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1.
CNS Neurosci Ther ; 29(11): 3446-3459, 2023 11.
Article in English | MEDLINE | ID: mdl-37269057

ABSTRACT

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of long-term disability in young adults and induces complex neuropathological processes. Cellular autonomous and intercellular changes during the subacute phase contribute substantially to the neuropathology of TBI. However, the underlying mechanisms remain elusive. In this study, we explored the dysregulated cellular signaling during the subacute phase of TBI. METHODS: Single-cell RNA-sequencing data (GSE160763) of TBI were analyzed to explore the cell-cell communication in the subacute phase of TBI. Upregulated neurotrophic factor signaling was validated in a mouse model of TBI. Primary cell cultures and cell lines were used as in vitro models to examine the potential mechanisms affecting signaling. RESULTS: Single-cell RNA-sequencing analysis revealed that microglia and astrocytes were the most affected cells during the subacute phase of TBI. Cell-cell communication analysis demonstrated that signaling mediated by the non-canonical neurotrophic factors midkine (MDK), pleiotrophin (PTN), and prosaposin (PSAP) in the microglia/astrocytes was upregulated in the subacute phase of TBI. Time-course profiling showed that MDK, PTN, and PSAP expression was primarily upregulated in the subacute phase of TBI, and astrocytes were the major source of MDK and PTN after TBI. In vitro studies revealed that the expression of MDK, PTN, and PSAP in astrocytes was enhanced by activated microglia. Moreover, MDK and PTN promoted the proliferation of neural progenitors derived from human-induced pluripotent stem cells (iPSCs) and neurite growth in iPSC-derived neurons, whereas PSAP exclusively stimulated neurite growth. CONCLUSION: The non-canonical neurotrophic factors MDK, PTN, and PSAP were upregulated in the subacute phase of TBI and played a crucial role in neuroregeneration.


Subject(s)
Brain Injuries, Traumatic , Nerve Growth Factors , Animals , Humans , Mice , Brain Injuries, Traumatic/genetics , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , Cytokines/metabolism , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Neurons/metabolism , RNA , Signal Transduction
2.
Front Microbiol ; 13: 862907, 2022.
Article in English | MEDLINE | ID: mdl-35401481

ABSTRACT

Based on a variant strain, we constructed a gE/gI/TK-deleted pseudorabies virus (PRV). A total of 18 female mice were randomized to a vaccination group to receive PRV XJ delgE/gI/TK, a vehicle group to receive Dulbecco's modified Eagle's medium, and a mock group to confirm the protection of PRV delgE/gI/TK on the central nervous system in mice. Subsequently, the vaccination and vehicle groups were infected with PRV XJ. The mice in the vehicle group showed more severe neurological symptoms and higher viral loads than those in the vaccination group. The exudation of Evans blue and the expression of tight junction protein showed no difference in all groups. HE staining showed vacuolar neuronal degeneration in the vehicle group brain, but no tissue lesions were observed in the vaccination group. TNF-α, IL-6, and synuclein were upregulated in the brain of mice in the vehicle group, while those were inhibited among mice in the vaccination group. IFN-ß, IFN-γ, ISG15, Mx1, and OAS1 showed no difference in the brain between the vaccination and vehicle groups. In addition, TNF-α and IL-6 were inhibited, and antiviral factors were increased in the intestine of the mice in the vaccination group compared to those in the vehicle group. Our study showed that PRV XJ delgE/gI/TK inhibited neurological damage and the inflammation of the intestine and brain induced by PRV and activated the innate immunity of the intestine.

3.
Cell Death Dis ; 9(10): 1033, 2018 10 10.
Article in English | MEDLINE | ID: mdl-30305621

ABSTRACT

Ischemic postconditioning provides robust neuroprotection, therefore, determining the molecular events may provide promising targets for stroke treatment. Here, we showed that the expression of functional mitochondrial voltage-dependent anion channel proteins (VDAC1, VDAC2, and VDAC3) reduced in rat vulnerable hippocampal CA1 subfield after global ischemia. Ischemic postconditioning restored VDACs to physiological levels. Stabilized VDACs contributed to the benefits of postconditioning. VDAC1 was required for maintaining neuronal Ca2+ buffering capacity. We found that microRNA-7 (miR-7) was responsible for postischemic decline of VDAC1 and VDAC3. Notably, miR-7 was more highly expressed in the peripheral blood of patients with acute ischemic stroke compared to healthy controls. Inhibition of miR-7 attenuated neuronal loss and ATP decline after global ischemia, but also diminished the infarct volume with improved neurological functions after focal ischemia. Thus, ischemic postconditioning protects against mitochondrial damage by stabilizing VDACs. MiR-7 may be a potential therapeutic target for ischemic stroke.


