds by fluorines improves some physicochemical parameters used to estimate the toxicity and environmental risk of these compounds, as well as the ligand-enzyme (GABAA receptor-chloride channel complex) interactions related to their insecticidal activity. This work is an effort to provide an improved new class of organofluorine pesticides.


Assuntos
Hidrocarbonetos Clorados/química , Hidrocarbonetos Fluorados/química , Modelos Teóricos , Praguicidas/química , Receptores de GABA-A/química , Animais , Fenômenos Químicos , Halogenação , Humanos , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Clorados/toxicidade , Hidrocarbonetos Fluorados/farmacologia , Hidrocarbonetos Fluorados/toxicidade , Simulação de Acoplamento Molecular , Praguicidas/farmacologia , Praguicidas/toxicidade
7.
J Pharmacol Exp Ther ; 373(2): 261-268, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32127372

RESUMO

In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography-tandem mass spectrometry-based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 µM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decreased by T0901317 treatment. Effects of decreased OCT1 levels on metformin were simulated using a physiologically-based pharmacokinetic (PBPK) model. Simulations showed a clear decrease in metformin hepatic exposure resulting in a decreased pharmacodynamic effect. This DDI would not be predicted by the modest changes in simulated metformin plasma concentrations. Altogether, the current study demonstrated that an approach combining SCHH, proteomic analysis, and PBPK modeling is useful for revealing tissue concentration-based DDIs caused by unexpected regulation of hepatic transporters by NR modulators. SIGNIFICANCE STATEMENT: This study utilized an approach combining sandwich-cultured human hepatocytes, proteomic analysis, and physiologically based pharmacokinetic modeling to evaluate alterations in pharmacokinetics (PK) and pharmacodynamics (PD) caused by transporter regulation by nuclear receptor modulators. The importance of this approach from a mechanistic and clinically relevant perspective is that it can reveal drug-drug interactions (DDIs) caused by unexpected regulation of hepatic transporters and enable prediction of altered PK and PD changes, especially for tissue concentration-based DDIs.


Assuntos
Hepatócitos/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/agonistas , Proteômica/métodos , Sulfonamidas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Adulto , Células Cultivadas , Interações Medicamentosas , Feminino , Hepatócitos/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Fator 1 de Transcrição de Octâmero/análise , Transportadores de Ânions Orgânicos Sódio-Independentes/análise , Sulfonamidas/farmacocinética
8.
PLoS One ; 15(1): e0227556, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929586

RESUMO

Oxathiapiprolin is a fungicide effective against downy mildews of cucumber (Pseudoperonospora cubensis) and basil (Peronospora belbahrii) and late blight of tomato (Phytophthora infestans). To avoid fungicide resistance, it is recommended to apply oxathiapiprolin as a mixture with a partner fungicide that have a different mode of action. Here it is shown that a single application of oxathiapiprolin, benthiavalicarb, or their mixture (3+7, w/w) to the root of nursery plants grown in multi-cell trays provided prolonged systemic protection against late blight and downy mildews in growth chambers and in field tests. Soil application of 1mg active ingredient per plant provided durable protection of up to four weeks in tomato against late blight, cucumber against downy mildew and basil against downy mildew. Not only did the mixture of oxathiapiprolin and benthiavalicarb provide excellent systemic control of these diseases but also mutual protection against resistance towards both oxathiapiprolin and benthiavalicarb.


Assuntos
Carbamatos/farmacologia , Fungicidas Industriais/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Peronospora/efeitos dos fármacos , Doenças das Plantas/prevenção & controle , Pirazóis/farmacologia , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/crescimento & desenvolvimento , Cucumis sativus/parasitologia , Lycopersicon esculentum/efeitos dos fármacos , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/parasitologia , Peronospora/patogenicidade , Doenças das Plantas/parasitologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/parasitologia
9.
Diabetes ; 69(3): 448-464, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31882567

RESUMO

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neuropatias Diabéticas/metabolismo , Receptores X do Fígado/metabolismo , NADPH Oxidase 4/metabolismo , Células de Schwann/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/agonistas , Masculino , Camundongos , Proteínas da Mielina/genética , NADPH Oxidase 4/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologia
10.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650182

