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1.
J Environ Sci Health B ; 57(3): 211-219, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35240941

RESUMO

We evaluated the biological effects of ingestion by gavage, for 28 days, of the pesticides cypermethrin (CP) and emamectin benzoate (EB) and their mixtures in female Swiss mice. The groups were Control (water); CP; EB and three distinct concentrations of CP and EB mixture expressed in mg/kg/day. The biological effects were analyzed in the complete blood count and plasma (alkaline phosphatase (ALP), alanine aminotransferase (ALT) and creatinine); the biochemical parameters of oxidative stress (substances reactive to thiobarbituric acid (TBARS); reduced glutathione (GSH); catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST)), and bone marrow cells obtained from the femur for the micronucleus (MN) test. In the heart, there was a reduction in GSH in the groups (0.5 + 0.67 and 2.5 + 3.37), although in the brain this effect appeared for the other groups, except EB. Brain TBARS increased in CP and in the group (2.5 + 3.37) and platelets increased in the group (12.5 + 16.87). Genotoxic/mutagenic effects, showing a consistent increase dose-dependent effect on micronucleus counting for in the female mice. After 28 days of treatment, we can observe that the pesticide mixtures promoted genotoxic damage and oxidative brain damage in female mice, which can damage the health of these animals and possibly their future offspring.


Assuntos
Mutagênicos , Praguicidas , Animais , Antioxidantes/metabolismo , Benzoatos/farmacologia , Catalase/metabolismo , Dissacarídeos , Feminino , Glutationa/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Ivermectina/análogos & derivados , Fígado , Camundongos , Estresse Oxidativo , Praguicidas/toxicidade , Piretrinas , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico
2.
J Mol Endocrinol ; 69(1): 259-268, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35354667

RESUMO

Telmisartan and irbesartan are angiotensin II receptor blockers (ARBs) and reportedly stimulate adiponectin secretion from adipocytes via partial peroxisome proliferator-activated receptor γ (PPARγ) activation. However, quantitative evaluation among different ARBs has not been performed. Adiponectin exerts strong protection against a number of pathological events by suppressing cell death, inhibiting inflammation, and enhancing cell survival, while leptin promotes inflammation, oxidative stress, atherogenesis, and thrombosis. The aim of this study was to identify the most effective ARB enhancing adiponectin secretion without raising leptin secretion from human white adipocytes (HWAs). Among seven ARBs (azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan), telmisartan was the most effective ARB for the increase of adiponectin secretion and irbesartan was the second, whereas the other ARBs at 1 µM had no effect on adiponectin secretion. GW9662, a PPARγ antagonist, completely blocked pioglitazone (PPARγ agonist)-induced adiponectin secretion and mRNA expression, whereas it unexpectedly blocked neither telmisartan- nor irbesartan-induced adiponectin secretion and mRNA expression but rather increased them. GW6471, PPARα antagonist, and siRNA for PPARα suppressed telmisartan- and irbesartan-induced adiponectin secretion, suggesting that PPARα is the main target of these ARBs to increase adiponectin secretion in HWAs. Leptin secretion was not affected by any ARBs at 1 µM and GW9662 significantly decreased the basal secretion of leptin, suggesting that basal leptin secretion is regulated in a PPARγ-dependent manner. We conclude that telmisartan is the most effective ARB to increase adiponectin secretion via PPARα without raising leptin secretion from HWAs.


Assuntos
Adiponectina , Antagonistas de Receptores de Angiotensina , Adipócitos/metabolismo , Adiponectina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Benzoatos/metabolismo , Benzoatos/farmacologia , Humanos , Inflamação/metabolismo , Irbesartana/farmacologia , Leptina/metabolismo , PPAR alfa/metabolismo , PPAR gama/metabolismo , RNA Mensageiro/metabolismo , Telmisartan/metabolismo , Telmisartan/farmacologia
4.
Int J Mol Sci ; 23(5)2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35269552

