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1.
J Cell Physiol ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33559155

RESUMO

The intestinal mucosa is in continuous contact with milliard of microorganisms, thus intestinal epithelial barrier is a critical component in the arsenal of defense mechanisms required to prevent infection and inflammation. Mucin 2 (MUC2), which is produced by the goblet cells, forms the skeleton of the intestinal mucus and protects the intestinal tract from self-digestion and numerous microorganisms. Dedicator of cytokinesis 4 (DOCK4) is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors. It is reported that DOCK4 plays a critical role in the repair of the barrier function of the intestinal epithelium after chemical damage. In this study, the role of DOCK4 in the goblet cell differentiation and MUC2 production is explored. Disordered intestinal epithelium and shortage of goblet cells were observed in DOCK4 gene knockout mice. Furthermore, DOCK4 deletion contributed to the low expression of MUC2 and the goblet cell differentiation/maturation factors including growth factor independent 1 (Gfi1) and SAM pointed domain epithelial-specific transcription factor (Spdef) in mouse ileums and colons. Overexpression of DOCK4 caused a marked increase in Gfi1, Spdef, and MUC2, while siRNA knockdown of endogenous DOCK4 significantly decreased Gfi1, Spdef, and MUC2 in HT-29 cells. In addition, MUC2, DOCK4, and the goblet cell differentiation/maturation factors mRNA levels were decreased in colorectal cancer samples compared with normal colons. A significant positive correlation was found between MUC2 and DOCK4. In conclusion, DOCK4 may serve as a critical regulator of goblet cell differentiation and MUC2 production in the intestine.

2.
Bioorg Med Chem Lett ; 35: 127778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

3.
Mol Cell Biochem ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33237453

RESUMO

In order to reveal circular RNAs (circRNAs) differential expression profiles and investigate the function and mechanism of circRNAs in the metastasis of salivary adenoid cystic carcinoma (SACC), microarray was used to detect differentially expressed circRNAs in SACC-83 and SACC-lung metastasis (LM) cell lines. Up-regulated circRNAs were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to further predict their function. Expression of candidate circRNA and microRNA (miRNA) was determined using quantitative real-time polymerase chain reaction (qRT-PCR). Constructed circRNA-miRNA-mRNA co-expression network was based on TargetScan, miRanda databases. Wound healing and transwell assays were completed to examine the effects of hsa_circRNA_001982 and miR-181a-5p on cell migration and invasion. qRT-PCR confirmed hsa_circRNA_092556, hsa_circRNA_101379, and hsa_circRNA_001982 up-regulation in SACC-LM. miR-181a-5p was down-regulated in SACC-LM and correlated with up-regulated hsa_circRNA_001982. Wound healing and transwell assays indicated that silencing hsa_circRNA_001982 inhibited the migration and invasion of the SACC-LM cells. Furthermore, over-expression of hsa_circRNA_001982 promoted the migration and invasion of SACC-83 cells. Interestingly, up-regulation or down-regulation of miR-181a-5p led to the opposite result in wound healing and transwell assays. Overall, differential expression circRNA profiles in SACC-83 and SACC-LM cells may reveal potential targets and a novel mechanism of circRNAs in the metastasis of SACC. Moreover, the interaction of hsa_circRNA_001982/miR-181a-5p is closely related to the metastasis of SACC cells.

