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1.
Chem Biol Interact ; : 109020, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32092300

RESUMO

Alzheimer's disease (AD), characterized by impairment of cognitive functions, mainly affects the elderly worldwide. We have previously designed and synthesized a series of memantine nitrate derivatives with vessel dilatory effects. Some of novel compounds have shown neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3ß and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Furthermore, calcium imaging showed that pretreatment of MN-06 prevented calcium influx through antagonizing the N-methyl-d-aspartate (NMDA) receptor, which has been further confirmed by molecular docking simulation. Preliminary evaluation and prediction in silicon indicated that MN-06 might penetrate the blood brain-barrier. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3ß pathway, indicating that MN-06 might be a potential drug for treating dementia.

2.
ACS Chem Neurosci ; 11(3): 314-327, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922720

RESUMO

We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO-cGMP pathway ex vivo. In the 2-vessel occlusion (2VO) rat model, MN-12 alleviated the impairments of spatial memory and motor dysfunction possibly via neuroprotection and improvement of the cerebral blood flow. Furthermore, the results of preliminary pharmacokinetic studies showed that MN-12 might quickly distribute to the major organs including the brain, indicating that MN-12 could penetrate the blood-brain barrier. Taken together, MN-12 might provide multifunctional therapeutic benefits for dementia associated with Alzheimer's disease, vascular dementia, and ischemic stroke, via neuroprotection and vessel dilation to improve the cerebral blood flow.

3.
Life Sci ; 241: 117164, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838135

RESUMO

AIMS: This study was to assess whether andrographolide derivative (AL-1) could restore mucosal homeostasis and regulate tight junctions through MLCK-dependent pathway in DSS-induced colitis mice. MAIN METHODS: Colitis mice model was induced by daily administration of 2.5% DSS for seven days. The therapeutic effect was determined by evaluating the histopathological changes and the pro-inflammatory cytokine level. In addition, the effects of AL-1 on tight junctions were examined by immunohistochemistry and Western blot. The expressions of factors in MLCK-dependent pathway were evaluated by immunofluorescence and Western blot. KEY FINDINGS: AL-1 protected the intestinal barrier function in DSS-induced colitis mice. These protective effects were achieved by maintaining the normal mucus secretion and preserving tight junctions via suppression of the MLCK-dependent pathway. SIGNIFICANCE: AL-1 could prevent the increase in the DSS-induced intestinal permeability. These data indicated that AL-1 could be a promising agent for UC treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Permeabilidade da Membrana Celular/fisiologia , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Diterpenos/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia
4.
Transplant Proc ; 51(10): 3474-3480, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810510

RESUMO

Patients with craniocerebral trauma often have intestinal mucosal dysfunction, and the claudin1 protein plays an important role in intestinal mucosal function. Our previous work has shown that the expression of microRNA-155 (miR-155) in the peripheral blood of patients with craniocerebral trauma is decreased. Animal experiments also suggest that the expression of miR-155 is increased in the intestinal mucosa of mice with brain injury and the expression of claudin1 is decreased. We recruited 56 samples (35 patients with traumatic brain injury [TBI] and 21 patients without history of head trauma) to detect the expression of miR-155 on claudin1 regulation by quantitative polymerase chain reaction, reverse transcriptase polymerase chain reaction, and so on. We also used the receiver operating characteristic curve (ROC) to further evaluate the diagnostic value of the 2 biomarkers. From the results, we found that the expression level of miR-155 and claudin1 in the case group was lower than that in the control group. Human miR-155 (Hsa-miR-155) may positively regulate intestinal mucosal function by inhibiting the expression of claudin1, leading to intestinal mucosal barrier dysfunction. Combining the ROC curve data, the results further prove that miR-155 and claudin1 might be the new clinical diagnostic markers and treatment targets for the intestinal mucosal barrier dysfunction after TBI.

5.
Oxid Med Cell Longev ; 2019: 8169125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827703

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3ß and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

6.
Oxid Med Cell Longev ; 2019: 6138723, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687082

RESUMO

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-κB p65 and IκBα, downregulated the expression of iNOS and COX-2, and attenuated the expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), ERK, and JNK. In conclusion, AL-1 alleviated DSS-induced murine colitis by inhibiting activation of the NF-κB and MAPK signaling pathways. Our data suggest that AL-1 could be a potential new treatment for UC.

