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1.
Brain Sci ; 13(8)2023 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-37626492

RESUMO

Vascular dementia is a type of dementia from brain damage caused by cerebrovascular lesions and vascular risk factors. Prevotella histicola is a species of Prevotella, belonging to the category of obligate anaerobe. The purpose of our work was to study the protection of Prevotella histicola on cognitive function in rats subjected to vascular dementia (VaD) and investigate underlying molecular mechanisms. The rats were randomly divided into three groups: control group, 2VO group and 2VO + Prevotella histicola group. The VaD rats (the 2VO group and 2VO + Prevotella histicola group) were generated by bilateral common carotid artery occlusion (2VO). Rats in the 2VO+ Prevotella histicola group were administered with Prevotella histicola twice daily. In comparison with the rats in the 2VO group, rats in the 2VO + Prevotella histicola group presented an enhanced cognitive ability, increased synapse-associated protein expression, a downregulation of proinflammatory factors and an upregulation of neurotrophic factors. The relevant mechanism of the protective effect of Prevotella histicola may be associated with the inhibition of glial cell-associated inflammation by regulating phosphorylation of CaMKII. In conclusion, Prevotella histicola attenuates neurological impairments via regulating synapse-associated protein expression and the liberation of inflammatory elements in vascular dementia rats. The findings above might benefit the development of Prevotella histicola transplantation as a promising treatment of VaD.

2.
Brain Sci ; 13(7)2023 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-37508923

RESUMO

INTRODUCTION: Neutrophil extracellular traps play a role in the pathophysiology of stroke and are associated with severity and mortality. We aimed to investigate whether the citrullinated histone H3 (CitH3), a biomarker for neutrophil extracellular traps formation, is associated with the white matter lesion (WML) burden in ischemic stroke patients. METHODS: Between September 2021 and April 2022, 322 patients were enrolled in this prospective observational cohort study. Serum CitH3 levels were measured after admission using an enzyme-linked immunosorbent assay. WMLs severity was graded according to the Fazekas scale and conceptually defined as mild (total Fazekas score 0-2) and severe (total Fazekas score 3-6). We used multivariable regression models to determine the relationship between CitH3 concentrations and the severity of WMLs burden. RESULTS: One-hundred and forty-eight (46.0%) patients were diagnosed with severe WMLs burden after admission. Increased CitH3 levels (first quartile vs. fourth quartile of H3Cit, odds ratio, 3.311, 95% confidence interval, 1.336-8.027; p = 0.011) were independently associated with a greater WML burden in the fully adjusted multivariable model. Similar results were found when the H3Cit was analyzed as a continuous variable. Furthermore, the multiple-adjusted spline regression model showed a linear association between H3Cit levels and severe WMLs (P = 0.001 for linearity). CONCLUSIONS: In the present study, increased CitH3 levels were positively associated with extensive WMLs in ischemic stroke patients, indicating a role of neutrophil extracellular traps formation in the pathogenesis of WMLs.

3.
Neurol Sci ; 44(6): 2081-2086, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36746844

RESUMO

BACKGROUND AND PURPOSE: The impact of serum caveolin-1 (Cav-1) on clinical outcomes in patients after mechanical thrombectomy (MT) is unclear. We aimed to investigate the association between serum cav-1 levels and the 3-month functional outcome. METHODS: We prospectively enrolled and analyzed patients with an anterior circulation large vessel occlusion who underwent MT. Serum cav-1 concentrations were tested after admission. The primary outcome was a 90-day modified Rankin Scale score of 3-6. RESULTS: Of the 237 recruited patients (mean age, 69.7 ± 12.1 years; 152 male), 131 (55.3%) experienced a 90-day poor outcome. After adjustment for demographic characteristics and other covariates, patients with higher serum Cav-1 levels had a reduced risk of poor outcome at 3 months (Per 1-standard deviation increase; odd ratios [OR], 0.59; 95% confidence interval [CI], 0.39 - 0.89, P = 0.013). Elevated Cav-1 concentrations (Per 1-standard deviation increase; OR, 0.59; 95% CI, 0.40 - 0.88, P = 0.011) were significantly associated with a favorable shift in modified Rankin Scale score distribution. Similar results were confirmed when the Cav-1 levels were analyzed as a categorical variable. Furthermore, the restricted cubic spline showed a linear association between Cav-1 levels and 90-day poor outcome (P = 0.032 for linearity). CONCLUSIONS: Increased serum Cav-1 levels were associated with improved prognosis at 3 months in ischemic stroke patients after MT, suggesting that Cav-1 may be a potential prognostic biomarker for ischemic stroke after reperfusion therapy.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Encefálica/cirurgia , Caveolina 1 , AVC Isquêmico/etiologia , Prognóstico , Estudos Retrospectivos , Acidente Vascular Cerebral/cirurgia , Trombectomia , Resultado do Tratamento
4.
J Inflamm Res ; 16: 391-406, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36755969

