Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.
Animals ; Humans ; Rats ; Cell Differentiation ; Intracellular Signaling Peptides and Proteins/therapeutic use* ; Leukemia/metabolism* ; Mesenchymal Stem Cells ; Neurogenesis ; Stem Cells ; Transcription Factor HES-1/metabolism*

OBJECTIVETo analyze the clinical diagnosis and treatment process of narcolepsy and epilepsy co-existence, and thereby to improve awareness of such cases.

METHODThe clinical manifestations of 2 cases were observed, and video-electroencephalogram (VEEG), multiple sleep latency tests (MSLT) were performed. Hypocretin 1 level in cerebrospinal fluid was examined in one case.

RESULTThe onset of disease of case one was started with epilepsy with myoclonic seizure. After half a year, catalepsy induced by emotion especially laughing and excessive daytime sleepiness appeared. MSLT was positive and hypocretin 1 level decreased. Narcolepsy-cataplexy was definitely diagnosed in this case. Valproate was given and seizure was controlled completely, but the excessive daytime sleepiness was aggravated. Combination of valproate, methylphenidate and clomipramine treatment improved the symptoms of narcolepsy and the patient was still free of epileptic seizures. The onset symptoms of case 2 were catalepsy and excessive daytime sleepiness. MSLT was positive. The treatment was ineffective because of bad compliance. After 2 years, episodes of impairment of consciousness with automatism occurred. VEEG showed slow waves and spikes in right temporal area. Complex partial seizure was determined. Oxcarbazepine was used and then the patients became seizures free, but the symptoms of narcolepsy were still obvious.

CONCLUSIONComorbidity of narcolepsy and epilepsy is a rare phenomenon. Clinical symptoms, predisposing factor, VEEG and MSLT can help diagnosis and differential diagnosis. The antiepileptic drugs might aggravate drowsiness. Based on therapy of epilepsy by using antiepileptic drugs, low dosage of central nervous system stimulants might improve the drowsiness and catalepsy symptoms of narcolepsy.

Adolescent ; Anticonvulsants ; administration & dosage ; therapeutic use ; Brain Waves ; physiology ; Central Nervous System Stimulants ; administration & dosage ; therapeutic use ; Child ; Comorbidity ; Diagnosis, Differential ; Electroencephalography ; Epilepsies, Myoclonic ; diagnosis ; drug therapy ; physiopathology ; Epilepsy ; diagnosis ; drug therapy ; physiopathology ; Humans ; Intracellular Signaling Peptides and Proteins ; cerebrospinal fluid ; Male ; Narcolepsy ; diagnosis ; drug therapy ; physiopathology ; Neuropeptides ; cerebrospinal fluid ; Orexins ; Polysomnography ; Sleep Stages ; physiology ; Treatment Outcome

OBJECTIVETo explore the correlation between Chinese medicine (CM) syndromes and the NPHS1 gene and NPHS2 gene polymorphism as well as corticosteroid sensitivity in patients with minimal change disease (MCD).

METHODSA total of 94 MCD patients were recruited, including 58 steroid-sensitive nephritic syndrome (SSNS) patients and 36 steroid-resistant nephritic syndrome (SRNS) patients. Genomic DNA was obtained from peripheral blood lymphocytes and sequence analysis of single nucleotide polymorphisms (SNPs) in the genes was performed.

RESULTS(1) The SNPs of G349A-3 in NPHS1 gene was found in MCD, but the SNPs of G686A-5 and C695T-5 in NPHS2 gene were not discovered in MCD. (2) When comparing the frequency of genotype AA and allele A in NPHS1 gene (G349A-3), genotype AA and allele A were higher in the SRNS group than in the SSNS group (P < 0.05). (3) When compared with the SRNS group, qi yang deficiency syndrome had a higher incidence in the SSNS group, and yin deficiency syndrome and qi-yin deficiency syndrome had a less incidence in the SSNS, but with no statistical difference (P > 0.05). The rheumatism syndrome had a higher incidence in the SSNS group (P < 0.05). The blood stasis syndrome had a lower incidence in the SSNS with statistical difference (P < 0.05). (4) There was no statistical difference in the correlation between GG, AA, GA and CM syndromes (P > 0.05).

