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1.
JAMA ; 324(1): 79-89, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32633805

RESUMO

Importance: Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe. Objective: To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis. Evidence Review: A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non-English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature. Findings: There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype. Conclusions and Relevance: All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.


Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Algoritmos , Benzoxazóis/uso terapêutico , Dexametasona/uso terapêutico , Diagnóstico Diferencial , Inativação Gênica , Insuficiência Cardíaca/etiologia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/mortalidade , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/terapia , Transplante de Fígado , Melfalan/uso terapêutico , Prognóstico , Proteinúria/etiologia , Transplante de Células-Tronco
2.
Microb Biotechnol ; 13(4): 844-887, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32406115

RESUMO

We have recently argued that, because microbes have pervasive - often vital - influences on our lives, and that therefore their roles must be taken into account in many of the decisions we face, society must become microbiology-literate, through the introduction of relevant microbiology topics in school curricula (Timmis et al. 2019. Environ Microbiol 21: 1513-1528). The current coronavirus pandemic is a stark example of why microbiology literacy is such a crucial enabler of informed policy decisions, particularly those involving preparedness of public-health systems for disease outbreaks and pandemics. However, a significant barrier to attaining widespread appreciation of microbial contributions to our well-being and that of the planet is the fact that microbes are seldom visible: most people are only peripherally aware of them, except when they fall ill with an infection. And it is disease, rather than all of the positive activities mediated by microbes, that colours public perception of 'germs' and endows them with their poor image. It is imperative to render microbes visible, to give them life and form for children (and adults), and to counter prevalent misconceptions, through exposure to imagination-capturing images of microbes and examples of their beneficial outputs, accompanied by a balanced narrative. This will engender automatic mental associations between everyday information inputs, as well as visual, olfactory and tactile experiences, on the one hand, and the responsible microbes/microbial communities, on the other hand. Such associations, in turn, will promote awareness of microbes and of the many positive and vital consequences of their actions, and facilitate and encourage incorporation of such consequences into relevant decision-making processes. While teaching microbiology topics in primary and secondary school is key to this objective, a strategic programme to expose children directly and personally to natural and managed microbial processes, and the results of their actions, through carefully planned class excursions to local venues, can be instrumental in bringing microbes to life for children and, collaterally, their families. In order to encourage the embedding of microbiology-centric class excursions in current curricula, we suggest and illustrate here some possibilities relating to the topics of food (a favourite pre-occupation of most children), agriculture (together with horticulture and aquaculture), health and medicine, the environment and biotechnology. And, although not all of the microbially relevant infrastructure will be within reach of schools, there is usually access to a market, local food store, wastewater treatment plant, farm, surface water body, etc., all of which can provide opportunities to explore microbiology in action. If children sometimes consider the present to be mundane, even boring, they are usually excited with both the past and the future so, where possible, visits to local museums (the past) and research institutions advancing knowledge frontiers (the future) are strongly recommended, as is a tapping into the natural enthusiasm of local researchers to leverage the educational value of excursions and virtual excursions. Children are also fascinated by the unknown, so, paradoxically, the invisibility of microbes makes them especially fascinating objects for visualization and exploration. In outlining some of the options for microbiology excursions, providing suggestions for discussion topics and considering their educational value, we strive to extend the vistas of current class excursions and to: (i) inspire teachers and school managers to incorporate more microbiology excursions into curricula; (ii) encourage microbiologists to support school excursions and generally get involved in bringing microbes to life for children; (iii) urge leaders of organizations (biopharma, food industries, universities, etc.) to give school outreach activities a more prominent place in their mission portfolios, and (iv) convey to policymakers the benefits of providing schools with funds, materials and flexibility for educational endeavours beyond the classroom.