4.
Cell Tissue Res ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33151455

RESUMO

Adipose-derived mesenchymal stem cells (ADSCs) are considered to be seed cells in bone tissue engineering and emerging evidence indicates that circular RNAs (circRNAs) function in the osteogenic differentiation of ADSCs. The mechanisms of osteoblastic differentiation of ADSCs from the perspective of circRNA modulation are examined in this study. First, circRNA-23525 was upregulated during osteoblastic differentiation of ADSCs. Second, overexpression of circRNA-23525 increased Runx2, ALP and OCN at both mRNA and protein levels. Alkaline phosphatase (ALP) and Alizarin Red staining indicated a similar tendency. Silencing circRNA-23525 produced the opposite effect. Bioinformatics analysis with luciferase assays confirmed that circRNA-23525 functioned as a sponge for miR-30a-3p. In the osteoblastic differentiation of ADSCs, the dynamic expression of miR-30a-3p and circRNA-23525 resulted in an opposite trend at 3, 7 and 14 days. Overexpression of circRNA-23525 downregulated miR-30a-3p and knockdown of circRNA-23525 promoted the expression of miR-30a-3p. Bioinformatics methods and luciferase assays suggested that miR-30a-3p modulated Runx2 expression by targeting 3'UTR. Knockdown of miR-30a-3p facilitated osteogenesis in ADSCs and enhancing miR-30a-3p interfered with the osteogenic process. Finally, circRNA-23525 overexpression significantly increased Runx2 expression, while co-transfection of miR-30a-3p mimics reversed it. Runx2 expression was decreased in circRNA-23525-knockdown ADSCs but expression was rescued by including the miR-30a-3p inhibitor in the osteoblastic process. ALP activity and mineralized bone matrix confirmed the function of circRNA-23525/miR-30a-3p in osteogenesis. Taken together, the current study demonstrated that circRNA-23525 regulates Runx2 expression via targeting miR-30a-3p and is thus a positive regulator in the osteoblastic differentiation of ADSCs.

5.
Front Mol Neurosci ; 13: 80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714143

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease in the elderly with a pathogenesis that remains unclear. We aimed to explore its pathogenesis through plasma integrated metabolomics and proteomics analysis. The clinical data of consecutively recruited PD patients and healthy controls were assessed. Fasting plasma samples were obtained and analyzed using metabolomics and proteomics methods. After that, differentially expressed metabolites and proteins were identified for further bioinformatics analysis. No significant difference was found in the clinical data between these two groups. Eighty-three metabolites were differentially expressed in PD patients identified by metabolomics analysis. These metabolites were predominately lipid and lipid-like molecules (63%), among which 25% were sphingolipids. The sphingolipid metabolism pathway was enriched and tended to be activated in the following KEGG pathway analysis. According to the proteomics analysis, forty proteins were identified to be differentially expressed, seven of which were apolipoproteins. Furthermore, five of the six top ranking Gene Ontology terms from cellular components and eleven of the other fourteen Gene Ontology terms from biological processes were directly associated with lipid metabolism. In KEGG pathway analysis, the five enriched pathways were also significantly related with lipid metabolism (p < 0.05). Overall, Parkinson's disease is associated with plasma lipid metabolic disturbance, including an activated sphingolipid metabolism and decreased apolipoproteins.

6.
Drug Des Devel Ther ; 14: 1481-1491, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368009

RESUMO

Background: "Unification of medicines and excipients" is the special principle which means fatty oil with pharmacodynamic activity derived from traditional Chinese medicine are taken as liquid lipids in perparation for dual-drug delivery,  which improve the treatment effect and reduce unnecessary excipients. Purpose: The aim of this study was to prepare a nanostructured lipid carrier (NLC) with naringin (NG) containing coix seed oil (CSO) as liquid lipid based on the theory (NCNLC) in order to achieve synergistic antitumor activity against hepatocellular carcinoma. Methods: We developed NCNLCs using ultrasonic melt-emulsification method. The antitumor effect in vivo/in vitro and drug release ability were compared to NLC prepared with conventional liquid lipids: neodecanoate triglycerides (NDNLC) and oleic acid (NONLC). Results: Transmission electron microscopy showed that NCNLCs had a well-defined spherical shape, small size, and narrow polydispersity index. Importantly, the release of drugs from NDNLCs and NONLCs was slower than NCNLCs. In the cell study, the result showed a significantly greater antiproliferative effect towards HepG2 cells, and the half-maximal inhibitory concentration of NCNLCs was 3.24-fold, 1.70-fold and 1.52-fold lower to that of free drug, NDNLCs and NONLCs, respectively. Moreover, NCNLCs significantly induced HepG2 cells apoptosis by being 2.12-fold and 9.28-fold higher to that of NDNLCs and NONLCs, respectively. In the study of antitumor efficacy in vivo, the synergistic effect of NCNLCs formulation showed markedly enhanced antitumor efficacy in a xenograft model of liver cancer. Conclusion: The advantages of "unification of medicines and excipients" in formulation characters, drug release and synergistic antitumor effect provide a new idea for the application of the fatty oil of traditional Chinese medicine in the nano-drug delivery for cancer therapy.

