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1.
Artigo em Inglês | MEDLINE | ID: mdl-32197379

RESUMO

Although drinking water safety has raised considerable concern, to date, the hidden health risks in newly released overnight water from a municipal pipeline have seldom received attention. In this study, bacterial community composition and the response of antibiotic-resistant bacteria (ARB) to ciprofloxacin, azithromycin, tetracycline, penicillin, and cephalosporin in overnight stagnant water were analyzed. With increases in heterotrophic bacteria plate count (HPC) during water stagnation, the numbers of ARB and the ARB/HPC ratios for the five antibiotics in resident water were observed to increase, which illustrated that the prevalence of ARB rose in the pipe network water during stagnation time (ST). Furthermore, during water stagnation for 12 h, an increase in bacteria related to fermentation was also observed. When the ST rose to 48 h, the fermentation bacteria become non-significant, and this was related to the exchange of pipe network water during daytime stagnation within the 48-h period. The antibiotic resistance index (ARI) showed that tetracycline had the highest resistance level in fresh water, and then decreased during water stagnation. When ST increased to 12 h, all ARI values of the five antibiotics were low, which was associated with changes in parameters during water retention and reduced resistance during short-term stagnation. When the ST increased to 24 and 48 h, the resistance to most antibiotics (except for tetracycline) increased, which showed that increasing antibiotic resistance is caused by the formation of biofilms in the pipeline during water stagnation.

2.
Pharmacol Res ; 153: 104657, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982488

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and constitutes a major risk factor for progression to cirrhosis, liver failure and hepatocellular carcinoma (HCC). The occurrence of NAFLD is closely associated with abnormal lipid metabolism and implies a high risk of type 2 diabetes and cardiovascular disease. Therefore, specific and effective drugs for the prevention and treatment of NAFLD are necessary. Hypericin (HP) is one of the main active ingredients of Hypericum perforatum L., and we previously revealed its protective role in islet ß-cells and its effects against type 2 diabetes. In this study, we aimed to explore the preventive and therapeutic effects of HP against NAFLD and the underlying mechanisms in vitro and in vivo. Here, we demonstrated that HP improved cell viability by reducing apoptosis and attenuated lipid accumulation in hepatocytes both in vitro and in vivovia attenuating oxidative stress, inhibiting lipogenesis and enhancing lipid oxidization. Thus, HP exhibited significant preventive and therapeutic effects against HFHS-induced NAFLD and dyslipidemia in mice. Furthermore, we demonstrated that HP directly bound to PKACα and activated PKA/AMPK signaling to elicit its effects against NAFLD, suggesting that PKACα is one of the drug targets of HP. In addition, the enhancing effect of HP on lipolysis in adipocytes through the activation of PKACα was also elucidated. Together, the conclusions indicated that HP, of which one of the targets is PKACα, has the potential to be used as a preventive or therapeutic drug against NAFLD or abnormal lipid metabolism in the future.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31414136

RESUMO

BACKGROUND: In preclinical studies, the Intracerebral Microinjection Instrument (IMI) has demonstrated the ability to deliver therapeutics within the brain in 3-dimensional arrays from a single overlying penetration while incurring minimal localized trauma. OBJECTIVE: To evaluate the safety and performance of the IMI in its first use in humans to deliver stem cells in complex configurations within brain regions affected by ischemic injury. METHODS: As part of a phase 1 study, 3 chronically hemiparetic motor stroke patients received intracerebral grafts of the therapeutic stem cell line, NSI-566, using the IMI and its supporting surgical planning software. The patients were 37 to 54 yr old, had ischemic strokes more than 1 yr prior to transplantation, and received Fugl-Meyer motor scale scores of 17-48 at screening. During a single surgical procedure, patients received several neural grafts (42 ± 3) within the peri-infarct region targeted strategically to facilitate neural repair. RESULTS: The IMI enabled multiple cellular deposits to be safely placed peripheral to stroke lesions. The procedure was well tolerated, recovery was uneventful, and there occurred no subsequent complications. The IMI performed reliably throughout the procedures without evident targeting errors. One year after transplantation, all 3 subjects displayed significant clinical improvement, and imaging analysis demonstrated occupation of infarct cavities with new tissue without tumor formation. CONCLUSION: IMI technology permits unprecedented numbers of injections to be tactically placed in 3-dimensional arrays safely and reliably in human subjects.This advanced methodology can optimize the benefits of novel therapeutics by enabling versatile 3-dimensional intracerebral targeting.