7.
Org Lett ; 21(20): 8275-8279, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31584284

RESUMO

Amino-acid-derived phthalazine catalysts have been designed and synthesized for enantioselective halolactonization of prochiral dienoic acids. The scope of the reaction is evidenced by 17 examples of spiro α-exo-methylene-halolactones with up to 99.8% enantiomeric excess. The resulting enantio-enriched spiro halolactone products are found to exhibit potent antitumor effects. In addition, both antipodes of products with equally excellent enantioselevity could be obtained since a pair of enantiomeric catalysts is guaranteed.

8.
Artif Cells Nanomed Biotechnol ; 47(1): 3559-3568, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446795

RESUMO

Objective: Osteosarcoma is one of the most common malignancies in children and adolescents. Studies have shown that miR-34c-5p is involved in the progression of various cancers. To explore the effects of miR-34c-5p on the proliferation, migration and invasion of osteosarcoma cells and its potential mechanism. Methods: qRT-PCR was used to detect the expression levels of miR-34c-5p and FLOT2 mRNA in osteosarcoma tissues and cells. Western Blot was used to detect protein expression. MTT assay used to detect cell viability. Transwell was used to detect cell migration and invasion in each group. Dual luciferase reporter gene assay was used to detect luciferase activity. Results: The expression of miR-34c-5pwas significantly decreased in osteosarcoma tissues and cells and the expression level of FLOT2 mRNA was significantly increased. Overexpression of miR-34c-5p and inhibition of FLOT2 inhibited the proliferation, migration and invasion of osteosarcoma cells and inhibited the expression of Cyclin D1, MMP-2 and MMP-9 proteins and promoted the expression of p21 protein. miR-34c-5p targeted to regulate the expression of FLOT2. Overexpression of FLOT2 reversed the inhibitory effect of miR-34c-5p overexpression on proliferation, migration and invasion of osteosarcoma cell lines. Conclusion: miR-34c-5p can inhibit the proliferation, migration and invasion of osteosarcoma cells. The mechanism may be related to targeting FLOT2, which will provide a new target for the prevention and treatment of osteosarcoma.


Assuntos
Neoplasias Ósseas/patologia , Movimento Celular/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Osteossarcoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica
9.
Front Pharmacol ; 10: 722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293428

RESUMO

Background: We previously demonstrated that a Danshensu-Tetramethylpyrazine conjugate DT-010 enhanced anticancer effect of doxorubicin (Dox) in Dox-sensitive human breast cancer cells, and protected against Dox-induced cardiotoxicity. This work was designed to see whether DT-010 overcomes Dox resistance in resistant human breast cancer cells. Methods: The effects of DT-010, Dox or their combination on cell viability of Dox-resistant human breast cancer MCF-7/ADR cells were conducted using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry after Annexin V-FITC/PI co-staining. Dox accumulation in MCF-7/ADR cells was detected by flow cytometry and fluorescence microscopy. A fluorometric multidrug resistance (MDR) assay kit was used to evaluate the effect of DT-010 on MDR transporter activity. P-glycoprotein (P-gp) expression and activity were analyzed by Western blot and rhodamine 123 (Rh123) efflux assay, respectively. The effects of DT-010 on glycolysis and mitochondrial stress were detected using an Extracellular Flux Analyzer. A Succinate Dehydrogenase Activity Assay kit was used to measure mitochondrial complex II activity. Results: At non-cytotoxic concentrations, DT-010 in combination with Dox led to a significant growth inhibition of MCF-7/ADR cells, suggesting a synergy between DT-010 and Dox to reverse Dox resistance. DT-010 restored Dox-mediated apoptosis and p53 induction in MCF-7/ADR cells. DT-010 increased Dox accumulation in MCF-7/ADR cells via inhibiting P-gp activity, but without changing P-gp expression. Further studies showed that DT-010 significantly inhibited glycolysis and mitochondrial function of MCF-7/ADR cells. Mitochondrial complex II activity was inhibited by DT-010 or DT-010/Dox combination, but not by Dox. The DT-010-mediated suppression of metabolic process may render cells more vulnerable to Dox treatment and thus result in enhanced efficacy. Conclusions: The results indicate that DT-010 overcomes Dox resistance in human breast cancer cells through a dual action via simultaneously inhibiting P-gp-mediated drug efflux and influencing metabolic process.

10.
Exp Neurobiol ; 28(3): 390-403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31308798

RESUMO

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.