RESUMO

(1) Background: Synovial fluid (SF) from knee joints with osteoarthritis (OA) has increased levels of phospholipids (PL). We have reported earlier that TGF-ß and IGF-1 stimulate fibroblast-like synoviocytes (FLS) to synthesize increased amounts of PLs. The current study examined whether IL-1ß induces the release of PLs in FLS and the underlying mechanism. (2) Methods: Cultured human OA FLS were treated with IL-1ß alone and with pathway inhibitors or with synthetic liver X receptor (LXR) agonists. Cholesterol hydroxylases, ABC transporters, apolipoproteins (APO), LXR, sterol regulatory binding proteins (SREBPs), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were analyzed by RT-PCR, Western blot, and ELISA. The release of radiolabeled PLs from FLS was determined, and statistical analysis was performed using R (N = 5-9). (3) Results: Like synthetic LXR agonists, IL-1ß induced a 1.4-fold greater release of PLs from FLS. Simultaneously, IL-1ß upregulated the level of the PL transporter ABCA1 and of cholesterol hydroxylases CH25H and CYP7B1. IL-1ß and T0901317 stimulated the expression of SREBP1c, whereas only T0901317 enhanced SREBP2, HMGCR, APOE, LXRα, and ABCG1 additionally. (4) Conclusions: IL-1ß partially controls PL levels in OA-SF by affecting the release of PLs from FLS. Our data show that IL-1ß upregulates cholesterol hydroxylases and thus the formation of oxysterols, which, as natural agonists of LXR, increase the level of active ABCA1, in turn enhancing the release of PLs.


Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Interleucina-1beta/farmacologia , Osteoartrite/metabolismo , Fosfolipídeos/metabolismo , Sinoviócitos/citologia , Transportador 1 de Cassete de Ligação de ATP/genética , Células Cultivadas , Família 7 do Citocromo P450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores X do Fígado/genética , Osteoartrite/genética , Esteroide Hidroxilases/genética , Líquido Sinovial/citologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo
5.
Proc Natl Acad Sci U S A ; 119(7)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35145035

RESUMO

The nuclear receptors liver X receptor (LXR) α and ß play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRß from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.


Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Fígado/metabolismo , Animais , Regulação da Expressão Gênica/fisiologia , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Camundongos , Camundongos Knockout
6.
J Ethnopharmacol ; 289: 115062, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35114339

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula hermonis is a small shrub renowned for its aphrodisiac abilities. Middle East herbalists have utilized Ferula hermonis seed and root as an aphrodisiac folk medicine to treat women's frigidity and male erectile and sexual dysfunction. AIM OF THE STUDY: Assessment of follicle-stimulating hormone-like (FSH), luteinizing hormone-like (LH), and estrogenic activities of the methanolic extract (ME) of the roots of Ferula hermonis on female reproductive function. MATERIALS AND METHODS: The methanolic extract was prepared from the root of F. hermonis and studied at dose level 6 mg/kg in immature female rats for FSH-like, LH-like, and estrogenic activities. These activities were determined by analyzing gross anatomical features, relative organ weight, and serum level of FSH, LH, progesterone and estrogen hormones, and histopathological characteristics. Quantification of the main phytoestrogenic component ferutinin carried out by HPLC. In addition, molecular docking for the binding affinity of ferutinin inside active sites of both estrogen receptor alpha (ERα) and FSH receptor (FSHR) was performed to predict the potential role of ferutinin in regulating the female reproductive process. RESULTS: Ferula hermonis (ME) showed potent FSH-like, LH-like activities and moderate estrogenic effect at the dose of 6 mg/kg. The content of ferutinin in F. hermonis was estimated to be 92 ± 1.33 mg/g of the methanolic extract. Molecular docking of ferutinin with ERα and FSHR displayed strong interaction with target proteins. CONCLUSIONS: Based on results, it can be concluded that Ferula hermonis can be considered as a suitable female fertility improving agent.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Fármacos para a Fertilidade/farmacologia , Ferula/química , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Animais , Benzoatos/isolamento & purificação , Compostos Bicíclicos com Pontes/isolamento & purificação , Compostos Bicíclicos com Pontes/farmacologia , Cromatografia Líquida de Alta Pressão , Cicloeptanos/isolamento & purificação , Feminino , Fertilidade , Fármacos para a Fertilidade/isolamento & purificação , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Simulação de Acoplamento Molecular , Ratos , Sesquiterpenos/isolamento & purificação
7.
Sci Rep ; 12(1): 3108, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210523

