Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31.061
Filtrar
1.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808880

RESUMO

Peroxisome proliferator activated receptor beta/delta (PPARß/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARß/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARß/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARß/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARß/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARß/δ agonists leads to a significant increase in Pdk-4 and Angptl-4 mRNA expression, which is significantly decreased in the presence of PPARß/δ antagonists. Docking using computational chemistry methods indicates that PPARß/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARß/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co-incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARß/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARß/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARß/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.


Assuntos
PPAR delta/química , PPAR beta/química , Animais , Benzamidas/química , Benzamidas/farmacologia , Sítios de Ligação , Biomarcadores , Expressão Gênica , Mediadores da Inflamação/metabolismo , Ligantes , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Masculino , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Óxido Nítrico/metabolismo , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , PPAR delta/genética , PPAR beta/agonistas , PPAR beta/antagonistas & inibidores , PPAR beta/genética , Ligação Proteica , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Tiazóis/química , Tiazóis/farmacologia
2.
Nat Commun ; 12(1): 2074, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824316

RESUMO

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.


Assuntos
Medo/fisiologia , Hipotermia/metabolismo , Hipóxia/metabolismo , Canal de Cátion TRPA1/metabolismo , Tiazóis/farmacologia , Animais , Bradicardia/patologia , Medo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Hipotermia/complicações , Hipóxia/complicações , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Sensação/efeitos dos fármacos , Tiazóis/química , Fatores de Tempo , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/metabolismo , Nervo Vago/efeitos dos fármacos
3.
Int J Nanomedicine ; 16: 2615-2631, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854311

RESUMO

Background: Plumbagin, a naphthoquinone extracted from the officinal leadwort presenting promising anti-cancer properties, has its therapeutic potential limited by its inability to reach tumors in a specific way at a therapeutic concentration following systemic injection. The purpose of this study is to assess whether a novel tumor-targeted, lipid-polymer hybrid nanoparticle formulation of plumbagin would suppress the growth of B16-F10 melanoma in vitro and in vivo. Methods: Novel lipid-polymer hybrid nanoparticles entrapping plumbagin and conjugated with transferrin, whose receptors are present in abundance on many cancer cells, have been developed. Their cellular uptake, anti-proliferative and apoptosis efficacy were assessed on various cancer cell lines in vitro. Their therapeutic efficacy was evaluated in vivo after tail vein injection to mice bearing B16-F10 melanoma tumors. Results: The transferrin-bearing lipid-polymer hybrid nanoparticles loaded with plumbagin resulted in the disappearance of 40% of B16-F10 tumors and regression of 10% of the tumors following intravenous administration. They were well tolerated by the mice. Conclusion: These therapeutic effects, therefore, make transferrin-bearing lipid-polymer hybrid nanoparticles entrapping plumbagin a highly promising anti-cancer nanomedicine.


Assuntos
Lipídeos/química , Melanoma Experimental/tratamento farmacológico , Nanopartículas/química , Naftoquinonas/administração & dosagem , Naftoquinonas/uso terapêutico , Polímeros/química , Neoplasias Cutâneas/tratamento farmacológico , Transferrina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Injeções Intravenosas , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Naftoquinonas/farmacologia , Neoplasias Cutâneas/patologia , Tiazóis/farmacologia , Tiazóis/uso terapêutico
4.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806369

RESUMO

Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Desinfetantes/toxicidade , Tiazóis/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Barreira Hematoencefálica/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Desinfetantes/antagonistas & inibidores , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Metabolismo Energético/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteólise/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Tiazóis/antagonistas & inibidores , Proteínas de Junções Íntimas/metabolismo
5.
Lancet Oncol ; 22(4): 489-498, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33794206

RESUMO

BACKGROUND: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. METHODS: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. FINDINGS: Between Aug 14, 2017, and Dec 17, 2019 (data cutoff), 127 patients with at least 6 months' follow-up were enrolled into cohort A. 121 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 11·7 months (IQR 8·5-15·9). 61 (50·4%; 95% CI 41·2-59·6) of 121 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (36 [28%] of 127 patients), rash (12 [9%]), and rash maculopapular (12 [9%]). Serious adverse events occurred in 33 (26%) of 127 patients. No treatment-related deaths were reported. INTERPRETATION: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. FUNDING: Novartis Pharmaceuticals.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Tiazóis/administração & dosagem , Adolescente , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Antagonistas do Receptor de Estrogênio/administração & dosagem , Feminino , Fulvestranto/administração & dosagem , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/genética
6.
Molecules ; 26(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803823