RESUMO

Purpose: Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer's disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer's disease. Materials and Methods: APP/PS1 mice and Aß-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aß in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. Results: We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aß deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer's disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. Conclusion: These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

5.
Int J Neurosci ; : 1-6, 2022 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-36448327

RESUMO

Aim of the study: Polymorphisms of DNA repair enzyme gene may alter the ability of damage repair, ischemic stroke susceptibility and outcome. This study aimed to explore the association of polymorphisms in PARP1 and the effects of interactions between genes in Chinese.Materials and methods: A total of 500 patients and 500 healthy controls were enrolled for genotyping. Results: Clinical information analysis revealed higher levels of alcohol and smoking exposure in patients with ischemic stroke, as well as chronic conditions such as diabetes, hypertension, and higher serum triglycerides concentration. In addition, Polymorphism in PARP1 rs8679 was significantly associated with the decreased ischemic stroke risk. Patients harboring the PARP1 rs8679 AG/GG genotype had a better initial stroke, and as for the mRNA level of PARP1, it was suppressed with mutant genotype in comparison with the wild genotype. Finally, the suppressed of PARP1 was induced by gain-binding ability of miR-124-5p through 3'UTR directly binding.Conclusions: In conclusion, our study demonstrates that the SNP rs8679 in PARP1 3'-UTR might act as a protective factor for the outcome of patients with ischemic stroke.

6.
J Leukoc Biol ; 112(4): 813-821, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35946307

RESUMO

Mesothelin (MSLN) is an emerging target that exists in soluble and membrane-associated forms. It is usually used for the diagnosis and treatment of MSLN-positive solid tumors. Interestingly, recent studies have shown that MSLN is highly expressed in 36% of acute myeloid leukemia (AML) patients and barely expressed in normal hematopoietic cells, which makes MSLN a promising target for the treatment of AML. It has been shown that MSLN is detectable as a diagnostic marker in its soluble form. Although the mechanism of action is unclear, MSLN remains a promising target for immunotherapy. Most MSLN research has been conducted in solid tumors, and less research has been conducted in hematopoietic tumors. Increasing research on MSLN is underway in AML, a hematopoietic neoplasm. For example, MSLN is related to extramedullary disease, minimal residual disease, and relapse in AML patients. Decreasing the expression of MSLN reduces the severity of the disease course. This information suggests that MSLN may be an ideal target for the treatment of many AML-related diseases to improve the prognosis and survival rate. At present, there are a few immunotherapies targeting MSLN in AML in preclinical and clinical trials, such as antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor-T cells, which opens new room for the treatment of MSLN-related AML.


Assuntos
Imunoconjugados , Leucemia Mieloide Aguda , Receptores de Antígenos Quiméricos , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunoterapia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Mesotelina
7.
Int J Gen Med ; 14: 2623-2630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34168488

