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1.
Mol Neurobiol ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008166

RESUMO

The complement C1q plays a critical role in microglial phagocytosis of glutamatergic synapses and in the pathogenesis of neuroinflammation in Alzheimer's disease (AD). We recently reported that upregulation of metabotropic glutamate receptor signaling is associated with increased synaptic C1q production and subsequent microglial phagocytosis of synapses in the rodent models of AD. Here, we explored the role of astrocytic glutamate transporter in the synaptic C1q production and microglial phagocytosis of hippocampal glutamatergic synapses in a rat model of AD. Activation of astrocyte and reduction glutamate transporter 1 (GLT1) were noted after bilateral microinjection of amyloid-beta (Aß1-40) fibrils into the hippocampal CA1 area of rats. Ceftriaxone is a ß-lactam antibiotic that upregulates GLT1 expression. Bilateral microinjection of ceftriaxone recovered GLT1 expression, decreased synaptic C1q production, suppressed microglial phagocytosis of glutamatergic synapses in the hippocampal CA1, and attenuated synaptic and cognitive deficits in rats microinjected with Aß1-40. In contrast, artificial suppression of GLT1 activity by DL-threo-beta-benzyloxyaspartate (DL-TBOA) in naïve rats induced synaptic C1q expression and microglial phagocytosis of glutamatergic synapses in the hippocampal CA1 area, resulting in synaptic and cognitive dysfunction. These findings demonstrated that impairment of astrocytic glutamate transporter plays a role in the pathogenesis of AD.

4.
Indian J Pathol Microbiol ; 62(3): 391-398, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31361226

RESUMO

Background: Hepatitis C virus (HCV) represents a serious worldwide healthcare problem. No protective vaccines against HCV have been developed yet due to the fact that HCV is rapidly mutable, allowing the virus to escape from the neutralizing antibodies. Understanding of HCV was initially hampered by the inability to achieve viral replication in cell culture. Given its essential roles in viral polyprotein processing and immune evasion, HCV NS3/4A protease is a prime target for antiviral chemotherapy. We aimed to establish in vivo cell-based assay system for monitoring the activity of NS3/4A protease from HCV genotype 4a, the predominant genotype in Egypt, and the Middle East. Furthermore, the developed system was used to evaluate the inhibitory potency of a series of computer-designed chemically-synthesized compounds against NS3/4A protease from HCV genotype 4a. Materials and Methods: Native as well as mutant cleavage sites to NS3/4A protease were cloned in frame into ß-galactosidase gene of TA cloning vector. The target specificity of HCV NS3/4A was evaluated by coexpression of ß-galactosidase containing the protease cleavage site with NS3/4A protease construct in bacterial cells. The activity of ß-galactosidase was colorimetrically estimated in the cell lysate using orthonitro phenyl ß-D-galactopyanoside (ONPG) as a substrate. Results and Conclusions: We successfully developed an efficient cell-based system based on the blue/white selection of bacterial cells that are able to express functional/nonfunctional ß-galactosidase enzyme.


Assuntos
Bioensaio/métodos , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/metabolismo , Clonagem Molecular , Colorimetria , Escherichia coli , Genótipo , Hepacivirus/genética , Humanos , Proteínas não Estruturais Virais/genética , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
6.
Anesth Analg ; 128(6): 1118-1126, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094776

RESUMO

BACKGROUND: In patients who receive a nondepolarizing neuromuscular blocking drug (NMBD) during anesthesia, undetected postoperative residual neuromuscular block is a common occurrence that carries a risk of potentially serious adverse events, particularly postoperative pulmonary complications. There is abundant evidence that residual block can be prevented when real-time (quantitative) neuromuscular monitoring with measurement of the train-of-four ratio is used to guide NMBD administration and reversal. Nevertheless, a significant percentage of anesthesiologists fail to use quantitative devices or even conventional peripheral nerve stimulators routinely. Our hypothesis was that a contributing factor to the nonutilization of neuromuscular monitoring was anesthesiologists' overconfidence in their knowledge and ability to manage the use of NMBDs without such guidance. METHODS: We conducted an Internet-based multilingual survey among anesthesiologists worldwide. We asked respondents to answer 9 true/false questions related to the use of neuromuscular blocking drugs. Participants were also asked to rate their confidence in the accuracy of each of their answers on a scale of 50% (pure guess) to 100% (certain of answer). RESULTS: Two thousand five hundred sixty persons accessed the website; of these, 1629 anesthesiologists from 80 countries completed the 9-question survey. The respondents correctly answered only 57% of the questions. In contrast, the mean confidence exhibited by the respondents was 84%, which was significantly greater than their accuracy. Of the 1629 respondents, 1496 (92%) were overconfident. CONCLUSIONS: The anesthesiologists surveyed expressed overconfidence in their knowledge and ability to manage the use of NMBDs. This overconfidence may be partially responsible for the failure to adopt routine perioperative neuromuscular monitoring. When clinicians are highly confident in their knowledge about a procedure, they are less likely to modify their clinical practice or seek further guidance on its use.