7.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

8.
Medicine (Baltimore) ; 99(4): e18879, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977893

RESUMO

RATIONALE: Myiasis is a parasitic disease caused by fly larvae of the Diptera order that infest human and other vertebrate animal tissues. Orbital myiasis is a potentially destructive infestation of the orbital tissues, which may affect individuals with previous ocular diseases or disorders of consciousness. PATIENT CONCERNS: A 72-year-old man presented with a complaint of repeated pain for two years after trauma to his right eyelid and aggravated symptoms with larvae wriggling out for 2 days. An orbital computed tomography scan revealed right eyeball protrusion and periocular soft tissue edema. Two days later, magnetic resonance imaging showed that the shape of the right eyeball was changed and that the normal structure of the eyeball could not be identified. DIAGNOSES: Due to the patient's symptoms and imaging examination results, the diagnosis of orbital myiasis was made. INTERVENTIONS: The patient was treated by exenteration of the right orbit, and all necrotic tissues and larvae were removed. The defect was repaired via reconstruction with a pedicled musculocutaneous flap from the forehead region. Antibiotics and tetanus toxoid therapy were utilized to prevent potential bacterial infection. OUTCOMES: The patient recovered well postoperatively and was discharged uneventfully. During the 6-month follow-up period, the wound healed well. LESSONS: Advanced age and untreated eye trauma are risk factors for orbital myiasis. Timely removal of larvae and elimination of infections are important measures for protecting the eyeball.


Assuntos
Enucleação Ocular/métodos , Miíase/cirurgia , Doenças Orbitárias/cirurgia , Idoso , Animais , Dípteros , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Miíase/diagnóstico , Doenças Orbitárias/diagnóstico por imagem
9.
J Craniofac Surg ; 30(7): 2253-2256, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31513037

RESUMO

This paper describes the application of a modified digital surgical guide, an occlusal template and a pre-formed reconstruction titanium plate in the open reduction and internal fixation of a bilateral mandibular fracture. Bilateral mandibular fracture is a commonly encountered simple type of fracture. However, even for an experience surgeon, achieving precise treatment remains a challenge due to the movable temporomandibular joint, unstable fractured segments, the difficulty in forming a reconstruction plate, and the lack of an effective stabilizing and locating device. In this case, the surgeon used a specially-designed modified guide together with a reconstruction plate and an occlusal template to treat a bilateral mandible fracture, effectively improving the accuracy and the medical outcome of the operation, saving operation time and reducing postoperative complications.


Assuntos
Fraturas Mandibulares/cirurgia , Reconstrução Mandibular , Adulto , Placas Ósseas , Fixação Interna de Fraturas , Humanos , Masculino , Fraturas Mandibulares/diagnóstico , Reconstrução Mandibular/instrumentação , Duração da Cirurgia , Complicações Pós-Operatórias , Cirurgia Assistida por Computador , Articulação Temporomandibular/cirurgia , Titânio
10.
BMC Endocr Disord ; 19(1): 83, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362731

