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1.
J Diabetes ; 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33710784

RESUMO

BACKGROUND: Parity, pregnancy loss, and breastfeeding duration were found to be associated with diabetes. However, the results are inconsistent. Also, no epidemiological studies have examined the association of these reproductive factors with diabetes in the same large population. We aim to investigate the associations between parity, pregnancy loss, breastfeeding duration, and the risk of maternal diabetes in middle-aged and elderly Chinese females. METHODS: We included 131 174 females aged ≥40 years from the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal Study). Multivariable linear regression and logistic regression were used to assess the association between parity, pregnancy loss, and breastfeeding duration and type 2 diabetes. RESULTS: The number of parities and breastfeeding duration were positively related to fasting plasma glucose, 2-hour postload glucose, glycosylated hemoglobin, and homeostatic model assessment of insulin resistance. Compared with those with one birth, nulliparous women or women with 2 or ≥3 births had a significantly increased risk of diabetes. The odds ratios (OR) and 95% confidence intervals (CI) were 1.27 (1.10-1.48), 1.17 (1.12-1.22), and 1.28 (1.21-1.35), respectively. Compared with women without pregnancy loss, those who underwent 2 (OR 1.09; 95% CI, 1.04-1.14) or ≥3 pregnancy losses (OR 1.11; 95% CI, 1.04-1.18) had an increased risk of diabetes. Moreover, women with a breastfeeding duration ≥0 to 6 months (OR 0.82; 95% CI, 0.75-0.90) and ≥6 to 12 months (OR 0.94; 95% CI, 0.89-0.99) had a significantly lower risk of diabetes. CONCLUSIONS: Nulliparous women or women with multiparity or more than one pregnancy loss have an increased risk of diabetes in later life, while women who breastfeed more than 0 to 12 months have a lower risk of diabetes.

2.
Oxid Med Cell Longev ; 2021: 5469849, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33510837

RESUMO

The antiaging benzoquinone-type molecule ehretiquinone was isolated in a previous study as a leading compound from the herbal medicine Onosma bracteatum wall. This paper reports the antiaging effect and mechanism of ehretiquinone by using yeasts, mammal cells, and mice. Ehretiquinone extends not only the replicative lifespan but also the chronological lifespan of yeast and the yeast-like chronological lifespan of mammal cells. Moreover, ehretiquinone increases glutathione peroxidase, catalase, and superoxide dismutase activity and reduces reactive oxygen species and malondialdehyde (MDA) levels, contributing to the lifespan extension of the yeasts. Furthermore, ehretiquinone does not extend the replicative lifespan of Δsod1, Δsod2, Δuth1, Δskn7, Δgpx, Δcat, Δatg2, and Δatg32 mutants of yeast. Crucially, ehretiquinone induces autophagy in yeasts and mice, thereby providing significant evidence on the antiaging effects of the molecule in the mammalian level. Concomitantly, the silent information regulator 2 gene, which is known for its contributions in prolonging replicative lifespan, was confirmed to be involved in the chronological lifespan of yeasts and participates in the antiaging activity of ehretiquinone. These findings suggest that ehretiquinone shows an antiaging effect through antioxidative stress, autophagy, and histone deacetylase Sir2 regulation. Therefore, ehretiquinone is a promising molecule that could be developed as an antiaging drug or healthcare product.

3.
J Med Chem ; 64(1): 677-694, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33370104

RESUMO

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.


Assuntos
Ciclopropanos/farmacologia , Descoberta de Drogas , Oxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Catálise , Cristalografia por Raios X , Ciclopropanos/química , Humanos , Camundongos , Oxazóis/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Psoríase/tratamento farmacológico , Relação Estrutura-Atividade , TYK2 Quinase/metabolismo
4.
Biopharm Drug Dispos ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33354831

RESUMO

Transforming growth factor beta (TGF-ß) is a pleiotropic cytokine that has a wide array of biological effects. For decades, tumor biology implicated TGF-ß as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-ß pathway. BMS-986260 is a small molecule, selective TGF-ßR1 kinase inhibitor that was under preclinical development for oncology. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clinical efficacious dose. The human clearance is predicted to be low, 4.25 ml/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclinical species. Taken together, the projected clinical efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclinical PK characterization and pharmacodynamics-based efficacious dose projection of a novel small molecule TGF-ßR1 inhibitor.