RESUMO

CONTEXT: Elagolix is an oral gonadotropin-releasing hormone (GnRH) antagonist recently approved for the treatment of endometriosis-associated pain and being developed for heavy menstrual bleeding associated with uterine fibroids. OBJECTIVE: The objective was to evaluate the effects of elagolix on ovulation and ovarian sex hormones. DESIGN AND SETTING: This was a randomized, open-label, multicenter study. PARTICIPANTS: Participants were healthy ovulatory women aged 18 to 40 years. INTERVENTIONS: Elagolix was administered orally for 3 continuous 28-day dosing intervals at 100 to 200 mg once daily (QD), 100 to 300 mg twice daily (BID), and 300 mg BID plus estradiol/norethindrone acetate (E2/NETA) 1/0.5 mg QD. MAIN OUTCOME MEASURES: The main outcomes measures were ovulation rates measured by transvaginal ultrasound, progesterone concentrations, and hormone suppression. RESULTS: Elagolix suppressed ovulation in a dose-dependent manner. The percentage of women who ovulated was highest at 100 mg QD (78%), intermediate at 150 and 200 mg QD and 100 mg BID (47%-57%), and lowest at 200 and 300 mg BID (32% and 27%, respectively). Addition of E2/NETA to elagolix 300 mg BID further suppressed the ovulation rate to 10%. Elagolix also suppressed luteinizing hormone and follicle stimulating hormone in a dose-dependent manner, leading to dose-dependent suppression of estradiol and progesterone. Elagolix had no effect on serum biomarker of ovarian reserve, and reduced endometrial thickness compared to the screening cycle. CONCLUSION: Women being treated with elagolix may ovulate and should use effective methods of contraception. The rate of ovulation was lowest with elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD.


Assuntos
Endométrio/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hidrocarbonetos Fluorados/administração & dosagem , Menorragia/tratamento farmacológico , Ovulação/efeitos dos fármacos , Pirimidinas/administração & dosagem , Adolescente , Adulto , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Humanos , Hidrocarbonetos Fluorados/farmacologia , Prognóstico , Pirimidinas/farmacologia , Fatores de Tempo , Adulto Jovem
11.
Med Chem ; 16(1): 63-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30734682

RESUMO

BACKGROUND: A convenient approach to modulation of the inflammation has an influence on the production of inflammatory mediators - icosanoids, generated in arachidonic acid (AA) metabolism. The common therapeutic activity of non-steroidal anti-inflammatory drugs (NSAID), such as aspirin, includes inhibition of two crucial enzymes of AA metabolism - cyclooxygenase- 1 and -2 (COX-1/2), with certain risk for gastrointestinal and renal intolerance. Ever since the enrolment of COX-2, particularly overabundance of its main products prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in numerous pathological processes was recognized, it became a significant therapeutic target. OBJECTIVE: The aim of this study was to examine the effects of synthesized organo-fluorine compounds on PGE2 and TXA2 production in the inflammation process. METHODS: Trifluoromethyl compounds were synthesized from N-benzyl trifluoromethyl aldimine, commercially available 2-methyl or 2-phenyl α-bromo esters (ß-lactams trans-1 and trans-2 and trifluoromethyl ß-amino ester, respectively) and methyl 2-isocyanoacetate (2-imidazoline trans-4). The reactions proceeded with high geometric selectivity, furnishing the desired products in good yields. The influence of newly synthesized compounds on PGE2 and TXA2 production in human leukemic U937 macrophages on both enzyme activity and gene expression levels was observed. RESULTS: Among the tested trifluoromethyl compounds, methyl trans-1-benzyl-5-(trifluoromethyl)- 4,5-dihydro-1H-imidazole-4-carboxylate (trans-4) can be distinguished as the most powerful antiinflammatory agent, probably due to its trifluoromethyl-imidazoline moiety. CONCLUSION: Some further structural modifications in tested compounds and particularly in the synthesis of different trifluoromethyl imidazolines could contribute to the development of new COX-2 inhibitors and potent anti-inflammatory agents.