RESUMO

BACKGROUND: Thyroid dysfunction is one of the prevalent endocrine disorders. The relationship between lifestyle factors and thyroid dysfunction was not clear and some of the factors seemed paradoxical. METHODS: We conducted this population-based study using data from 5154 She ethnic minority people who had entered into the epidemic survey of diabetes between July 2007 to September 2009. Life style information was collected using a standard questionnaire. Body mass index (BMI), Blood pressure and serum TSH, TPOAb, triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL) were collected. RESULTS: The study showed that people who drank, had higher education or suffered from insomnia have lower incidence of hyperthyroidism. On the other hand, smoking, alcohol consumption, exercise, undergoing weight watch and chronic headache were associated with decreased incidence of hypothyroidism. Using multivariable logistic regression analysis, we found that alcohol consumption was associated with decreased probability of hyperthyroidism, hypothyroidism, as well as positive TPOAb. The amounts of cigarettes smoked daily displayed a positive correlation with hyperthyroidism among smokers. Accordingly, smoking seemed to be associated with decreased risk for hypothyroidism and positive TPOAb. Exercise and maintaining a healthy weight might have a beneficial effect on thyroid health. Interestingly, daily staple amount showed an inverse correlation with incidence of positive TPOAb. CONCLUSIONS: Within the Chinese She ethnic minority, we found associations between different lifestyle factors and the incidence of different thyroid diseases. Understanding the nature of these associations requires further investigations.


Assuntos
Grupos Étnicos/estatística & dados numéricos , Estilo de Vida , Grupos Minoritários/estatística & dados numéricos , Doenças da Glândula Tireoide/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , China/epidemiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Doenças da Glândula Tireoide/sangue , Adulto Jovem
11.
Int J Mol Med ; 44(3): 857-870, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257525

RESUMO

Although miRNAs have been implicated in the osteogenic differentiation of stem cells, their role in bone repair and reconstruction in tissue­engineered bone grafts remains unclear. We previously reported that microRNA (miR)­26a­5p inhibited the osteogenic differentiation of adipose­derived mesenchymal stem cells (ADSCs), and that antimiR­26a­5p exerted the opposite effect. In the present study, the role of miR­26a­5p­ and antimiR­26a­5p­modified ADSCs combined with biphasic calcium phosphate (BCP) scaffolds was evaluated in a rat femur defect model. The aim of the present study was to improve the understanding of the role of miR­26a­5p in bone regeneration in vivo, as well as to provide a new method to optimize the osteogenic ability of BCPs. ADSCs were infected with Lv­miR­26a­5p, Lv­miR­NC, Lv­antimiR­26a­5p or Lv­antimiR­NC respectively, and then combined with BCP scaffolds to repair rat femoral defects. Using X­rays, micro­computed tomography and histology at 2, 4, and 8 weeks postoperatively, the quantity and rate of bone regeneration were analyzed, revealing that they were the highest in animals treated with antimiR­26a­5p and the lowest in the miR­26a­5p treatment group. The expression levels of osteocalcin, collagen I, Runt­related transcription factor 2, Wnt family member 5A and calmodulin­dependent protein kinase II proteins were positively correlated with the bone formation rate. Taken together, the present results demonstrated that miR­26a­5p inhibited bone formation while antimiR­26a­5p accelerated bone formation via the Wnt/Ca2+ signaling pathway. Therefore, antimiR­26a­5p­modified ADSCs combined with BCP scaffolds may be used to construct an effective tissue­engineering bone graft for bone repair and reconstruction.