RESUMO

In addition to their wide therapeutic application, benzoates and benzoic acid derivatives are the most commonly utilized food preservatives. The purpose of this study was to estimate the antioxidant, anti-diabetic, and anti-obesity activities of four 2-(phenylthio)-ethyl benzoate derivatives utilizing standard biomedical assays. The results revealed that the 2a compound has potent antidiabetic activity through the inhibition of α-amylase and α-glycosidase with IC50 doses of 3.57 ± 1.08 and 10.09 ± 0.70 µg/ml, respectively, compared with the positive control acarbose (IC50 = 6.47 and 44.79 µg/ml), respectively. In addition, by utilizing the ß-carotene linoleic acid and DPPH methods, the 2a compound showed the highest antioxidant activity compared with positive controls. Moreover, the 2a compound showed potential anti-lipase activity with an IC50 dose of 107.95 ± 1.88 µg/ml compared to orlistat (IC50 = 25.01 ± 0.78 µg/ml). A molecular docking study was used to understand the interactions between four derivatives of (2-(phenylthio)-ethyl benzoate with α-amylase binding pocket. The present study concludes that the 2a compound could be exploited for further antidiabetic, antioxidant, and anti-obesity preclinical and clinical tests and design suitable pharmaceutical forms to treat these global health problems.


Assuntos
Benzoatos/farmacologia , Ácido Benzoico/farmacologia , Amilases , Fármacos Antiobesidade/farmacologia , Antioxidantes/farmacologia , Diabetes Mellitus/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , alfa-Amilases/antagonistas & inibidores
8.
J Biol Chem ; 298(3): 101621, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35074429

RESUMO

Inhibition of P300 acetyltransferase activity by specific inhibitor C646 has been shown to improve insulin signaling. However, the underlying molecular mechanism of this improvement remains unclear. In this study, we analyzed P300 levels of obese patients and found that they were significantly increased in liver hepatocytes. In addition, large amounts of P300 appeared in the cytoplasm. Inhibition of P300 acetyltransferase activity by C646 drastically increased tyrosine phosphorylation of the insulin receptor protein substrates (IRS1/2) without affecting the tyrosine phosphorylation of the beta subunit of the insulin receptor (IRß) in hepatocytes in the absence of insulin. Since IRS1/2 requires membrane translocation and binding to inositol compounds for normal functions, we also examined the role of acetylation on binding to phosphatidylinositol(4,5)P2 and found that IRS1/2 acetylation by P300 reduced this binding. In contrast, we show that inhibition of IRS1/2 acetylation by C646 facilitates IRS1/2 membrane translocation. Intriguingly, we demonstrate that C646 activates IRß's tyrosine kinase activity and directly promotes IRß interaction with IRS1/2, leading to the tyrosine phosphorylation of IRS1/2 and subsequent activation of insulin signaling even in the absence of insulin. In conclusion, these data reveal the unique effects of C646 in activating insulin signaling in patients with obesity and diabetes.


Assuntos
Benzoatos , Inibidores Enzimáticos , Proteínas Substratos do Receptor de Insulina , Nitrobenzenos , Pirazolonas , Receptor de Insulina , Fatores de Transcrição de p300-CBP , Benzoatos/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Nitrobenzenos/farmacologia , Fosforilação , Pirazolonas/farmacologia , Receptor de Insulina/metabolismo , Tirosina/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Fatores de Transcrição de p300-CBP/metabolismo
9.
J Med Entomol ; 59(2): 788-794, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35043202

RESUMO

Methyl benzoate (MBe) is a volatile organic molecule found in various plants; it is used as an insect semiochemical. MBe also has a biorational insecticidal effect against various agricultural and urban arthropod pests. The present study was the first to assess the larvicidal potential of MBe against fourth-instar larvae of the mosquitoes Aedes albopictus (Skuse) and Culex pipiens (L.). A positive association was observed between MBe concentrations and larval mortality in both the species. The highest mortality recorded was 100% for Ae. albopictus and 56% for Cx. pipiens after 24 h of exposure to 200 ppm MBe. The lethal median concentration (LC50) values of MBe against fourth-instar larvae of Ae. albopictus and Cx. pipiens were 61 ppm and 185 ppm, respectively. These results suggest that MBe has great potential for use as an environmentally friendly larvicidal agent for mosquito control.


