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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Arthroscopy ; 35(10): 2825-2831, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31604499

RESUMO

PURPOSE: To (1) evaluate the individual and combined effects of traction time and traction force on postoperative neuropathy following hip arthroscopy, (2) determine if perioperative fascia iliaca block has an effect on the risk of this neuropathy, and (3) identify if the these items had a significant association with the presence, location, and/or duration of postoperative numbness. METHODS: Between February 2015 and December 2016, a consecutive cohort of hip arthroscopy patients was prospectively enrolled. Traction time, force, and postoperative nerve block administration were recorded. The location and duration of numbness were assessed at postoperative clinic visits. Numbness location was classified into regions: 1, groin; 2, lateral thigh; 3, medial thigh; 4, dorsal foot; and 5,preoperative thigh or radiculopathic numbness. RESULTS: A total of 156 primary hip arthroscopy patients were analyzed, 99 (63%) women and 57 (37%) men. Mean traction time was 46.5 ± 20.3 minutes. Seventy-four patients (47%) reported numbness with an average duration of 157.5 ± 116.2 days. Postoperative fascia iliaca nerve block was a significant predictor of medial thigh numbness (odds ratio, 3.36; 95% confidence interval, 1.46-7.76; P = .04). Neither traction time nor force were associated with generalized numbness (P = .85 and P = .40, respectively). However, among those who experienced numbness, traction time and force were greater in patients with combined groin and lateral thigh numbness compared with those with isolated lateral thigh or medial thigh numbness (P = .001 and P = .005, respectively). CONCLUSIONS: Postoperative neuropathy is a well-documented complication following hip arthroscopy. Concomitant pudendal and lateral femoral cutaneous nerve palsy may be related to increased traction force and time, even in the setting of low intraoperative traction time (<1 hour). Isolated medial thigh numbness is significantly associated with postoperative fascia iliaca blockade. LEVEL OF EVIDENCE: IV, case series.

3.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

4.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
5.
J Hand Surg Am ; 43(7): 606-614.e1, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29861126

RESUMO

PURPOSE: Distal radius fracture open reduction and internal fixation (ORIF) represents a considerable cost burden to the health care system. We aimed to elucidate demographic-, injury-, and treatment-specific factors influencing surgical encounter costs for distal radius ORIF. METHODS: We retrospectively reviewed adult patients treated with isolated distal radius ORIF between November 2014 and October 2016 at a single tertiary academic medical center. Using our institution's information technology value tools-which allow for comprehensive payment and cost data collection and analysis on an item-level basis-we determined relative costs (RC) for each factor potentially influencing total direct costs (TDC) for distal radius ORIF using univariate and multivariable gamma regression analyses. RESULTS: Of the included 108 patients, implants and facility utilization costs were responsible for 48.3% and 37.9% of TDC, respectively. Factors associated with increased TDC include plate manufacturer (RC 1.52 for the most vs least expensive manufacturer), number of screws (RC 1.03 per screw) and distal radius plates used (RC 1.67 per additional plate), surgery setting (RC 1.32 for main hospital vs ambulatory surgery center), treating service (RC 1.40 for trauma vs hand surgeons), and surgical time (RC 1.04 for every 10 min of additional surgical time). Open fracture was associated with increased costs (RC 1.55 vs closed fracture), whereas other estimates of fracture severity were nonsignificant. In the multivariable model controlling for injury-specific factors, variables including implant manufacturer, and number of distal radius plates and screws used, remained as significant drivers of TDC. CONCLUSIONS: Substantial variations in surgical direct costs for distal radius ORIF exist, and implant choice is the predominant driver. Cost reductions may be expected through judicious use of additional plates and screws, if hospital systems use bargaining power to reduce implant costs, and by efficiently completing surgeries. CLINICAL RELEVANCE: This study identifies modifiable factors that may lead to cost reduction for distal radius ORIF.