Assuntos
Regeneração Óssea , Fêmur/metabolismo , Hidroxiapatitas/metabolismo , MicroRNAs/genética , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Proliferação de Células , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Hidroxiapatitas/farmacologia , Processamento de Imagem Assistida por Computador , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Ratos , Via de Sinalização Wnt , Microtomografia por Raio-X
12.
Menopause ; 26(5): 463-468, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30516712

RESUMO

OBJECTIVE: To assess the effect of early life exposure to famine, as endured during 1959 to 1961 in China, on reproductive aging in adult women. METHODS: Between 2011 and 2012, 2,868 women born around the Chinese famine period (1956-1964) were enrolled in this study from three communities in China. Age at natural menopause was obtained retrospectively from a structured questionnaire. The associations of early life famine exposure with reproductive aging during adulthood were estimated, with adjustment of socioeconomic status, lifestyle factors, and body mass index. RESULTS: Women exposed to prenatal famine had a higher risk of early menopause (ie, natural menopause <45 years, odds ratio: 1.59, 95% confidence interval [CI]: 1.07, 2.36), and a nonsignificant trend of higher risk of premature ovarian failure (ie, natural menopause <40 y, odds ratio: 1.94, 95% CI: 0.93, 4.00), compared to unexposed women. Exposure to famine during childhood was not significantly associated with reproductive aging. In a secondary analysis focusing on the fetal exposure, prenatal famine exposure was associated with a higher risk of premature ovarian failure (odds ratio: 2.07, 95% CI: 1.08, 3.87), and a nonsignificant trend of higher risk of early menopause (odds ratio: 1.37, 95% CI: 0.98, 1.91), compared to those unexposed to prenatal famine. CONCLUSIONS: Our study showed that fetal exposure to famine was associated with an increased risk of early menopause. Such findings provided evidence in favor of the thrifty phenotype theory in reproductive aging and helped better understand the etiology of early menopause.


Assuntos
Fome Epidêmica , Menopausa , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Insuficiência Ovariana Primária/etiologia , Reprodução , Inanição/complicações , Fatores Etários , Índice de Massa Corporal , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Autorrelato , Classe Social , Estresse Fisiológico
13.
Biol Trace Elem Res ; 176(2): 401-406, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27660074

RESUMO

This study was conducted to investigate the effects of chromium from chromium propionate (CrPro) on serum lipids, carcass traits, and breast meat quality in heat-stressed birds. A total of 210 1-day-old male broilers were randomly allotted by initial body weight (BW) into 5 treatments with 7 replicates with 6 birds per replicate pen for 42 days. The treatments included a basal corn-soybean meal diet and basal diet supplemented with 0.2, 0.4, 0.8, or 1.6 mg Cr/kg diet. Birds had ad libitum access to feed and distilled-deionized water at normal conditions for 1-3 weeks with little or no stress, and then birds were housed under heat stress conditions with 35 ± 2 °C ambient temperature for 4-6 weeks. Results showed that serum triglyceride (TG) (P = 0.0006) and low-density lipoprotein cholesterol (LDLC) (P = 0.0038) concentrations were decreased linearly as Cr dose increased. Compared with other groups, birds receiving 0.8 or 1.6 mg Cr/kg had lower TG (P = 0.0015). Compared to control birds, birds fed diets with 0.2, 0.4, 0.8, or 1.6 mg Cr/kg supplementation had lower LDLC (P = 0.0006). However, the total cholesterol (TC) and high density lipoprotein cholesterol (HDLC) concentrations in serum were not affected by treatment (P > 0.05). No difference was observed in BW, the relative weights of breast muscle, thigh muscle and abdominal fat (P > 0.05), and breast meat quality (Ph15min, Ph24h, L*, a*, b*, cooking loss, shear force) among the treatments (P > 0.05). Results from this study indicated that CrPro supplementation could be beneficial to serum lipids metabolism of heat-stressed broiler chickens by decreasing TG and LDLC contents, but had no impacts on meat quality and carcass traits of the heat-stressed broilers.


Assuntos
LDL-Colesterol/sangue , Suplementos Nutricionais , Transtornos de Estresse por Calor/metabolismo , Carne/normas , Propionatos/administração & dosagem , Propionatos/farmacologia , Triglicerídeos/sangue , Animais , Galinhas , Transtornos de Estresse por Calor/sangue , Temperatura Alta , Masculino , Carne/análise , Propionatos/metabolismo
14.
Bioorg Med Chem ; 25(2): 496-513, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27914948

RESUMO

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.


