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Objective:To analyze the clinical characteristics of a child with developmental epileptic encephalopathy caused by NR4A2 gene mutation, and to summarize the clinical phenotypes and genotypes to improve the clinician′s understanding of this disease. Methods:The clinical data of a child with developmental epileptic encephalopathy admitted to Linyi People′s Hospital in August 2022 were collected, video electroencephalogram, craniocerebral magnetic resonance imaging and family whole exon sequencing were improved, and the suspected mutation sites were verified by Sanger sequencing. Relevant literature was consulted to summarize the clinical phenotypes and genetic characteristics of nervous system diseases caused by NR4A2 gene. Results:It was found that there was a heterozygous missense mutation at the locus c.866G>A (p.A289H) of NR4A2 gene in the child, which was a de novo mutation, and both parents were wild type. According to the American Society of Medical Genetics and Genomics variation classification, it was assessed as a suspected pathogenic variation. Through literature review, there were 16 related cases reported internationally, with clinical phenotypes including mental retardation/mental retardation, language disorders, seizures, muscle tone changes and different psychological and behavioral problems. Conclusions:The NR4A2 gene is not only associated with dopa responsive disorders, but also with neurological development, intellectual impairment, language development delay, and epilepsy. The mutation of NR42A gene c.866G>A (p.A289H) is the genetic cause of the patient, and the detection of this locus expands the NR4A2 gene spectrum. NR4A2 gene is one of the pathogenic genes of developmental epileptic encephalopathy.
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Objective To explore the effect of acupuncture-rehabilitation therapy on the expression of transcription factor forkheadbox P3 (Foxp3) and retinoic acid-related orphan receptor γt (RORγt) protein in cerebral ischemic mice. Methods Forty-five female C57BL/6 mice were randomly assigned to sham operation group, model group, acupuncture group, rehabilitation group, and acupuncture-rehabilitation group, with nine mice in each group. Subsequently, each group was divided into three days, seven days and 14 days subgroups. The permanent middle cerebral artery occlusion models were established by the suture method, except the sham operation group. The sham operation group and the model group received no treatment. The acupuncture group received scalp cluster acupuncture, the rehabilitation group received treadmill training, and the acupuncture-rehabilitation group received scalp cluster acupuncture combined with treadmill training. Three days, seven days and 14 days after modeling, the modified Neurological Severity Score (mNSS) was obtained, and the expression of Foxp3 and RORγt in brain tissue of ischemic side was analyzed by Western blotting. Results The mNSS in the sham operation group was 0, and was higher in the model group than in the sham operation group at each postoperative time point. Three days after operation, the mNSS decreased in the rehabilitation group and the acupuncture-rehabilitation group, compared to the model group (P < 0.05). Fourteen days after operation, the mNSS decreased in the acupuncture-rehabilitation group, compared to the model group and acupuncture group (P < 0.05). The expression of Foxp3 protein was significantly lower in the acupuncture-rehabilitation group than in other groups at all time points after surgery( P < 0.05). Three days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in other groups (P < 0.05). Seven days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in the acupuncture group and sham operation group (P < 0.05). Conclusion Acupuncture-rehabilitation therapy may improve the tissue injury of cerebral ischemia mice, and promote the recovery of neural function, possibly by regulating Foxp3 and RORγT expression to reduce the level of inflammation, and then exert neuroprotective effects.
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Objective To explore the effect of acupuncture-rehabilitation therapy on the expression of transcription factor forkheadbox P3 (Foxp3) and retinoic acid-related orphan receptor γt (RORγt) protein in cerebral ischemic mice. Methods Forty-five female C57BL/6 mice were randomly assigned to sham operation group, model group, acupuncture group, rehabilitation group, and acupuncture-rehabilitation group, with nine mice in each group. Subsequently, each group was divided into three days, seven days and 14 days subgroups. The permanent middle cerebral artery occlusion models were established by the suture method, except the sham operation group. The sham operation group and the model group received no treatment. The acupuncture group received scalp cluster acupuncture, the rehabilitation group received treadmill training, and the acupuncture-rehabilitation group received scalp cluster acupuncture combined with treadmill training. Three days, seven days and 14 days after modeling, the modified Neurological Severity Score (mNSS) was obtained, and the expression of Foxp3 and RORγt in brain tissue of ischemic side was analyzed by Western blotting. Results The mNSS in the sham operation group was 0, and was higher in the model group than in the sham operation group at each postoperative time point. Three days after operation, the mNSS decreased in the rehabilitation group and the acupuncture-rehabilitation group, compared to the model group (P < 0.05). Fourteen days after operation, the mNSS decreased in the acupuncture-rehabilitation group, compared to the model group and acupuncture group (P < 0.05). The expression of Foxp3 protein was significantly lower in the acupuncture-rehabilitation group than in other groups at all time points after surgery( P < 0.05). Three days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in other groups (P < 0.05). Seven days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in the acupuncture group and sham operation group (P < 0.05). Conclusion Acupuncture-rehabilitation therapy may improve the tissue injury of cerebral ischemia mice, and promote the recovery of neural function, possibly by regulating Foxp3 and RORγT expression to reduce the level of inflammation, and then exert neuroprotective effects.