Assuntos
Anestesiologia/métodos , Competência Clínica , Recuperação Demorada da Anestesia/induzido quimicamente , Monitorização Intraoperatória/métodos , Bloqueio Neuromuscular/métodos , Monitoração Neuromuscular/métodos , Tomada de Decisões , Humanos , Internacionalidade , Internet , Pneumopatias/etiologia , Fármacos Neuromusculares , Complicações Pós-Operatórias , Psicometria , Reprodutibilidade dos Testes , Risco , Inquéritos e Questionários
7.
Heliyon ; 5(3): e01404, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30976685

RESUMO

This study was conducted to evaluate the antimicrobial activities and cytotoxicity of both crude extracts of Scenedesmus obliquus and their fractions. In vitro cytotoxicity assay against human hepatocellular carcinoma (HepG2), colon cancer (HCT116) and breast cancer (MCF7) cell line was monitored. The highest inhibition was observed using diethyl ether crude extract (DEE) recording between 12.5 and 19.5 mm inhibition zone against all tested bacteria and between 8.7 and 18.3 mm against tested fungi. The highest anticancer effect of DEE was observed at IC50 against HCT116 and HepG2 cell lines using just 24.6 and 42.8 µg ml-1, respectively. While, high concentration, 93.8 µg ml-1, was required to exhibit its effect against MCF7. Column chromatography technique was used to separate DEE crude extract to its main components using 7 different mobile phases. Fractions F1 and F7 were the highest fractions that had antimicrobial activity against tested bacteria and fungi. High IC50 > 80 µg ml-1 were required to exhibit anticancer activity at IC50 against the tested cancer cell lines. The main compounds responsible for the bioactivity were identified using GC-MS, nonadecane and butylated hydroxytoluene in F1 and 9-octadecadienoic acid and quercetin 7,3',4'-trimethoxy in F7 were identified. The current study highlights the potential use of S. Obliquus extract and their fractions as a source of antimicrobial and anticancer compounds.

9.
Mol Neurobiol ; 56(8): 5568-5585, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30652266

RESUMO

Microglia and complements appear to be involved in the synaptic and cognitive deficits in Alzheimer's disease (AD), though the mechanisms remain elusive. In this study, utilizing two types of rodent model of AD, we reported increased complement C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses, which led to synaptic and cognitive deficits. We also found increased activity of the metabotropic glutamate receptor 1 (mGluR1) in hippocampal CA1 in the modeled rodents. Artificial activation of mGluR1 signaling promoted dephosphorylation of fragile X mental retardation protein (FMRP) and facilitated the local translation machinery of synaptic C1q mRNA, thus mimicking the C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses and synaptic and cognitive deficiency in the modeled rodents. However, suppression of mGluR1 signaling inhibited the dephosphorylation of FMRP and repressed the local translation of synaptic C1q mRNA, which consequently alleviated microglial phagocytosis of synapses and restored the synaptic and cognitive function in the rodent models. These findings illustrate a novel molecular mechanism underlying C1q-mediated microglial phagocytosis of hippocampal glutamatergic synapses in AD.


Assuntos
Doença de Alzheimer/patologia , Complemento C1q/metabolismo , Microglia/patologia , Fagocitose , Receptores de Glutamato Metabotrópico/metabolismo , Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Glutamatos , Hipocampo/patologia , Humanos , Masculino , Camundongos Transgênicos , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Sinapses/metabolismo
10.
J Pain ; 20(5): 501-514, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30414958

RESUMO

Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl- cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats. Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy.

11.
Anesthesiology ; 129(2): 383-384, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30020186

Assuntos
Neostigmina
12.
Curr Opin Anaesthesiol ; 31(4): 407-414, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29794855

RESUMO

PURPOSE OF REVIEW: This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions. RECENT FINDINGS: The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer's disease. SUMMARY: The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.