11.
Artif Cells Nanomed Biotechnol ; 47(1): 3094-3100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31343278

RESUMO

To evaluate the long-term biological and clinical results of anterior cervical corpectomy and fusion (ACCF) with a synthesized nano-graphene oxide (nano-GO) loaded hydroxyapatite/polyamide (HAp/PA) strut in the implantation treatment of cervical reconstruction. Bio-ceramic Hydroxyapatite (HAp) combined with suitable polymer matrix is one of the furthermost naturally occurring biomaterial form for hard tissues and dental regeneration therapies due to their bone-like chemical compositional structure and biocompatibility similarity to native bone of the human body. In the present investigation, the development of nano-GO loaded HAp/PA composite strut for anterior cervical reform and fusion properties after corpectomy is studied. Forty patients who suffered from first or second level ACCF, treated with nano-GO loaded HAp/PA strut, were investigated. At final follow-up period, the fusion rate was 99%, and the subsidence value of the prepared strut was 5%. The results of cell viability and proliferation analyses indicated that the prepared nanocomposites did not exhibit non-cytotoxicity with the human cells. In summary, the satisfactory consequences in this research work designated that the nano-GO loaded HAp/PA strut was an active implant in the treatment of cervical reconstruction. Furthermore, the osteoconductive and osseointegration properties of the prepared struts need to be analyzed and optimized for future bio-medical usages.


Assuntos
Vértebras Cervicais/fisiologia , Vértebras Cervicais/cirurgia , Durapatita/química , Grafite/química , Nanocompostos/química , Nylons/química , Titânio/química , Adulto , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular , Feminino , Humanos , Masculino , Teste de Materiais , Pessoa de Meia-Idade , Osseointegração/efeitos dos fármacos
12.
Med Sci Monit ; 25: 5580-5588, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31350990

RESUMO

BACKGROUND The factors associated with osteoporosis are poorly understood in the Chinese population. This study aimed to examine the factors associated with osteoporosis and with fractures in a Chinese elderly population. MATERIAL AND METHODS This was a cross-sectional study of elderly people living in Tianjin between 2012 and 2014. Bone mineral density was measured by dual X-ray absorptiometry. The subjects completed a questionnaire about lifestyle habits, personal and family medical history, calcium intake, and exercising. Data were gathered on occurrence of fracture at 5 years or August 2018, whichever occurred first. RESULTS There were 298 individuals with osteoporosis (18.5% male, median age 67 years) and 397 without (46.3% male, median age 62 years). Male sex (OR=0.051, 95% CI: 0.021-0.126), age (OR=1.049, 95% CI: 1.099-1.202), being divorced/widowed (OR=2.445, 95% CI: 1.219-4.904), digestive ulcer history (OR=3.805, 95% CI: 1.539-9.405), family history of hunchback (OR=2.659, 95% CI: 1.145-6.175), family history of osteoarthropathy (OR=4.222, 95% CI: 2.128-8.375), fracture history (OR=2.138, 95% CI: 1.307-3.496), drinking green tea (OR=0.352, 95% CI: 0.217-0.574), and exercising (OR=0.303, 95% CI: 0.193-0.475) were independently associated with osteoporosis. Digestive ulcer history (OR=3.183, 95% CI: 1.178-8.5992), exercising (OR=0.354, 95% CI: 0.139-0.903), and taking calcium supplements during follow-up (OR=0.262, 95% CI: 0.112-0.611) were independently associated with fractures in patients with osteoporosis. CONCLUSIONS Female sex, age, marital status, history of digestive ulcer and fracture, and family history of hunchback and osteoarthropathy are associated with osteoporosis among elderly subjects, while drinking green tea and exercising are inversely associated. Among the patients with osteoporosis, a history of digestive ulcer is associated with fractures, while exercising and taking calcium supplements are inversely associated.