4.
Mult Scler Relat Disord ; 34: 137-140, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31272070

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is a common neuroinflammatory demyelinating disease associated with aquaporin-4 (AQP4) antibody in the central nervous system. Neurosyphilis is a neurological disease caused by Treponema pallidum infection. NMOSD commonly occurs concurrently with autoimmune diseases. However, they have rarely been associated with infectious diseases. In this report we describe a rare case of concurrent AQP4-positive NMOSD and neurosyphilis. A 60-year-old man was admitted to our hospital with a complaint of progressive weakness in his legs for one month. T2-weighted magnetic resonance images of the spinal cord showed longitudinal extensive lesions at C7-T7. The rapid plasma reagin test and T. pallidum particle agglutination assay performed using patient serum and cerebrospinal fluid (CSF) were positive. Additionally, the AQP4-immunoglobulin (Ig) G was detected in the serum and CSF. The patient's symptom gradually improved after penicillin and methylprednisolone treatment. This case report highlights the possibility of the presence of an infectious disease in patients with NMOSD.


Assuntos
Aquaporina 4/imunologia , Neuromielite Óptica/complicações , Neuromielite Óptica/imunologia , Neurossífilis/complicações , Neurossífilis/imunologia , Diagnóstico Diferencial , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/terapia , Neurossífilis/diagnóstico , Neurossífilis/terapia , Medula Espinal/diagnóstico por imagem
5.
Anim Sci J ; 90(9): 1239-1247, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31281994

RESUMO

This study was conducted to investigate the effects of different levels of dietary partial MEs and coated cysteamine (CC) supplementation on gut microbiota in finishing pigs. Results showed that whittling down dietary partial MEs (Cu, Fe, Zn, Mn) by 20% and 40% had little effect on the microbial diversity, community structure, and bacterial relative abundance in the ileum of finishing pigs. Supplementation with 1,600 mg/kg CC also had no obvious effect on the microbial diversity, community structure, and bacterial relative abundance in the finishing pig ileum when fed diets with a normal MEs level. However, the abundance of Peptostreptococcaceae, Pasteurella, and Pasteurella_aerogenes was higher, and the abundance of Actinobacillus_minor was lower in the 20% ME reduction diet treatment than that in the 20% ME reduction with 1,600 mg/kg CC diet group (p < 0.05). In conclusion, our results suggested that there is no obvious effect on gut microbiota when dietary partial MEs are reduced by 20% or 40%, which indicates the feasibility of reducing dietary partial MEs by 20% or 40% in finishing pigs. Supplementation with CC changed the relative abundance of some bacteria related to opportunistic pathogenicity in the finishing pig ileum when were fed a 20% ME reduction diet.


Assuntos
Cisteamina/farmacologia , Dieta/veterinária , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Íleo/microbiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Minerais , Suínos
6.
Sci Total Environ ; 681: 365-378, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31108357

RESUMO

Endotoxins, also referred to as lipopolysaccharides or pyrogens, are major components embedded in the outer cell wall membrane of most Gram-negative bacteria and some cyanobacteria. As common pyrogens and strong immune stimulators, health hazards associated with endotoxins in water and wastewater have been attracting attention in recent years. In this paper, the characteristics, existing forms, and detection assays of endotoxins in water and wastewater are reviewed. Cellular response and pathophysiological effects, and main exposure tracts of endotoxins in water and wastewater are discussed. Levels of endotoxin contamination in water, wastewater, and their aerosols are presented. The removal effects of different water and wastewater treatment processes are summarized. Hence, it is important to: (i) Improve investigations into endotoxin contamination in water and wastewater in order to identify their source, occurrence, and fate. (ii) Implement water and wastewater treatment processes capable of ensuring low levels of endotoxins. This review aims to identify efficient water and wastewater treatment processes capable of ensuring the production of WTPs and WWTPs effluents with a low level of endotoxin activity, and to guarantee the reduction of endotoxin exposure risks to the consumers of water and wastewater.