5.
ACS Med Chem Lett ; 11(11): 2195-2203, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33214829

RESUMO

Bruton's tyrosine kinase (BTK) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of BTK with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

6.
J Mol Model ; 26(11): 310, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084983

RESUMO

First-principle density functional theory calculations have been performed to investigate the adsorption of C2H2 on Ni(111) and Sn@Ni(111) at different coverages. At low coverage, the C2H2 molecule is strongly adsorbed on Ni(111) and the dissociation of the H atom is not favorable. Furthermore, the more the H atom dissociated, the more unstable the system is. However, the dissociation structure of C2H+H has the largest adsorption energy on Sn@Ni(111), indicating that the dissociation structure is more stable than molecular adsorbed C2H2. At moderate coverage, there is some repulsive interaction between two C2H2 molecules, inducing the decrease in adsorption energy. On Ni(111), the two C2H2 tend to adsorb separately, however, the dimer C4H4 has the largest adsorption energy on Sn@Ni(111). At high coverage, the trimer derivative benzene has the largest adsorption energy on both Ni(111) and Sn@Ni(111) surfaces. The adsorption energies of the formed benzene are very high on the two systems, even larger than those of three individual adsorbed C2H2.

7.
Oxid Med Cell Longev ; 2020: 3184019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32831994

RESUMO

In the present study, the replicative lifespan assay of yeast was used to guide the isolation of antiaging substance from Gentiana rigescens Franch, a traditional Chinese medicine. A compound with antiaging effect was isolated, and the chemical structure of this molecule as amarogentin was identified by spectral analysis and compared with the reported data. It significantly extended the replicative lifespan of K6001 yeast at doses of 1, 3, and 10 µM. Furthermore, amarogentin improved the survival rate of yeast under oxidative stress by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), and these enzymes' gene expression. In addition, this compound did not extend the replicative lifespan of sod1, sod2, uth1, and skn7 mutants with K6001 background. These results suggested that amarogentin exhibited antiaging effect on yeast via increase of SOD2, CAT, GPx gene expression, enzyme activity, and antioxidative stress. Moreover, we evaluated antioxidant activity of this natural products using PC12 cell system, a useful model for studying the nervous system at the cellular level. Amarogentin significantly improved the survival rate of PC12 cells under H2O2-induced oxidative stress and increased the activities of SOD and SOD2, and gene expression of SOD2, CAT, GPx, Nrf2, and Bcl-x1. Meanwhile, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) of PC12 cells were significantly reduced after treatment of the amarogentin. These results indicated that antioxidative stress play an important role for antiaging and neuroprotection of amarogentin. Interestingly, amarogentin exhibited neuritogenic activity in PC12 cells. Therefore, the natural products, amarogentin from G. rigescens with antioxidant activity could be a good candidate molecule to develop drug for treating neurodegenerative diseases.

8.
Oxid Med Cell Longev ; 2020: 9125752, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832008

RESUMO

Gentiopicroside (GPS), an antiaging secoiridoid glycoside, was isolated from Gentiana rigescens Franch, a traditional Chinese medicine. It prolonged the replicative and chronological lifespans of yeast. Autophagy, especially mitophagy, and antioxidative stress were examined to clarify the mechanism of action of this compound. The free green fluorescent protein (GFP) signal from the cleavage of GFP-Atg8 and the colocation signal of MitoTracker Red CMXRos and GFP were increased upon the treatment of GPS. The free GFP in the cytoplasm and free GFP and ubiquitin of mitochondria were significantly increased at the protein levels in the GPS-treated group. GPS increased the expression of an essential autophagy gene, ATG32 gene, but failed to extend the replicative and chronological lifespans of ATG32 yeast mutants. GPS increased the survival rate of yeast under oxidative stress condition; enhanced the activities of catalase, superoxide dismutase, and glutathione peroxidase; and decreased the levels of reactive oxygen species and malondialdehyde. The replicative lifespans of Δsod1, Δsod2, Δuth1, and Δskn7 were not affected by GPS. These results indicated that autophagy, especially mitophagy, and antioxidative stress are involved in the antiaging effect of GPS.

9.
Oxid Med Cell Longev ; 2019: 2935315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737168

RESUMO

Excessive food intake and metabolic disorder promote obesity and diabetes. In China, peanut skin is used as a herbal medicine to treat hemophilia, thrombocytopenic purpura, and hepatic hemorrhage. In the present study, we demonstrated that peanut skin extract (PSE) safely reduced appetite, body weight, fat tissue, plasma TG and TC, and blood glucose level in mice with diet-induced obesity (DIO). Moreover, the leptin/leptin receptor/neuropeptide Y (NPY) and adiponectin signaling pathways involved in the antiobesity effects of PSE are confirmed through leptin and adiponectin overexpression and leptin receptor silencing in mice. PSE consisted of oligosaccharide and polyphenol in a mass ratio of 45 : 55, and both parts were important for the antiobesity function of PSE. Our results suggested that PSE can be developed as functional medical food to treat metabolic disorders and obesity.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Leptina/metabolismo , Extratos Vegetais/uso terapêutico , Receptores para Leptina/metabolismo , Adiponectina/genética , Tecido Adiposo/fisiologia , Animais , Arachis/química , Peso Corporal/efeitos dos fármacos , China , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Leptina/genética , Camundongos , Camundongos Endogâmicos ICR , Neuropeptídeo Y/metabolismo , Obesidade , Extratos Vegetais/química , Receptores para Leptina/genética , Transdução de Sinais
11.
Polymers (Basel) ; 11(7)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319580