Assuntos
Analgésicos Opioides/uso terapêutico , Terapia de Alvo Molecular/métodos , Neuralgia/tratamento farmacológico , Manejo da Dor/métodos , Receptor CB2 de Canabinoide/metabolismo , Analgésicos Opioides/farmacologia , Animais , Canabinoides/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/patologia , Microglia/efeitos dos fármacos , Microglia/patologia , Neuralgia/etiologia , Neuralgia/patologia , Receptor CB2 de Canabinoide/agonistas
13.
Hippocampus ; 28(8): 549-556, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29704282

RESUMO

Silent glutamatergic synapses lacking functional AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Aß1-40 ) into the hippocampal CA1. Also, pairing low-frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Aß1-40 . Taken together, this study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils.


Assuntos
Amiloide/toxicidade , Região CA1 Hipocampal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Sinapses/efeitos dos fármacos , Peptídeos beta-Amiloides/farmacologia , Animais , Cofilina 1/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Estimulação Elétrica , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
14.
Macromol Rapid Commun ; 39(7): e1700794, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29333747

RESUMO

The synthesis of a range of alkyl esters (methyl, n-butyl, and n-decyl) prepared via Steglich esterification of the thermodynamically controlled exo, exo Diels-Alder adduct of furfuryl alcohol and maleic anhydride is reported. Subsequent ring-opening metathesis polymerization of these bio-derivable tricyclic oxanorbornene analogs delivers polymers with targeted molar mass and low molar mass dispersity. The polymerizations are rapid with complete monomer conversion achieved within 15 min. Significantly, the presence of the cyclic lactone at the bridgehead of these monomers leads to polymers with high regioregularity (>85% head-to-tail) and high stereoregularity (>75% trans). The resultant polymers display both high thermal stability and high glass transition temperatures. This new class of oxanorbornene monomer, accessed from bio-derivable furfuryl alcohol and maleic anhydride, may be further tailored to incorporate a range of functional moieties. Furthermore, the exceptional properties of the derived polymers indicate potential in a range of applications.


Assuntos
Furanos/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Anidridos Maleicos/química
15.
Anesth Analg ; 127(1): 71-80, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29200077

RESUMO

A panel of clinician scientists with expertise in neuromuscular blockade (NMB) monitoring was convened with a charge to prepare a consensus statement on indications for and proper use of such monitors. The aims of this article are to: (a) provide the rationale and scientific basis for the use of quantitative NMB monitoring; (b) offer a set of recommendations for quantitative NMB monitoring standards; (c) specify educational goals; and (d) propose training recommendations to ensure proper neuromuscular monitoring and management. The panel believes that whenever a neuromuscular blocker is administered, neuromuscular function must be monitored by observing the evoked muscular response to peripheral nerve stimulation. Ideally, this should be done at the hand muscles (not the facial muscles) with a quantitative (objective) monitor. Objective monitoring (documentation of train-of-four ratio ≥0.90) is the only method of assuring that satisfactory recovery of neuromuscular function has taken place. The panel also recommends that subjective evaluation of the responses to train-of-four stimulation (when using a peripheral nerve stimulator) or clinical tests of recovery from NMB (such as the 5-second head lift) should be abandoned in favor of objective monitoring. During an interim period for establishing these recommendations, if only a peripheral nerve stimulator is available, its use should be mandatory in any patient receiving a neuromuscular blocking drug. The panel acknowledges that publishing this statement per se will not result in its spontaneous acceptance, adherence to its recommendations, or change in routine practice. Implementation of objective monitoring will likely require professional societies and anesthesia department leadership to champion its use to change anesthesia practitioner behavior.


Assuntos
Anestesiologia/normas , Monitorização Neurofisiológica Intraoperatória/normas , Bloqueio Neuromuscular/normas , Bloqueadores Neuromusculares/administração & dosagem , Junção Neuromuscular/efeitos dos fármacos , Assistência Perioperatória/normas , Período de Recuperação da Anestesia , Consenso , Estimulação Elétrica , Mãos , Humanos , Monitorização Neurofisiológica Intraoperatória/instrumentação , Bloqueio Neuromuscular/efeitos adversos , Bloqueadores Neuromusculares/efeitos adversos , Segurança do Paciente/normas , Assistência Perioperatória/instrumentação , Fatores de Risco
17.
Endosc Ultrasound ; 6(3): 156-161, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28621291