Assuntos
Fraturas Ósseas/etiologia , Osteoporose/epidemiologia , Osteoporose/fisiopatologia , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Densidade Óssea , Cálcio/metabolismo , China , Estudos Transversais , Suplementos Nutricionais , Exercício , Feminino , Fraturas Ósseas/fisiopatologia , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Fatores de Risco
13.
Neurotherapeutics ; 16(4): 1225-1236, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313223

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α-syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly promote α-syn degradation in a cellular PD model. Moreover, we illustrate that T-006 inhibits the accumulation of both Triton-soluble and -insoluble forms of α-syn and protects against α-syn-induced neurotoxicity in A53T-α-syn transgenic mice. The mechanism of action of T-006 was verified by evaluation of a potential protein degradation pathway. We found that T-006 promotes α-syn degradation in a proteasome-dependent and autophagy-independent manner. We further confirmed that T-006 enhances proteasome activity by upregulating 20S proteasome subunit ß5i (LMP7) protein expression. A functional study revealed that T-006 activates the PKA/Akt/mTOR/p70S6K pathway to trigger LMP7 expression and enhance chymotrypsin-like proteasomal activity. These findings indicate that T-006 is a potent proteasome activator and a potential therapeutic agent for the prevention and treatment of PD and related diseases.

14.
Br J Pharmacol ; 176(17): 3318-3335, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31180578

RESUMO

BACKGROUND AND PURPOSE: Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH: Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS: MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS: MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

15.
World Neurosurg ; 128: e782-e786, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078802

RESUMO

BACKGROUND: The Hoffmann sign is usually used as an indicator of upper motor neuron lesion, but its clinical effect remains controversial in previous reports. METHODS: A retrospective case control study including 107 patients with cervical complaints was carried out. According to the presence of Hoffmann sign, patients were divided into 2 groups. The radiographic results were assessed and the sensitivity, specificity, positive and negative predictive values, and false positive and false negative values of Hoffmann sign for cervical pathology, segment, cervical spine canal ratio, and S-index were calculated. RESULTS: There were 56 patients in the positive Hoffmann group and 51 patients in negative group. The sensitivity, specificity, positive and negative predictive values, and false positive and false negative values of Hoffmann sign for cervical pathology were found to be 61.6%, 85.7%, 94.6%, 35.3%, 14.3%, 38.4% and 60.5%, 81.0%, 92.9%, 33.3%, 19.0%, 39.5%, respectively. The ratio of cervical spine canal was lower in the positive Hoffmann group than in control group. CONCLUSIONS: Although the Hoffmann sign is not foolproof in the diagnosis of cervical spinal cord compression, it can be used to assess symptomatic patients. The narrower the cervical spine canal or the higher the cervical segment compression, the higher of the incidence of positive Hoffmann sign.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Exame Neurológico/métodos , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
16.
Neuromolecular Med ; 21(3): 262-274, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31134485

RESUMO

Cerebral vasospasm is one of the deleterious complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and permanent neurological deficits or even death. Free radicals and oxidative stress are considered as crucial causes contributing to cerebral vasospasm and brain damage after SAH. Tetramethylpyrazine nitrone (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical scavenging nitrone moiety, has been reported to prevent brain damage from ischemic stroke. The present study aimed to investigate the effects of TBN on vasospasm and brain damage after SAH. Two experimental SAH models were used, a rat model by endovascular perforation and a rabbit model by intracisternal injection of autologous blood. The effects of TBN on SAH were evaluated assessing basilar artery spasm, neuronal apoptosis, and neurological deficits. TBN treatment significantly attenuated vasospasm, improved neurological behavior functions and reduced the number of apoptotic neurons in both the SAH rats and rabbits. Mechanistically, TBN suppressed the increase in 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immuno-positive cells in the cortex of SAH rat brain. Western blot analyses indicated that TBN effectively reversed the altered expression of Bcl-2, Bax and cytochrome C, and up-regulated nuclear factor erythroid-derived 2-like 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expressions. In the in vitro studies, TBN inhibited H2O2-induced bEnd.3 cell apoptosis and reduced ROS generation. Additionally, TBN alleviated the contraction of rat basilar artery rings induced by H2O2 ex vivo. In conclusion, TBN ameliorated SAH-induced cerebral vasospasm and neuronal damage. These effects of TBN may be attributed to its anti-oxidative stress effect and up-regulation of Nrf2/HO-1.

