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1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
2.
ACS Pharmacol Transl Sci ; 4(2): 980-1000, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33860215

RESUMO

Neuroinflammation contributes to delayed secondary cell death following traumatic brain injury (TBI), has the potential to chronically exacerbate the initial insult, and represents a therapeutic target that has largely failed to translate into human efficacy. Thalidomide-like drugs have effectively mitigated neuroinflammation across cellular and animal models of TBI and neurodegeneration but are complicated by adverse actions in humans. We hence developed N-adamantyl phthalimidine (NAP) as a new thalidomide-like drug to mitigate inflammation without binding to cereblon, a key target associated with the antiproliferative, antiangiogenic, and teratogenic actions seen in this drug class. We utilized a phenotypic drug discovery approach that employed multiple cellular and animal models and ultimately examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) TBI in mice. NAP mitigated LPS-induced inflammation across cellular and rodent models and reduced oligomeric α-synuclein and amyloid-ß mediated inflammation. Following CCI TBI, NAP mitigated neuronal and synaptic loss, neuroinflammation, and behavioral deficits, and is unencumbered by cereblon binding, a key protein underpinning the teratogenic and adverse actions of thalidomide-like drugs in humans. In summary, NAP represents a new class of thalidomide-like drugs with anti-inflammatory actions for promising efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

3.
Molecules ; 25(23)2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33276504

RESUMO

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Inibidores da Angiogênese/farmacologia , Aorta/efeitos dos fármacos , Simulação de Acoplamento Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Inibidores da Angiogênese/química , Animais , Simulação por Computador , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
4.
Elife ; 92020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32589144

RESUMO

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Encefalite/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
5.
J Cell Physiol ; 235(2): 993-1000, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31332778

RESUMO

Cervical cancer is a tumor with the second highest morbidity and mortality in the world, and it is also the most common cancer and the eighth lethal factor among malignant tumors in Chinese female. This study aimed to identify long noncoding RNAs (lncRNAs) that related to diagnosis and prognosis in cervical cancer to improve early diagnosis and treatment. First, we extracted transcriptome profilings of cervical cancer samples from the cancer genome atlas (TCGA) database, and then extracted the lncRNAs and mRNAs expression profiles. Based on the lncRNAs expression profiles of test set, we screened lncRNAs that related to progression of cervical cancer tumors. We found six lncRNAs associated with tumor progression in cervical cancer patients, in which five lncRNAs have highly similar expression patterns but the other one has the opposite expression pattern. We found that these six lncRNAs might be related to keratinization and immunity by enrichment analysis, and two of them (AC126474 and C5orf66-AS1) were associated with prognosis in patients with cervical cancer. And these results were validated using the validation set. Overall, we identified six lncRNAs that played an important role in the development of cervical cancer, and two of them might be associated with the prognosis of cervical cancer, which provides new insight into the diagnosis and treatment of cervical cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias do Colo do Útero/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
6.
Int J Mol Sci ; 19(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347766

RESUMO

Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer's disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.


Assuntos
Antioxidantes/farmacologia , Apoptose , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Talidomida/análogos & derivados , Animais , Células Cultivadas , Córtex Cerebral/citologia , Peróxido de Hidrogênio/toxicidade , Neurônios/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia
7.
Cancer Cell Int ; 18: 60, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713243

RESUMO

Background: Lung adenocarcinoma (LUAD) is the main subtype of non-small cell lung cancer with a low survival prognosis. We aimed to generate a prognostic model for the postoperative recurrence of LUAD. Methods: The methylated DNA data of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA). The differentially methylated genes were identified and protein-protein interacting network was constructed, with which prognostic signature of this cancer was generated. Survival and functional pathways analysis w used to evaluate the clustering ability of the prognostic signature. Results: We identified 151 differentially methylated genes related to relapse-free survival of patients with LUAD. Nine hub genes were identified in PPI network, with which 4 gene pair signature was selected as prognostic signature. The potential functions of 6 genes (JDP2, SERPINA5, PLG, SEMG2, RFX5, and POLR3B) in the 4-gene pair signature were enriched in intracellular protein synthesis and transportation. Conclusion: The four gene pair signature can predict the prognosis of patients with stage I LUAD. Our study provides a reference for patients with postoperative adjuvant therapy.