Subject(s)
Brain Ischemia/metabolism , Neuroprotection/physiology , Voltage-Dependent Anion Channels/metabolism , Animals , Ischemic Postconditioning/methods , Male , MicroRNAs/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Rats , Rats, Sprague-Dawley , Stroke/metabolism
4.
Exp Ther Med ; 8(2): 657-661, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25009636

ABSTRACT

The aim of the present study was to determine the roles of the chemotactic factor, chemokine ligand 2 (CCL2), and its receptor, chemokine receptor type 2 (CCR2), in the hippocampus of rats with cerebral ischemia/reperfusion injury. In total, 24 Sprague-Dawley rats, weighting 250-300 g, were randomly divided into three groups (n=8): Sham-operated (C group), cerebral ischemia/reperfusion injury (I/R group) and propofol-intervention (P group) groups. The rats were sacrificed at 6 h after the ischemia/reperfusion surgery, and the brains were obtained to isolate the hippocampus. The mRNA expression levels of CCL2 and CCR2 in the hippocampus were analyzed by quantitative polymerase chain reaction, while the protein expression levels of CCL2 and CCR2 were determined by western blot analysis. The expression levels of CCL2 and CCR2 in the procerebrum were markedly elevated in the I/R and P groups at 6 h after the ischemia/reperfusion surgery when compared with the C group (P<0.05). In addition, the mRNA expression levels of CCL2 and CCR2 decreased significantly in the P group as compared with that in the I/R group (P<0.05). Therefore, CCL2 and CCR2 may be involved in the mechanisms underlying cerebral ischemia/reperfusion injury, and propofol may protect the brain through regulating the expression of CCL2 and CCR2.

5.
World J Surg Oncol ; 9: 37, 2011 Mar 29.
Article in English | MEDLINE | ID: mdl-21443810

ABSTRACT

Hepatic solitary fibrous tumor (SFT) is a rare tumor originating from the mesenchyme. Here we report a new case of SFT in the liver and review the clinical presentation, radiological and operative findings, diagnosis, treatment, and outcome. The patient was a 59-year-old man who presented with progressive fatigue for 3 months and an abdominal mass for 3 days. On laboratory tests, no abnormality was detected except that abdominal ultrasonography revealed a 9.0 × 6.2 cm hypoechogenic mass in the left lobe of the liver. A computed tomographic scan confirmed a hypodense lesion in the left lobe of the liver. The patient underwent left hepatectomy. SFT was diagnosed on the basis of histopathological findings. The patient was free from all symptoms and had no signs of local recurrence after 24 months' follow up.


Subject(s)
Liver Neoplasms/pathology , Solitary Fibrous Tumors/pathology , Diagnosis, Differential , Humans , Liver Neoplasms/chemistry , Liver Neoplasms/diagnosis , Male , Middle Aged , Neoplasm Metastasis , Solitary Fibrous Tumors/chemistry , Solitary Fibrous Tumors/diagnosis
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 39(5): 506-10, 2010 09.
Article in Chinese | MEDLINE | ID: mdl-20936726

ABSTRACT

OBJECTIVE: To investigate the loss of heterozygosity (LOH) at mitofusin-2 (Mfn2) gene in hepatocellular carcinoma (HCC) and its clinicopathological significance. METHODS: Four high polymorphic microsatellite markers flanking Mfn2 were selected for LOH analysis in 29 cases of HCC. RESULT: The frequencies of LOH on D1S2667, D1S2740, D1S434 and D1S228 were 21%, 23%, 21% and 22%, respectively. LOH at Mfn2 was closely correlated with tumor size, age, capsule, differentiation and t HBV infection (P<0.05), not with gender, thrombosis, cirrhosis and serum AFP levels (P>0.05). CONCLUSION: LOH at Mfn2 gene in HCC is associated with the clinicopathological features of patients.


Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Loss of Heterozygosity , Membrane Proteins/genetics , Mitochondrial Proteins/genetics , Adult , Aged , Female , GTP Phosphohydrolases , Humans , Male , Middle Aged
7.
J Cell Physiol ; 217(2): 544-57, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18615577