Assuntos
Éteres/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Esquizofrenia/tratamento farmacológico , Triazóis/farmacologia , Administração Oral , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éteres/administração & dosagem , Éteres/química , Haplorrinos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/metabolismo , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
15.
Bioorg Med Chem Lett ; 26(17): 4165-9, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27496211

RESUMO

Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.


Assuntos
Convulsivantes/química , Oxazolidinonas/química , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Convulsivantes/metabolismo , Convulsivantes/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacologia , Ratos , Receptor de Glutamato Metabotrópico 5/agonistas , Receptor de Glutamato Metabotrópico 5/química , Reconhecimento Psicológico/efeitos dos fármacos , Relação Estrutura-Atividade
16.
J Pharmacol Exp Ther ; 358(3): 371-86, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27411717

RESUMO

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.


Assuntos
Neuralgia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/fisiopatologia
17.
Sci Total Environ ; 565: 519-528, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27196989

RESUMO

Foshan is a major international ceramic center and the most polluted city in the Pearl River Delta (PRD). Here we present the results of the first long-term PM2.5 (particles <2.5µm) sampling and chemical characterization study of the city. A total of 2774 samples were collected at six sites from 2008 to 2014, and analyzed for water soluble species, elements and carbonaceous species. The major constituents of PM2.5 were sulfate, OC (Organic Carbon), nitrate, ammonium and EC (Elemental Carbon), which accounted for 50%-88% of PM2.5. PM2.5 and the most abundant chemical species decreased from 2008 to 2011, but rebounded in 2012-2013. After 2008, the chemical composition of PM2.5 changed dramatically due to the implementation of pollution control measures. From 2008 to 2011, SO4(2-) and NO3(-) were the two largest components; subsequently, however, OC was the largest component. The respective contributions of SO4(2-), NO3(-) and OC to the sum of water soluble species and carbonaceous species were 30.5%, 22.9% and 19.9% in 2008; and 20.2%, 16.5% and 30.2% in 2014. Distinct differences in nitrate and sulfate, and in mass ratio [NO3(-)]/[SO4(2-)] imply that mobile sources tended to more important in Foshan during 2012-2014. The results indicate that pollution control measures implemented during 2008-2014 had a large effect on anthropogenic elements (Pb, As, Cd, Zn and Cu) and water soluble species, but little influence on crustal elements (V, Mn, Ti, Ba and Fe) and carbonaceous species. The PMF method was used for source apportionment of PM2.5. Industry (including the ceramic industry and coal combustion), vehicles and dust were the three most important sources and comprised 39.2%, 20.0% and 18.4% of PM2.5 in 2008, respectively. However, secondary aerosols, vehicles and industry were the three most important sources and comprised 29.5%, 22.4% and 20.4% of PM2.5 in 2014, respectively. During the seven year study interval, the contributions of primary sources (industry and dust) decreased significantly, but secondary sources increased dramatically. Industry, dust and vehicles contributed 36.6µgm(-3), 13.9µgm(-3), and 9.2µgm(-3) to the reduction of PM2.5, respectively.


Assuntos
Poluição do Ar/análise , Material Particulado/química , Poluição do Ar/estatística & dados numéricos , China , Monitoramento Ambiental , Tamanho da Partícula
18.
ACS Med Chem Lett ; 7(3): 289-93, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985317