Assuntos
Dinoprostona/biossíntese , Hidrocarbonetos Fluorados/farmacologia , Macrófagos/efeitos dos fármacos , Tromboxano A2/biossíntese , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Células U937
12.
Artigo em Inglês | MEDLINE | ID: mdl-31678517

RESUMO

Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.


Assuntos
Meios de Cultura/farmacologia , Receptores X do Fígado/antagonistas & inibidores , Cultura Primária de Células/métodos , Pele/efeitos dos fármacos , Sulfonamidas/farmacologia , Ceramidas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Avaliação Pré-Clínica de Medicamentos/métodos , Ácidos Graxos não Esterificados , Humanos , Hidrocarbonetos Fluorados/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Morfogênese/efeitos dos fármacos , Pele/crescimento & desenvolvimento , Pele/metabolismo , Estearoil-CoA Dessaturase/metabolismo
13.
J Nat Med ; 74(1): 142-152, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31463669

RESUMO

Cynandione A (CA), isolated from ethyl acetate extract of Cynanchum wilfordii (CW), is a bioactive phytochemical that has been found to be beneficial for the treatment of several diseases. Hepatic de novo lipogenesis is one of the main causes of non-alcoholic fatty liver disease (NAFLD), which is thought to be a hepatic manifestation of certain metabolic syndromes. However, it has not yet been reported if CA has any therapeutic value in these diseases. Here, we investigated whether CA can inhibit hepatic lipogenesis induced by liver X receptor α (LXRα) using an in vitro model. We found that the extract and ethyl acetated layer of CW decreased the mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c), which plays a crucial role in hepatic lipogenesis. Additionally, we observed that CA could suppress the level of SREBP-1c, which was increased using two commercial LXRα agonists, GW3954 and T0901317. Moreover, the enzymes that act downstream of SREBP-1c were also inhibited by CA treatment. To understand the mechanism underlying this effect, the levels of phosphorylated AMP kinase (pAMPK) were measured after CA treatment. Therefore, CA might increase the pAMPK level by inducing phosphorylation of liver kinase B1 (LKB1), which can then convert AMPK to pAMPK. Taken together, we conclude that CA has an alleviative effect on hepatic lipogenesis through the stimulation of the LKB1/AMPK pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Compostos de Bifenilo/farmacologia , Cynanchum/química , Lipogênese/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Células Hep G2 , Humanos , Hidrocarbonetos Fluorados/farmacologia , Fígado/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosforilação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Sulfonamidas/farmacologia
14.
Org Lett ; 21(24): 9846-9851, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31789041

RESUMO

A convenient synthetic route to α,α-difluoroalkylphosphonates is described. Structurally diverse aldehydes are condensed with LiF2CP(O)(OCH2CH═CH2)2. The resultant alcohols are captured as the pentafluorophenyl thionocarbonates and efficiently deoxygenated with HSnBu3, BEt3, and O2, and then smoothly deblocked with CpRu(IV)(π-allyl)quinoline-2-carboxylate (1-2 mol %) in methanol as an allyl cation scavenger. These mild deprotection conditions provide access to free α,α-difluoroalkylphosphonates in nearly quantitative yield. This methodology is used to rapidly construct new bis-α,α-difluoroalkyl phosphonate inhibitors of PTPIB (protein phosphotyrosine phosphatase-1B).


Assuntos
Compostos Alílicos/química , Hidrocarbonetos Fluorados/farmacologia , Organofosfonatos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Rutênio/química , Catálise , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
15.
J Med Chem ; 62(24): 11348-11358, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31774672

RESUMO

The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target ß-catenin in this pathway. We now report that several "Wnt inhibitors" that allegedly target ß-catenin actually function as mitochondrial proton uncouplers that independently activate AMPK and concomitantly inhibit Wnt signaling. As expected for a process in which mitochondrial uncoupling diminishes ATP production, a mitochondrial proton uncoupler, FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and inhibited Wnt signaling. Also consistent with these findings, a well-known "Wnt inhibitor", FH535, functioned as a proton uncoupler, and in support of this finding, the N-methylated analog, 2,5-dichloro-N-methyl-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535-M), was inactive as an uncoupler and Wnt inhibitor. Apart from suggesting an opportunity to develop dual Wnt inhibitors and AMPK activators, these findings provide a cautionary tale that claims for Wnt inhibition alone require scrutiny as possible mitochondrial proton uncouplers or inhibitors of the electron transport chain.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Encéfalo/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Mitocôndrias/efeitos dos fármacos , Ureia/farmacologia , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Metabolismo Energético , Ativação Enzimática , Ativadores de Enzimas/química , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocarbonetos Fluorados/química , Mitocôndrias/metabolismo , Consumo de Oxigênio , Sulfonamidas/química , Sulfonamidas/farmacologia , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
16.
Pharmacol Rep ; 71(6): 1219-1226, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669886