RESUMO

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a-d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a-d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a-d and 7a-d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10-12 to afford the respective thiazole derivatives 13-15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, 1H-NMR, 13C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Tiazóis/química , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Células 3T3 BALB , Sítios de Ligação , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Proteínas rho de Ligação ao GTP/química
7.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805299

RESUMO

BACKGROUND: Adherent-invasive Escherichia coli (AIEC) have been implicated in the etiology of Crohn's disease. The AIEC reference strain LF82 possesses a pathogenicity island similar to the high pathogenicity island of Yersinia spp., which encodes the yersiniabactin siderophore required for iron uptake and growth of the bacteria in iron-restricted environment. Here, we investigated the role of yersiniabactin during AIEC infection. METHODS: Intestinal epithelial T84 cells and CEABAC10 transgenic mice were infected with LF82 or its mutants deficient in yersiniabactin expression. Autophagy was assessed by Western blot analysis for p62 and LC3-II expression. RESULTS: Loss of yersiniabactin decreased the growth of LF82 in competitive conditions, reducing the ability of LF82 to adhere to and invade T84 cells and to colonize the intestinal tract of CEABAC10 mice. However, yersiniabactin deficiency increased LF82 intracellular replication. Mechanistically, a functional yersiniabactin is necessary for LF82-induced expression of HIF-1α, which is implicated in autophagy activation in infected cells. CONCLUSION: Our study highlights a novel role for yersiniabactin siderophore in AIEC-host interaction. Indeed, yersiniabactin, which is an advantage for AIEC to growth in a competitive environment, could be a disadvantage for the bacteria as it activates autophagy, a key host defense mechanism, leading to bacterial clearance.


Assuntos
Autofagia , Doença de Crohn/etiologia , Infecções por Escherichia coli/complicações , Escherichia coli/patogenicidade , Mucosa Intestinal/fisiopatologia , Fenóis/metabolismo , Tiazóis/metabolismo , Animais , Doença de Crohn/fisiopatologia , Escherichia coli/metabolismo , Infecções por Escherichia coli/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos
8.
Medicine (Baltimore) ; 100(11): e25216, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33726018

RESUMO

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for stroke prevention in atrial fibrillation (AF) and the treatment and prevention of venous thromboembolism. There is an issue with safety, especially in clinically relevant bleeding. We performed a network meta-analysis to evaluate the risk of major gastrointestinal (GI) bleeding associated with NOACs. METHODS: Interventions were warfarin, enoxaparin, apixaban, dabigatran, edoxaban, and rivaroxaban. The primary outcome was the incidence of major GI bleeding. A subgroup analysis was performed according to the following indications: AF, deep venous thrombosis/pulmonary embolism, and postsurgical prophylaxis. RESULTS: A total of 29 randomized controlled trials (RCTs) and 4 large observation population studies were included. Compared with warfarin, apixaban showed a decreased the risk of major GI bleeding (relative risk [RR] 0.54, 95% confidence interval [CI] 0.25-0.76), and rivaroxaban tended to increase this risk (RR 1.40, 95% CI 1.06-1.85). Dabigatran (RR 1.25, 95% CI 0.98-1.60), edoxaban (RR 1.07, 95% CI 0.69-1.65), and enoxaparin (RR 1.24, 95% CI 0.63-2.43) did not significantly increase the risk of GI bleeding than did warfarin. In the subgroup analysis, according to indications, apixaban showed a decreased risk of major GI bleeding (RR 0.50, 95% CI 0.34-0.74) than did warfarin in AF studies. Dabigatran (RR 2.36, 95% CI 1.55-3.60, and rivaroxaban (RR 1.75, 95% CI 1.10-6.41) increased the risk of major GI bleeding than did apixaban. An analysis of studies on venous thromboembolism or pulmonary embolism showed that no individual NOAC or enoxaparin was associated with an increased risk of major GI bleeding compared to warfarin. CONCLUSION: Individual NOACs had varying profiles of GI bleeding risk. Results of analyses including only RCTs and those including both RCTs and population studies showed similar trends, but also showed several differences.