RESUMO

Glass fiber with different content and different kinds of compatibilizers were used to prepare glass fiber-reinforced polypropylene (GFRP) composites. ß-nucleating agent with different content was used to prepare ß-polypropylene (PP), after which the toughness, crystallization ability and heat resistance were all enhanced. Differential scanning calorimetry (DSC) and wide-angle X-ray diffraction (WAXD) showed that the crystallite degree and crystallization ability were all greatly improved and ß-PP was in dominant position. At last, both ß-nucleating agent and glass fiber were used to modify the PP composites (ß-GFRP). The formation of ß-form PP made the matrix softer, which was beneficial for energy absorption and enhancement of toughness. The tensile strength, flexural strength and flexural modulus were improved dramatically, which were attributed to the coeffect of framework structure of GF and ß-form PP.

12.
Sci Transl Med ; 11(502)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.


Assuntos
Autoimunidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , TYK2 Quinase/química , Animais , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos/farmacologia , Humanos , Interferon alfa-2/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores
13.
J Med Chem ; 62(20): 8973-8995, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Cristalografia por Raios X , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/uso terapêutico , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
14.
J Med Chem ; 62(20): 8953-8972, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.


Assuntos
Niacinamida/análogos & derivados , Ácidos Nicotínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Regulação Alostérica , Animais , Humanos , Ligantes , Camundongos , Niacinamida/metabolismo , Niacinamida/farmacologia , Ácidos Nicotínicos/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade
15.
J Adv Nurs ; 75(11): 3068-3077, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31197839

RESUMO

AIM: The aims of this study are: (a) to determine the incidence of postoperative delirium (POD) among surgical intensive care unit (ICU) patients in China and identify risk factors, especially, which are modifiable and have value for developing a prediction model; (b) to develop and validate a prediction model of delirium to recognize high-risk patients in surgical ICUs; (c) to investigate the short- and long-term outcomes of delirious patients and identify the predictors of patient outcomes. DESIGN: A single-centre prospective cohort study. METHODS: Patients will be enrolled from three surgical ICUs in a tertiary teaching hospital. Delirium assessment and perioperative data will be collected throughout the hospitalization. Delirious patients will be followed up for 2 years. The study was approved by the ethics committee in May 2018 and was funded by the clinical research grant from Zhongshan hospital, Fudan University, Shanghai. DISCUSSION: Developing POD can be a burden to patients both for the short- and long-term period. Due to the lack of effective treatments for POD, prevention remains the best strategy. This study will provide an effective tool for early screening of high-risk patients of POD and provide a better understanding of the aetiology and outcome of delirium. IMPACT: In clinical practice, a prediction model will offer an effective tool for ICU nurses to assess high-risk patients, which can support them to implement preventive strategies at the early stages to targeted patients. The follow-up results will help us better understand the impact of delirium on patients' long-term outcome.


Assuntos
Delírio/diagnóstico , Delírio/enfermagem , Previsões , Unidades de Terapia Intensiva/estatística & dados numéricos , Complicações Cognitivas Pós-Operatórias/diagnóstico , Complicações Cognitivas Pós-Operatórias/enfermagem , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos de Coortes , Delírio/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Cognitivas Pós-Operatórias/epidemiologia , Estudos Prospectivos , Fatores de Risco
16.
Nanotechnology ; 30(37): 375703, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31163404