ABSTRACT

Focal adhesion kinase (FAK) plays key roles in cell adhesion and migration. We now report that the delayed rectifier Kv2.1 potassium channel, through its LD-like motif in N-terminus, may interact with FAK and enhance phosphorylation of FAK(397) and FAK(576/577). Overlapping distribution of Kv2.1 and FAK was observed on soma and proximal dendrites of cortical neurons. FAK expression promotes a polarized membrane distribution of the Kv2.1 channel. In Kv2.1-transfected CHO cells, formation of the Kv2.1-FAK complex was stimulated by fibronectin/integrin and inhibited by the K(+) channel blocker tetraethylammonium (TEA). FAK phosphorylation was minimized by shRNA knockdown of the Kv2.1 channel, point mutations of the N-terminus, and TEA, respectively. Cell migration morphology was altered by Kv2.1 knockdown or TEA, hindering cell migration activity. In wound healing tests in vitro and a traumatic injury animal model, Kv2.1 expression and co-localization of Kv2.1 and FAK significantly enhanced directional cell migration and wound closure. It is suggested that the Kv2.1 channel may function as a promoting signal for FAK activation and cell motility.


Subject(s)
Cell Movement , Cell Polarity , Cerebral Cortex/enzymology , Focal Adhesion Kinase 1/metabolism , Neurons/enzymology , Shab Potassium Channels/metabolism , Animals , CHO Cells , Cell Adhesion , Cell Membrane/enzymology , Cell Movement/drug effects , Cell Polarity/drug effects , Cell Shape , Cerebral Cortex/drug effects , Cornea/physiopathology , Corneal Injuries , Cricetinae , Cricetulus , Disease Models, Animal , Enzyme Activation , Fibronectins/metabolism , Humans , Integrins/metabolism , Mice , Multiprotein Complexes , Neurons/drug effects , Phosphorylation , Point Mutation , Potassium Channel Blockers/pharmacology , Protein Interaction Mapping , Pseudopodia/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Recombinant Fusion Proteins/metabolism , Shab Potassium Channels/antagonists & inhibitors , Shab Potassium Channels/genetics , Tetraethylammonium/pharmacology , Transfection , Wound Healing
8.
J Urol ; 180(1): 361-6, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18499162

ABSTRACT

PURPOSE: We investigated the expression of Notch receptors and ligands in normal bladder transitional epithelium and transitional cell carcinoma of the bladder. We also explored its clinical and pathological implications. MATERIALS AND METHODS: The expression of Notch-1 to 3, Jagged-1 and Delta-like-1 was detected respectively in 70 cases of bladder carcinoma, 10 of normal urothelium and the 2 cell lines T24 and BIU-87 using immunohistochemistry. Reverse transcriptase-polymerase chain reaction and Western blot were used to assay the expression level of Notch-1 and Jagged-1. The predictive value of this expression for prognosis was investigated by Kaplan-Meier curves and Cox proportional hazards analysis in a multivariate model. RESULTS: All 5 kinds of Notch factors were intensively stained in normal bladder transitional epithelium immunohistochemically but expression was significantly decreased in tumor tissues. Moreover, expression of the 5 genes in papillary tumors was lower than in invasive tumors but only Notch-1 and Jagged-1 showed a statistically significant difference. Postoperative disease-free survival time in patients with low Notch-1 plus Jagged-1 expression was significantly shorter than that in patients with other expression patterns in papillary tumors (p = 0.014). Multivariate Cox proportional hazards model analysis identified Jagged-1 expression as an independent prognostic factor for disease-free survival (RR 3.09, p = 0.011). CONCLUSIONS: The Notch family expression pattern in papillary bladder transitional cell carcinoma is different from that in invasive bladder transitional cell carcinoma. Low expression of Notch-1 as well as Jagged-1 is potentially a useful marker for survival in patients with papillary bladder transitional cell carcinoma.


Subject(s)
Calcium-Binding Proteins/biosynthesis , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/mortality , Intercellular Signaling Peptides and Proteins/biosynthesis , Membrane Proteins/biosynthesis , Receptor, Notch1/biosynthesis , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Cell Line , Female , Humans , Jagged-1 Protein , Male , Middle Aged , Prognosis , Serrate-Jagged Proteins , Survival Rate
9.
World J Gastroenterol ; 11(20): 3080-4, 2005 May 28.
Article in English | MEDLINE | ID: mdl-15918194

ABSTRACT

AIM: NF-kappaB, regulate the expression of cytokine-inducible genes involving immune and inflammatory responses, will be potential therapy approach for allograft from rejection. In this study, we use pCMV- IkappaBalphaM vector to inhibit NF-kappaB activation and investigate the effect of pCMV- IkappaBalphaM in inhibition of T cells adhesion to endothelial cells. METHODS: The NF-kappaB activity was detected with pNF-kappaB reporter gene and electrophoretic mobility shift assay. Expression of cell surface molecules was detected by RT-PCR and flow cytometer. The cell-cell adhesion assay was performed to determine the effect of pCMV-IkappaBalphaM in inhibition of T cells adhesion to endothelial cells. RESULTS: We could find that NF-kappaB activity is inhibited by over-expression of non-degraded IkappaBalpha protein. Expression of adhesion molecules like ICAM-1, VCAM-1, and P-selectin as well as cell-cell adhesion were inhibited significantly by transfection of the pCMV- IkappaBalphaM vector. CONCLUSION: Our results indicate that the pCMV- IkappaBalphaM, which inhibit the activity of NF-kappaB through over-expression of non-degraded IkappaBalpha protein, can be used for gene therapy in diseases involving NF-kappaB activation abnormally like organ transplantation via inhibiting cell adhesion.