RESUMO

OBJECTIVE: To explore the alteration of pattens of anatomical and functional connectivity (FC) of posterior cingulate cortex (PCC) in Parkinson's disease (PD) patients with cognitive dysfunction and the relationship between the connection strengths and cognitive state. METHODS: We prospectively enrolled 20 PD patients with mild cognitive impairment (PD-MCI), 13 PD patients with normal cognition (PD-NC) and 13 healthy controls (HCs). By collecting, preprocessing and FC analyzing resting-state functional magnetic resonance imaging (rs-fMRI) data, we extracted default mode network (DMN) patterns, compared the differences in DMN between the three groups and the analyzed the correlation between FC value with the commonly used neuropsychological testing. RESULTS: The PD-MCI showed significant worse performances in general cognition, and PD-NC and HCs showed comparable performances of cognitive function. Cognitive-related differences in DMN were detected in the bilateral precuneus (BPcu). Compared with the HCs, PD-NC and PD-MCI showed significantly decreased FC within BPcu (both P < 0.001). For PD-MCI, the rho of the Fisher's Z-transformed FC (zFC) value within BPcu with the TMTA, DSST and CFT-20min were 0.50, 0.66 and 0.47, respectively. For PD-NC, the rho of the zFC value within BPcu with the MMSE was 0.58. DISCUSSION: BPcu was the cognitive-related region in DMN. As cognition declines, FC within BPcu weakens. For PD-MCI, the higher the FC values within BPcu were likely to be related to the better the performances of TMTA, DSST and CFT-20 min DR, which needs to be further confirmed by large-sample studies.

8.
MAbs ; 12(1): 1689027, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31795802

RESUMO

The immunoglobulin (Ig) CH2 domain is a promising scaffold for the development of candidate therapeutics. We have previously shown that the stability of isolated CH2 could be increased by the introduction of an additional disulfide bond and removal of seven N-terminal residues (m01s). However, both isolated CH2 and m01s aggregate, likely due to the existence of aggregation-prone regions (APRs) that we identified by using computational methods. This knowledge was used to generate a phage display library of mutants. The library was incubated at high temperature to remove aggregating CH2 domains, and then panned against a mouse anti-human CH2 monoclonal antibody targeting a conformational epitope to remove misfolded CH2s. After two rounds of panning, one clone, m01s5, with smaller APRs, was identified. After additional mutagenesis one clone, m01s5.4, which aggregated much less than m01s as measured by a turbidity assay and dynamic light scattering, was identified. m01s5.4 also exhibited much lower nonspecific binding than m01s. Engineering of a previously identified m01s-based tumor antigen-specific binder led to a dramatic reduction of its aggregation without affecting its binding. In summary, we describe a new approach for reducing aggregation based on a combination of computational and phage display methodologies, and show that aggregation of CH2-based scaffolds can be significantly reduced by the newly identified mutants, which can improve the developability of potential CH2-based therapeutics.


Assuntos
Imunoglobulina G/genética , Mutação/genética , Agregação Patológica de Proteínas/genética , Engenharia de Proteínas/métodos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Biologia Computacional , Epitopos/metabolismo , Humanos , Imunoglobulina G/química , Mutagênese Sítio-Dirigida , Biblioteca de Peptídeos , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética
9.
Antiviral Res ; 170: 104556, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299269

RESUMO

Subtype H7 avian influenza viruses have been found to be associated with human infection and represent a risk for global public health. In 2013, the emergence of H7N9 virus in human beings and persistent human infection in China raised the most serious pandemic threat. Here we identified a human monoclonal antibody, P52E03, targeting the hemagglutinin (HA) of subtype H7 influenza viruses (H7 antigen), from a convalescent patient infected with H7N9 in 2017. P52E03 showed in vitro hemagglutination inhibiting (HI) and neutralizing activity against subtype H7 viruses belonging to both North American and Eurasian lineages. Moreover, it could prophylactically protect mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo and, therefore, is a candidate for development of antiviral agent against H7N9 infection. By generating escape mutant variants, we found that a single G151E substitution in the viral H7 antigenic site A could abort the neutralizing activity. Computational structural prediction of the P52E03/H7 complex revealed that residues including G151 in and around the conserved antigenic site A region are important for antigen recognition by the H7 cross-reactive antibody. Finally, we found that the P52E03 germline precursor (gHgL) antibody recognizes HA with measurable affinity, suggesting that its epitope is vulnerable to the human immune system and might elicit neutralizing antibodies (nAbs) in vivo after vaccination.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunização Passiva , Subtipo H7N9 do Vírus da Influenza A/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Antígenos Virais/imunologia , Reações Cruzadas , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Infecções por Orthomyxoviridae/prevenção & controle
10.
Exp Ther Med ; 16(6): 5258-5264, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542483

