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Role of p300 in the pathogenesis of Henoch-Schonlein purpura nephritis and as a new target of glucocorticoid therapy in mice

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Chinese Medical Journal 2019年第16期132卷 1942-1950页

作者： Ming-Yu Jiang Wei Li Xiang-Ping Xu Jie-Qing Zhou Hong Jiang Department of Pediatrics The First Affiliated Hospital of China Medical UniversityShenyangLiaoning 110001China Department of Pediatrics The First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiang 150001China

Background: Henoch-Schonlein purpura nephritis (HSPN) is a very common secondary kidney disease of childhood. Its pathogenesis and the treatment mechanism of glucocorticoid have not been fully elucidated. The aim of this study was to determine the relationship between p300 and the pathogenesis, glucocorticoid therapy in mice with HSPN, respectively. Methods: Forty-eight C57BL/6N male mice, weighing 18 to 20 g, were selected (3–4 weeks old, n = 8 per group). The mice in the normal control group (Group I) were given normal solvent and the HSPN model group (Group II) were given sensitizing drugs. The mice in Group III were injected intraperitoneally with dexamethasone after being given sensitizing drugs. Meanwhile, mice in Groups IV, V and VI with conditional knockout of p300 were also given normal solvent, sensitizing drugs and dexamethasone. The levels of serum IgA, creatinine, and circulating immune complex (CIC) concentrations, 24 h urinary protein and urinary erythrocyte in C57 wild mice, and p300 conditional knockout mice in each group were measured. The expression of p300 in renal tissues and the expression of glucocorticoid receptor (GR)α and β, transforming growth factor (TGF)-β1, and activator protein (AP)-1 after dexamethasone treatment were determined by real-time polymerase chain reaction and Western blotting. Results: Compared with the normal solvent control group (Group I), the expression of p300 mRNA in the model group (Group II) was significantly up-regulated. Western blotting further confirmed the result. Urinary erythrocyte count, 24 h urinary protein quantification, serum IgA, CIC, and renal pathologic score in Group V were distinctly decreased compared with non-knockout mice in Group II (9.7 ± 3.8 per high-power field [/HP] vs. 18.7 ± 6.2/HP, t = 1.828, P = 0.043;0.18 ± 0.06 g/24 h vs. 0.36 ± 0.08 g/24 h, t = 1.837, P = 0.042;18.78 ± 0.85 mg/mL vs. 38.46 ± 0.46 mg/mL, t = 1.925, P = 0.038;0.80 ± 0.27 μg/mL vs. 1.64 ± 0.47 μg/mL, t = 1.892, P = 0.04

关键词： p300 Henoch-Schonlein purpura nephritis Pathogenesis glucocorticoid treatment

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Effects of glucocorticoid?Induced Transcript 1 Gene Deficiency on glucocorticoid Activation in Asthmatic Mice

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Chinese Medical Journal 2018年第23期131卷 2817-2826页

作者： Cheng-Ping Hu Qiu-Fen Xun Xiao-Zhao Li Xin-Yue Hu Ling Qin Ruo-Xi He Jun-Tao Feng Department of Respiratory and Critical Care Medicine Key Cite of National Clinical Research Center for Respiratory DiseaseXiangya HospitalCentral South UniversityChangshaHunan 410008China Department of Respiratory Medicine The Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi 330006China Department of Nephrology Xiangya HospitalCentral South UniversityChangshaHunan 410008China

Background: glucocorticoid (GC) is the first?line therapy for asthma, but some asthmatics are insensitive to it. glucocorticoid?induced transcript 1 gene (GLCCI1) is reported to be associated with GCs efficiency in asthmatics, while its exact mechanism remains unknown. Methods: A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV1) and GLCCI1 expression were detected. Asthma model was constructed in wild?type and GLCCI1 knockout (GLCCI1?/?) mice. glucocorticoid receptor (GR) and mitogen?activated protein kinase phosphatase 1 (MKP?1) expression were detected by polymerase chain reaction and Western blotting (WB). The phosphorylation of p38 mitogen?activated protein kinase (MAPK) was also detected by WB. Results: In asthmatic patients, the change of FEV1 was well positively correlated with change of GLCCI1 expression (r = 0.430, P = 0.022). In animal experiment, GR and MKP?1 mRNA levels were significantly decreased in asthmatic mice than in control mice (wild?type: GR: 0.769 vs. 1.000, P = 0.022; MKP?1: 0.493 vs. 1.000, P < 0.001. GLCCI1?/?: GR: 0.629 vs. 1.645, P < 0.001; MKP?1: 0.377 vs. 2.146, P < 0.001). Hydroprednisone treatment significantly increased GR and MKP?1 mRNA expression levels than in asthmatic groups; however, GLCCI1?/?.asthmatic mice had less improvement (wild?type: GR: 1.517 vs. 0.769, P = 0.023; MKP?1: 1.036 vs. 0.493, P = 0.003. GLCCI1?/?: GR: 0.846 vs. 0.629, P = 0.116; MKP?1: 0.475 vs. 0.377, P = 0.388). GLCCI1?/? asthmatic mice had more obvious phosphorylation of p38 MAPK than wild?type asthmatic mice (9.060 vs. 3.484, P < 0.001). It was still higher even though after hydroprednisone treatment (6.440 vs. 2.630, P < 0.001). Conclusions: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP?1 and leads to more obvious phosphorylation of p38 MAPK, leading to a decremental sensitivity to GCs.