Subject(s)
Endothelial Cells/immunology , Endothelium, Vascular/cytology , I-kappa B Proteins/biosynthesis , T-Lymphocytes/immunology , Cell Adhesion , Cell Line , Endothelial Cells/drug effects , Graft Rejection/immunology , Humans , NF-KappaB Inhibitor alpha , T-Lymphocytes/cytology , Tetradecanoylphorbol Acetate/pharmacology
10.
World J Gastroenterol ; 11(2): 204-7, 2005 Jan 14.
Article in English | MEDLINE | ID: mdl-15633216

ABSTRACT

AIM: To evaluate the effects of NS-398, a cyclooxygenase-2 (COX-2) inhibitor, on the proliferation and apoptosis of HepG2 cells. METHODS: The effects of NS-398 on the proliferation of HepG2 cells were evaluated by MTT. DNA fragmentation gel analysis was used to analyze the apoptotic cells. DNA ploidy and apoptotic cell percentage were calculated by flow cytometry. The expression of COX-2 and Bcl-2 mRNA was identified by competitive RT-PCR. Furthermore, expression level of Bcl-2 was detected using Western blot in HepG2 after treated with NS-398. RESULTS: NS-398 inhibited cell proliferation and induced apoptosis of HepG2 cells in a concentration-dependent manner. DNA ploidy analysis showed that S phase cells were significantly decreased with increase of NS-398 concentration. The quiescent G0/G1 phase was accumulated with decrease of Bcl-2 mRNA. Whereas NS-398 had no effect on the expression of COX-2 mRNA, and no correlations were found between COX-2 mRNA and HepG2 cell proliferation and apoptosis induced by NS-398 (r = 0.056 and r = 0.119, respectively). Bcl-2 protein level was inhibited after treated with NS-398. CONCLUSION: NS-398 significantly inhibits the proliferation and induces apoptosis of HepG2 cells. Mechanisms involved may be accumulation of quiescent G0/G1 phase and decrease of Bcl-2 expression.


Subject(s)
Apoptosis/drug effects , Cyclooxygenase Inhibitors/pharmacology , Nitrobenzenes/pharmacology , Proto-Oncogene Proteins c-bcl-2/genetics , Sulfonamides/pharmacology , Base Sequence , Carcinoma, Hepatocellular , Cell Cycle/drug effects , Cell Division/drug effects , Cell Line, Tumor , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , DNA Primers , Humans , Liver Neoplasms , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/genetics , Prostaglandin-Endoperoxide Synthases/metabolism , Reverse Transcriptase Polymerase Chain Reaction
11.
Zhonghua Wai Ke Za Zhi ; 42(4): 207-9, 2004 Feb 22.
Article in Chinese | MEDLINE | ID: mdl-15062036

ABSTRACT

OBJECTIVE: To elucidate the profile of serum cytokines and adhesion molecules in stable survivors with clinical liver transplantation. METHODS: Flow cytometric analysis was used to analyse the phenotype of T cell subsets in peripheral blood mononuclear cells (PBMCs) from group of liver transplantation (LTx) (n = 22), primary liver carcinoma (PLC) (n = 13) and healthy control (n = 12). Enzyme-linked immunoabsorbent assay (ELISA) was used to determine the serum cytokines and adhesion molecules profiles in stable survivors with clinical liver transplantation. RESULTS: Percentage of CD3(+) T cell and CD8(+) T cell, as well as ratio of CD4(+) to CD8(+) revealed no difference among three groups. The percentage of CD3(+)CD25(+) T cells in LTx group was found higher than that in healthy group (P = 0.022). Th1 cytokines (IL-2, IFN-gamma) and Th2 cytokines (IL-4, IL-10), as well as TNF-alpha displayed no significant difference among three groups. The levels of IL-6, ICAM-1 and P-selectin in serum were not found any difference between LTx group and PLC group, while the levels of IL-6, ICAM-1 and P-selectin in serum shown significant difference between LTx and healthy groups (P = 0.048, 0.000 and 0.025, respectively). CONCLUSIONS: Our data demonstrates that effector T-cells can also be activated and exert immunoresponse to grafts permanently under the treatment of immunosuppressant. Adhesion molecules (ICAM-1, P-Selectin) and pro-inflammatory cytokines (IL-6, TNF-alpha) might be involved in the process of chronic graft damage induced by allo-immunoresponse.