RESUMO

Single-nucleotide polymorphisms (SNPs) play an important role in our susceptibility to disease, the severity of illness and the way our body responds to treatment. This study evaluated the impact of three polymorphisms on the susceptibility and functional outcome of ischemic stroke (IS). Three hundred and eight patients and 300 healthy volunteers were enrolled. Polymorphisms of NOX4 rs11018628, MTHFR rs1801133 and NEIL3 rs12645561 were detected in both groups. Smoking (P<0.001), drinking (P<0.001), hypertension (P<0.001) and diabetes (P=0.006), as traditional vascular risk factors for IS, were confirmed in our study. Logistic regression analyses with adjustment for age, sex, smoking, drinking, diabetes, hypertension and total cholesterol showed that the variant genotypes of NOX4 rs11018628 were associated with a significantly decreased risk (Dominant model: OR=0.32, 95% CI=0.22-0.48, P<0.001) and a better short-term recovery of IS (Dominant model: OR=0.57, 95% CI=0.35-0.95, P=0.029). This study demonstrates that the NOX4 rs11018628 SNP is associated with decreased risk in developing IS and better short-term recovery of patients. This suggests that the genetic variant of NOX4 rs11018628 may contribute to the etiology of IS.

11.
J Renin Angiotensin Aldosterone Syst ; 19(3): 1470320318799587, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30223703

RESUMO

INTRODUCTION: This study aimed to evaluate the influence of central angiotensin IV (Ang IV) infusion on chronic cerebral hypoperfusion (CCH)-related neuropathological changes including amyloid-ß (Aß), hyperphosphorylated tau (p-tau) and the inflammatory response. MATERIALS AND METHODS: Rats with CCH received central infusion of Ang IV, its receptor AT4R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for six weeks. During this procedure, the systolic blood pressure (SBP) was monitored, and the levels of Aß42, p-tau and pro-inflammatory cytokines in the brain were detected. RESULTS: Rats with CCH exhibited higher levels of Aß42, p-tau and pro-inflammatory cytokines in the brain when compared with controls. Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines in the brains of rats with CCH. Meanwhile, the reduction of pro-inflammatory cytokines levels caused by Ang IV was reversed by divalinal-Ang IV. During the treatment, the SBP in rats was not significantly altered. CONCLUSION: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation through AT4R in the brains of rats with CCH, which is independent from SBP. These findings suggest that Ang IV/AT4R may represent a potential therapeutic target for CCH-related neurological diseases.


Assuntos
Angiotensina II/análogos & derivados , Isquemia Encefálica/tratamento farmacológico , Encéfalo/patologia , Inflamação/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Animais , Isquemia Encefálica/patologia , Doença Crônica , Inflamação/patologia , Fosforilação/efeitos dos fármacos , Ratos Wistar
12.
Aging (Albany NY) ; 10(4): 645-657, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29667931

RESUMO

During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.


Assuntos
Envelhecimento/metabolismo , Angiotensina I/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Imidazóis/farmacologia , Fragmentos de Peptídeos/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Encéfalo/patologia , Inflamação/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
13.
Zhonghua Wei Chang Wai Ke Za Zhi ; 18(11): 1132-5, 2015 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-26616809

RESUMO

OBJECTIVE: To investigate the effect of ligation level of inferior mesenteric artery (IMA) on postoperative defecation function in patients with rectal cancer. METHODS: A total of 128 rectal cancer patients who were planned to undergo low anterior resection in the First Hospital of Zibo City between January 1, 2012 and December 31, 2013 were prospectively enrolled and randomly divided into IMA high ligation group(63 cases, cutting distance of 1.0 to 1.5 cm to the root of IMA) and low ligation group(65 cases, cutting distance of 0.5 to 1.0 cm to the root of left colic artery originated from IMA). The efficacy, especially the defecation function, was observed and compared 3 months and 1 year after surgery between the two groups. RESULTS: No significant difference was found in the number of harvested lymph nodes between two groups[8(1-30) vs. 7(2-28), P=0.125], but high ligation group had greater number of metastatic lymph nodes[1(0-9) vs. 0(0-8), P=0.041]. Frequency of defecation in high ligation group was significantly higher than that in low ligation group during postoperative 3-month follow-up[5(2-10)/d vs. 3(1-8)/d, P=0.035], whereas other indexes of defecation function were not significantly different(all P>0.05). The proportion of patients needing laxatives in high ligation group was higher than that in low ligation group during postoperative 1-year follow-up [11.3%(6/53) vs. 1.7%(1/58), P=0.038], whereas other indexes of defecation function were not significantly different as well (all P>0.05). Three cases and 2 cases showed recurrence in high ligation group and low ligation group respectively during postoperative 1-year follow-up without significant difference(P=0.623). CONCLUSION: Low ligation of IMA in low anterior resection for rectal cancer is beneficial to the protection against defecation function.