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<p><b>OBJECTIVE</b>To observe the effect of norcantharidin (NCTD) on collagen-induced arthritis (CIA) rats.</p><p><b>METHODS</b>Sixty Sprague-Dawley(SD) rats were randomly divided into 6 groups (n=10): normal group, CIA model group(model group), NCTD low-dose group [1.35 mg/(kg•d)], NCTD middle-dose group [2.7 mg/(kg•d)], NCTD high-dose group [5.4 mg/(kg•d)] and methotrexate (MTX) group [1.8 mg/(kg/w)]. Anesthetized rats were sacrificed by luxation of cervical vertebra after 4 weeks of administration. The arthritis scores were evaluated twice a week. The pathological changes in the ankle joints of rats were observed by hematoxylin-eosin (H&E) staining. The serum levels of interleukin (IL) 1β, IL-6, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), IL-17 and transform growth factor (TGF) β were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expression of retinoid-related orphan nuclear receptorγt (RORγt) and forkhead box P3 (Foxp3) in peripheral blood lymphocytes were confirmed by real-time polymerase chain reaction.</p><p><b>RESULTS</b>MTX and high-dose NCTD not only decreased the arthritis scores but also alleviated the pathological changes in CIA rats' ankle joints compared with the model group (P<0.05 or P<0.01). All doses of NCTD significantly inhibited the serum levels of IL-6, IL-17 and TNF-α in CIA rats (P<0.05). Only middle- and high-dose of NCTD prominently decreased serum IL-1β and TGF-β levels of CIA rats (P<0.05). However, NCTD has no effect on vascular endothelial growth factor (VEGF) level in CIA rats. The Foxp3 mRNA expression in all NCTD groups were increased significantly than in the model group (P<0.05). The mRNA expression of RORγt in NCTD high-dose group was decreased apparently in comparison with the model group (P<0.05).</p><p><b>CONCLUSIONS</b>NCTD showed therapeutic effect on CIA rats by inhibition of cytokines and regulation of Th17/Treg cells.</p>
Subject(s)
Animals , Male , Arthritis, Experimental , Blood , Drug Therapy , Pathology , Bridged Bicyclo Compounds, Heterocyclic , Pharmacology , Therapeutic Uses , Cytokines , Blood , Forkhead Transcription Factors , Metabolism , Joints , Pathology , Nuclear Receptor Subfamily 1, Group F, Member 3 , Metabolism , RNA, Messenger , Genetics , Metabolism , Rats, Sprague-DawleyABSTRACT
The nuclear receptor superfamily consists of the steroid and non-steroid hormone receptors and the orphan nuclear receptors. Small heterodimer partner (SHP) is an orphan family nuclear receptor that plays an essential role in the regulation of glucose and cholesterol metabolism. Recent studies reported a previously unidentified role for SHP in the regulation of innate immunity and inflammation. The innate immune system has a critical function in the initial response against a variety of microbial and danger signals. Activation of the innate immune response results in the induction of inflammatory cytokines and chemokines to promote anti-microbial effects. An excessive or uncontrolled inflammatory response is potentially harmful to the host, and can cause tissue damage or pathological threat. Therefore, the innate immune response should be tightly regulated to enhance host defense while preventing unwanted immune pathologic responses. In this review, we discuss recent studies showing that SHP is involved in the negative regulation of toll-like receptor-induced and NLRP3 (NACHT, LRR and PYD domains-containing protein 3)-mediated inflammatory responses in innate immune cells. Understanding the function of SHP in innate immune cells will allow us to prevent or modulate acute and chronic inflammation processes in cases where dysregulated innate immune activation results in damage to normal tissues.