6.
Artigo em Inglês | MEDLINE | ID: mdl-29861437

RESUMO

This study aimed to determine if short-term exposure to particulate matter (PM2.5) and ozone (O3) is associated with increased symptoms or lung function decline in fibrotic sarcoidosis. Sixteen patients with fibrotic sarcoidosis complicated by frequent exacerbations completed pulmonary function testing and questionnaires every three months for one year. We compared 7-, 10-, and 14-day average levels of PM2.5 and O3 estimated at patient residences to spirometry (forced expiratory volume in 1 s (FEV1), to forced vital capacity (FVC), episodes of FEV1 decline > 10%) and questionnaire outcomes (Leicester cough questionnaire (LCQ), Saint George Respiratory Questionnaire (SGRQ), and King's Sarcoidosis Questionnaire (KSQ)) using generalized linear mixed effect models. PM2.5 level averaged over 14 days was associated with lower KSQ general health status (score change -6.60 per interquartile range (IQR) PM2.5 increase). PM2.5 level averaged over 10 and 14 days was associated with lower KSQ lung specific health status (score change -6.93 and -6.91, respectively). PM2.5 levels were not associated with FEV1, FVC, episodes of FEV1 decline > 10%, or respiratory symptoms measured by SGRQ or LCQ. Ozone exposure was not associated with any health outcomes. In this small cohort of patients with fibrotic sarcoidosis, PM2.5 exposure was associated with increased severity of respiratory and quality of life symptoms.

7.
J Hand Surg Am ; 43(11): 971-977.e1, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29784549

RESUMO

PURPOSE: Carpal tunnel release (CTR) is a common surgical procedure, representing a financial burden to the health care system. The purpose of this study was to test whether the choice of CTR technique (open carpal tunnel release [OCTR] vs endoscopic carpal tunnel release [ECTR]), surgical setting (operating room vs procedure room [PR]), and anesthetic type (local, monitored anesthesia care [MAC], Bier block, general) affected costs or payments. METHODS: Consecutive adult patients undergoing isolated unilateral CTR between July 2014, and October 2017, at a single academic medical center were identified. Patients undergoing ECTR converted to OCTR, revision surgery, or additional procedures were excluded. Using our institution's information technology value tools, we calculated total direct costs (TDCs), total combined payment (TCP), hospital payment, surgeon payment, and anesthesia payment for each surgical encounter. Cost data were normalized using each participant's surgical encounter cost divided by the average cost in the data set and compared across 8 groups (defined by surgery type, operation location, and anesthesia type). RESULTS: Of 479 included patients, the mean age was 55.3 ± 16.1 years, and 68% were female. Payer mix included commercial (45%), Medicare (37%), Medicaid (13%), workers' compensation (2%), self-pay (1%), and other (3%) insurance types. The TDC and TCP both differed significantly between each CTR group, and OCTR in the PR under local anesthesia was the lowest. The OCTR/local/operating room, OCTR/MAC/operating room, and ECTR/operating room, were associated with 6.3-fold, 11.0-fold, and 12.4-16.6-fold greater TDC than OCTR/local/PR, respectively. CONCLUSIONS: Performing OCTR under local anesthetic in the PR setting significantly minimizes direct surgical encounter costs relative to other surgical methods (ECTR), anesthetic methods (Bier block, MAC, general), and surgical settings (operating room). CLINICAL RELEVANCE: This study identifies modifiable factors that may lead to cost reductions for CTR surgery.

8.
J Reconstr Microsurg ; 34(6): 428-435, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29452440

RESUMO

BACKGROUND: There is an increasing trend toward bilateral breast reconstruction. Using the National Surgical Quality Improvement Program (NSQIP) database, we sought to understand the association between unilateral and bilateral free flap breast reconstruction and operative time and flap failure. METHODS: We selected a cohort of patients undergoing free flap breast reconstruction using the 2005 to 2010 NSQIP database. Cases were divided into unilateral and bilateral reconstruction. Subgroup analyses were performed dividing cases into delayed and immediate reconstruction. The effect of patient characteristics including age, body mass index (BMI), history of diabetes, and the American Society of Anesthesiologists' classification on operative time and flap failure was examined using univariable and multivariable regression models. Rates and odds ratios (OR) were reported using the multivariable gamma and logistic regression models, respectively. RESULTS: There were 691 free flap breast reconstructions performed in the cohort and 29.1% were bilateral cases. There was a 78-minute increase in the median operative time when comparing unilateral and bilateral reconstruction (p = 0.005). Patients undergoing bilateral reconstructions were generally younger and had fewer comorbidities compared with unilateral reconstructions. There was no significant association between bilateral reconstruction and flap failure. Immediate bilateral reconstructions had a significant increase in median operative time compared with immediate unilateral reconstructions (563 versus 480 minutes, p = 0.002) but no significant increase in operative time was noted when comparing delayed unilateral and delayed bilateral reconstructions. Prolonged operative time was associated with flap failure after adjusting for age and BMI (OR 1.17, p < 0.001). CONCLUSIONS: Bilateral free flap breast reconstruction can be performed safely despite an increase in operative time when compared with unilateral reconstruction.