Assuntos
Defecação , Artéria Mesentérica Inferior/cirurgia , Neoplasias Retais/cirurgia , Humanos , Ligadura , Excisão de Linfonodo , Recidiva Local de Neoplasia
14.
Mol Med Rep ; 12(1): 475-81, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25760059

RESUMO

Serine/threonine-protein kinase-1 (SMG-1) belongs to the phosphatidylinositol 3­kinase­related kinase family. Altered expression of SMG-1 contributes to human carcinogenesis and cancer progression. The present study detected the expression levels of SMG-1 in normal and cancerous pancreatic tissues and then assessed the effects of SMG-1-knockdown in pancreatic cancer cell lines in vitro. A pancreatic cancer tissue array and pancreatic cancer cell lines were used to detect the expression levels of SMG-1 and a lentivirus expressing either SMG-1 or negative control short hairpin (sh)RNA were used to knock down the expression of SMG-1 in the pancreatic cancer cell lines. Western blot, cell proliferation, Cell Counting kit-8, Transwell tumor cell migration and invasion assays, and flow cytometric analysis of cell apoptosis with or without gemcitabine or cisplatin treatment were performed to assess the tumor cells. The protein expression of SMG-1 was higher in the pancreatic cancer tissues and cells compared with the normal tissues. sh-SMG-1 lentivirus infection significantly suppressed the expression of SMG-1 in the pancreatic cancer cell lines, resulting in the inhibition of tumor cell proliferation and increased chemosensitivity to treatment with gemcitabine and cisplatin. However, SMG-1 knockdown had no effect on pancreatic cancer cell migration or invasion capacities. The protein expression of SMG-1 was increased in the pancreatic cancer tissues and was associated with an advanced tumor stage. Knock down of the expression of SMG-1 inhibited tumor cell proliferation and induced the chemosensitivity of pancreatic cancer cells in vitro.


Assuntos
Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases/biossíntese , Adulto , Idoso , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases , Gencitabina
15.
Dig Dis Sci ; 59(7): 1452-60, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24532253

RESUMO

BACKGROUND: Pancreatic cancer is aggressive; 80-90 % of pancreatic cancer patients have already developed metastatic cancer at the time of diagnosis. Inflammation has been shown to facilitate pancreatic cancer migration. The toll-like receptors (TLRs) pathway is an important inflammatory signal transduction pathway. However, the mechanism of inflammation pathway to induce pancreatic cancer migration is unclear. AIMS: The purpose of this study was to investigate how inflammation affects pancreatic cancer migration. METHODS: RT-PCR was used to detect the TLRs expression files in pancreatic cancer cells and tissues. Pancreatic cancer cells migration was assessed after treatment with TLR4 agonist, lipopolysaccharide (LPS). Moreover, two tumor suppressors, PTEN and MAP2K4, were detected. Then we predicted and proved the miRNA which targeted PTEN and MAP2K4. RESULTS: We found that the expression of TLR4 was increased in pancreatic cancer cells and tissues. After treatment with LPS, the migration of pancreatic cancer cells was increased and the protein levels of two tumor suppressors, PTEN and MAP2K4, were inhibited. To investigate the possible mechanism, we checked the expression of miR-181a. The result showed that miR-181a was decreased by LPS. Furthermore, we predicted and confirmed that both PTEN and MAP2K4 were miR-181a targets. Pancreatic cancer tissues analysis showed that PTEN and MAP2K4 were all negatively correlated with miR-181a. CONCLUSIONS: These results suggest that the LPS-TLR4-miR-181a signaling pathway plays a significant role in pancreatic cancer invasion and progression.


