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1.
J Med Chem ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32073845

RESUMO

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

2.
J Sep Sci ; 43(2): 531-546, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654547

RESUMO

As a representative formulation of Radix Salviae miltiorrhizae (Danshen)-Lignum Dalbergiae odoriferae (Jiangxiang), Xiangdan injection is widely prescribed for cardio- and cerebrovascular diseases in practice. This necessitates a pharmacokinetic investigation of this formulation to make it safer and more broadly applicable. We developed and validated a sensitive, selective, and reliable high-performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of 11 phenolic compounds including danshensu plus two diterpenoid quinones like cryptotanshinone and tanshinone IIA in rat. We applied this method for the pharmacokinetic studies of the 13 compounds in a rat model of middle cerebral artery occlusion after intravenous injection of Xiangdan injection or Danshen injection. In sham-operated rats, the animals taking Xiangdan injection exhibited significant growth of the area under the curve for danshensu, protocatechuic aldehyde, and tanshinone IIA compared with the changes seen in the data of those administrated with Danshen injection. Such a pattern was also observed in middle cerebral artery occlusion rats, whereas increased the area under the curve values were observed for danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid, and tanshinone IIA. These results demonstrated that synergistic interactions occurred between the components of Danshen and the active compounds of Jiangxiang both in sham-operated and middle cerebral artery occlusion rats, increasing the bioavailability of Danshen. The results presented herein can be used to determine a reference dose for the clinical application of Xiangdan injection, and to elucidate the synergistic mechanism of Danshen and Jiangxiang.

3.
Acta Trop ; 203: 105283, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31811863

RESUMO

Echinococcosis is considered by the World Health Organization (WHO) to be a neglected zoonotic disease in the world. Some Tibetan communities were found to be highly endemic for echinococcosis just 20 years ago. Until recently, we were able to understand the overall disease burden of echinococcosis in Tibetan communities after prevalence data being available from nationwide investigations from 2012 to 2016. Data were abstracted from 9 publications regarding to echinococcosis prevalence between 2016-2018; from 10 data bases on echinococcosis prevalence for 151 Tibetan counties; and statistics of population, Gross Domestic Product (GDP) and health staff from 44 local statistic bureaus and government websites at provincial, prefecture and county level, and 2 books of provincial yearly statistics. These data were used to estimate the Disability Adjusted Life Years (DALYs) due to cystic echinococcosis (CE) and alveolar echinococcosis (AE). The distribution of DALYs was presented geographically and economically. The echinococcosis DALYs in the Tibetan communities were estimated to be 126,159 (95%UI 122,415-137,675) annually using the method recommended by WHO. AE DALYs were estimated to be 105,829 (95%UI 101,969-117,090), which were more than CE DALYs of 20,330 (95%UI 19,690-21,581). Echinococcosis affects people more in underdeveloped areas. There was a tendency that a higher echinococcosis DALYs were usually correlated a higher altitude. Health services are also poorly provided in terms of number of health staff of 5.05 per 1000 population in comparison with the national average of 5.8 per 1000 population. The data suggest that the echinococcosis burden in the center region of Qinghai-Tibet plateau is higher than that of other regions, and consequently more control and health services should be provided to the region.

4.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Fármacos , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
5.
Infect Dis Poverty ; 8(1): 68, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362789