CONCLUSIONSHomozygous mutations of AA and allele A in NPHS1 gene were correlated to SRNS patients of MCD. Rheumatism syndrome patients were prone to be sensitive to corticosteroids, while patients of blood stasis syndrome were prone to be insensitive to corticosteroids. We didn't discover the correlation between NPHS1 gene polymorphism and CM syndrome distribution.

Adolescent ; Adrenal Cortex Hormones ; therapeutic use ; Adult ; Aged ; Female ; Genotype ; Homozygote ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; Male ; Medicine, Chinese Traditional ; Membrane Proteins ; genetics ; Middle Aged ; Nephrosis, Lipoid ; diagnosis ; genetics ; Nephrotic Syndrome ; congenital ; genetics ; Polymorphism, Single Nucleotide ; Yang Deficiency ; Yin Deficiency ; Young Adult

BACKGROUND/AIMS: DNA double strand breaks (DSB) is one of the critical types of DNA damage. If unrepaired, DSB is accumulated in the nucleus of cells, the cells become apoptotic or transform to tumor by way of genomic instability. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. There was no report that Helicobacter pylori (H. pylori), the gastric carcinogen, induce DNA DSB in gastric epithelium in vivo. The aim of this study was to investigate whether H. pylori induce DSB in the gastric epithelial cells of chronic gastritis. METHODS: Immunohistochemical stains were performed for the DSB markers, phospho-53BP1 and gammaH2AX, in the gastric epithelium derived from 44 peptic ulcer disease patients before and after H. pylori eradication. DNA fragmentation assay was performed in the cell line to investigate the DNA damage by H. pylori infection. RESULTS: The mean expression score of gammaH2AX was significantly higher in the H. pylori infected gastric epithelium as compared to the H. pylori eradicated gastric epithelium (8.8+/-5.5 vs. 6.2+/-5.3 respectively; p=0.008). The expression score of phospho-53BP1 between before and after eradication of H. pylori was not statistically different, but tended to be higher in H. pylori infection. DNA fragmentation was developed significantly more in the cell lines after infection with H. pylori. CONCLUSIONS: DSB of DNA damage was typical feature of H. pylori infection in the gastric epithelium.
Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents/therapeutic use ; Cell Line, Tumor ; DNA/metabolism ; *DNA Breaks, Double-Stranded ; Female ; Gastric Mucosa/*metabolism ; Helicobacter Infections/drug therapy/*metabolism ; Helicobacter pylori/*drug effects/pathogenicity ; Histones/genetics/metabolism ; Humans ; Immunohistochemistry ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Male ; Middle Aged ; Peptic Ulcer/genetics/pathology

OBJECTIVETo investigate the mechanism through which Liuweidihuangwan improves hepatic insulin resistance in type 2 diabetic rats.

METHODSWith LETO rats as the normal control group, OLETF rats were treated daily with or without Liuweidihuangwan. At 8, 32, and 40 weeks of the treatment, 3 rats were randomly selected from each group for histological examination of the liver tissues and for detection of phosphoenolpyruvate carboxylase kinase (PEPCK) mRNA expression using RT-PCR and insulin receptor substrate-1 (IRS-1) and IRS-2 protein expressions using Western blotting.

RESULTSCompared with LETO rats, OLETF rats showed progressive destruction of the lobular structures and hepatic steatosis in the liver over time. OLETF rats with Liuweidihuangwan treatment had basically normal lobular structure with only mild fatty degeneration in the liver. RT-PCR detection demonstrated a significantly higher PEPCK mRNA expression in untreated OLETF rats than in LETO rats (P<0.01), but a significantly lowered PEPCK expression in OLETF rats after Liuweidihuangwan dosing (P<0.01). Western blotting showed that significantly lower p-IRS-1 and p-IRS-2 protein expressions in untreated OLETF rats than those in LETO rats and treated OLTEF rats (P<0.05).