Assuntos
Biomarcadores Tumorais/metabolismo , Movimento Celular/fisiologia , Lipopolissacarídeos , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Receptor 4 Toll-Like/metabolismo , Western Blotting , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/fisiopatologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Receptor 4 Toll-Like/agonistas
16.
Int J Oncol ; 44(2): 459-66, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285464

RESUMO

Expression of the transmembrane-4-L-six-family-1 (TM4SF1) is high in human pancreatic cancer cells, but the underlying mechanism remains unclear. In this study, we aimed to identify and characterize microRNAs that regulate TM4SF1 expression in PC cells. Western blot analysis and quantitative polymerase chain reaction were used to detect TM4SF1 and hsa-miR-141 levels in four PC cell lines. SW1990 and BxPc-3 cells were transfected with the inhibitor miR-141, the inhibitor negative control, the miR-141 mimic and the mimic negative control; and cell invasion, migration, proliferation, cell cycle progression and apoptosis were detected by Transwell, MTT and flow cytometry assays, respectively. The miR-141 levels negatively correlated with the TM4SF1 protein levels in PC cells. The TM4SF1 protein levels were lower in the 141M group but higher in the 141I group, although the TM4SF1 mRNA levels had no significant changes, compared to the negative controls. Luciferase assays demonstrated that hsa-miR-141 directly targeted the 3'-untranslated region of the TM4SF1 gene. In addition, miR-141 downregulated TM4SF1 expression to inhibit invasion and migration of PC cells but had no effects on cell proliferation, cell cycle progression or apoptosis. TM4SF1 is a direct target of miR-141. Our findings that TM4SF1 expression was inhibited by miR-141 provide new insights into the oncogenic mechanism of TM4SF1 and suggest that miR-141 represents a novel molecular target for PC therapy.


Assuntos
Antígenos de Superfície/metabolismo , Movimento Celular , Proliferação de Células , MicroRNAs/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Antígenos de Superfície/genética , Apoptose , Western Blotting , Adesão Celular , Ciclo Celular , Citometria de Fluxo , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
17.
Mol Med Rep ; 8(2): 379-84, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23732815

RESUMO

MicroRNAs have emerged as crucial regulators of tumorigenesis. However, the mechanism by which miR­203 is involved in the pathogenesis of pancreatic cancer (PC) remains elusive. In the present study, PC cell lines were used as an experimental model to investigate the expression and functional role of miR­203 in PC. miR­203 mimic virus, miRNA negative control virus and Survivin shRNA virus were transfected into the PC cell line, CFPAC­1. mRNA and protein levels of Survivin were detected using qPCR and western blot analysis. Proliferation, apoptosis and cell cycle profiles were detected by an MTT assay and flow cytometry. Female BALB/cA­nu nude mice were used to validate the role of miR­203 in vivo. The protein levels of Survivin were found to negatively correlate with miR­203 levels in four PC cell lines. A luciferase assay revealed that Survivin was a direct target of miR­203. Transfection with miR­203 mimic inhibited CFPAC­1 cell proliferation and induced apoptosis and G1 phase cell cycle arrest, similar to knockdown of Survivin. In the in vivo nude mouse model, the downregulation of Survivin by knockdown of Survivin or transfection with miR­203 mimic inhibited tumor growth. Results of the current study indicate that miR­203 regulates the proliferation, apoptosis and cell cycle progression of PC cells by targeting Survivin.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Proteínas Inibidoras de Apoptose/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , MicroRNAs/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Interferência de RNA , Survivina , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Brain Res ; 1483: 82-8, 2012 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-22820298