Assuntos
Amiloidose , Pré-Albumina , Adulto , Benzoxazóis , Criança , Humanos
3.
Kardiologiia ; 60(3): 155-160, 2020 Jan 20.
Artigo em Russo | MEDLINE | ID: mdl-32375630

RESUMO

Transthyretin amyloidosis (ATTR) is a threatening and severe genetic disease characterized by damages to organs and systems caused by a pathological protein transthyretin produced in the liver. Clinical manifestations of this disease vary from injuries of the nervous system to injuries of the cardiovascular system. Prognosis for ATTR-amyloidosis remains unfavorable. The absence of pathognomonic symptoms complicates diagnostics of this disease, which tends to simulate other conditions. At present, medicines exist, which are pathogenetic in the treatment of ATTR-amyloidosis. The article describes a clinical case of ATTR-amyloidosis with primary heart injury complicated with functional class III chronic heart failure during the tafamidis treatment.


Assuntos
Neuropatias Amiloides Familiares , Benzoxazóis/uso terapêutico , Neuropatias Amiloides Familiares/tratamento farmacológico , Humanos , Pré-Albumina
4.
Life Sci ; 253: 117539, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165213

RESUMO

AIMS: Lipopolysaccharide (LPS)-induced intestinal injury is a common clinical feature of sepsis. Aggravated inflammation and higher sensitivity to infection are associated with high-fat diet (HFD) in patients with type 2 diabetes and/or obesity. However, the mechanism by which HFD exacerbates LPS-induced intestinal injury has not been elucidated. This study aims to examine the effects of HFD on intestinal injury induced by LPS and the underlying mechanism. MAIN METHODS: Mice were fed with HFD or regular chow for 12weeks and were then challenged with LPS. Vas2870 was administered to mice that received HFD before the initiation of the diet. The levels of tight junction protein expression, oxidative stress, organ injury, and nicotinamide adenine dinucleotide phosphate (NADPH)-associated proteins were assessed periodically. KEY FINDINGS: LPS treatment resulted in severe intestinal pathological injury and increased oxidative stress, evidenced by significantly increased serum diamine oxidase, reactive oxygen species, malondialdehyde, and intestinal fatty acid binding protein contents. Additionally, a decrease in tight junction protein expression was observed, indicating a loss of tight junction integrity. LPS treatment induced the expression of Nox2 and Nox4. All the effects were more severe in HFD mice. Treatment with vas2870 conferred protection against LPS-induced intestinal injury in HFD-fed mice, partially reduced oxidative stress, and rescued the expression of tight junction proteins. CONCLUSION: HFD aggravated LPS-induced intestine injury through exacerbating intestinal Nox-related oxidative stress, which led to a loss of the integrity of tight junctions and consequently increased intestinal permeability.


Assuntos
Dieta Hiperlipídica , Intestinos/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , NADP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adsorção , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Oxirredução , Permeabilidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Triazóis/administração & dosagem , Triazóis/metabolismo
5.
Can J Cardiol ; 36(2): 159-169, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32036861

RESUMO

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.


Assuntos
Amiloidose/complicações , Amiloidose/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Benzoxazóis/uso terapêutico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/cirurgia , Neprilisina/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Cardiopatias/complicações , Cardiopatias/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Insuficiência da Valva Mitral/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Volume Sistólico
7.
Appl Microbiol Biotechnol ; 104(5): 2017-2028, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31930453

RESUMO

This paper focuses on the production of a high-affinity monoclonal antibody (mAb) that can efficiently detect and block purinergic ligand-gated ion channel 7 receptor (P2X7R). To achieve this goal, the extracellular domain of human P2X7R, P2X7R-ECD, was used as an immunogen for BALB/c mice, inducing them to produce spleen lymphocytes that were subsequently fused with myeloma cells. Screening of the resultant hybridoma clones resulted in the selection of one stable positive clone that produced a qualified mAb, named 4B3A4. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis demonstrated that the purity of the purified 4B3A4 mAb was above 85%, with prominent bands corresponding to molecular weights of 55 kDa (heavy chain) and 25 kDa (light chain), and the BCA assay showed that the concentration of the purified 4B3A4 mAb was 0.3 mg/mL. Western blot analysis revealed that the 4B3A4 mAb could specifically recognize and bind both P2X7R-ECD and the full-length P2X7R protein. Laser scanning confocal microscopy (LSCM) revealed that the 4B3A4 mAb specifically bound to P2X7R on the membrane of human peripheral blood mononuclear cells (PBMCs). P2X7R expression was significantly different between healthy individuals and people with certain cancers as determined by flow cytometry (FCM). In addition, the 4B3A4 mAb significantly reduced ATP-stimulated Ca2+ entry and YO-PRO-1 uptake, which indicated that the 4B3A4 mAb effectively blocked P2X7R activity. These data indicate that the 4B3A4 mAb can be further used as not only an antibody to detect cell surface P2X7R but also as a therapeutic antibody to target P2X7R-related signaling pathways.