9.
J Pediatr ; 195: 213-219.e3, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29426688

RESUMO

OBJECTIVES: To investigate the variation in care and cost of spinal fusion for adolescent idiopathic scoliosis (AIS), and to identify opportunities for improving healthcare value. STUDY DESIGN: Retrospective cohort study from the Pediatric Health Information Systems database, including children 11-18 years of age with AIS who underwent spinal fusion surgery between 2004 and 2015. Multivariable regression was used to evaluate the relationships between hospital cost, patient outcomes, and resource use. RESULTS: There were 16 992 cases of AIS surgery identified. There was marked variation across hospitals in rates of intensive care unit admission (0.5%-99.2%), blood transfusions (0%-100%), surgical complications (1.8%-32.3%), and total hospital costs ($31 278-$90 379). Hospital cost was 32% higher at hospitals that most frequently admitted patients to the intensive care unit (P = .009), and 8% higher for each additional 25 operative cases per hospital (P = .003). Hospital duration of stay was shorter for patients admitted to hospitals with highest intensive care unit admission rates and higher surgical volumes. There was no association between cost and duration of stay, 30-day readmission, or surgical complications. The largest contribution to hospital charges was supplies (55%). Review of a single hospital's detailed cost accounting system also found supplies to be the greatest single contributor to cost, the majority of which were for spinal implants, accounting for 39% of total hospital costs. CONCLUSIONS: The greatest contribution to AIS surgery cost was supplies, the majority of which is likely attributed to spinal implant costs. Opportunities for improving healthcare value should focus on controlling costs of spinal instrumentation, and improving quality of care with standardized treatment protocols.

10.
J Trauma Acute Care Surg ; 84(3): 418-425, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29298242

RESUMO

BACKGROUND: The rarity of renal trauma limits its study and the strength of evidence-based guidelines. Although management of renal injuries has shifted toward a nonoperative approach, nephrectomy remains the most common intervention for high-grade renal trauma (HGRT). We aimed to describe the contemporary management of HGRT in the United States and also evaluate clinical factors associated with nephrectomy after HGRT. METHODS: From 2014 to 2017, data on HGRT (American Association for the Surgery of Trauma grades III-V) were collected from 14 participating Level-1 trauma centers. Data were gathered on demographics, injury characteristics, management, and short-term outcomes. Management was classified into three groups-expectant, conservative/minimally invasive, and open operative. Descriptive statistics were used to report management of renal trauma. Univariate and multivariate logistic mixed effect models with clustering by facility were used to look at associations between proposed risk factors and nephrectomy. RESULTS: A total of 431 adult HGRT were recorded; 79% were male, and mechanism of injury was blunt in 71%. Injuries were graded as III, IV, and V in 236 (55%), 142 (33%), and 53 (12%), respectively. Laparotomy was performed in 169 (39%) patients. Overall, 300 (70%) patients were managed expectantly and 47 (11%) underwent conservative/minimally invasive management. Eighty-four (19%) underwent renal-related open operative management with 55 (67%) of them undergoing nephrectomy. Nephrectomy rates were 15% and 62% for grades IV and V, respectively. Penetrating injuries had significantly higher American Association for the Surgery of Trauma grades and higher rates of nephrectomy. In multivariable analysis, only renal injury grade and penetrating mechanism of injury were significantly associated with undergoing nephrectomy. CONCLUSION: Expectant and conservative management is currently utilized in 80% of HGRT; however, the rate of nephrectomy remains high. Clinical factors, such as surrogates of hemodynamic instability and metabolic acidosis, are associated with nephrectomy for HGRT; however, higher renal injury grade and penetrating trauma remain the strongest associations. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III; Therapeutic study, level IV.