Assuntos
Aedes , Culex , Inseticidas , Óleos Voláteis , Compostos Orgânicos Voláteis , Animais , Benzoatos/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Larva , Óleos Voláteis/química , Compostos Orgânicos Voláteis/farmacologia
10.
Invest Ophthalmol Vis Sci ; 63(1): 4, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34982146

RESUMO

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve. Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated. Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration. Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/fisiologia , Axônios/efeitos dos fármacos , Benzoatos/farmacologia , Degeneração Neural/prevenção & controle , Nervo Óptico/efeitos dos fármacos , Fator de Necrose Tumoral alfa/toxicidade , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Axônios/enzimologia , Axônios/patologia , Compostos de Bifenilo/farmacologia , Inibidores Enzimáticos/farmacologia , Imuno-Histoquímica , Injeções Intravítreas , Masculino , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/metabolismo , Degeneração Neural/enzimologia , Nervo Óptico/ultraestrutura , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Pironas/farmacologia , Ratos , Ratos Wistar , Proteína Sequestossoma-1/metabolismo , Tiofenos/farmacologia , beta-Alanina/farmacologia
11.
J Nat Prod ; 85(1): 176-184, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35007072

RESUMO

As a complement to vaccines, small-molecule therapeutic agents are needed to treat or prevent infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants, which cause COVID-19. Affinity selection-mass spectrometry was used for the discovery of botanical ligands to the SARS-CoV-2 spike protein. Cannabinoid acids from hemp (Cannabis sativa) were found to be allosteric as well as orthosteric ligands with micromolar affinity for the spike protein. In follow-up virus neutralization assays, cannabigerolic acid and cannabidiolic acid prevented infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells. Importantly, cannabigerolic acid and cannabidiolic acid were equally effective against the SARS-CoV-2 alpha variant B.1.1.7 and the beta variant B.1.351. Orally bioavailable and with a long history of safe human use, these cannabinoids, isolated or in hemp extracts, have the potential to prevent as well as treat infection by SARS-CoV-2.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Canabinoides/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/química , Antivirais/metabolismo , Benzoatos/farmacologia , COVID-19/prevenção & controle , Canabinoides/química , Canabinoides/metabolismo , Chlorocebus aethiops , Humanos , Ligantes , Espectrometria de Massas , Modelos Moleculares , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero
12.
J Clin Invest ; 132(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35085104

RESUMO

Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant-associated or TET deficiency-associated myeloid malignancies.


Assuntos
Anemia Aplástica , Benzoatos/farmacologia , Proliferação de Células , Proteínas de Ligação a DNA , Dioxigenases , Células-Tronco Hematopoéticas/enzimologia , Hidrazinas/farmacologia , Pirazóis/farmacologia , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/antagonistas & inibidores , Dioxigenases/genética , Dioxigenases/metabolismo , Humanos , Camundongos , Camundongos Knockout
13.
Platelets ; 33(1): 82-88, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33251910

RESUMO

This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 109/L and 80 × 109/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 109/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 109/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit-risk ratio in Chinese chronic ITP patients.Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Benzoatos/farmacologia , Doença Crônica , Humanos , Hidrazinas/farmacologia , Estadiamento de Neoplasias , Pirazóis/farmacologia , Resultado do Tratamento
14.
Chem Biol Interact ; 351: 109768, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34864007