Assuntos
Anticorpos Monoclonais/imunologia , Receptores Purinérgicos P2X7/imunologia , Animais , Anticorpos Monoclonais/química , Especificidade de Anticorpos , Benzoxazóis/metabolismo , Cálcio/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular , Domínios Proteicos , Compostos de Quinolínio/metabolismo , Receptores Purinérgicos P2X7/química
8.
Sci Rep ; 10(1): 1292, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992742

RESUMO

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Transportador 1 de Aminoácidos Neutros Grandes/biossíntese , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/microbiologia , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
9.
Talanta ; 206: 120217, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514897

RESUMO

MicroRNAs (miRNA) involve in regulating different physiological processes whose dysregulation is associated with a wide range of diseases including cancers, diabetes and cardiovascular problems. Herein, we report a direct, sensitive and highly selective detection assay for circulating microRNA (miRNA). This detection strategy employs magnetic nanoparticles as the reaction platform which can not only allow online pre-concentration and selective separation but also integrates ligation reaction with amplification to enhance the sensitivity of the detection assay. With the presence of the target miRNA, the locked nucleic acid (LNA)-modified molecular beacon (MB) opens up, exposing the binding sites at two ends. The 3'- and 5'-end of the MB responsible for the attachment onto the magnetic nanoparticles, and reporting probe for the attachment of the pair of amplification probes respectively. The ligase ligate RNA to DNA enhance the amplification efficiency. Upon labelled with intercalating fluorophores (YOYO-1) on the hybrids, the quantification of the target miRNA was determined by measuring the fluorescence intensity. A detection limit of 314 fM was achieved with trace amount of sample consumption (~20 µL). As a proof of concept, miRNA-149 was chosen as the target miRNA. This assay is capable of discriminating single-base and reliably quantifying circulating miRNA-149 in both healthy and cancer patient's serums. The result obtained was comparable with that of quantitative reverse transcription polymerase chain reaction (qRT-PCR), suggesting that this direct and sensitive assay can be served as a promising, non-invasive tool for early diagnosis of breast cancer and colorectal cancer.


Assuntos
MicroRNA Circulante/sangue , MicroRNAs/sangue , Microscopia de Fluorescência/métodos , RNA Ligase (ATP)/química , Proteínas Virais/química , Benzoxazóis/química , MicroRNA Circulante/genética , DNA/química , DNA/genética , Corantes Fluorescentes/química , Humanos , Substâncias Intercalantes/química , Limite de Detecção , Nanopartículas de Magnetita/química , MicroRNAs/genética , Hibridização de Ácido Nucleico , Oligonucleotídeos/química , Oligonucleotídeos/genética , Estudo de Prova de Conceito , Compostos de Quinolínio/química
10.
Int J Mol Sci ; 20(22)2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31698825

RESUMO

Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the "with-statin" group and 576 in the "without-statin" group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the "with-statin" group, the estimated percent change from baseline was -2.0% for placebo and -45.1%, -48.5%, and -50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the "with-statin" group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among "with-statin" patients who had renal dysfunction.


