Drug Resistance ; Glucocorticoids ; therapeutic use ; Humans ; Intracellular Signaling Peptides and Proteins ; genetics ; Membrane Proteins ; genetics ; Mutation ; Nephrotic Syndrome ; drug therapy ; genetics

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*

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

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 ; 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

OBJECTIVETo investigate the effects of sodium ferulate (SF), an intravenous drug made from traditional Chinese herbs, on activation of postsynaptic density-95 (PSD-95) and neuroprotection after transient cerebral artery occlusion in rats.

METHODSForty-six male Sprague-Dawley rats were randomized into 2 groups (n=23 in each group): the control group and the SF group. After anesthesia, the middle cerebral artery occlusion (MCAO) was conducted with the intraluminal filament technique. The neurological deficit was assessed with the method devised by Bederson et al. The 2,3,4-triphenyltetrazolium chloride staining was used to assess the infarct volume. We adopted a modified six-point scale to conduct neurobehavioral evaluation. Immediately the activation of postsynaptic density-95 (PSD-95) was studied with Western blot analysis system in the cortex and striatum of rat brain.

RESULTSThe neurologic deficit score of the SF group decreased substantially compared with that of the control group (P<0.05). The infarct volume of the control group (168.1 mm3 +/- 42.2 mm3) was significantly larger than that of the SF group (61.5 mm3 +/- 28.7 mm3) at 24 hours after reperfusion (P<0.01). And the rats showed some neurological deficit. The activity of PSD-95 in the SF group at most timepoints was less than that in the control group. No upregulation of PSD-95 protein could be detected in the contralateral cortex.

CONCLUSIONSSodium ferulate can induce a neuroprotective effect against the transient focal cerebral ischemic injury and weaken the activation of PSD-95 in ischemic area after MCAO.

Animals ; Blotting, Western ; Brain Infarction ; drug therapy ; etiology ; Coumaric Acids ; therapeutic use ; Disks Large Homolog 4 Protein ; Intracellular Signaling Peptides and Proteins ; drug effects ; metabolism ; Ischemic Attack, Transient ; complications ; drug therapy ; metabolism ; Male ; Membrane Proteins ; drug effects ; metabolism ; Neuroprotective Agents ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome

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 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

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 examine the effect of multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) on proteinuria and expression of slit diaphragm-associated molecules such as nephrin and podocin in glomerulonephritis induced by anti-Thy1.1 antibody (anti-Thy1 . 1 GN).

METHODSAnti-Thy1.1 GN was induced in rats by a single intravenous injection with 500 microg of anti-Thy1.1 mAb 1-22-3. Fourteen rats were randomly divided into 2 groups, the GTW-treated group and vehicle treated group, and sacrificed on day 14 in Experiment 1 or on day 7 in Experiment 2 after induction of Anti-Thy1.1 GN. Daily oral administration of GTW and vehicle as a control was started from 3 days before injection or at the same time of injection to the day of sacrifice in Experiment 1 or 2. Proteinuria was determined during 14 days in Experiment 1 or during 7 days in Experiment 2. From kidneys taken at sacrifice, glomerular morphological changes, glomerular macrophage infiltration, glomerular expression of nephrin and podocin, and its mRNA expression in renal tissue were examined.

RESULTSIn Experiment 1, proteinuria and mesangial matrix expansion were significantly attenuated by GTW treatment. No difference in staining intensity of nephrin and podocin in glomeruli was observed between GTW treated group and vehicle treated group on day 14. In Experiment 2, GTW treatment significantly ameliorated proteinuria, mesangial injury and activated macrophage infiltration in glomerulus. In addition, it significantly increased the expression of nephrin and podocin and its mRNA expression in glomeruli on day 7.

CONCLUSIONIn anti-Thy1.1 GN, the reduced expression of nephrin and podocin may contribute to the development of mesangial injury and proteinuria. The findings suggest that GTW ameliorates not only proteinuria but also mesangial lesions in anti-Thy1 . 1 GN most likely by increasing the expression of nephrin and podocin.

Animals ; Female ; Fluorescent Antibody Technique ; Glomerulonephritis, Membranoproliferative ; drug therapy ; immunology ; Glycosides ; therapeutic use ; Intracellular Signaling Peptides and Proteins ; genetics ; Isoantibodies ; immunology ; Membrane Proteins ; biosynthesis ; genetics ; Phytotherapy ; Podocytes ; drug effects ; metabolism ; pathology ; Proteinuria ; drug therapy ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Thy-1 Antigens ; immunology ; Tripterygium ; chemistry