RESUMO

Secondary metabolites from fungi, algae and lichens have remarkable biological activities as antibiotics, fungicides, antiviral drugs, and cancer therapeutics. This review focuses on the lichen-derived metabolite gyrophoric acid and other select secondary metabolites (e.g., usnic acid, salazinic acid, physodic acid, vulpinic acid ceratinalone, flavicansone, ramalin, physciosporin, tumidulin, atranorin, parmosidone) that modulate a number of cellular pathways relevant to several biomedical diseases and disorders, including cancer, diabetes and cardiovascular disease. We discuss the chemical structure and biochemical activities of gyrophoric acid and other compounds relative to the molecular mechanisms and cellular processes that these metabolites target in a distinct human and rodent cell types. The therapeutic promise of gyrophoric acid and similar lichen derived metabolites is associated with the chemical versatility of these compounds as polyaromatic depsides with functional carboxyl and hydroxyl side-groups that may permit selective interactions with distinct enzymatic active sites. Gyrophoric acid has been examined in a series of studies as an effective anticancer drug because it impinges on topoisomerase 1 activity, as well as causes cell cycle arrest, comprises cell survival, and promotes apoptosis. Because gyrophoric acid has cytostatic properties, its biological roles and possible medicinal utility may extend beyond effects on cancer cells and be relevant to any process that is controlled by cell growth and differentiation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoatos/farmacologia , Proliferação de Células/efeitos dos fármacos , Líquens/química , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Humanos
15.
Nitric Oxide ; 119: 1-8, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34871799

RESUMO

In heart failure with reduced ejection fraction (HFrEF), nitric oxide-soluble guanylyl cyclase (sGC) pathway dysfunction impairs skeletal muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake (V̇O2) kinetics. Targeting this pathway with sGC activators offers a new treatment approach to HFrEF. We tested the hypotheses that sGC activator administration would increase the O2 delivery (Q̇O2)-to-V̇O2 ratio in the skeletal muscle interstitial space (PO2is) of HFrEF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (fRBC), velocity (VRBC), and capillary hematocrit (Hctcap). HFrEF was induced in male Sprague-Dawley rats via myocardial infarction. After 3 weeks, rats were treated with 0.3 mg/kg of the sGC activator BAY 60-2770 (HFrEF + BAY; n = 11) or solvent (HFrEF; n = 9) via gavage b.i.d for 5 days prior to phosphorescence quenching (PO2is, in contracting muscle) and intravital microscopy (resting) measurements in the spinotrapezius muscle. Intravital microscopy revealed higher fRBC (70 ± 9 vs 25 ± 8 RBC/s), VRBC (490 ± 43 vs 226 ± 35 µm/s), Hctcap (16 ± 1 vs 10 ± 1%) and a greater number of capillaries supporting flow (91 ± 3 vs 82 ± 3%) in HFrEF + BAY vs HFrEF (all P < 0.05). Additionally, PO2is was especially higher during 12-34s of contractions in HFrEF + BAY vs HFrEF (P < 0.05). Our findings suggest that sGC activators improved resting Q̇O2 via increased fRBC, VRBC, and Hctcap allowing for better Q̇O2-to-V̇O2 matching during the rest-contraction transient, supporting sGC activators as a potential therapeutic to target skeletal muscle vasomotor dysfunction in HFrEF.


Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Capilares/metabolismo , Insuficiência Cardíaca/sangue , Hidrocarbonetos Fluorados/farmacologia , Músculo Esquelético/metabolismo , Oxigênio/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Monitorização Transcutânea dos Gases Sanguíneos , Hemodinâmica , Masculino , Ratos Sprague-Dawley
17.
Br J Haematol ; 197(1): 110-119, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34961933

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disease caused by platelet destruction mediated by auto-antibody production. It is characterized by a compromised immune system and alteration of the inflammatory response. Mesenchymal stromal cells (MSCs) play an important role in modulating immune and inflammatory processes, exerting immune-suppressing and anti-inflammatory properties. In ITP-MSCs the activity and survival are strongly impaired. Eltrombopag (ELT) is a thrombopoietin receptor agonist approved in chronic ITP for stimulating platelet production. It has immunomodulating properties by stimulating T and B regulatory cell activity and by promoting a macrophage switch from the pro-inflammatory to the anti-inflammatory phenotype. ELT also exhibits iron-chelating properties. Iron is a crucial element involved in several physiologic processes, but its intracellular accumulation determines cell damages. Therefore, for the first time we analysed the effect of ELT on ITP-MSCs demonstrating its ability to restore survival and activity of MSCs directly and to promote their survival and proliferation indirectly, by iron metabolism modulation.