RESUMO

To investigate spatial patterns of intrinsic neural activity of depressed patients with vascular risk factors using resting-state functional magnetic resonance imaging (fMRI) and to examine the relationship between regional activity abnormalities and symptom severity factor, we analyzed spatial patterns of spontaneous brain activity in 19 depressed patients with vascular risk factors and 18 healthy subjects. Intrinsic brain activity was measured by the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level dependent signal. Depressed patients with vascular risk factors showed decrease in ALFF in the limbic-cortical-striatal-pallidal-thalamic circuit. Specifically, the altered ALFF values (i.e., left insula and right superior frontal gyrus) were significantly correlated with depression severity in the depressed group. In addition, higher ALFF values in the right middle temporal gyrus and right superior temporal gyrus were observed in depressed patients with vascular risk factors. Our findings reveal distinct functional patterns of abnormal brain activity in depressed patients with vascular risk factors and have implications for the understanding of the pathophysiology of this understudied population.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/patologia , Depressão/patologia , Adulto , Idoso , Depressão/etiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Escalas de Graduação Psiquiátrica , Descanso/fisiologia , Fatores de Risco , Índice de Gravidade de Doença , Doenças Vasculares/complicações
19.
Neurochem Int ; 58(2): 224-33, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21167243

RESUMO

Cerebral ischemia is a major cause of adult disability and death worldwide. Evidence suggests that Bax-dependent initiation and activation of intrinsic apoptotic pathways contribute to ischemic brain injury. We investigated the Bax-inhibiting peptide VPALR, designed from the rat Ku70-Bax inhibiting domain, on the apoptotic neuronal cell death and behavioral deficits following global cerebral ischemia. The pentapeptide was infused into the left lateral ventricle of the rat brain by intracerebroventricular (i.c.v.) injection 1 h after cerebral ischemia, and results showed that it highly permeated hippocampal neurons and bound to Bax protein in vivo. Post-treatment with VPALR reduced the delayed neuronal damage by approximately 78% compared to the non-treated ischemic control and scrambled peptide-treated rats. TUNEL analysis revealed that VPALR markedly reduced the ischemia-induced increase in apoptotic neuronal death in rat hippocampal CA1 region. VPALR post-treatment also significantly attenuated Bax activation and its mitochondrial translocation as compared with scrambled peptide-treated animals. Concomitantly, Bax-inhibiting peptide-treated rats showed reduced cytochrome c release from mitochondria to cytosol and reduced caspase-3 activation in response to cerebral ischemia, indicating that activation of the intrinsic apoptotic pathway was reduced. Furthermore, Bax-inhibiting peptide improved spatial learning and memory performance in the Morris water maze, which was seriously affected by global cerebral ischemia. In conclusion, Bax inhibition by cell-permeable pentapeptides reduced apoptotic neuronal injury in the hippocampal CA1 region and behavioral deficits following global ischemia. These results suggest that Bax is a potential target for pharmacological neuroprotection and that Bax-inhibiting peptide may be a promising neuroprotective strategy for cerebral ischemia.


Assuntos
Apoptose/fisiologia , Isquemia Encefálica/metabolismo , Degeneração Neural/metabolismo , Oligopeptídeos/fisiologia , Proteína X Associada a bcl-2/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Injeções Intraventriculares/métodos , Masculino , Degeneração Neural/tratamento farmacológico , Degeneração Neural/patologia , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
20.
Brain Res Bull ; 83(5): 272-7, 2010 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-20638460

RESUMO

In vitro and in vivo studies have demonstrated that lithium treatment can protect neurons against excitotoxic and ischemic damage. Yet the possible beneficial effect of chronic low dose lithium on a model of traumatic brain injury (TBI) has not been intensively investigated. In this study, lithium (1 mmol/kg) was given daily, intraperitonealy, for 14 days before the onset of moderate controlled TBI and was continued until the mice were sacrificed. The results showed that in brain injured animals, chronic lithium treatment attenuated the loss of hemispheric tissue, cerebral edema and the expression of pro-inflammatory cytokine interleukin-1ß. The neuronal degeneration in hippocampal CA3 and dentate gyrus sub-regions was also attenuated in the chronic lithium-treated mice as shown by Fluoro-Jade B staining. Moreover, chronic lithium treatment enhanced spatial learning and memory performance of injured mice in the Morris water maze. Our current study extended the protective role of lithium in the model of TBI and suggested that chronic lithium treatment might be a helpful therapeutic strategy for brain injury with multiple beneficial effects.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Cognição , Lítio , Fármacos Neuroprotetores , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Fluoresceínas , Corantes Fluorescentes/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Lítio/farmacologia , Lítio/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Compostos Orgânicos/metabolismo
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