Assuntos
Benzoxazóis/efeitos adversos , Benzoxazóis/uso terapêutico , Butiratos/efeitos adversos , Butiratos/uso terapêutico , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , PPAR alfa/metabolismo , Benzoxazóis/farmacologia , Butiratos/farmacologia , Creatina Quinase/metabolismo , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/fisiopatologia , Feminino , Humanos , Rim/fisiopatologia , Lipídeos/sangue , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
SAR QSAR Environ Res ; 30(12): 919-933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702401

RESUMO

Folates are essential biomolecules required to carry out many crucial processes in leishmania parasite. Dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) involved in folate biosynthesis in leishmania have been established as suitable targets for development of chemotherapy against leishmaniasis. In the present study, various computational tools such as homology modelling, pharmacophore modelling, docking, molecular dynamics and molecular mechanics have been employed to design dual DHFR-TS and PTR1 inhibitors. Two designed molecules, i.e. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were synthesized. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to evaluate in vitro activity of molecules against promastigote form of Leishmania donovani using Miltefosine as standard. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were found to be moderately active with showed IC50 = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Complexos Multienzimáticos/química , Oxirredutases/química , Proteínas de Protozoários/química , Tetra-Hidrofolato Desidrogenase/química , Timidilato Sintase/química , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Descoberta de Drogas , Concentração Inibidora 50 , Leishmania donovani/metabolismo , Modelos Moleculares , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Relação Estrutura-Atividade
12.
Int J Mol Sci ; 20(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766193

RESUMO

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.


Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , PPAR alfa/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Modelos Moleculares , Oxirredução/efeitos dos fármacos , PPAR alfa/agonistas , PPAR alfa/química
13.
Arch Pharm (Weinheim) ; 352(12): e1900178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31596514

RESUMO

A novel series of benzoxazole/benzothiazole derivatives 4a-c-11a-e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT-116, and MCF-7 cells, with IC50 values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC50 values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT-116 cells with IC50 values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF-7 cells with IC50 values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC50  values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a-c, 9b,c,e,f,h, and 11c,e were further evaluated for their VEGFR-2 inhibition. Compounds 4c and 4b potently inhibited VEGFR-2 at IC50 values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC50 value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.


Assuntos
Antineoplásicos/síntese química , Benzoxazóis/química , Desenho de Fármacos , Tiadiazóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
14.
Pharmacol Rep ; 71(6): 1147-1150, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31655279

RESUMO

BACKGROUND: The orexin system regulates various functions, including sleep/wake cycles, feeding, and cognition. Orexin A and orexin B are endogenous neuropeptides for both orexin 1 (OX1) and orexin 2 (OX2) receptors. Orexin A has a potent agonistic activity for both the receptors and is known to increase locomotor activity in rats. However, it has not been elucidated how each receptor contributes to orexin A-induced hyperlocomotion. METHODS: We examined the effects of an OX1 receptor antagonist, SB 334867, and an OX2 receptor antagonist, EMPA, as well as an OX1 and OX2 receptor antagonist on hyperlocomotion caused by intracerebroventricular administration of orexin A or an OX2 receptor agonist, ADL-OXB ([Ala11,d-Leu15]-orexin B), in rats. RESULTS: EMPA (100 mg/kg, ip) but not SB 334867 (3-10 mg/kg, ip) showed antagonistic effects on ADL-OXB-induced hyperlocomotion without affecting the spontaneous locomotor activity. Both EMPA (100 mg/kg, ip) and the OX1 and OX2 receptor antagonist (3-30 mg/kg, po) antagonized orexin A-induced hyperlocomotion, while SB 334867 (3‒-10 mg/kg, ip) showed no effects. CONCLUSIONS: Our results suggest that orexin A-induced hyperlocomotion is mainly mediated by the activation of the OX2 receptor.


Assuntos
Locomoção/fisiologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Aminopiridinas/farmacologia , Animais , Benzoxazóis/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Naftiridinas/farmacologia , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia
15.
J Enzyme Inhib Med Chem ; 34(1): 1722-1729, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31576761