RESUMO

BACKGROUND: The pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with dyslipidemia, an established co-morbidity. Statins treat hypercholesterolemia, but more recently have been trailed in the setting of COPD for their potential anti-inflammatory benefits. The outcomes of prospective trials however have been inconsistent. Thus, we hypothesize that the variation in results may have been due to statin-induced downregulation of ATP-binding cassette transporter A1 (ABCA1), thereby reducing cholesterol export. This study aims to elucidate whether statin treatment in a cellular model of COPD leads to a decrease in ABCA1 protein expression. METHODS: To mimic the inflammatory environment of COPD, two commonly used lung epithelial cell lines (BEAS-2B and A549) were treated with tumor necrosis factor (TNF), and co-treated with cholesterol/25-hydroxycholesterol (25-OH) to mimic dyslipidemia. ABCA1 protein was detected by Western Blotting. RESULTS: We unexpectedly showed that statins did not affect ABCA1 expression. However, the LXR agonist T0901317 significantly increased ABCA1 expression in both cell lines, while TNF, cholesterol or 25-OH induced ABCA1 protein upregulation in BEAS-2B cells, indicating cell line differences in response. There was also evidence of synergistic impacts of combined treatments on ABCA1 upregulation in BEAS-2B cells. CONCLUSION: Statins did not have an impact on ABCA1 expression in lung epithelial cell lines, disproving our original hypothesis. However, we showed for the first time, the effect of the inflammatory cytokine TNF, cholesterol/25-OH, statins and the LXR agonist T0901317 on expression of ABCA1 transporter protein in human lung epithelial cell lines in vitro. We hope that these in vitro studies may prove beneficial for addressing dyslipidemia in COPD in the future.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Células Epiteliais/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Receptores X do Fígado/metabolismo , Pulmão/efeitos dos fármacos , Sulfonamidas/farmacologia , Células A549 , Linhagem Celular , Linhagem Celular Tumoral , Colesterol/metabolismo , Células Epiteliais/metabolismo , Humanos , Hidroxicolesteróis/metabolismo , Inflamação/metabolismo , Pulmão/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
17.
Molecules ; 24(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652970

RESUMO

Metal tetrapyrrole macrocycles such as porphyrins and chlorins are ubiquitous in nature. Synthetic analogs, including phthalocyanines, have found applications in medicine, particularly as photosensitizers for photodynamic therapy and as fluorescent imaging probes. Tripyrrolic macrocycles, called subphthalocyanines (SPcs) with a smaller boron atom at their core, have similar potential as optical agents. We have recently reported a series of mixed fluorinated SPcs with varying aromaticity, showing that electronic absorption and emission are synthetically tunable across the far visible region, and that the inclusion of 4-12 peripheral fluorine atoms results in strong fluorescence within MDA-MB-231 breast tumor cells. Further probing this system, we report herein the synthesis and characterization of boron trifluorosubphthalocyanine chloride (F3SPc). The constitutional isomers F3SPc(C3) and F3SPc(C1) are readily separable by chromatography, and their identity and purity have been confirmed by 1H NMR, 19F NMR, HR APCI-MS, and HPLC. Unsurprisingly, these structurally similar F3SPcs have identical electronic absorption (λmax = 557 nm; tetrahydrofuran (THF)) and emission (λem = 574 nm; Φf = 0.27-0.28; THF). Strong fluorescence from MDA-MB-231 breast tumor cells was observed following treatment with F3SPc(C3) and F3SPc(C1) (50 µM F3SPc, 15 min), further highlighting the importance of even a limited number of peripheral fluorine atoms for this type of application.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Corantes Fluorescentes , Hidrocarbonetos Fluorados , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Microscopia de Fluorescência , Fotoquimioterapia
18.
Plant Dis ; 103(11): 2812-2820, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31486739