Assuntos
Endotoxinas/análise , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Águas Residuárias/química , Água/química
7.
J Biomed Inform ; 94: 103170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30959205

RESUMO

Strategic allocation of limited operating room (OR) capacity to surgeons is crucial for the coordination of surgical work flow, including planning of consultation and surgery days, and staff assignment to perioperative teams. However, it is a challenging problem in practice, since the capacity allocation needs to be cyclic for schedule predictability and surgical team coordination, and also needs to satisfy surgeons' preferences. It is further complicated by the practice of surgeons sharing ORs. In this study, we propose a mathematical optimization model to coordinate capacity allocation among surgeons in order to improve the utilization of surgical capacity. We introduce the concept of capacity allocation patterns to account for schedule cyclicity and surgeons' preferences. Further, we develop a data-driven approach to coordinate OR sharing among surgeons based on their historical OR usage. The proposed methodology is applied to a case study with data from a surgical division at Mayo Clinic. Compared with the state-of-the-practice, the proposed approach shows a substantial potential in reducing the maximum number of ORs allocated daily to the division with little overtime. With a solution time of less than 0.5 s, the proposed methodology can be readily used as a decision support tool in surgical practice.

8.
Sci Total Environ ; 649: 146-155, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30172134

RESUMO

The aim of this study was to gain comprehensive insights into the characteristics of antibiotic resistance genes (ARGs) in multiphase samples from drinking water distribution pipelines using a simulated biofilm reactor. During 120 d of continuous operation, common parameters and six ARGs (ermA, ermB, aphA2, ampC, sulII, and tetO) in samples of three phases (water, particle, and biofilm) from the reactor were investigated, which demonstrated secondary contamination by ARGs. Abundances of the six ARGs in the reactor effluent increased gradually, and in the 120 d effluent, the relative abundances of aphA2 and sulII were the highest, at 9.9 × 10-4 and 1.3 × 10-3, respectively, with a 1.5-fold and 2.8-fold increase, compared with those in the influent. The relative abundances of the six ARGs in the biofilm phase increased significantly (P < 0.05) at 120 d, which was caused by robust bacteria in biofilm that was newly exposed following the detachment of a large piece of aging biofilm. In the particle phase, four of the ARGs did not change significantly during the 120 d period. The six ARGs in the samples of three phases showed a negative correlation with residual chlorine in the pipe water, which demonstrated that low abundance of ARGs in the samples of three phases was related to the improvement of residual chlorine. The proportion of cultivable bacteria illustrated that the robust and active bacteria were negatively correlated with the six ARGs in the biofilm. Total organic carbon (TOC) in the pipeline showed a positive correlation with the proportion of cultivable bacteria in both the water and biofilm phases, which indicated that a TOC reduction in the pipeline contributed to low abundance of ARGs. With low-pressure ultraviolet (LP-UV) irradiation of 20 mJ/cm2, ARGs in the samples of three phases were efficiently controlled, which showed that LP-UV can be used for ARG removal in terminal water for supplemental bactericidal treatment of pipeline effluent.


Assuntos
Bactérias/efeitos da radiação , Fenômenos Fisiológicos Bacterianos , Biofilmes/efeitos da radiação , Água Potável/análise , Resistência Microbiana a Medicamentos/genética , Fotólise , Purificação da Água , Bactérias/genética , Raios Ultravioleta , Abastecimento de Água
9.
Angew Chem Int Ed Engl ; 57(34): 10980-10984, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29956881

RESUMO

Reported is a modular one-step three-component synthesis of tetrahydroisoquinolines using a Catellani strategy. This process exploits aziridines as the alkylating reagents, through palladium/norbornene cooperative catalysis, to enable a Catellani/Heck/aza-Michael addition cascade. This mild, chemoselective, and scalable protocol has broad substrate scope (43 examples, up to 90 % yield). The most striking feature of this protocol is the excellent regioselectivity and diastereoselectivity observed for 2-alkyl- and 2-aryl-substituted aziridines to access 1,3-cis-substituted and 1,4-cis-substituted tetrahydroisoquinolines, respectively. Moreover, this is a versatile process with high step and atom economy.