RESUMO

In this study, new chalcone compounds having the chemical structure of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones (1-8) were synthesised and were characterised by 1H-NMR, 13 C-NMR, and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity results pointed out that compound 4, 6-[3-(4-trifluoromethylphenyl)-2-propenoyl]-3H-benzoxazol-2-one, showed the highest cytotoxicity (CC50) and potency-selectivity expression (PSE) value, and thus can be considered as a lead compound of this study. According to the CA inhibitory results, IC50 values of the compounds 1-8 towards hCA I were in the range of 29.74-69.57 µM, while they were in the range of 18.14 - 48.46 µM towards hCA II isoenzyme. Ki values of the compounds 1-8 towards hCA I were in the range of 28.37 ± 6.63-70.58 ± 6.67 µM towards hCA I isoenzyme and they were in the range of 10.85 ± 2.14 - 37.96 ± 2.36 µM towards hCA II isoenzyme.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzoxazóis/química , Benzoxazóis/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/toxicidade , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalcona/química , Criança , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
16.
J Gastrointestin Liver Dis ; 28(3): 359-361, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517333

RESUMO

Transthyretin amyloidosis (ATTR) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene. Due to the phenotypic heterogeneity, ATTR is difficult to recognize and it is often diagnosed very late. In ATTR gastrointestinal (GI) disorders play an important role in the patients' morbidity and mortality. In some cases, GI symptoms are present even before the onset of the peripheral polyneuropathy. However, the complaints are various and it is really difficult to differentiate them from other GI disorders. We present a 61-year old male referred for diarrhea, unintentional weight loss and early satiety. He had hypotension after longstanding hypertension, numbness and tingling in the feet. We considered a broad differential diagnosis spectrum of chronic diarrhea syndrome and performed numerous laboratory, biochemical, imaging, endoscopic, histological and genetic tests. Transthyretin amyloidosis with a Glu89Gln mutation was diagnosed. Transthyretin amyloidosis is frequently misdiagnosed, representing a diagnostic challenge in GI practice. The presence of certain clinical combinations could help gastroenterologists to include ATTR in their diagnostic work-up.


Assuntos
Neuropatias Amiloides Familiares/complicações , Diarreia/etiologia , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Benzoxazóis/uso terapêutico , Doença Crônica , Análise Mutacional de DNA , Diagnóstico Diferencial , Diarreia/diagnóstico , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pré-Albumina/genética , Valor Preditivo dos Testes
17.
Chemosphere ; 235: 1030-1040, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31561292

RESUMO

Organic pesticides are one of the main environmental pollutants, and how to reduce their environmental risks is an important issue. In this contribution, we disclose the molecular basis for the resistance of American sloughgrass to aryloxyphenoxypropionic acid pesticides using site-directed mutagenesis and molecular modeling and then construct an effective screening model. The results indicated that the target-site mutation (Trp-1999-Leu) in acetyl-coenzyme A carboxylase (ACCase) can affect the effectiveness of the pesticides (clodinafop, fenoxaprop, cyhalofop, and metamifop), and the plant resistance to fenoxaprop, clodinafop, cyhalofop, and metamifop was found to be 564, 19.5, 10, and 0.19 times, respectively. The established computational models (i.e. wild-type/mutant ACCase models) could be used for rational screening and evaluation of the resistance to pesticides. The resistance induced by target gene mutation can markedly reduce the bioreactivity of the ACCase-clodinafop/fenoxaprop adducts, and the magnitudes are 10 and 102, respectively. Such event will seriously aggravate environmental pollution. However, the biological issue has no distinct effect on cyhalofop (RI=10), and meanwhile it may markedly increase the bioefficacy of metamifop (RI=0.19). We could selectively adopt the two chemicals so as to decrease the residual pesticides in the environment. Significantly, research findings from the computational screening models were found to be negatively correlated with the resistance level derived from the bioassay testing, suggesting that the screening models can be used to guide the usage of pesticides. Obviously, this story may shed novel insight on the reduction of environmental risks of pesticides and other organic pollutants.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Biologia Computacional/métodos , Resistência a Herbicidas/genética , Praguicidas/toxicidade , Proteínas de Plantas/antagonistas & inibidores , Poaceae/crescimento & desenvolvimento , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Anilidas/toxicidade , Benzoxazóis/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Mutação , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Poaceae/efeitos dos fármacos , Poaceae/enzimologia , Propionatos/toxicidade , Conformação Proteica , Piridinas/toxicidade , Estados Unidos
18.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31510109

RESUMO

Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Benzoxazóis/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Imidazóis/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
19.
Eur J Med Chem ; 182: 111656, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494467