RESUMO

BACKGROUND: Echinococcosis caused by Echinococcus is one of the most major infectious diseases in north-west highland of China. E. granulosus sensu strict, E. multilocularis, and E. canadensis are known to be the only three species related to human health transmitting in the areas. To achieve targeted treatment and control of echinococcosis, the accurate identification and discrimination of the species are important. However, currently the available diagnostic approaches do not present ideal results either in accuracy or efficiency. METHODS: In the study, a set of primers were designed to aim at the three human-pathogenic Echinococcus species in China. The one-step multiplex PCR assay was developed and evaluated for the specificity and sensitivity. A total of 73 parasitic lesions and 41 fecal materials obtained from human and various animals collected in the clinic and the field were tested to assess the applicability of this method. RESULTS: The multiplex PCR effectively detected the individual DNA from the targeted species and their random mixtures generating with distinguishable expected size of products. The detection limit of the assay for each of the three species was 5 pg/µl when they were tested separately. When DNA mixtures of the targeted species containing the same concentration were used as templates, the lowest amount of DNA which can be detected was 50 pg/µl, 10 pg/µl and 5 pg/µl for E. granulosus s. s., E. multilocularis, and E. canadensis respectively. No cross-reactivity was observed when DNA from eight genetically close species was used as control templates. The multiplex PCR identifications of all samples were in line with the original sequencing results except for those infected with E. shiquicus, which showed negative signals in the developed assay. Of all the tested stool materials, 16 were previously found positive for Echinococcus by visual and microscopic examination. Among these 16 samples, 13 were confirmed by the multiplex PCR, and the other three tested negative. Additionally, the multiplex PCR identified another 14 positive feces from the remained 25 stool samples which absence of worms. CONCLUSIONS: The developed multiplex PCR shows advantages in fast diagnosis and large-scale epidemiological investigation, which proven to be a promising tool utilized in clinic and surveillance system.


Assuntos
Equinococose/diagnóstico , Echinococcus/isolamento & purificação , Reação em Cadeia da Polimerase Multiplex/métodos , Animais , China , Diagnóstico Diferencial , Equinococose/classificação , Equinococose/parasitologia , Echinococcus granulosus/isolamento & purificação , Echinococcus multilocularis/isolamento & purificação , Humanos
6.
Parasitology ; 146(12): 1595-1601, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31307567

RESUMO

Echinococcus granulosus sensu stricto (s.s.), Echinococcus multilocularis and Echinococcus canadensis are the common causes of human echinococcosis in China. An accurate species identification tool for human echinococcosis is needed as the treatments and prognosis are different among species. The present work demonstrates a method for the simultaneous detection of these three Echinococcus species based on multiplex polymerase chain reaction (mPCR). Specific primers of this mPCR were designed based on the mitochondrial genes and determined by extensive tests. The method can successfully detect either separated or mixed target species, and generate expected amplicons of distinct size for each species. Sensitivity of the method was tested by serially diluted DNA, showing a detection threshold as less as 0.32 pg for both E. granulosus s.s. and E. canadensis, and 1.6 pg for E. multilocularis. Specificity assessed against 18 other parasites was found to be 100% except weakly cross-react with E. shiquicus. The assay was additionally applied to 69 echinococcosis patients and 38 healthy persons, confirming the high reliability of the method. Thus, the mPCR described here has high application potential for clinical identification purposes, and can further provide a useful tool for evaluation of serology and imaging method.

7.
Sheng Wu Gong Cheng Xue Bao ; 35(6): 1041-1049, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31232000

RESUMO

Nerve growth factor (NGF) can promote the development, differentiation and regeneration of neurons. Recently, in order to efficiently produce human NGF (hNGF) drugs with better efficacy, we created transgenic mice expressing hNGF specifically in their salivary glands, and purified highly active hNGF protein from their saliva. Some studies reported that the NGF secretion in mouse saliva is affected by gender and age. Here, in order to select hNGF transgenic mice with high NGF secretion for saliva collection and hNGF purification, we divided transgenic mice into 4 groups, including 28-day-old young males and females, 63-day-old adult males and females. We compared their saliva volume, total salivary protein amount, salivary mNGF protein amount and salivary hNGF protein amount. The results showed that the saliva volume as well as amounts of total salivary protein, salivary mNGF protein and salivary hNGF protein secreted by 63-day-old transgenic mice were significantly higher than those secreted by sex-match 28-day-old transgenic mice, and the salivary hNGF protein amount secreted by male transgenic mice at the age of 63 days was significantly higher than that of female transgenic mice at the same age; Among 4 groups of mice, 63-day-old male transgenic mice secreted the highest salivary hNGF content, which was about 46 times higher than that secreted by the 28-day-old female transgenic mice. Therefore, 63-day-old male transgenic mice should be selected for saliva collection and hNGF purification.