RESUMO

BACKGROUND AND OBJECTIVES: Many cases of gastrointestinal (GI) tumors as lymphoma, adenocarcinoma, and most of submucosal tumors (SMT) such as gastrointestinal stromal tumor (GIST) and leiomyoma are difficult to diagnose as they frequently yield negative endoscopic biopsies. We evaluated the accuracy of endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis of endoscopic biopsy negative GI tumors. PATIENTS AND METHODS: One hundred and nine patients with biopsy negative GI tumors were included in this prospective study. EUS and EUS-FNA were performed to all patients with cytopathologic examination. RESULTS: There were 109 patients with endoscopic biopsy negative GI lesions, including 61 males (56%) and 48 females (44%), with the mean age of 54 years. Sixty-three cases (57.8%) were proved to have malignant lesions, among them there were 15 cases with high-risk GIST as proved by FNA and excision biopsy. Forty-six cases (42.2%) were proved to be benign; among them there were 21 cases presented with non-high-risk GIST. Endoscopic ultrasound had a sensitivity of 96.8%, specificity of 89.1%, positive predictive value (PPV) of 92.4%, negative predictive value (NPV) of 95.3%, and accuracy of 93.6%. EUS-FNA had a sensitivity of 87.3%, specificity of 100%, PPV of 100%, NPV of 85.2%, and accuracy of 92.7%. CONCLUSION: EUS with EUS-FNA is an accurate procedure in the diagnosis of GI tumors with negative endoscopic biopsies.

18.
Eur J Pharmacol ; 811: 12-20, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28551012

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuroinflammation, extensive deposits of amyloid-ß aggregates, and loss of memory and cognitive abilities. The brains of patients with AD show increased expression of cannabinoid receptor type 2 (CB2) receptors and glial markers. CB2 receptors act as a negative feedback regulator; when activated by a CB2 agonist, they can help limit the extent of the neuroinflammatory response and the subsequent development of neuronal damage in the central nervous system. In a double transgenic APP/PS1 mice model of AD, we evaluated the effect of MDA7, a CB2 agonist, on several neuropathological conditions of AD including amyloid deposition, inflammatory reaction, Sox2 (sex-determining region Y-box 2) expression, and spatial memory. Activation of microglia CB2 receptors by MDA7 suppressed neuroinflammation, demonstrated by decreased immunosignal of Iba1 in the hippocampal CA1 and dentate gyrus (DG) areas, promoted clearance of amyloid plaques in the DG area, restored Sox2 expression, and promoted recovery of the neuronal synaptic plasticity in hippocampal CA1. In addition, treatment with MDA7 improved the behavioral performance in the Morris water maze in APP/PS1mice. Collectively, these findings suggest that MDA7 has a potential therapeutic effect in the setting of AD.


Assuntos
Doença de Alzheimer/metabolismo , Cognição/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptor CB2 de Canabinoide/agonistas , Fatores de Transcrição SOXB1/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Benzofuranos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Ácido Glutâmico/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Piperidinas/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Urology ; 107: 103-106, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28456539

RESUMO

OBJECTIVE: To evaluate the role of preoperative testicular shear wave elastography (SWE) in the prediction of improvement of semen analysis parameters after subinguinal microsurgical varicocele ligation in patients with primary infertility and clinically detectable varicocele. PATIENTS AND METHODS: Testicular SWE before the surgical intervention was done. Forty-eight patients were scheduled for subinguinal microsurgical varicocele ligation as a treatment option. Computer-assisted semen analysis was repeated 6 months after the intervention. RESULTS: At a cutoff value of 4.5 kPa, the stiffness index had a sensitivity of 86.4% and a specificity of 84.2% for semen parameter improvement after varicocelectomy. Correlation between different parameters of semen analysis and SWE showed a statistically significant negative correlation between SWE stiffness index and both sperm count (million/mL) and total motility. On the other hand, a nonsignificant negative correlation was found between SWE stiffness index and percentage of normal form. CONCLUSION: Testicular SWE is a good test that can be used in the assessment of male infertility with clinically detectable varicocele, and its results may predict semen parameter improvement after varicocelectomy. Further studies on a larger number of patients are needed to verify our results.


Assuntos
Infertilidade Masculina/cirurgia , Sêmen/diagnóstico por imagem , Motilidade Espermática/fisiologia , Testículo/diagnóstico por imagem , Ultrassonografia Doppler em Cores/métodos , Procedimentos Cirúrgicos Urológicos Masculinos/métodos , Varicocele/cirurgia , Adulto , Diagnóstico por Computador , Seguimentos , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/etiologia , Ligadura , Masculino , Microcirurgia/métodos , Reprodutibilidade dos Testes , Fatores de Tempo , Varicocele/complicações , Varicocele/diagnóstico
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