Subject(s)
Cytokines/blood , Liver Neoplasms/therapy , Liver Transplantation , Adult , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Intercellular Adhesion Molecule-1/blood , Interleukin-10/blood , Interleukin-2/blood , Interleukin-4/blood , Interleukin-6/blood , Liver Neoplasms/blood , Male , Middle Aged , P-Selectin/blood , Survivors , T-Lymphocytes/classification , T-Lymphocytes/cytology , Tumor Necrosis Factor-alpha/analysis
12.
Hepatobiliary Pancreat Dis Int ; 2(2): 180-3, 2003 May.
Article in English | MEDLINE | ID: mdl-14599965

ABSTRACT

Nuclear factor-kappa B (NF-kappa B) as an essential transcription factor in the control of expression of the cytokine-induced genes in immune and inflammatory responses regulates cytokines in allograft rejection. In this review, we summarize the general properties of NF-kappa B and the principal findings to shed new light on transplantation.


Subject(s)
Graft Rejection/physiopathology , Islets of Langerhans Transplantation , NF-kappa B/physiology , Animals , Humans , Transplantation, Homologous
13.
Zhonghua Yi Xue Za Zhi ; 83(7): 588-92, 2003 Apr 10.
Article in Chinese | MEDLINE | ID: mdl-12887751

ABSTRACT

OBJECTIVE: To investigate the expression of tumor necrosis factor-alpha(TNF-alpha), interleukin-1 beta (IL-1beta), and intercellular adhesion molecule-1 (ICAM-1) in the lung of rat with small-for-size liver transplantation and the significance of the expression of these cytokine in lung injury after liver transplantation. METHODS: 150 SD rats were randomly divided into 4 groups: sham operation group (n = 6), whole graft liver transplantation group (n = 48), 50% size graft liver transplantation group (n = 48), and 30% size liver transplantation group (n = 48). Six rats from each group were killed 0.5, 2, 6, and 24 hours after operation. Blood samples from subhepatic inferior vena cava were obtained to examine the plasma TNF-alpha by ELISA. Specimens of lung were obtained to be examined pathologically. RT-PCR was used to examine the expression of TNF-alpha mRNA, IL-1beta mRNA, and ICAM-1 mRNA in lung, and chromatometry was performed to detect the activity of myeloperoxidase (MPO). RESULTS: (1) The plasma TNF-alpha at any time point was higher in the 3 transplantation groups than in the sham operation group. The plasma TNF-alpha 2 hours after operation in the whole graft group was significantly higher than that in the 30% size group (P < 0.05). (2) The expression levels of TNF-alpha mRNA 2 and 6 hours after operation in the whole graft group and in the 50% graft group were significantly higher than those in the 30% graft group (all P < 0.01). The expression levels of TNF-alpha mRNA remained significantly higher than those in the sham operation group since the second hour after operation (all P < 0.01). (3) IL-1beta mRNA was expressed in the 3 liver transplantation groups without significant differences between any levels at all the time points and was not expressed in the sham operation group. The expression of ICAM-1 mRNA was higher at all the time points in the liver transplantation groups than in the sham operation group (P < 0.01 or P < 0.05) without significant difference between the values of any transplantation group at any time point (all P > 0.05). The MPO activity was stronger in the 3 liver transplantation groups at any time point than in the sham operation group (all P < 0.01). The peak occurred 2 hours after operation in the whole graft group and 50% size group and occurred 6 hours after operation in the 30% graft group. The plasma TNF-alpha level was positively correlated to the MPO activity in lung tissue with a correlation coefficient of 0.422 (P < 0.05). (4) The morphology of lung was normal in the sham operation group. Obvious interstitial hyperemia and hemorrhage, neutrophil infiltration, and pulmonary septal thickening were found in the 3 transplantation groups, in particular being severe at the 2-hour time point. CONCLUSION: Increase of plasma TNF-alpha is one of the causes of lung injury after small-for-size liver transplantation. Upregulation of TNF-alpha mRNA, IL-1beta mRNA, and ICAM-1 mRNA expression may be also responsible for the lung injury and their expression may be correlated to the size of graft.


Subject(s)
Interleukin-1/genetics , Liver Transplantation , Lung/metabolism , Tumor Necrosis Factor-alpha/genetics , Animals , Lung/pathology , Male , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/analysis
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