Assuntos
Saliva , Animais , Diferenciação Celular , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fator de Crescimento Neural
8.
Br J Pharmacol ; 176(17): 3143-3160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31116880

RESUMO

BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.

9.
J Med Chem ; 62(9): 4656-4668, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-30995036

RESUMO

Complement factor D (FD), a highly specific S1 serine protease, plays a central role in the amplification of the alternative complement pathway (AP) of the innate immune system. Dysregulation of AP activity predisposes individuals to diverse disorders such as age-related macular degeneration, atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria. Previously, we have reported the screening efforts and identification of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation of our drug discovery program, we designed compounds applying structure-based approaches to improve interactions with FD and gain selectivity against S1 serine proteases. We report herein the design, synthesis, and medicinal chemistry optimization of the benzylamine series culminating in the discovery of 12, an orally bioavailable and selective FD inhibitor. 12 demonstrated systemic suppression of AP activation in a lipopolysaccharide-induced AP activation model as well as local ocular suppression in intravitreal injection-induced AP activation model in mice expressing human FD.

10.
Proc Natl Acad Sci U S A ; 116(16): 7926-7931, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30926668

RESUMO

Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

11.
Biomed Chromatogr ; 33(3): e4438, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30444936

RESUMO

Tanshinol borneol ester (DBZ) is a potential drug candidate composed of danshensu and borneol. It shows anti-ischemic and anti-atherosclerosis activity. However, little is known about its metabolism in vivo. This research aimed to elucidate the metabolic profile of DBZ through analyzing its metabolites using high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. Chromatographic separation was performed on an Agilent TC-C18 column (150 × 4.6 mm, 5.0 µm) with gradient elution using methanol and water containing 0.2% (v/v) formic acid as the mobile phase. Metabolite identification involved analyzing the retention behaviors, changes in molecular weights and MS/MS fragment patterns of DBZ and its metabolites. As a result, 20 potential metabolites were detected and tentatively identified in rat plasma, urine and feces after administration of DBZ. DBZ could be metabolized to O-methylated DBZ, DBZ-O-glucuronide, O-methylated DBZ-O-glucuronide, hydroxylated DBZ and danshensu. Danshensu, a hydrolysis product of DBZ, could further be transformed into 12 metabolites. The proposed method was confirmed to be a reliable and sensitive alternative for characterizing metabolic pathways of DBZ and providing valuable information on its druggability.


Assuntos
/análise , Cromatografia Líquida de Alta Pressão/métodos , Lactatos/análise , Lactatos/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Masculino , Ratos , Ratos Sprague-Dawley
12.
Acta Trop ; 190: 45-51, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30278154