18.
Neuroreport ; 30(9): 658-663, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-30969248

RESUMO

Neuronal death is among the deleterious pathological changes that occur after cerebral ischemia and can lead to transient or permanent neurological deficits. The tetramethylpyrazine analog T-006 has been shown to be a multifunctional neuroprotective agent; however, its neuroprotective effect and mechanism of action have not been studied in ischemic stroke model rats. This study investigated the neuroprotective effects of T-006 in rat stroke model using a battery of behavioral and molecular biological tests. Results indicated that T-006 treatment significantly improved neurological function and behavior. Double immunofluorescence staining showed that T-006 visibly improved the number of NeuN/BrdU, Nestin/BrdU, and DCX/BrdU cells and induced neuronal regeneration. Western blot analyses indicated that T-006 upregulated neurogenesis-related protein expression of postsynaptic density protein 95, brain-derived neurotrophic factor, synaptophysin, and myelin basic protein. Collectively, these data suggest that T-006 stimulated neurogenesis in rats with middle cerebral artery occlusion and restored neurological functions.


Assuntos
Hidrazonas/farmacologia , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirazinas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Animais , Modelos Animais de Doenças , Masculino , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
Int J Oncol ; 54(5): 1809-1820, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816476

RESUMO

Several microRNAs (miRNAs or miRs) that regulate a variety of cancer­related events are dysregulated in osteosarcoma (OS). An exploration of the specific roles of miRNAs in OS is crucial for the identification of suitable therapeutic targets. Previous studies have shown that miR­873 plays tumor suppressive or oncogenic roles in different types of cancer. However, whether miR­873 is implicated in OS carcinogenesis and cancer progression remains poorly understood. In the present study, we demonstrated that the miR­873 levels were decreased in OS tissues and cell lines. The decreased expression of miR­873 was related to tumor size, clinical stage and distant metastasis in patients with OS. The introduction of miR­873 significantly inhibited tumor cell proliferation, migration and invasion in vitro, promoted apoptosis in vitro and restricted tumor growth in vivo. Furthermore, homeobox A9 (HOXA9) was validated as a direct target gene of miR­873 in OS cells. HOXA9 was markedly expressed in OS tissues, and its upregulation inversely correlated with the miR­873 levels. Moreover, HOXA9 silencing produced similar effects as observed with miR­873 overexpression in OS cells. Consistently, the exogenous expression of HOXA9 partially reversed the suppression of the aggressive phenotype induced by miR­873 overexpression in OS cells. Notably, miR­873 was able to deactivate the Wnt/ß­catenin pathway in OS cells by regulating HOXA9, both in vitro and in vivo. On the whole, the present study demonstrates that miR­873 suppresses the development of OS by directly targeting HOXA9 and inhibiting the Wnt/ß­catenin pathway, and suggests that miR­873 may prove to be useful as a diagnostic biomarker of OS, as well as in the development of novel therapies.


Assuntos
Neoplasias Ósseas/patologia , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Osteossarcoma/patologia , Via de Sinalização Wnt , Regiões 3' não Traduzidas , Adolescente , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Criança , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Osteossarcoma/genética , Osteossarcoma/metabolismo , Fenótipo , Prognóstico
20.
Biochem Pharmacol ; 163: 416-424, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878550

RESUMO

The therapeutic efficacy of immunosuppressive agents has been intensively studied for colitis management. We synthesized a series of andrographolide derivatives and reported their structure-activity-relationship and anti-inflammatory activity in our previous studies. Among these derivatives, compound 3b exhibited the most potent immunosuppressive activity. In the present study, we assessed the efficacy of 3b in dextran sulfate sodium (DSS)-induced model of acute colitis. Compound 3b was administered intragastrically. The therapeutic effect of 3b was evaluated using disease score and immune cell infiltration. The effect of 3b on Toll-like receptor 4/NF-κB and ß-catenin signaling was primarily determined by using immunohistochemistry staining and quantitative real-time PCR. The crosstalk between NF-κB and ß-catenin signaling was then assessed in HCT-116 cells. Treatment with 3b significantly downregulated the disease activity index and suppressed the histologic evidence of inflammation in DSS-induced model of acute colitis. Compound 3b inhibited proinflammatory cytokine expression at both the serum and transcription levels. Treatment with 3b also upregulated the number of PCNA-positive and goblet cells in the intestinal crypt and the intestinal expression of mRNA levels of ß-catenin target genes. ß-Catenin level regulation affected the antiinflammation and anti-apoptotic activities of 3b. This study demonstrated that 3b, a novel andrographolide derivative, suppressed inflammation and significantly reversed colitis pathology. The outcome of colitis treatment with an immunosuppressive agent depends upon the intestinal expression and mutation status of ß-catenin.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/química , Animais , Anti-Inflamatórios/química , Células HCT116 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade
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