Assuntos
Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Hemorragia Gastrointestinal/induzido quimicamente , Embolia Pulmonar/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Adulto , Idoso , Fibrilação Atrial/complicações , Dabigatrana/efeitos adversos , Enoxaparina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Estudos Observacionais como Assunto , Embolia Pulmonar/complicações , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Rivaroxabana/efeitos adversos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/efeitos adversos , Tromboembolia Venosa/complicações , Varfarina/efeitos adversos
9.
Bull Environ Contam Toxicol ; 106(5): 892-898, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33709159

RESUMO

Clothianidin is drenched at planting to manage the termites of sugarcane. The application of organic manures at planting is also in vogue to conserve the soil moisture in the tropical ecosystem. Hence, the persistence behaviour of clothianidin was studied in the sandy clay loam soil of tropical sugarcane ecosystem under different organic manuring. The clothianidin residues persisted up to 90th DAT and reached below the limit of quantification (LOQ = 0.005 µg/g) on 105th DAT both in the manurial and non-manurial soils. The half-lives of clothianidin were in the range of 22.4-24.8 days in the manurial soils as against 21 days in the non-manurial soil, indicating the insignificant positive impact of organic manures on the soil persistence of clothianidin. The clothianidin residues in the soil were predicted to pose unacceptable to medium level of risk to earthworms during the course of its dissipation in the tropical sugarcane environment.


Assuntos
Saccharum , Poluentes do Solo , Ecossistema , Guanidinas , Esterco , Neonicotinoides , Medição de Risco , Solo , Poluentes do Solo/análise , Tiazóis
10.
Environ Pollut ; 278: 116880, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33743269

RESUMO

The house fly, Musca domestica L., is a cosmopolitan insect pest of public and animal health importance that serves as a mechanical vector of pathogens. Aimed at prospective resistance management to reduce environmental pollution, we characterized the inheritance pattern, realized heritability, fitness cost, cross resistance, stability and mechanism of clothianidin resistance in M. domestica that were collected from the poultry farm. By continuous selection with clothianidin for 11 generations, the clothianidin selected M. domestica strain (Clotha-SEL) developed a 3827-fold resistance compared to a susceptible strain. However, resistance to clothianidin was proved to be unstable when selection with clothianidin was removed for five generations (G7 to G12). Inheritance pattern analysis at G8 of Clotha-SEL (RR = 897) revealed that resistance to clothianidin was polygenic, autosomal and incompletely dominant. Realized heritability (h2) for resistance value was 0.38 (at G11) in the tested strain. Synergist bioassays showed that microsomal oxidases and esterases might not contribute significantly in resistance evolution. Fitness costs of clothianidin resistance were present, for example, reduction in growth potential of the Clotha-SEL strain in comparison to the untreated counterpart strain (UNSEL) was observed. No cross resistance to bifenthrin and fipronil and a very low cross-resistance to spinosad were observed. These insecticides could be alternated with clothianidin as an insecticide resistance management tool to sustain its efficacy for a longer time period. These results shall be utilized to devise a proactive resistance management strategy for use of clothianidin against M. domestica that will be helpful to alleviate the allied threats to environmental and human health.


Assuntos
Moscas Domésticas , Inseticidas , Animais , Guanidinas , Moscas Domésticas/genética , Humanos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Neonicotinoides , Estudos Prospectivos , Tiazóis
11.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33649841

RESUMO

Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133+ U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1­knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133+ U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ­Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Receptor Notch1/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Ácidos Cafeicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Diaminas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos Nus , Interferência de RNA , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Transdução de Sinais/genética , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669069

RESUMO

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Lipídeos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Tiazóis/uso terapêutico , Actinas/genética , Actinas/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Sobrevivência Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Janus Quinases/metabolismo , Lipídeos/farmacologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/genética , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fatores de Transcrição NFATC/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Osteoclastos/metabolismo , Osteogênese/genética , Fosforilação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Ligante RANK/farmacologia , Fosfatase Ácida Resistente a Tartarato/genética , Fosfatase Ácida Resistente a Tartarato/metabolismo , Tiazóis/farmacologia
14.
J Vis Exp ; (168)2021 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-33720130