RESUMO

Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are highly co-endemic in Sichuan, a part of Qinghai-Tibet Plateau where is a typical Tibetan nomadic community living area. In order to better understand the Echinococcus spp. of human being infected origins in this area, 140 lesions were collected from echinococcosis patients who were received operations during the period of 2014-2016 in different geographic districts in this region. Partial DNA sequences of the mitochondrial cox1 gene were analyzed. The genetic characterization of the isolates from 3 different places including Ganzi, Aba and Liangshan were assessed. Of all the 140 samples, the great majority was identified as Echinococcus granulosus sensu stricto (n = 108). Echinococcus multilocularis was confirmed to be another important pathogen of the human infections (n = 31). Additionally, one Echinococcus canadensis (G6/7) isolate from Ganzi was confirmed. Comparing the clinical diagnosis with the sequencing results, 6.4% (9/140) of the cases were misdiagnosed between AE and CE, and another 8.6% (12/140) were unclassified to sub-type in echinococcosis. Higher rates of misdiagnosis and unclassified diagnosis were found in AE cases (12.9%, 4/31 and 16.1%, 5/31 respectively) compared to CE (4.6%, 5/109 and 6.4%, 7/109 respectively). In E.granulosus s.s., a total of 34 haplotypes were detected, and 4 haplotypes were inferred from E.multilocularis. The haplotype networks of the 2 species exhibited a similar star-shaped feature with a dominant haplotype in the center. Geographically specific haplotypes were observed in Ganzi and Aba respectively. This study provides insight into the current species causing human echinococcosis in the Tibetan districts of Sichuan. E.granulosus s.s. and E.multilocularis are confirmed to be the main causative agents, and the existence of E.canadensis (G6/7) is also observed in the region. Molecular diagnosis was proven to be essential for the confirmation of human echinococcosis in the area.


Assuntos
Echinococcus granulosus/genética , Echinococcus multilocularis/genética , Adulto , Idoso , Animais , Equinococose/parasitologia , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade
14.
Infect Dis Poverty ; 7(1): 104, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30384860

RESUMO

BACKGROUND: Echinococcosis is a parasitic zoonosis caused by Echinococcus larvae parasitism causing high mortality. The Tibetan Region of Sichuan Province is a high prevalence area for echinococcosis in China. Understanding the geographic distribution pattern is necessary for precise control and prevention. In this study, a spatial analysis was conducted to explore the town-level epidemiology of echinococcosis in the Sichuan Tibetan Region and to provide guidance for formulating regional prevention and control strategies. METHODS: The study was based on reported echinococcosis cases by the end of 2017, and each case was geo-coded at the town level. Spatial empirical Bayes smoothing and global spatial autocorrelation were used to detect the spatial distribution pattern. Spatial scan statistics were applied to examine local clusters. RESULTS: The spatial distribution of echinococcosis in the Sichuan Tibetan Region was mapped at the town level in terms of the crude prevalence rate, excess hazard and spatial smoothed prevalence rate. The spatial distribution of echinococcosis was non-random and clustered with the significant global spatial autocorrelation (I = 0.7301, P = 0.001). Additionally, five significant spatial clusters were detected through the spatial scan statistic. CONCLUSIONS: There was evidence for the existence of significant echinococcosis clusters in the Tibetan Region of Sichuan Province, China. The results of this study may assist local health departments with developing better prevention strategies and prompt more efficient public health interventions.


Assuntos
Equinococose/epidemiologia , Análise Espacial , Animais , Teorema de Bayes , China/epidemiologia , Echinococcus/isolamento & purificação , Geografia , Humanos , Saúde Pública , Tibet/epidemiologia , Zoonoses/epidemiologia , Zoonoses/parasitologia
15.
J Ocul Pharmacol Ther ; 34(7): 489-499, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30188257

RESUMO

PURPOSE: Mononuclear phagocytes (MNPs) are present in neovascular age-related macular degeneration (nv AMD) which is also called choroidal neovascularization (CNV). The number and phenotype of the MNPs depend upon the local environment in the CNV and effect of nv AMD therapy. We investigated ocular cell infiltration and conditions that modulate angiogenesis in a laser-induced mouse CNV model. METHODS: We developed assays to quantify MNPs in our established mouse CNV model. One MNP assay quantified the number of subretinal cells peripheral to the CNV lesions. A second assay semiquantitatively assesses the number of MNPs localized to the CNV lesion. We used these assays to measure the effect of toll-like receptor-2 (TLR-2) activation, anti-vascular endothelial growth factor (VEGF) therapy, and chemokine (C-C motif) ligand 2 (Ccl2) genetic deletion on MNP infiltration after laser injury. RESULTS: Laser injury induced blood vessel growth and infiltration of MNPs. Systemic administration of a TLR-2 activating peptide increased laser-induced CNV area, MNP cell numbers, and MNP density over the CNV lesions. Systemic administration of a VEGF antibody reduced CNV area, while Ccl2 genetic deletion increased CNV area. Despite the change in amount of angiogenesis, MNP infiltration was, surprisingly, unchanged in these 2 conditions. CONCLUSIONS: MNP quantification provides biological insights for candidate AMD therapies. The number of infiltrating MNP cells does not correlate with the amount of laser-induced CNV area.