RESUMO

Chemical probes of epigenetic 'readers' of histone post-translational modifications (PTMs) have become powerful tools for mechanistic and functional studies of their target proteins in physiology and pathology. However, only limited 'reader' probes have been developed, which restricted our understanding towards these macromolecules and their roles in cells or animals. Here, we reported a structure-guided approach to develop and characterize benzo [d]oxazol-2(3H)-one analogs as the first potent and selective small-molecule inhibitors of chromodomain Y-like (CDYL), a histone methyllysine reader protein. The binding conformation between the chromodomain of CDYL and the modified peptidomimetics was studied via molecular docking and dynamic simulations, facilitating subsequent virtual screening of tens of hits from Specs chemical library validated by SPR technique (KD values: from 271.1 µM to 5.4 µM). Further design and synthesis of 43 compounds helped to interpret the structure-activity relationship (SAR) that lead to the discovery of novel small-molecule inhibitors of CDYL. Compound D03 (KD: 0.5 µM) was discovered and showed excellent selectivity among other chromodomain proteins, including CDYL2 (>140 folds), CDY1 (no observed binding) and CBX7 (>32 folds). Moreover, we demonstrated that D03 engaged with endogenous CDYL in a dose-dependent manner, and perturbed the recruitment of CDYL onto chromatin, resulting in transcriptional derepression of its target genes. Finally, the results showed that D03 promoted the development and branching of neurodendrites by inhibiting CDYL in hippocampal and cortical cultured neurons. This study not only discovers the first selective small-molecule inhibitors of CDYL, but provids a new chemical tool to intervene the dynamic nature of bio-macromolecules involved in epigenetic mechanism.


Assuntos
Benzoxazóis/farmacologia , Proteínas Correpressoras/antagonistas & inibidores , Hidroliases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Benzoxazóis/síntese química , Benzoxazóis/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Hidroliases/genética , Hidroliases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Neurônios/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
20.
Int Immunopharmacol ; 76: 105874, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499270

RESUMO

Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE), with unclear etiopathogenesis. We evaluated the role of macrophage migration inhibitory factor (MIF), which has been implicated in idiopathic pulmonary hypertension (PH), in SLE-associated PAH. Circulating MIF was measured in SLE patients, SLE-PAH patients, and healthy donors. In situ pulmonary artery MIF protein expression was determined in spontaneous SLE mice (MRL/lpr) and hypoxia-induced C57BL/6J mice. Daily MIF098 was administered to C57BL/6J mice, and these mice were maintained in a hypoxic chamber for 4 weeks. The right ventricular systolic pressure (RVSP) and pathological characteristics of the pulmonary artery (PA), such as hyperproliferation, muscularization, and fibrosis were then measured in each group of mice. Data were also obtained in vitro using pulmonary smooth muscle cells (PASMC) challenged with platelet-derived growth factor (PDGF)-BB or 1% O2 hypoxia. As a result, circulating MIF was elevated in SLE-PAH patients compared with SLE patients or healthy donors. Higher RVSP SLE mice produced more MIF protein than lower RVSP SLE mice in the pulmonary artery. MIF098 decreased RVSP and inhibited distal pulmonary artery hyperproliferation, muscularization, and collagen deposition in hypoxia challenged mice. In addition, MIF098 inhibited PASMC proliferation and migration by regulating mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) signal- and cell-cycle-related proteins. MIF098 also reduced collagen synthesis by inhibiting the TGFß1/Smad2/Smad3 pathway in cell-based experiments. In conclusion, MIF may serve as a biomarker and a therapeutic target of SLE-associated PAH. Pharmacologic MIF antagonism may be an effective means to ameliorate SLE-PAH.


Assuntos
Benzoxazóis/uso terapêutico , Oxirredutases Intramoleculares/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Hipertensão Arterial Pulmonar/tratamento farmacológico , Adulto , Animais , Benzoxazóis/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Oxirredutases Intramoleculares/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Fatores Inibidores da Migração de Macrófagos/sangue , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Hipertensão Arterial Pulmonar/sangue , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia
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