8.
Bioorg Med Chem ; 26(8): 1547-1559, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29472124

RESUMO

A library of 15 novel and heretofore uncharacterized adamantyl and noradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF-α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Fármacos , Fármacos Neuroprotetores/farmacologia , Nitritos/antagonistas & inibidores , Ftalimidas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Nitritos/metabolismo , Ftalimidas/síntese química , Ftalimidas/química , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismo
10.
J Neuroinflammation ; 13(1): 168, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27353053

RESUMO

BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). RESULTS: Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α. CONCLUSIONS: Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.


Assuntos
Encefalite/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Transtornos Motores/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Transtornos Psicomotores/tratamento farmacológico , Distúrbios Somatossensoriais/tratamento farmacológico , Talidomida/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Lateralidade Funcional/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Transtornos Motores/etiologia , Degeneração Neural/etiologia , Fosfopiruvato Hidratase/metabolismo , Transtornos Psicomotores/etiologia , Ratos , Ratos Sprague-Dawley , Distúrbios Somatossensoriais/etiologia , Talidomida/uso terapêutico
11.
Oncotarget ; 7(22): 33237-45, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27120781

RESUMO

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Embrião de Galinha/efeitos dos fármacos , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala , Talidomida/farmacologia , Peixe-Zebra/embriologia , Anormalidades Induzidas por Medicamentos/etiologia , Inibidores da Angiogênese/toxicidade , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/toxicidade , Relação Dose-Resposta a Droga , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Neovascularização Fisiológica/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Medição de Risco , Talidomida/análogos & derivados , Talidomida/toxicidade , Fluxo de Trabalho , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
12.
J Neuroinflammation ; 12: 45, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25879458

RESUMO

BACKGROUND: The treatment of traumatic brain injury (TBI) represents an unmet medical need, as no effective pharmacological treatment currently exists. The development of such a treatment requires a fundamental understanding of the pathophysiological mechanisms that underpin the sequelae resulting from TBI, particularly the ensuing neuronal cell death and cognitive impairments. Tumor necrosis factor-alpha (TNF-α) is a cytokine that is a master regulator of systemic and neuroinflammatory processes. TNF-α levels are reported to become rapidly elevated post TBI and, potentially, can lead to secondary neuronal damage. METHODS: To elucidate the role of TNF-α in TBI, particularly as a drug target, the present study evaluated (i) time-dependent TNF-α levels and (ii) markers of apoptosis and gliosis within the brain and related these to behavioral measures of 'well being' and cognition in a mouse closed head 50 g weight drop mild TBI (mTBI) model in the presence and absence of post-treatment with an experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide. RESULTS: mTBI elevated brain TNF-α levels, which peaked at 12 h post injury and returned to baseline by 18 h. This was accompanied by a neuronal loss and an increase in astrocyte number (evaluated by neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) immunostaining), as well as an elevation in the apoptotic death marker BH3-interacting domain death agonist (BID) at 72 h. Selective impairments in measures of cognition, evaluated by novel object recognition and passive avoidance paradigms - without changes in well being, were evident at 7 days after injury. A single systemic treatment with the TNF-α synthesis inhibitor 3,6'-dithiothalidomide 1 h post injury prevented the mTBI-induced TNF-α elevation and fully ameliorated the neuronal loss (NeuN), elevations in astrocyte number (GFAP) and BID, and cognitive impairments. Cognitive impairments evident at 7 days after injury were prevented by treatment as late as 12 h post mTBI but were not reversed when treatment was delayed until 18 h. CONCLUSIONS: These results implicate that TNF-α in mTBI induced secondary brain damage and indicate that pharmacologically limiting the generation of TNF-α post mTBI may mitigate such damage, defining a time-dependent window of up to 12 h to achieve this reversal.