Assuntos
Neovascularização de Coroide/metabolismo , Fagócitos/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Fagócitos/efeitos dos fármacos , Fagócitos/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Invest Ophthalmol Vis Sci ; 59(2): 940-951, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29450541

RESUMO

Purpose: Genome-wide association studies suggest a role for the complement system in age-related macular degeneration (AMD). We characterized ocular complement activation and evaluated a complement factor D (FD) neutralizing antibody. Methods: Mice were treated with toll-like receptor (TLR) ligands, intravitreal injection (IVT), or corneal debridement. Levels of complement proteins and mRNA were measured. A FD neutralizing antibody was administered IVT into eyes of rabbits that were challenged with LPS (lipopolysaccharide) administered intravenously. Results: Levels of C3 and factor B (FB) mRNA and protein in the eye were increased following intraperitoneal injection of TLR4 ligand LPS. Increased levels of C3 and FB breakdown products were observed in both eye tissues and plasma. Complement activation products were markedly reduced in C3-/- and Cfb-/- mice challenged with LPS. Ocular complement levels were also elevated in mice treated systemically with TLR2 and -3 ligands, injured by IVT injection or corneal debridement, or even in normal aging. IVT administration of a complement FD neutralizing antibody in rabbits inhibited LPS-induced complement activation in the posterior segment of the eye, but not in the anterior segment of the eye or in plasma. Conclusions: Systemic TLR stimulation and eye tissue injury induced time-dependent alternative complement pathway activation in the eye. Ocular complement levels were also gradually elevated during aging. An anti-FD antibody IVT potently inhibited LPS-induced complement activation in the posterior segment of the eye. This study provides insights into the dynamic profile of ocular complement activation, which is valuable for complement research in eye diseases and for developing complement therapeutics for AMD.


Assuntos
Anticorpos Neutralizantes/farmacologia , Fator D do Complemento/antagonistas & inibidores , Via Alternativa do Complemento/fisiologia , Inflamação/imunologia , Modelos Animais , Animais , Western Blotting , Complemento C3/metabolismo , Fator B do Complemento/metabolismo , Feminino , Injeções Intraperitoneais , Injeções Intravítreas , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Coelhos , Receptor 4 Toll-Like/metabolismo
17.
J Trace Elem Med Biol ; 44: 104-108, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28965563

RESUMO

Sodium, potassium, calcium, magnesium, zinc, copper and iron are associated with the sequela of hypertension. The most reliable method for testing those elements is by collecting 24-h urine samples. However, this is cumbersome and collection of spot urine is more convenient in some circumstance. The aim of this study was to compare the concentrations of different elements in 24-h urine and spot urine. METHODS: Data was collected from a sub-study of China Salt Substitute and Stroke Study. 240 participants were recruited randomly from 12 villages in two counties in Ningxia, China. Both spot and 24-h urine specimens were collected from each patient. Routine urine test was conducted, and concentration of elements was measured using microwave digestion and Inductively Coupled Plasma-Optical Emission Spectrometry. Partial correlation analysis and Spearman correlation analysis were used to investigate the concentration of different elements and the relationship between 24- h urine and spot urine. RESULTS: A partial correlation in sodium, potassium, calcium, magnesium and iron was found between paired 24-h urine and spot urine samples except copper and zinc: 0.430, 0.426, 0.550, 0.221 and 0.191 respectively. CONCLUSIONS: Spot urine can replace 24-h urine for estimating some of the elements in hypertensive patients with normal renal function.