RESUMO

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

19.
Br J Nutr ; 115(9): 1509-20, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26983845

RESUMO

The aim of the present study was to assess the effects of dietary supplementation with epidermal growth factor (EGF)-expressing Saccharomyces cerevisiae on duodenal development in weaned piglets. In total, forty piglets weaned at 21-26 d of age were assigned to one of the five groups that were provided basic diet (control group) or diet supplemented with S. cerevisiae expressing either empty-vector (INVSc1(EV) group), tagged EGF (T-EGF) (INVSc1-TE(-) group), extracellular EGF (EE-EGF) (INVSc1-EE(+) group) or intracellular EGF (IE-EGF) (INVSc1-IE(+) group). All treatments were delivered as 60·00 µg/kg body weight EGF/d. On 0, 7, 14 and 21 d, eight piglets per treatment were sacrificed to analyse the morphology, activities and mRNA expressions of digestive enzymes, as well as Ig levels (IgA, IgM, IgG) in duodenal mucosa. The results showed significant improvement on 7, 14 and 21 d, with respect to average daily gain (P<0·05), mucosa morphology (villus height and crypt depth) (P<0·05), Ig levels (P<0·01), activities and mRNA expressions of digestive enzymes (creatine kinase, alkaline phosphatase, lactate dehydrogenase and sucrase) (P<0·05) and the mRNA expression of EGF-receptor (P<0·01) in NVSc1-TE(-), INVSc1-EE(+) and INVSc1-IE(+) groups compared with control and INVSc1(EV) groups. In addition, a trend was observed in which the INVSc1-IE(+) group showed an improvement in Ig levels (0·05

Assuntos
Suplementos Nutricionais , Duodeno/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Creatina Quinase/genética , Creatina Quinase/metabolismo , Duodeno/crescimento & desenvolvimento , Duodeno/metabolismo , Fator de Crescimento Epidérmico/administração & dosagem , Receptores ErbB/genética , Receptores ErbB/metabolismo , Imunoglobulinas/metabolismo , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/metabolismo , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Lactococcus lactis , RNA Mensageiro/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Sacarase/genética , Sacarase/metabolismo , Suínos , Desmame
20.
Biol Trace Elem Res ; 170(1): 216-23, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26184120

RESUMO

The objective of this study was to investigate the effects of dietary supplemental chromium (Cr) on growth performance, carcass traits, and meat quality of broilers reared under heat stress. A total of 252 1-d-old Cobb 500 commercial female broilers were randomly allotted by body weight (BW) to one of six replicate cages (six broilers per cage) for each of seven treatments in a completely randomized design involving a 2 × 3 factorial arrangement of treatments with three Cr sources (Cr propionate, CrPro; Cr picolinate, CrPic; Cr chloride, CrCl3) and two concentrations of added Cr (0.4, or 2.0 mg of Cr/kg) plus a Cr-unsupplemented control group. Feed and distilled-deionized water were available ad libitum for an experimental phase of 42 days. For induction of heat stress, the house temperature was set at 33 ± 2 °C from 15 to 42 days of age. Results showed that birds supplemented with Cr, regardless of Cr source, had increased ADG (P = 0.032) than controls. Birds fed 2.0 mg Cr/kg diet had greater ADG (P = 0.005) than birds fed 0.4 mg Cr/kg diet. Compared to controls, birds fed with Cr had greater dressing percentage (P = 0.021). Percentage of abdominal fat decreased (P = 0.013), whereas, breast intramuscular fat (IMF) remained unaffected (P = 0.147) in Cr supplemented vs control broilers. Broilers supplemented Cr had decreased b* values of meat color (P = 0.042) in breast muscle. B*values were also lesser (P = 0.049) in birds fed CrPro than birds supplemented with CrCl3 or CrPic. Regardless of Cr source, the percentage of cooking loss was decreased (P = 0.025) with Cr supplementation in breast muscle when compared to controls. Results from this study indicate that Cr supplementation, independent of its source, could promote growth and improve carcass traits and meat quality of broilers under heat stress conditions. Chromium propionate seems to have greater beneficial effects on meat color in comparison with CrPic and CrCl3.


Assuntos
Galinhas/crescimento & desenvolvimento , Cromo/administração & dosagem , Resposta ao Choque Térmico , Animais , Feminino , Aves Domésticas
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