Assuntos
Lesões Encefálicas/complicações , Encéfalo/patologia , Transtornos Cognitivos , Neurônios/enzimologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/terapia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fosfopiruvato Hidratase/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/química , Talidomida/uso terapêutico , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
13.
Med Oncol ; 31(10): 186, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25245010

RESUMO

The pathogenesis of glioma remains largely unknown now. It has been suggested that the X-ray cross-complementing group 1 (XRCC1) gene may influence the capacity to repair DNA damage leading to an increased gliomas susceptibility. This study aimed to evaluate the relationship between XRCC1 polymorphisms and glioma risk. Genotypes were assessed in 368 Chinese glioma patients and 346 healthy controls. XRCC1 Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487) and three additional polymorphisms were directly sequenced. The frequency of Arg280His A allele was significant lower in glioma group than in healthy controls [9.6 vs 16%, OR=0.60 (0.46-0.80), P<0.001]; the frequencies of GA or AA genotypes were different in two groups (16.6 vs 22.8%, 1.3 vs 4.7%). The frequency of Arg399Gln A allele was significant higher in glioma group than in healthy controls [38.7 vs 30.1%, OR=1.29 (1.11-1.49), P=0.001]; the frequencies of GA or AA genotypes were different in two groups (45.4 vs 38.2%, 16 vs 10.9%). This study demonstrates that the rs25489 (Arg280His) and Arg399Gln (rs25487) polymorphisms in XRCC1 gene might influence the risk of developing glioma in Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Glioma/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
14.
Artigo em Inglês | MEDLINE | ID: mdl-23360256

RESUMO

A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of ß-amyloid peptide (Aß) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aß levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1ß release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Fisostigmina/análogos & derivados , Precursor de Proteína beta-Amiloide/biossíntese , Humanos , Interleucina-1beta/biossíntese , Fisostigmina/química , Fisostigmina/farmacocinética , Fisostigmina/farmacologia , Placa Amiloide/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Estereoisomerismo , alfa-Sinucleína/biossíntese
15.
World J Surg ; 37(1): 227-32, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23052807

RESUMO

BACKGROUND: The aim of the present study was to investigate the usefulness of the transanal drainage tube for prevention of anastomotic leakage and bleeding after anterior resection for rectal cancer. METHODS: Between January 2007 and May 2011 a nonrandomized prospective study of patients undergoing anterior resection for rectal cancer was done. The patients were divided into the transanal drainage tube (TDT) and non-transanal drainage tube (NTDT) groups according to whether the transanal drainage tube was used in the operation. Clinical characteristics and postoperative complications were compared between the TDT and NTDT groups. RESULTS: The study included 81 patients in the TDT group and 77 patients in the NTDT group. In the TDT group, anastomotic leakage occurred in 2 patients and no anastomotic bleeding occurred. In the NTDT group, anastomotic leakage occurred in 7 patients and anastomotic bleeding occurred in 2 patients. The TDT group had significantly fewer anastomotic complications compared with the NTDT group (2.5 vs 11.7 %; P = 0.029). Furthermore, the TDT group showed an obvious reduction in the rate of anastomotic leakage and anastomotic bleeding compared with the NTDT group (2.5 vs 7.8 % and 0.0 vs 2.6 %), but because the number of cases is relatively small, the difference did not reach statistical significance (P = 0.160 and P = 0.236). CONCLUSIONS: The use of a transanal drainage tube in anterior resection for rectal cancer may be a simple, safe, and effective means of preventing or reducing the occurrence of anastomotic leakage and bleeding. A larger-scale single or multi-center prospective randomized study or a meta-analysis including similar studies is necessary for further elucidation of this issue.


Assuntos
Fístula Anastomótica/prevenção & controle , Drenagem/métodos , Hemorragia/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Neoplasias Retais/cirurgia , Idoso , Canal Anal , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
16.
J Neuroinflammation ; 9: 106, 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22642825

RESUMO

BACKGROUND: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD. METHODS: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aß(1-42) challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide. RESULTS: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with A(ß1-42) peptide, prior systemic 3,6'-dithiothalidomide suppressed Aß-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aß peptide and Aß-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. CONCLUSIONS: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Talidomida/análogos & derivados , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Endogâmicos F344 , Talidomida/farmacologia , Talidomida/uso terapêutico
17.
J Neuroinflammation ; 9: 23, 2012 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-22277195

RESUMO

BACKGROUND: Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. METHODS: Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. RESULTS: Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1ß in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1ß. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. CONCLUSION: Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Encefalite/complicações , Inibidores Enzimáticos/uso terapêutico , Talidomida/análogos & derivados , Análise de Variância , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Transtornos Cognitivos/etiologia , Modelos Animais de Doenças , Encefalite/induzido quimicamente , Encefalite/patologia , Comportamento Exploratório/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Testes Neuropsicológicos , Polissacarídeos/toxicidade , Ratos , Ratos Endogâmicos F344 , Reconhecimento Psicológico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Talidomida/uso terapêutico , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
18.
Open Biochem J ; 5: 37-44, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21792375