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Child , Humans , Chemokines , Child, Orphaned , Cholesterol , Cytokines , Glucose , Immune System , Immunity, Innate , Inflammasomes , Inflammation , Metabolism , Orphan Nuclear Receptors , Social Control, Formal , Toll-Like ReceptorsABSTRACT
Orphan nuclear receptor NR4A1 from the NR4A subfamily is one of the transcriptional factors that have not identified specific ligands .Previous studies have found that NR4A1 could regulate cell proliferation ,apoptosis ,differentiation and stress responses by changing gene expression ,post-translational modification and interactions between coregulatory pro-teins .Recently ,it has shown that NR4A1 has an abnormal expression in human atherosclerotic lesions and has been identified as a key regulator gene in vascular cells dysfunction .Regulating NR4A1 expression can have an important impact on the prolif-eration of smooth muscle cell and endothelial cell activation ,meanwhile it could reduce inflammation ,foam cell formation and lipid deposition ,inhibit vascular remodeling ,and prevent the development of atherosclerosis .These studies suggest that NR4A1 might be a novel target for drug development in prevention and treatment of atherosclerosis .
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Objective To study the changes in number and function of peripheral blood T helper cell 17(Th17) in acute urticaria patients .Methods The percentages of Th17 in peripheral blood from 50 acute urticaria patients and 50 healthy persons were ana‐lyzed by immunofluorescence staining and bicolor flow cytometry (FCM ) in vitro .Retinoic acid‐related orphan nuclear receptor γt (RORγt) mRNA from the same research objects were detected by quantitative realtime PCR (qPCR) method .Peripheral blood transforming growth factor‐β(TGF‐β) ,interleukin(IL)‐6 ,IL‐17A and IL‐17F were tested by enzyme linked immunosorbent assay (ELISA) from the same research objects .Results The quantity of percentages of Th17(t= 36 .634 1 ,P< 0 .05) and levels of RORγt mRNA(t=23 .840 1 ,P<0 .05) in urticaria patients were higher than those in healthy persons obviously .Meanwhile ,the levels of TGF‐β(t=15 .521 1 ,P<0 .05) ,IL‐6(t=7 .247 3 ,P<0 .05) ,IL‐17A(t=15 .415 3 ,P<0 .05) and IL‐17F(t=13 .032 1 , P<0 .05) in urticaria patients were higher than those in healthy persons significantly .Conclusion Dysfunction of Th17 in periph‐eral blood may involve in the immunopathogenesis of acute urticaria .
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Orphan nuclear receptor Tailless like protein(TLX) is a transcription factor like a nucleoprotein. The newest research has found that TLX had an mportant influence on maintenance of cell functions, and played a critical role n neural stem cell proliferation. This review discusses the roles that the orphan nuclear receptor TLX plays on the process of neural stem cell proliferation and analyzes the molecular mechanisms of TLX. This review may also provide a new potential drug target for the treatment of neurode-generative diseases.