CONCLUSIONLiuweidihuangwan improves hepatic insulin resistance in OLETF rats by inhibiting the activity of gluconeogenic key enzyme (PEPCK) in the liver and enhancing IRS-1 and IRS-2 expressions in the insulin signaling pathway.

Animals ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Insulin Receptor Substrate Proteins ; metabolism ; Insulin Resistance ; Intracellular Signaling Peptides and Proteins ; metabolism ; Liver ; drug effects ; metabolism ; pathology ; Male ; Phosphoenolpyruvate Carboxykinase (GTP) ; metabolism ; Rats ; Rats, Inbred OLETF ; Signal Transduction

OBJECTIVETo observe the clinicopathologic and genetic features of follicular variant of peripheral T-cell lymphoma (FV-PTCL), with particular attention to the relationship of this type of lymphoma with angioimmunoblastic T-cell lymphoma (AITL).

METHODSThe clinical data, hematoxylin and eosin-stained sections of lymph node biopsies from 2 FV-PTCL cases were reviewed. Immunohistochemical phenotyping and detection of EBV-encoded RNAs (EBER) through in situ hybridization (ISH) were performed. The EnVision two-step method was used for all antibodies except CXCL13 (by using three-step streptavidin immunoperoxidase method). Analysis of clonality and ITK/SYK gene rearrangement was conducted using PCR and RT-PCR assays, respectively.

RESULTSClinically, the two patients presented with superficial lymphadenopathy similarly. Histologically, case 1 showed a follicular/nodular lymphoid proliferation without marked germinal centers. The neoplastic cells comprised mainly medium sized cells with abundant, sometimes clear cytoplasms. Similar histologic findings were seen in case 2 in addition to a concurrent component mimicking typical AITL noticed. Of both cases, the neoplastic cells showed positive reactivity to CD3, CD4, CD10, PD1, and CXCL13. Positive hybridization signals for EBER were only seen in case 2, and double stains demonstrated that those EBV-positive cells were mostly the reactive transformed B-cells. Monoclonal T-cell proliferation was proved by the rearranged TCR gene detection in both cases. Neither of the current cases expressed ITK/SYK fusion transcripts.

CONCLUSIONFV-PTCL shows the similar or overlapped morphological and immunophenotypic features to those of AITL, possibly suggesting the presence of a potential relationship between these two types of lymphomas.

Aged ; Antigens, CD ; metabolism ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Apoptosis Regulatory Proteins ; metabolism ; Chemokine CXCL13 ; metabolism ; Cyclophosphamide ; therapeutic use ; Doxorubicin ; therapeutic use ; Endostatins ; therapeutic use ; Female ; Gene Rearrangement, T-Lymphocyte ; Humans ; Immunoblastic Lymphadenopathy ; genetics ; metabolism ; pathology ; Intracellular Signaling Peptides and Proteins ; genetics ; Keratins ; metabolism ; Lymphoma, Follicular ; drug therapy ; genetics ; metabolism ; pathology ; Lymphoma, T-Cell ; genetics ; metabolism ; pathology ; Lymphoma, T-Cell, Peripheral ; drug therapy ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Oncogene Proteins, Fusion ; metabolism ; Prednisone ; therapeutic use ; Programmed Cell Death 1 Receptor ; Protein-Tyrosine Kinases ; genetics ; Remission Induction ; Syk Kinase ; Vincristine ; therapeutic use