RESUMO

Multiple sclerosis (MS) is a neuroinflammatory disease with expanding axonal and neuronal degeneration and demyelination in the central nervous system, leading to motor dysfunctions, psychical disability, and cognitive impairment during MS progression. Positron emission tomography (PET) is an imaging technique able to quantify in vivo cellular and molecular alterations. Radiotracers with affinity to intact myelin can be used for in vivo imaging of myelin content changes over time. It is possible to detect either an increase or decrease in myelin content, what means this imaging technique can detect demyelination and remyelination processes of the central nervous system. In this protocol we demonstrate how to use PET imaging to detect myelin changes in the lysolecithin rat model, which is a model of focal demyelination lesion (induced by stereotactic injection) (i.e., a model of multiple sclerosis disease). 11C-PIB PET imaging was performed at baseline, and 1 week and 4 weeks after stereotaxic injection of lysolecithin 1% in the right striatum (4 µL) and corpus callosum (3 µL) of the rat brain, allowing quantification of focal demyelination (injection site after 1 week) and the remyelination process (injection site at 4 weeks). Myelin PET imaging is an interesting tool for monitoring in vivo changes in myelin content which could be useful for monitoring demyelinating disease progression and therapeutic response.


Assuntos
Esclerose Múltipla/diagnóstico por imagem , Bainha de Mielina/patologia , Tomografia por Emissão de Pósitrons , Compostos de Anilina/química , Animais , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador , Lisofosfatidilcolinas , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Ratos , Técnicas Estereotáxicas , Tiazóis/química
15.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652850

RESUMO

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.


Assuntos
Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Proteínas Mutantes/genética , Aminoimidazol Carboxamida/química , Benzodioxóis/química , Fibrose Cística/genética , Fibrose Cística/patologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Humanos , Mutação/efeitos dos fármacos , Mutação/genética , Dobramento de Proteína/efeitos dos fármacos , Tiazóis/química
16.
Medicine (Baltimore) ; 100(3): e23969, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33545981

RESUMO

ABSTRACT: This study aimed to evaluated the clinical impact of adding [11C] Pittsburgh compound-B (11C-PiB) PET for clinical diagnosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia.Twenty six (mean age 78.5 ±â€Š5.18 years, 21 females) AD (n = 7), amnestic MCI (n = 12), non-amnestic MCI (n = 3), vascular dementia, progressive supranuclear palsy (PSP) with frontotemporal dementia (FTD), FTD (n = 1 each), and normal (n = 1) patients underwent 11C-PiB-PET, MRI, and SPECT scanning. 11C-PiB-PET was compared with MRI and SPECT for clinical impact.11C-PiB-PET showed positivity in 6, 9, and 0 of the AD, amnestic MCI, and non-amnestic MCI patients, respectively, and 0 of those with another disease. Parahippocampal atrophy at VSASD was observed in 5 AD patients, 6 amnestic and PiB-positive MCI patients, 1 amnestic and PiB-negative MCI patient, and 1 vascular dementia patient. Parietal lobe hypoperfusion in SPECT findings was observed in 6, 4, and 2 of those, respectively, as well as 1 each of non-amnestic MCI, vascular dementia, and normal cases. Sensitivity/specificity/accuracy for selecting PiB-positive patients among the 15 MCI patients for 11C-PiB-PET were 100% (9/9)/100% (6/6)/100% (15/15), for VSRAD were 66.7% (6/9)/83.3% (5/6)/73.3% (11/15), and for SPECT were 44.4% (4/9)/50.0% (3/6)/46.7% (7/15), while those were 88.9% (8/9)/33.3% (2/6)/66.7% (10/15)/for combined VSRAD and SPECT. 11C-PiB-PET accuracy was significantly higher than that of SPECT.11PiB-PET alone may be useful for selecting patients who will progress from MCI to AD in the future, although follow-up study is necessary to clarify the outcome of MCI patients.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Tiazóis/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único/métodos
17.
Ecotoxicol Environ Saf ; 212: 112015, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33561775