11.
J Neurooncol ; 135(1): 161-171, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28685405

RESUMO

Glioblastoma is an aggressive primary brain tumor with devastatingly poor prognosis. Multiple studies have shown the benefit of wider extent of resection (EOR) on patient overall survival (OS) and worsened survival with larger preoperative tumor volumes. However, the concomitant impact of postoperative tumor volume and eloquent location on OS has yet to be fully evaluated. We performed a retrospective chart review of adult patients treated for glioblastoma from January 2006 through December 2011. Adherence to standardized postoperative chemoradiation protocols was used as an inclusion criterion. Detailed volumetric and location analysis was performed on immediate preoperative and immediate postoperative magnetic resonance imaging. Cox proportional hazard modeling approach was employed to explore the modifying effects of EOR and eloquent location after adjusting for various confounders and associated characteristics, such as preoperative tumor volume and demographics. Of the 471 screened patients, 141 were excluded because they did not meet all inclusion criteria. The mean (±SD) age of the remaining 330 patients (60.6% male) was 58.9 ± 12.9 years; the mean preoperative and postoperative Karnofsky performance scores (KPSs) were 76.2 ± 10.3 and 80.0 ± 16.6, respectively. Preoperative tumor volume averaged 33.2 ± 29.0 ml, postoperative residual was 4.0 ± 8.1 ml, and average EOR was 88.6 ± 17.6%. The observed average follow-up was 17.6 ± 15.7 months, and mean OS was 16.7 ± 14.4 months. Survival analysis showed significantly shorter survival for patients with lesions in periventricular (16.8 ± 1.7 vs. 21.5 ± 1.4 mo, p = 0.03), deep nuclei/basal ganglia (11.6 ± 1.7 vs. 20.6 ± 1.2, p = 0.002), and multifocal (12.0 ± 1.4 vs. 21.3 ± 1.3 months, p = 0.0001) locations, but no significant influence on survival was seen for eloquent cortex sites (p = 0.14, range 0.07-0.9 for all individual locations). OS significantly improved with EOR in univariate analysis, averaging 22.3, 19.7, and 13.2 months for >90, 80-90, and 70-80% resection, respectively. Survival was 22.8, 19.0, and 12.7 months for 0, 0-5, and 5-10 ml postoperative residual, respectively. A hazard model showed that larger preoperative tumor volume [hazard ratio (HR) 1.05, 95% CI 1.02-1.07], greater age (HR 1.02, 95% CI 1.01-1.03), multifocality (HR 1.44, 95% CI 1.01-2.04), and deep nuclei/basal ganglia (HR 2.05, CI 1.27-3.3) were the most predictive of poor survival after adjusting for KPS and tumor location. There was a negligible but significant interaction between EOR and preoperative tumor volume (HR 0.9995, 95% CI 0.9993-0.9998), but EOR alone did not correlate with OS after adjusting for other factors. The interaction between EOR and preoperative tumor volume represented tumor volume removed during surgery. In conclusion, EOR alone was not an important predictor of outcome during GBM treatment once preoperative tumor volume, age, and deep nuclei/basal ganglia location were factored. Instead, the interaction between EOR and preoperative volume, representing reduced disease burden, was an important predictor of reducing OS. Removal of tumor from eloquent cortex did not impact postoperative KPS. These results suggest aggressive surgical treatment to reduce postoperative residual while maintaining postoperative KPS may aid patient survival outcomes for a given tumor size and location.


Assuntos
Neoplasias Encefálicas/cirurgia , Glioblastoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Quimiorradioterapia , Feminino , Seguimentos , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
12.
Int J Mol Med ; 38(1): 337-44, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27221032

RESUMO

Icariin, a flavonoid and a major constituent of Herba Epimedii, has been previously demonstrated to possess potential antidepressant-like effects. In the present study, we established a rat model of depression induced by unpredictable chronic mild stress (CMS) in order to examine the effects of icariin treatment. The rats were allocated into the control group or one of the treatment groups [exposure to CMS plus oral administration of saline, icariin (20 or 40 mg/kg) or fluoxetine (10mg/kg)]. We examined the therapeutic effects of icariin administration on depression­like behaviors (with a sucrose preference test), on the mRNA and protein expression of glucocorticoid receptor (GR), FK506 binding protein 5 (FKBP5) and serum- and glucocorticoid-inducible kinase 1 (SGK1), as well as on the distribution of GR (in the cytoplasm and nucleus) in both the hippocampus and the prefrontal cortex following exposure to CMS. Our results revealed that the oral administration of icariin (20 and 40 mg/kg) for 35 consecutive days attenuated the development of depression-like behaviors induced by exposure to CMS. The increased mRNA expression of GR and SGK1 in the prefrontal cortex was reversed by icariin treatment. Moreover, the CMS-induced increases in the levels of cytosolic GR and SGK1 were partially restored by icariin administration in both the hippocampus and the prefrontal cortex, particularly in the hippocampus. Icariin also partially reversed the upregulated epxression of nuclear GR in the prefrontal cortex and that of FKBP5 in the hippocampus. On the whole, our findings indicate that icariin may have therapeutic applications as a potential antidepressant with multiple targets in both the hippocampus and prefrontal cortex. It exerts antidepressant-like effects by restoring the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, which is at least partially attributed to normalization of the distribution of GR, and decreases in the expression levels of FKBP5 and SGK1.