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Background In the past few decades,the balance of Th1/Th2 is often used to explain the immune mechanisms of fungal infection and fungal disease.More recently,a novel subset of CD4+ effector Th cells has been found to participate in anti-fungal infection response.However,whether Th17 is involved in the immune response in fungal keratitis is unclear up to now.Objective Present study was to investigate the expression change of Th17 type cytokine and its specific transcription factor,retinoid-related orphan nuclear receptor gamma t (RORγt),in the cornea of Fusarium solani keratitis.Methods Ninety-six clean BALB/c mice were divided into Fusarium solani keratitis model group and control group by randomized digital table.Fusarium solani keratitis models were established by epikeratophakia-assisted corneal epithelial erasion and interlayerly injection of 5 μl (1 × 106 CFU/ml) Fusarium solani solution in the right eyes,and the equal volume of PBS was injected in the same way in the control group.10％ KOH wet film was used to examine the fungal hyphea and funga strain was identified by inoculation.The corneas were examined under the slit lamp microscope 1 day,3,5,7 days after modeling and the inflammatory response was scored based on the criteria of Wu and Hu.The histopathological examination of corneas was performed in the time points above.Real time fluorescence quantitative PCR was used to detect the expression levels of interleukin-17 (IL-17) mRNA and RORγt mRNA in the corneas.The expression of IL-17 protein in the corneas was detected by ELISA.The use and raise of the mice followed the Statement of Association for Research in Vision and Ophthalmology.Results The inflammatory scores were 3.2±0.8,6.6± 1.1,9.4± 1.1 and 6.8±0.8 in 1 day,3,5,7 days after modeling,showing a significant difference among them (F =89.786,P =0.010).The inflammatory scores were higher in the third and seventh day than that in the first day (P＜0.05),but they were significantly lower than that in the fifth day (P＜0.05).The infiltration of inflammatory cells showed a coincident tendency with the score.The expressing levels of IL-17 mRNA (2-ΔΔCt) in the corneas were 4.12±0.73,20.72±1.81 and 14.16±1.88 in 3,5,7 days after modeling,with statistically significant differences in comparison with those in the control group (P＜0.01),and the expression level was significantly higher in the fifth day than those in the first,third and seventh day in the model group(P＜0.01).The expression levels of IL-17 protein (ng/g) were significantly increased 1 day,3,5,7 days in the model group compared with the control group (P＜0.01).A similar change was found in the expression of RORγt mRNA to that of IL-17 mRNA.Conclusions Expressions of IL-17 and its transcription factor RORγt upregulate in the fungal keratitis and has an association with inflammatory degree,which suggests that Th17 subset may play an important role in the immune responses of fungal keratitis.
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In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-alpha transcriptional activity. We found that Nur77 associates and stabilizes HIF-1alpha via indirect interaction. Nur77 was found to interact with pVHL in vivo via the alpha-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1alpha and ultimately increased the stability and transcriptional activity of HIF-1alpha. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1alpha. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-alpha. Moreover, Nur77 could not further stabilize HIF-2alpha in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-alpha by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-alpha transcriptional activity under the non- hypoxic conditions.
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Animals , Humans , Rats , DNA-Binding Proteins/chemistry , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Models, Biological , PC12 Cells , Protein Binding , Protein Processing, Post-Translational , Protein Structure, Tertiary , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Steroid/chemistry , Thermodynamics , Transcription Factors/chemistry , Transcriptional Activation/genetics , Ubiquitination , Up-Regulation/genetics , Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitorsABSTRACT
Objective To study the effect of Nurrl gene on the differentiation of rats' marrow stromal cells(MSCs) into neurous under the co-inducement of total panax notoginserg saponins(tPNS) and all-trans-retineic acid(ATRA) by coloning the Nurrl gene and transfecting it into MSCs. Methods Expressing plasmids pcDNA3.1-hygro-Nurrl were cloned,then transfected into MSCs with lipofectamine 2000.To begin with,MSCs were subcultured into 6-wells cultured plate at about 5?10~5 cells/well density and the wells were divided into four groups randomly which were Nurrl+tPNS/ATRA group,tPNS/ATRA group,Nurrl group and control group.Secondly,the plasmids were introduced to the MSCs in Nurrl+tPNS/ATRA group and Nurrl group,then protein expression of Nurrl was identified with immunocytochemistry.Thirdly,after the MSCs and plasmids had been co-cultured for 48 hours,cells in Nurrl+tPNS/ATRA group and tPNS/ATRA group were induced with BME in advance then with tPNS/ATRA in due form.For cells in Nurrl and control group,the only difference was that tPNS/ATRA was replaced with the culture.Finally we compared the different percentage of positive cells in four groups with TH,AChE and GABA antibodies by immunocytochemistry method. Results The immunocytochemical test showed that the MSCs transfected with Nurrl gene expressed Nurrl protein.The percentage of positive cells of TH antibody in Nurrl+tPNS/ATRA group was(38.4?4.6)% distinctly higher than that of tPNS/ATRA group,which was(5.9?3.4)%.Conclusion With tPNS/ATRA induced and immunocytochemistry of TH,positive cells percentage in Nurrl+tPNS/ATRA group was higher than that in tPNS/ATRA group,which showed a statistic difference.And the inducing function of tPNS and ATRA in MSCs differentiating into neurons was definite.