RESUMO

Upconversion nanoparticle (UCNP)-based luminescence resonance energy transfer (LRET) systems are a powerful tool widely used to detect organic molecules or metal ions because of their simplicity and high sensitivity. The sandwich structure NaYF4:Er3+,Yb3+@NaYF4@NH2 UCNPs, as a highly selective and sensitive aqueous probe for detecting nitroaromatics, has been designed and prepared by a cothermolysis method and modified with polyetherimide to acquire amine groups on the surface of the core/shell UCNPs. The detection principle of nitroaromatics is based on LRET, which forms the Meisnheimer complex between the electron-deficient cyclobenzene of nitroaromatics and the electron-rich amino group on the surface of the sandwich structure UCNPs. As a consequence, nitroaromatics can be brought into close proximity to the sandwich structure UCNPs. With the increase of nitroaromatics (2,4,6-trinitrophenol and 2,4,6-trinitrotoluene) concentrations, the sandwich structure NaYF4:Er3+,Yb3+@NaYF4@NH2 UCNPs display a dramatic luminescent quenching effect at 407 nm and 540 nm under 980 nm excitation. The luminescent quenching intensity of the sandwich structure UCNPs is linearly correlated to the concentration of the nitroaromatics. The detection limit of 2,4,6-trinitrophenol (TNP) and 2,4,6-trinitrotoluene (TNT) are 0.78 and 0.77 ng ml-1, respectively. Therefore, the sandwich structure of NaYF4:Er3+,Yb3+@NaYF4@NH2 UCNPs can act as a valuable probe to detect nitroaromatics in public safety and security conditions.

17.
J Neuroinflammation ; 16(1): 116, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31153377

RESUMO

BACKGROUND: Microglia and CNS-infiltrating monocytes/macrophages (CNS-MPs) perform pro-inflammatory and protective anti-inflammatory functions following ischemic stroke. Selective inhibition of pro-inflammatory responses can be achieved by Kv1.3 channel blockade, resulting in a lower infarct size in the transient middle cerebral artery occlusion (tMCAO) model. Whether beneficial effects of Kv1.3 blockers are mediated by targeting microglia or CNS-infiltrating monocytes/macrophages remains unclear. METHODS: In the 30-min tMCAO mouse model, we profiled functional cell-surface Kv1.3 channels and phagocytic properties of acutely isolated CNS-MPs at various timepoints post-reperfusion. Kv1.3 channels were flow cytometrically detected using fluorescein-conjugated Kv1.3-binding peptide ShK-F6CA as well as by immunohistochemistry. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was performed to measure Kv1.3 (Kcna3) and Kir2.1 (Kcnj2) gene expression. Phagocytosis of 1-µm microspheres by acutely isolated CNS-MPs was measured by flow cytometry. RESULTS: In flow cytometric assays, Kv1.3 channel expression by CD11b+ CNS-MPs was increased between 24 and 72 h post-tMCAO and decreased by 7 days post-tMCAO. Increased Kv1.3 expression was restricted to CD11b+CD45lowLy6clow (microglia) and CD11b+CD45highLy6Clow CNS-MPs but not CD11b+CD45highLy6chigh inflammatory monocytes/macrophages. In immunohistochemical studies, Kv1.3 protein expression was increased in Iba1+ microglia at 24-48 h post-tMCAO. No change in Kv1.3 mRNA in CNS-MPs was observed following tMCAO. CONCLUSIONS: We conclude that resident microglia and a subset of CD45highLy6clow CNS-MPs are the likely cellular targets of Kv1.3 blockers and the delayed phase of neuroinflammation is the optimal therapeutic window for Kv1.3 blockade in ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Canal de Potássio Kv1.3/biossíntese , Fagócitos/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Expressão Gênica , Canal de Potássio Kv1.3/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagócitos/patologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Fatores de Tempo
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 217: 107-112, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928835

RESUMO

Usually, the luminescence intensity and mechanism of rare-earth ions doped materials are dependent on both doping concentration and sample temperature. In this study, we attempt to explore the concentration effect on up-conversion (UC) luminescence and the dependence of luminescence temperature quenching on excitation wavelength in YNbO4: Ho3+/Yb3+ phosphors. The YNbO4: Ho3+/Yb3+ phosphors with various Ho3+ and Yb3+ concentrations were synthesized via a high-temperature solid-state reaction technique. Intense green UC emission peaked at 543 nm was observed, accompanying with weak red and near infrared (NIR) UC emissions centered at 659 and 745 nm. Based on the laser working current dependence of UC luminescence, two-photon processes were responsible for both the green and the red UC emissions under 980 nm excitation, which have no apparent dependence on both Ho3+ and Yb3+ concentrations. According to the Arrhenius model, crossover process was responsible for the temperature-dependent down-conversion (DC) luminescence quenching of Ho3+ under 452 nm excitation. However, the temperature quenching processes of the green and the red UC luminescence cannot be well explained by Arrhenius model. It was found that the UC luminescence intensity decayed with increasing sample temperature, which was caused by both the crossover and temperature-dependent energy transfer processes.

19.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

20.
J Med Chem ; 62(7): 3228-3250, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Indóis/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Concentração Inibidora 50 , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Macaca fascicularis , Camundongos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico
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