10.
J Clin Neurosci ; 54: 20-24, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29779725

RESUMO

The efficacy and safety of surgery for patients with primary pontine hemorrhage (PPH) remain debatable. Twenty-eight consecutive patients with huge upper PPH were included in this study. They underwent surgical management through a subtemporal approach between January 2009 and October 2013. We analyzed clinical and radiological parameters to assess the patient outcomes. The near-complete (>90%) evacuation rate was 67.9%, and there was no surgery-related death. The overall survival rate at 3 months was 64.3% (17/28), including 28.6% (8/28) with good function, 10.7% (3/28) with disability and 25% (7/28) in a vegetative state. The mortality rate was 35.7% (10/28). Preoperative hemorrhage volume (P = 0.019), preoperative (P = 0.017) and postoperative (P = 0.001) Glasgow coma scale (GCS) score, coma on admission (P = 0.001), ventricular extension (P = 0.001), preoperative mechanical ventilation (P = 0.001) and hydrocephalus (P = 0.007) were found to be statistically significant predictors for mortality on univariate analysis. On multivariate regression analysis, only GCS on admission and coma were found to be significant prognostic predictors. The subtemporal approach was found to be a safe method to treat upper PPH. Microsurgery may be beneficial for the treatment of PPH, but these results need further validation in a more comprehensive and comparative study. GCS on admission and coma were found to be the only significant prognostic predictors for mortality with multivariate regression analysis.


Assuntos
Hemorragia Cerebral/cirurgia , Hematoma/cirurgia , Ponte/cirurgia , Adulto , Idoso , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/mortalidade , Feminino , Escala de Coma de Glasgow , Hematoma/diagnóstico , Hematoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de Sobrevida
11.
J Hazard Mater ; 318: 15-23, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27388420

RESUMO

Low-temperature plasma was used to control bacteria, endotoxins and natural organic matter (NOM) in water by a dielectric barrier discharge (DBD) device. Results indicate that DBD plasma has an obvious inactivation effect on various bacteria in water. The degree of inactivation from difficult to easy is as follows: Bacillus subtilis>Escherichia coli>Staphylococcus aureus. Activated ultrapure water treated using DBD plasma exhibited a sustained sterilization effect, but this sterilization effect decreased gradually after 1h. The total-endotoxin (free-endotoxin and bound-endotoxin) released by Escherichia coli during inactivation, as well as artificially simulated endotoxin in a control solution, was significantly controlled by DBD plasma. Both the metabolites that appeared after inactivation of microorganisms by plasma treatment, and the NOM in filtration effluent of a water treatment plant were well removed by DBD plasma if the treatment duration was sufficiently long. However, the acute toxicity increased significantly, and persisted for at least 2h, indicating that some long-life active substances were generated during the DBD process. Therefore, the removal of bacteria, endotoxins or NOM does not mean a safe water is produced. It is also important to eliminate the toxicity and byproducts produced during water treatment for the continuous promotion and industrial application of DBD plasma.


Assuntos
Endotoxinas/isolamento & purificação , Purificação da Água/métodos , Água/química , Bactérias/química , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Carga Bacteriana , Técnicas Eletroquímicas , Endotoxinas/toxicidade , Filtração , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Espectrometria de Fluorescência , Eliminação de Resíduos Líquidos , Poluição Química da Água
12.
Neuropharmacology ; 108: 1-13, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27067919

RESUMO

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive cognitive impairment and multiple distinct neuropathological features. Currently, there are no available therapies to delay or block the disease progression. Thus, the disease-modifying therapies are urgent for this devastating disorder by simultaneously targeting multiple distinct pathological processes. Morin, a natural bioflavonoid, have been shown to be strongly neuroprotective in vitro and in vivo. In this study, we first investigated the disease-modifying effects of chronic morin administration on the neuropathological and cognitive impairments in APPswe/PS1dE9 double transgenic mice. Our results showed that chronic morin administration prevented spatial learning and memory deficits in the APPswe/PS1dE9 mice. Morin treatment in the APPswe/PS1dE9 mice markedly reduced cerebral Aß production and Aß plaque burden via promoting non-amyloidogenic APP processing pathway by increasing ADAM10 expression, inhibiting amyloidogenic APP processing pathway by decreased BACE1 and PS1 expression, and facilitating Aß degradation by enhancing Aß-degrading enzyme expression. In addition, we also found that morin treatment in the APPswe/PS1dE9 mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway. Furthermore, morin treatment in the APPswe/PS1dE9 mice markedly reduced the activated glial cells and increased the expression of synaptic markers. Collectively, our findings demonstrate that chronic morin treatment restores cognitive functions and reverses multiple distinct neuropathological AD-like hallmarks in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective actions and neurobiological mechanisms of morin against AD, suggesting that morin is a potently promising disease-modifying agent for treatment of AD.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Precursor de Proteína beta-Amiloide , Disfunção Cognitiva/tratamento farmacológico , Flavonoides/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Presenilina-1 , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Antioxidantes/administração & dosagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Feminino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/genética
14.
Huan Jing Ke Xue ; 36(5): 1674-7, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26314115