Assuntos
Hipertensão/fisiopatologia , Hipertensão/urina , Rim/fisiopatologia , Oligoelementos/urina , Idoso , Idoso de 80 Anos ou mais , Cálcio/urina , Cobre/urina , Feminino , Humanos , Ferro/urina , Magnésio/urina , Masculino , Pessoa de Meia-Idade , Potássio/urina , Sódio/urina , Estatísticas não Paramétricas , Zinco/urina
18.
Ann Clin Microbiol Antimicrob ; 16(1): 67, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28974222

RESUMO

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Peso Corporal , Parede Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Interações Medicamentosas , Humanos , Metabolismo/efeitos dos fármacos , Mutação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Estado Nutricional , Obesidade , Soro , Falha de Tratamento , Resultado do Tratamento , Tuberculose/fisiopatologia
19.
Biochem Biophys Res Commun ; 494(3-4): 634-640, 2017 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-28851653

RESUMO

The ß2 adrenergic receptor (ß2-AR) is a prototypical family A G protein-coupled receptor (GPCR) and an excellent model system for studying the mechanism of GPCR activation. Purified ß2-AR was immobilized on macroporous silica gel to obtain liquid chromatographic stationary phase. The resulting phase was packed into a stainless steel column (4.6 × 50 mm, 7 µm) and used for on-line chromatographic system. When column oven temperature increased from 20.0 °C to 40.0 °C, uncomplete separate chromatographic peaks of ephedrine and pseudoephedrine as receptor conformational probe were gradually merged into one peak, meanwhile retention time and resolution of the probes were reduced correspondingly, which suggested that temperature could regulate protein conformation. Temperature-induced conformational change of immobilized ß2-AR, especially changes at higher temperatures, indicated that constructed receptor chromatography could simulate fever disease state of human body and clarify receptor conformation change at pathological condition. At the same time this study could also provide new ideas for screening active components in pathological conditions.


Assuntos
Efedrina/química , Conformação Proteica , Desnaturação Proteica , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/ultraestrutura , Temperatura , Adsorção , Ligação Proteica
20.
PLoS One ; 12(8): e0182273, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28786989

RESUMO

Although experimental studies have shown that adiponectin and leptin modulate glucose tolerance and insulin resistance, it remains unclear whether these adipocytokines exert similar effects in general human populations. We evaluated the associations of serum adiponectin and leptin with ß-cell function and insulin resistance in a population with low obesity prevalence. A cross-sectional study of 783 rural residents, aged 25-74 years, recruited in Ningxia, China was conducted during 2008-2012. ß-cell function and insulin resistance were estimated using the Homeostasis Model Assessment. Serum adiponectin and leptin were measured with ELISA. Serum adiponectin concentrations (mean ± SD) were highest in subjects with normal glucose tolerance (36.65 ± 61.13 µg/ml), intermediate in those with impaired fasting glucose (25.92 ± 34.48 µg/ml), and lowest in those with diabetes (15.08 ± 12.14 µg/ml) (p = 0.001). A similar pattern of differences was found for ß-cell function, whereas opposite results were observed for insulin resistance and blood glucose. After adjustment for confounders including metabolic syndrome components, serum adiponectin (µg/ml) was inversely associated with ß-cell function (%ß) [ß (95% CI): -7.57 (-12.33, -2.81)] and insulin resistance (100/%S) [ß (95% CI): -0.21 (-0.33, -0.09)]. A significant inverse association also existed between serum leptin and ß-cell function, but serum leptin was not significantly associated with insulin resistance. The present study suggests that adiponectin and leptin play a role in the development of insulin resistance and diabetes independent of metabolic syndrome.


Assuntos
Adipocinas/sangue , Teste de Tolerância a Glucose , População Rural , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , China , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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