RESUMO

Oxathiapiprolin, a novel oomycete fungicide recently registered by DuPont, was reported to have high intrinsic activity against cucurbit downy mildew (Pseudoperonospora cubensis). The goal of this study was to characterize disease control attributes of oxathiapiprolin-based fungicides critical to effective management of cucurbit downy mildew. In growth chamber and greenhouse studies, oxathiapiprolin-based fungicides were compared with mandipropamid, mefenoxam + mancozeb, fluopicolide + propamocarb, cymoxanil + mancozeb, and ametoctradin + dimethomorph products for pre- and postinfection activity, local systemic movement, and protection of new growth produced after fungicide application. In preventive application, oxathiapiprolin-based fungicides significantly (P < 0.0001) inhibited downy mildew development, with the highest level of disease observed being 0.4% compared with 86.7% observed for mandipropamid. When applied postinfection, oxathiapiprolin-based fungicides significantly (P < 0.0001) suppressed disease development, but disease control was reduced relative to that observed for preventive application. There was a significant effect of formulation on the postinfection activity of oxathiapiprolin, whereby the oil dispersion (OD) formulation was more inhibitory than the water-dispersible granule formulation (0.001 ≤ P ≤ 0.049). Disease severity on the outer half leaf portion protected from spray deposition during fungicide application was lower for oxathiapiprolin-based fungicides (1.6 to 6.6%) than observed for fluopicolide + propamocarb (10.9 to 23.7%), mefenoxam + mancozeb (40.3 to 51.4%), and the nontreated controls (83.3 to 84.9%), which indicates significant acropetal movement within the leaf. Postinfection applications of oxathiapiprolin-based formulations had the greatest effect on lesion growth and sporangia production compared with the other fungicides in the experiment. When applied preventively to rapidly growing plants in a greenhouse, oxathiapiprolin-based fungicides consistently protected new growth that was not present at the time of application, with the OD formulation reducing disease severity by >75% relative to nontreated plants. The practical implications of these observations are discussed.


Assuntos
Fungicidas Industriais , Hidrocarbonetos Fluorados , Oomicetos , Doenças das Plantas , Pirazóis , Cucurbitaceae/microbiologia , Fungicidas Industriais/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Oomicetos/efeitos dos fármacos , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Pirazóis/farmacologia
19.
PLoS One ; 14(9): e0222827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31545821

RESUMO

Plenaris (oxathiapiprolin) applied to sunflower seedlings was highly effective in controlling downy mildew incited by the oomycete Plasmopara halstedii. In vitro assays revealed strong suppression of zoospore release and cystospore germination of P.halstedii by Plenaris. Bion (acibenzolar-S-methyl) and Apron (mefenoxam) were partially effective when used singly, but performed synergistically when mixed with Plenaris. Seed treatment (coating) with Plenaris provided dose-dependent control of the disease whereas Bion and Apron provided partial or poor control. However, seeds treated with mixtures containing reduced rates of Plenaris and full rates of Bion and/or Apron provided complete control of the disease due to the synergistic interaction between these components. Such mixtures should be used for seed treatment in the field to minimize selection pressure imposed on the pathogen.


Assuntos
Fungicidas Industriais/farmacologia , Helianthus/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Oomicetos/efeitos dos fármacos , Pirazóis/farmacologia , Sementes/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/farmacologia , Alcadienos/farmacologia , Sinergismo Farmacológico , Helianthus/crescimento & desenvolvimento , Helianthus/microbiologia , Oomicetos/fisiologia , Doenças das Plantas/microbiologia , Polímeros/farmacologia , Sementes/crescimento & desenvolvimento , Sementes/microbiologia
20.
J Med Chem ; 62(17): 8115-8139, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393122

RESUMO

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 µM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-ß-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Desenvolvimento de Medicamentos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases do Álcool/metabolismo , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Dinitrobenzenos/síntese química , Dinitrobenzenos/química , Dinitrobenzenos/farmacologia , Relação Dose-Resposta a Droga , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
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