RESUMO

The quenching agents such as histidine, glycine, ascorbic acid, Tween-80, sodium sulfite and sodium hyposulfite are commonly used for quenching the residual disinfectant in water. In this paper, in order to select the optimal type and concentration range of quenching agents prior to the Limulus assays, the interference effects of each quenching agent at different concentrations on endotoxin detection were investigated by the Limulus assays of kinetic-turbidity. Our results identified that, as for 0-1.0% concentration of histidine, ascorbic acid, Tween-80, sodium sulfite (pH unadjusted and pH neutral), interference on the Limulus assays was existed. Hence, these quenching agents could not be applied as neutralizers prior to Limulus assays. Although, there was no interference on endotoxin detection for the glycine, a yellow color, developed by the quenching products of glycine and glutaric dialdehyde, contributed to false positive results. Hence, glycine should not be used as quenching agents in Limulus assays for samples containing glutaric dialdehyde. Compared with other quenching agents as histidine, glycine, ascorbic acid, Tween-80, sodium sulfite, 0-1.0% concentration of sodium hyposulfite elicited no obvious interference, while 1.0%-5.0% concentration of sodium hyposulfite illustrated exhibition effect for endotoxin detection. All in all, compared with other quenching agents as histidine, glycine, ascorbic acid, Tween-80 and sodium sulfite, sodium hyposulfite is suitable for quenching chemicals prior to endotoxin detection and less than 0.5% of concentration is allowable.


Assuntos
Desinfetantes/química , Endotoxinas/análise , Purificação da Água , Água/química , Bioensaio , Cinética , Polissorbatos , Sulfitos , Tiossulfatos
15.
BMC Microbiol ; 15: 5, 2015 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-25636983

RESUMO

BACKGROUND: The fungus Pochonia chlamydosporia parasitizes nematode eggs and has become one of the most promising biological control agents (BCAs) for plant-parasitic nematodes, which are major agricultural pests that cause tremendous economic losses worldwide. The complete mitochondrial (mt) genome is expected to open new avenues for understanding the phylogenetic relationships and evolution of the invertebrate-pathogenic fungi in Hypocreales. RESULTS: The complete mitogenome sequence of P. chlamydosporia is 25,615 bp in size, containing the 14 typical protein-coding genes, two ribosomal RNA genes, an intronic ORF coding for a putative ribosomal protein (rps3) and a set of 23 transfer RNA genes (trn) which recognize codons for all amino acids. Sequence similarity studies and syntenic gene analyses show that 87.02% and 58.72% of P. chlamydosporia mitogenome sequences match 90.50% of Metarhizium anisopliae sequences and 61.33% of Lecanicillium muscarium sequences with 92.38% and 86.04% identities, respectively. A phylogenetic tree inferred from 14 mt proteins in Pezizomycotina fungi supports that P. chlamydosporia is most closely related to the entomopathogenic fungus M. anisopliae. The invertebrate-pathogenic fungi in Hypocreales cluster together and clearly separate from a cluster comprising plant-pathogenic fungi (Fusarium spp.) and Hypocrea jecorina. A comparison of mitogenome sizes shows that the length of the intergenic regions or the intronic regions is the major size contributor in most of mitogenomes in Sordariomycetes. Evolutionary analysis shows that rps3 is under positive selection, leading to the display of unique evolutionary characteristics in Hypocreales. Moreover, the variability of trn distribution has a clear impact on gene order in mitogenomes. Gene rearrangement analysis shows that operation of transposition drives the rearrangement events in Pezizomycotina, and most events involve in trn position changes, but no rearrangement was found in Clavicipitaceae. CONCLUSIONS: We present the complete annotated mitogenome sequence of P. chlamydosporia. Based on evolutionary and phylogenetic analyses, we have determined the relationships between the invertebrate-pathogenic fungi in Hypocreales. The invertebrate-pathogenic fungi in Hypocreales referred to in this paper form a monophyletic group sharing a most recent common ancestor. Our rps3 and trn gene order results also establish a foundation for further exploration of the evolutionary trajectory of the fungi in Hypocreales.