RESUMO

An unregulated neuroinflammation accompanies numerous chronic and acute neurodegenerative disorders and it is postulated that such a neuroinflammatory component likely exacerbates disease progression. A key player in brain inflammation is the microglial cell; a vital soluble factor synthesized by activated microglial cells is the key cytokine, tumor necrosis factor-alpha (TNF-α). Additionally, microglial cells release IL-1α/ß, reactive oxygen species (ROS), such as superoxide (O(2) (-)) and reactive nitrogen species (RNS) like nitric oxide (NO). Nitric oxide reactive oxygen species can undergo various forms of interactions in cells whereby the synthesis of RNS / ROS intermediates are generated that can damage cell membranes. The presence of oxidative damaged cells is implicated with the abnormal cellular activity in brain or in the spinal cord, and is a classical feature of neurodegenerative disorders. To aid characterize this process, a quantitative analysis of nitrite generation was undertaken on agents developed to lower TNF-α levels in cell culture. Nitrite is a stable end product of nitric oxide metabolism and, thereby, acts as a surrogate measure of the highly unstable nitric oxide. Utilizing a RAW 264.7 cellular model of lipopolysaccharide-induced inflammation that induces high levels of TNF-α protein accompanied by a robust generation of nitrite, the properties of a series of thalidomide-based TNF-α synthesis inhibitors were evaluated to reduce the levels of both. Specific analogues of thalidomide effectively suppressed the generation of both TNF-α and nitrite at well-tolerated doses.

19.
J Neurochem ; 118(6): 1032-42, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21740439

RESUMO

Mild traumatic brain injury (mTBI) patients do not show clear structural brain defects and, in general, do not require hospitalization, but frequently suffer from long-lasting cognitive, behavioral and emotional difficulties. Although there is no current effective treatment or cure for mTBI, tumor necrosis factor-alpha (TNF-α), a cytokine fundamental in the systemic inflammatory process, represents a potential drug target. TNF-α levels increase after mTBI and may induce or exacerbate secondary damage to brain tissue. The present study evaluated the efficacy of the experimental TNF-α synthesis inhibitor, 3,6'-dithiothalidomide, on recovery of mice from mTBI in a closed head weight-drop model that induces an acute elevation in brain TNF-α and an impairment in cognitive performance, as assessed by the Y-maze, by novel object recognition and by passive avoidance paradigms at 72 h and 7 days after injury. These impairments were fully ameliorated in mice that received a one time administration of 3,6'-dithiothalidomide at either a low (28 mg/kg) or high (56 mg/kg) dose provided either 1 h prior to injury, or at 1 or 12 h post-injury. Together, these results implicate TNF-α as a drug target for mTBI and suggests that 3,6'-dithiothalidomide may act as a neuroprotective drug to minimize impairment.


Assuntos
Comportamento Animal/fisiologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/psicologia , Talidomida/análogos & derivados , Fator de Necrose Tumoral alfa/biossíntese , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/prevenção & controle , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Masculino , Aprendizagem em Labirinto , Memória/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Reconhecimento Psicológico/efeitos dos fármacos , Talidomida/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
20.
Bioorg Med Chem ; 19(13): 3965-72, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21658960

RESUMO

Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3-substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds 9-14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-α in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds 9, 14 and 16 exhibited potent TNF-α lowering activity, reducing TNF-α by up to 48% at 30 µM, compounds 12, 17 and 18 presented moderate TNF-α inhibitory action. The TNF-α lowering properties of these analogs proved more potent than that of revlimid (3) and thalidomide (1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2,6-dioxopiperidine 14 not only possessed the greatest potency of the analogs to reduce TNF-α synthesis, but achieved this with minor cellular toxicity at 30 µM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation, that is, commonly associated with neurodegenerative disorders, epitomized by Alzheimer's disease and Parkinson's disease.


Assuntos
Ftalimidas/química , Piperidinas/química , Talidomida/análogos & derivados , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Lenalidomida , Camundongos , Piperidinas/síntese química , Piperidinas/toxicidade , Talidomida/síntese química , Talidomida/química , Talidomida/toxicidade , Fator de Necrose Tumoral alfa/metabolismo
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