RESUMO

Osmia excavata is an important pollinator in commercial fruit orchards. Little information has been published about ecotoxicity to O. excavata, especially the larvae. To clarify the risk of commonly used insecticides with different modes of action to the larvae of O. excavata, six insecticides (clothianidin, acetamiprid, sulfoxaflor, lambda-cyhalothrin, chlorfenapyr and abamectin) were selected for evaluation of their acute lethal toxicity and sublethal effects. Clothianidin and abamectin were the two most toxic insecticides to the larvae of O. excavata with LD50 values of 0.007 (0.006-0.008) and 0.0004 (0.0003-0.0006) µg active ingredient (a.i.) bee-1, respectively. And their ecological risks were high according to the hazard quotient values (HQ > 2500). Sulfoxaflor was identified as the only safe insecticide for O. excavata (HQ < 50) under field conditions. Sublethal toxicity tests showed that larval weight was significantly decreased by ingesting food treated with clothianidin, lambda-cyhalothrin and abamectin (less than the maximum field registered concentrations on fruit trees) due to interference with consumption per larva and reduction of the efficiency of conversion of ingested food. Additionally, above three insecticides significantly prolonged larval developmental duration before cocooning and decreased eclosion rate. Overall, there results suggested that clothianidin and abamectin should not be applied, especially during the flowering phase, the application frequency of lambda-cyhalothrin should be minimized for the purpose of conserving O. excavata. Our results provided important evidences for selecting appropriate insecticides for use in fruit orchards.


Assuntos
Abelhas/efeitos dos fármacos , Inseticidas/toxicidade , Larva/efeitos dos fármacos , Animais , Abelhas/crescimento & desenvolvimento , Produtos Agrícolas/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Ecotoxicologia , Guanidinas/toxicidade , Dose Letal Mediana , Neonicotinoides/toxicidade , Nitrilos/toxicidade , Polinização , Piretrinas/toxicidade , Piridinas/toxicidade , Medição de Risco , Compostos de Enxofre/toxicidade , Tiazóis/toxicidade
18.
J Med Virol ; 93(5): 3176-3183, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33590901

RESUMO

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.


Assuntos
/tratamento farmacológico , Ivermectina/uso terapêutico , Nitrocompostos/uso terapêutico , Ribavirina/uso terapêutico , Tiazóis/uso terapêutico , Zinco/uso terapêutico , Adulto , Antimetabólitos/administração & dosagem , Antimetabólitos/uso terapêutico , Antiparasitários/administração & dosagem , Antiparasitários/uso terapêutico , Feminino , Humanos , Ivermectina/administração & dosagem , Masculino , Nitrocompostos/administração & dosagem , Ribavirina/administração & dosagem , Tiazóis/administração & dosagem , Oligoelementos/administração & dosagem , Oligoelementos/uso terapêutico , Zinco/administração & dosagem
20.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33625354

RESUMO

Introduction. Cryptosporidium parvum causes intestinal parasitic infections affecting both immunosuppressed and immunocompetent individuals.Gap statement. Given the absence of effective treatments for cryptosporidiosis, especially in immunodeficient patients, the present study was designed to assess the therapeutic efficacy of secnidazole (SEC) and its combination with nitazoxanide (NTZ) in comparison to single NTZ treatment in relation to the immune status of a murine model of C. parvum infection.Methodology. The infected groups were administered NTZ, SEC or NTZ-SEC for three or five successive doses. At days 10 and 12 post-infection (p.i.), the mice were sacrificed, and the efficacy of the applied drugs was evaluated by comparing the histopathological alterations in ileum and measuring the T helper Th1 (interferon gamma; IFN-γ), Th2 [interleukin (IL)-4 and IL-10] and Th17 (IL-17) cytokine profiles in serum.Results. The NTZ-SEC combination recorded the maximal reduction of C. parvum oocyst shedding, endogenous stages count and intestinal histopathology, regardless of the immune status of the infected mice. The efficacy of NTZ-SEC was dependent on the period of administration, as the 5 day-based treatment protocol was also more effective than the 3 day-based one in terms of immunocompetence and immunosuppression. The present treatment schedule induced an immunomodulatory effect from SEC that developed a protective immune response against C. parvum infection with reduced production of serum IL-17, IFN-γ, IL-4 and IL-10.Conclusions. Application of NTZ-SEC combined therapy may be useful in treatment of C. parvum, especially in cases involving immunosuppression.


Assuntos
Antiprotozoários/uso terapêutico , Criptosporidiose/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Metronidazol/análogos & derivados , Nitrocompostos/uso terapêutico , Tiazóis/uso terapêutico , Animais , Criptosporidiose/imunologia , Criptosporidiose/parasitologia , Criptosporidiose/patologia , Cryptosporidium parvum/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Íleo/efeitos dos fármacos , Íleo/parasitologia , Íleo/patologia , Hospedeiro Imunocomprometido , Masculino , Metronidazol/uso terapêutico , Camundongos , Carga Parasitária
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...