Assuntos
DNA Fúngico/genética , DNA Mitocondrial/genética , Genoma Mitocondrial , Hypocreales/classificação , Hypocreales/genética , Análise por Conglomerados , DNA Fúngico/química , DNA Mitocondrial/química , Ordem dos Genes , Genes Fúngicos , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Homologia de Sequência , Sintenia
16.
Ann Neurol ; 77(4): 637-54, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25611954

RESUMO

OBJECTIVE: Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. METHODS: Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. RESULTS: Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, ß-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. INTERPRETATION: Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Antracenos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Presenilina-1/genética , Doença de Alzheimer/tratamento farmacológico , Animais , Antracenos/uso terapêutico , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo
17.
Br J Pharmacol ; 171(15): 3702-15, 2014 08.
Artigo em Inglês | MEDLINE | ID: mdl-24758388

RESUMO

BACKGROUND AND PURPOSE: Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. EXPERIMENTAL APPROACH: We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. KEY RESULTS: BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. CONCLUSION AND IMPLICATIONS: Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Rutina/uso terapêutico , Acetilcolina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Transtornos Cognitivos/metabolismo , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Rutina/farmacologia , Superóxido Dismutase/metabolismo
18.
Microbiol Res ; 169(11): 835-43, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24755311

RESUMO

The Fusarium oxysporum species complex consists of fungal pathogens that cause serial vascular wilt disease on more than 100 cultivated species throughout the world. Gene function analysis is rapidly becoming more and more important as the whole-genome sequences of various F. oxysporum strains are being completed. Gene-disruption techniques are a common molecular tool for studying gene function, yet are often a limiting step in gene function identification. In this study we have developed a F. oxysporum high-efficiency gene-disruption strategy based on split-marker homologous recombination cassettes with dual selection and electroporation transformation. The method was efficiently used to delete three RNA-dependent RNA polymerase (RdRP) genes. The gene-disruption cassettes of three genes can be constructed simultaneously within a short time using this technique. The optimal condition for electroporation is 10µF capacitance, 300Ω resistance, 4kV/cm field strength, with 1µg of DNA (gene-disruption cassettes). Under these optimal conditions, we were able to obtain 95 transformants per µg DNA. And after positive-negative selection, the transformants were efficiently screened by PCR, screening efficiency averaged 85%: 90% (RdRP1), 85% (RdRP2) and 77% (RdRP3). This gene-disruption strategy should pave the way for high throughout genetic analysis in F. oxysporum.


Assuntos
Biomarcadores/análise , Proteínas Fúngicas/genética , Fusarium/genética , Inativação Gênica , Marcação de Genes/métodos , Eletroporação
19.
Neurobiol Learn Mem ; 109: 7-19, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24315928

RESUMO

Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimer's disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.


Assuntos
Transtornos Cerebrovasculares/complicações , Transtornos Cognitivos/etiologia , Transtornos da Memória/etiologia , Neurônios/patologia , Estresse Oxidativo , Acetilcolina/análise , Acetilcolinesterase/análise , Animais , Colina O-Acetiltransferase/análise , Doença Crônica , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Neuroglia/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Pharmazie ; 68(6): 449-52, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23875253

RESUMO

The present study aimed to evaluate the potential risk of drug-drug interactions associated with acitretin which is a drug for therapy of psoriasis approved by the Food and Drug Administration (FDA). The initial screening of acitretin's inhibition towards 4-methylumbelliferone (4-MU) glucuronidation catalyzed by important UDP-glucuronosyltransferase (UGT) isoforms in the liver showed that UGT1A9 activity was strongly inhibited by acitretin with other UGT isoforms negligibly influenced. The inhibition type is best fit to competitive inhibition, and the inhibition kinetic parameter (K(i)) was determined to be 3.5 microM. The inhibition behaviour of acitretin towards UGT1A9 activity did not exhibit probe substrate-dependent behaviour when selecting human liver microsomes (HLMs)-catalyzed propofol-O-glucuronidation as probe reaction of UGT1A9. The same inhibition type and similar inhibition parameters (K(i) = 3.2 microM) were obtained. Using the maximum plasma exposure dose of acitretin (C(max)), the C(max)/K(i) values were calculated to be 0.23 and 0.25 when selecting 4-MU and propofol as probe substrates, respectively. All these results indicate a potential clinical drug-drug interaction between acitretin and 4-MU or propofol.


Assuntos
Acitretina/farmacologia , Glucuronosiltransferase/antagonistas & inibidores , Himecromona/metabolismo , Ceratolíticos/farmacologia , Propofol/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Humanos , Técnicas In Vitro , Isoenzimas/metabolismo , Cinética , Fígado/enzimologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo
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