Assuntos
Células-Tronco Mesenquimais , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Anti-Inflamatórios/uso terapêutico , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Criança , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Ferro/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Trombocitopenia/tratamento farmacológico
18.
J Enzyme Inhib Med Chem ; 37(1): 109-117, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34894976

RESUMO

Invasive fungal infections including Candidiasis and Aspergillosis are associated with considerable morbidity and mortality in immunocompromised individuals, such as cancer patients. Aurora B is a key mitotic kinase required for the cell division of eukaryotes from fungus to man. Here, we identified a novel Aurora B inhibitor GSK650394 that can inhibit the recombinant Aurora B from human and Aspergillus fumigatus, with IC50 values of 5.68 and 1.29 µM, respectively. In HeLa and HepG2 cells, GSK650394 diminishes the endogenous Aurora B activity and causes cell cycle arrest in G2/M phase. Further cell-based assays demonstrate that GSK650394 efficiently suppresses the proliferation of both cancer cells and Aspergillus fumigatus. Finally, the molecular docking calculation and site-directed mutagenesis analyses reveal the molecular mechanism of Aurora B inhibition by GSK650394. Our work is expected to provide new insight into the combinational therapy of cancer and Aspergillus fumigatus infection.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Aurora Quinase B/antagonistas & inibidores , Benzoatos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Descoberta de Drogas , Antifúngicos/química , Antineoplásicos/química , Aurora Quinase B/metabolismo , Benzoatos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Biochimie ; 194: 35-42, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34965461

RESUMO

The gut microbiota contributes to mammalian host biology by supplying metabolites from nutrients and pro-inflammatory molecules. We have recently shown that urinary hippurate is associated with reduced risk of obesity, increased gut microbiome diversity and gene richness, and functional modules for microbial production of its precursor benzoate. Obese mice infused with hippurate exhibit profound alterations of glucose homeostasis. Here, we tested the biological effects of chronic administration of benzoate on cardiometabolic phenotypes in lean and obese mice. Benzoate induced glucose intolerance, enhanced insulin secretion, increased adiposity and stimulated liver inflammation in lean mice fed control diet. In contrast, in condition of obesity and diabetes induced by high fat diet feeding, benzoate infusion resulted in reduction of glucose intolerance, stimulation of both glucose-induced insulin secretion and ß-cell proliferation, and reduction of liver triglyceride and collagen accumulation. These results combined with those previously obtained in mice treated with hippurate underline the importance of the benzoate-hippurate pathway in cardiometabolic diseases and pave the way to diagnostic and therapeutic solutions.


Assuntos
Benzoatos , Diabetes Mellitus , Animais , Benzoatos/farmacologia , Diabetes Mellitus/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo
20.
Int J Mol Sci ; 22(23)2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34884889

RESUMO

GPR55 recognizes several lipid molecules such as lysophosphatidylinositol. GPR55 expression was reported in human monocytes. However, its role in monocyte adhesion and atherosclerosis development has not been studied. The role of GPR55 in monocyte adhesion and atherosclerosis development was investigated in human THP-1 monocytes and ApoE-/- mice using O-1602 (a potent agonist of GPR55) and CID16020046 (a specific GPR55 antagonist). O-1602 treatment significantly increased monocyte adhesion to human umbilical vein endothelial cells, and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides -750 and -503 as GPR55 responsive elements. O-1602 induction of Mac-1 was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In Apo-/- mice, administration of CID16020046 ameliorated high-fat diet-induced atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to the adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Compostos Azabicíclicos/farmacologia , Benzoatos/farmacologia , Antígeno de Macrófago 1/genética , Monócitos/efeitos dos fármacos , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Dieta Hiperlipídica , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Knockout para ApoE , Monócitos/metabolismo , Substâncias Protetoras/farmacologia , Receptores de Canabinoides/efeitos dos fármacos , Receptores de Canabinoides/metabolismo , Transdução de Sinais
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