Allergic diseases have become global social health problems. The binding of IgE with its high affinity receptor FcepsilonRI plays a key step in I-type allergy. Recently, more and more key molecules on the IgE/FcepsilonRI signaling transduction pathway were to be the drug candidates against allergic diseases, with in-depth study of FcepsilonRI signal pathway gradually. The main drugs include molecule antibodies, peptides, vaccines, fusion proteins, small molecules, and other drugs related to IgE/FcepsilonRI. The recent progress in the study of mechanisms of representative drugs targeting on IgE/FcepsilonRI signaling pathway was reviewed in this article.
Aminophenols ; pharmacology ; therapeutic use ; Animals ; Anti-Allergic Agents ; pharmacology ; therapeutic use ; Antibodies, Anti-Idiotypic ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; pharmacology ; therapeutic use ; Humans ; Hypersensitivity ; drug therapy ; immunology ; Immunoglobulin E ; metabolism ; Intracellular Signaling Peptides and Proteins ; antagonists & inhibitors ; Molecular Targeted Therapy ; Omalizumab ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacology ; therapeutic use ; Receptors, IgE ; metabolism ; Signal Transduction ; Syk Kinase

Animals ; Antineoplastic Agents ; therapeutic use ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p27 ; Fenretinide ; therapeutic use ; Hepatocyte Nuclear Factor 3-alpha ; genetics ; metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; metabolism ; Prognosis ; Receptors, Estrogen ; metabolism

Animals ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; antagonists & inhibitors ; metabolism ; Lung Neoplasms ; drug therapy ; metabolism ; Protein-Serine-Threonine Kinases ; antagonists & inhibitors ; metabolism ; Signal Transduction ; drug effects ; Sirolimus ; therapeutic use ; TOR Serine-Threonine Kinases

BACKGROUNDThe RhoA/Rho kinase pathway may participate in the pathogenesis of hypoxia and monocrotaline induced pulmonary hypertension. This study tested whether RhoA/Rho kinase pathway is involved in the pathogenesis of high flow induced pulmonary hypertension in rats.

METHODSMale Wistar rats (4 weeks) were randomly divided into 4 shunt groups, 4 treated groups and 4 control groups. Shunt and treated groups underwent left common carotid artery/external jugular vein shunt operation. Control groups underwent sham operation. Treated groups received fasudil treatment and the others received same dose of saline. At weeks 1, 2, 4 and 8 of the study, right ventricular systolic pressure was measured and blood gases were analysed to calculate Qp/Qs. The weight ratio of right ventricle to left ventricle plus septum and the mean percentage of medial wall thickness in moderate sized pulmonary arteries were obtained. RhoA activity in pulmonary arteries was detected using Rho activity assay reagent. Rho kinase activity was quantified by the extent of MYPT1 phosphorylation with Western blot. Proliferating cells were evaluated using proliferating cell nuclear antigen immunohistological staining.

RESULTSCarotid artery/jugular vein shunt resulted in high pulmonary blood flow, both an acute and a chronic elevation of right ventricular systolic pressure, significant medial wall thickening characterized by smooth muscle cells proliferation, right ventricular hypertrophy and increased activation of RhoA and Rho kinase. Fasudil treatment lowered pulmonary artery systolic pressure, suppressed pulmonary artery smooth muscle cells proliferation, attenuated pulmonary artery medial wall thickening and inhibited right ventricular hypertrophy together with significant suppression of Rho kinase activity but not Rho activity.

CONCLUSIONSActivated RhoA/Rho kinase pathway is associated with both the acute pulmonary vasoconstriction and the chronic pulmonary artery remodelling of high flow induced pulmonary hypertension. Fasudil treatment could improve pulmonary hypertension by inhibiting Rho kinase activity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; therapeutic use ; Animals ; Cell Proliferation ; drug effects ; Enzyme Activation ; drug effects ; Hypertension, Pulmonary ; drug therapy ; etiology ; Hypertrophy, Right Ventricular ; prevention & control ; Intracellular Signaling Peptides and Proteins ; antagonists & inhibitors ; physiology ; Male ; Muscle, Smooth, Vascular ; drug effects ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Serine-Threonine Kinases ; antagonists & inhibitors ; physiology ; Pulmonary Artery ; pathology ; Pulmonary Circulation ; drug effects ; Rats ; Rats, Wistar ; Systole ; drug effects ; Vasoconstriction ; drug effects ; rho-Associated Kinases ; rhoA GTP-Binding Protein ; physiology