Assuntos
Encéfalo/metabolismo , Flavonoides/farmacologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Comportamento de Escolha , Citosol/efeitos dos fármacos , Citosol/metabolismo , Depressão/complicações , Depressão/genética , Modelos Animais de Doenças , Flavonoides/química , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Estresse Psicológico/complicações , Estresse Psicológico/genética , Sacarose , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
13.
Int Immunopharmacol ; 28(2): 1050-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26321117

RESUMO

Toll-like receptor-4 (TLR4) signaling has been implicated in innate immunity and acute inflammation following acute lung injury (ALI). As such, modulating inflammatory response through TLR4 represents an attractive therapeutic approach to treat ALI. Increasing evidence demonstrates that hyaluronan (HA) can modulate TLR4 activation and has shown early promise as a therapeutic agent in ALI. However, the mechanism associated with HA has not been fully elucidated. In the current study, we sought to determine the effects of HA on lipopolysaccharide (LPS)-induced inflammatory response and gain insights into the mechanism of action in mice with intratracheal instillation of LPS. Our results demonstrate that in contrast to mice challenged with LPS, pretreatment with HA significantly inhibited inflammatory cell recruitment, attenuated lung injury and suppressed the level of cytokine/chemokine in bronchial alveolar lavage fluid (BALF). Investigation of the mechanism responsible for inhibition of LPS activation showed HA treatment significantly inhibited the nuclear translocation of NF-κB p65 and protein expression of myeloid differentiation primary response protein (MyD88) and TIR-domain-containing adapter-inducing interferon-ß (TRIF) and p38 MAPK, JNK and ERK activation in lung tissue. Furthermore, we compared the protection effect of HA in TLR4-deficient mice with those of genetically matched wild type (WT) mice in an acute model of lung injury. However, in TLR4-deficient mice, HA pretreatment before LPS instillation fail to affect the LPS response. Therefore, our findings suggest that HA pretreatment attenuated LPS-induced ALI and the anti-inflammatory function of HA was partial dependent on TLR4, which shed new light on potential elements that regulate the lung injury response.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Ácido Hialurônico/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética
14.
Pharmacol Biochem Behav ; 98(2): 273-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21256148

RESUMO

Icariin is a major constituent of flavonoids isolated from the herb Epimedium. It displays antidepressant-like activity in mice behavioral despair models and chronic mild stress models. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the social avoidance effects of icariin administration are investigated. The data indicate that social defeat significantly reduces mice social interaction time and that icariin administered at 25 mg/kg and 50 mg/kg for 28 consecutive days produce remarkable increases in social interaction time. Impaired glucocorticoid receptor (GR) function is related to depression and normalization of GR function is closely associated with the recovery from depression. In this study, GR binding affinity and protein expression were evaluated by radioactive ligand and western blot, respectively. Our results demonstrate that both GR binding affinity and protein expression in the social defeat model are remarkably decreased and that icariin administration attenuates social defeat-induced GR down-regulation. In the present study, our data also show that icariin administration significantly inhibits social defeat-induced increases of corticosterone and IL-6 levels. The potential mechanisms of icariin induced GR modulation, such as effects on HPA-axis function, proinflammatory signaling pathway and membrane steroid transporters, need further study.


Assuntos
Flavonoides/farmacologia , Receptores de Glucocorticoides/metabolismo , Comportamento Social , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Corticosterona/sangue , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fluoxetina/farmacologia , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Immunopharmacol Immunotoxicol ; 33(1): 49-54, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20337501

RESUMO

Icariin is the major active constituent of Epimedii Herba. Our recent study showed that icariin displayed anti-inflammatory potential. One novel derivate of icariin is 3,5,7-Trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT). Little is known about ICT's pharmacological activities. In our study, the anti-inflammatory properties of ICT were evaluated. Murine RAW264.7 cells and C57BL/6J mice stimulated by lipopolysaccharide (LPS) was used as in vitro and in vivo inflammatory model, respectively. Our data showed that ICT (1-100 µg/mL) significantly inhibited LPS-induced tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2) production in vitro. These effects did not depend on cytotoxicity. The in vivo assay displayed that pretreatment of C57BL/6J mice with ICT (25-100 mg/kg, by gavage) for 3 days decreased LPS-induced serum levels of TNF-α, PGE2, and neutrophils CD11b expression dose-dependently. Furthermore, our data suggested that ICT reduced NO and PGE2 levels by inhibiting inducible NO synthase and cyclooxygenase-2 protein expression. To our knowledge, it is the first time that the anti-inflammatory effects of ICT have been evaluated.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Flavonas/uso terapêutico , Flavonoides/uso terapêutico , Inflamação/prevenção & controle , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Western Blotting , Antígeno CD11b/imunologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Dinoprostona/sangue , Dinoprostona/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Flavonas/isolamento & purificação , Flavonas/farmacologia , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Citometria de Fluxo , Inflamação/sangue , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Óxido Nítrico/biossíntese , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
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