关键词： Asthma glucocorticoid Receptor glucocorticoid-Induced Transcript 1 glucocorticoids Mitogen-Activated Protein Kinase Phosphatase-1

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Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2020年第9期21卷 727-739页

作者： Jing-wen DENG Qin YANG Xiao-peng CAI Jia-ming ZHOU Wei-gao E Yan-dong AN Qiu-xian ZHENG Meng HONG Yan-li REN Jun GUAN Gang WANG Shu-jing LAI Zhi CHEN State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003China Center for Stem Cell and Regenerative Medicine Zhejiang University School of MedicineHangzhou 310058China Becton Dickinson and CompanyShanghai 200126China

Background and objective:Acute liver failure(ALF)is a type of disease with high mortality and rapid progression with no specific treatment methods currently *** exert beneficial clinical effects on therapy for ***,the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to *** purpose of this study was to investigate the specific immunological mechanism of dexamethasone(Dex)on treatment of ALF induced by lipopolysaccharide(LPS)/D-galactosamine(D-Ga IN)in ***:Male C57 BL/6 mice were given LPS and D-Ga IN by intraperitoneal injection to establish an animal model of *** was administrated to these mice and its therapeutic effect was *** and eosin(H&E)staining was used to determine liver *** flow cytometry,cytometric bead array(CBA)method,and next-generation sequencing were performed to detect changes of messenger RNA(m RNA)in immune cells,cytokines,and Kupffer cells,***:A mouse model of ALF can be constructed successfully using LPS/D-Ga IN,which causes a cytokine storm in early disease *** immune cells change markedly with progression of liver *** use of Dex,at 0 h rather than 1 h,could significantly improve the progression of ALF induced by LPS/D-Ga IN in *** of innate immune cells,especially Kupffer cells and neutrophils,increased significantly in the Dex-treated *** vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor(Gr).Sequencing of Kupffer cells revealed that Dex could increase m RNA transcription level of nuclear receptor subfamily 4 group A member 1(Nr4 a1),and that this effect disappeared after Gr ***:In LPS/D-Ga IN-induced ALF mice,early administration of Dex improved ALF by increasing the numbers of innate immune cells,especially Kupffer cells and ***-dependent Nr4 a1 upregul

关键词： glucocorticoid Dexamethasone Kupffer cells Acute liver failure Nuclear receptor subfamily 4 group A member 1(Nr4a1)

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Cathelicidin LL-37 restoring glucocorticoid function in smoking and lipopolysaccharide-induced airway inflammation in rats

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Chinese Medical Journal 2019年第5期132卷 569-576页

作者： Jian-Zhen Weng Yan Wang Tie-Ying Sun Department of Respiratory and Critical Care Medicine Beijing Hospital National Center of Gerontology Beijing 100730 China

Background glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD). Nevertheless, corticosteroid insensitivity is a major barrier to the effective treatment of COPD and its mechanism remains unclear. This study aimed to evaluate the effect of cathelicidin LL-37 on corticosteroid insensitivity in COPD rat model, and to explore the involved mechanisms. Methods COPD model was established by exposing male Wistar rats to cigarette smoke combined with intratracheal instillation of lipopolysaccharide (LPS). Inhaled budesonide and LL-37 were consequently applied to COPD models separately or collectively to confirm the effects on inflammatory cytokines (tumor necrosis factor [TNF]-α and transforming growth factor [TGF]-β)by enzymelinked immunosorbent assay (ELISA) and lung tissue histopathological morphology. Expression of histone deacetylase-2 (HDAC2) and phosphorylation of Akt (p-AKT) in lung were also measured. Results Briefly, COPD model rats showed an increased basal release of inflammatory cytokines (lung TNF-α:45.7±6.1 vs. 20.1 ± 3.8pg/mL, P<0.01;serum TNF-α:8.9±1.2 vs. 6.7±0.5pg/mL, P = 0.01;lung TGF-β:122.4±20.8 vs. 81.9±10.8pg/mL, P<0.01;serum TGF-β:38.9±8.5 vs. 20.6±2.3 pg/mL, P<0.01) and COPD related lung tissue histopathological changes, as well as corticosteroid resistance molecular profile characterized by an increase in phosphoinositide 3-kinase (PI3K)/Akt (0.5±0.1 fold of control vs. 0.2±0.1 fold of control, P = 0.04) and a decrease in HDAC2 expression and activity (expression: 13.1 ±0.4 μmol/μg vs. 17.4± 1.1 μmol/μg, P<0.01;activity: 1.1 ±0.1 unit vs. 1.4±0.1 unit, P< 0.01), compared with control group. In addition, LL-37 enhanced the anti-inflammatory effect of budesonide in an additive manner. Treatment with combination of inhaled corticosteroids (ICS) and LL-37 led to a significant increase of HDAC2 expression and activity (expression: 15.7±0.4 μmol/μg vs. 14.1 ±0.9 μmol/μg, P<0.01;activity: 1.3±0.1 unit

关键词： Chronic obstructive pulmonary disease glucocorticoid insensitivity Histone deacetylase-2 Phosphoinositide 3-kinase/Akt pathway

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A patient with glucocorticoid hypersensitivity syndrome

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Chinese Medical Journal 2022年第21期135卷 2611-2613页

作者： Chenwei Wu Anran Ma Quanya Sun Xiaolong Zhao Department of Endocrinology and Metabolism Shanghai Public Health Clinical CenterShanghai Medical SchoolFudan UniversityShanghaiChina Department of Endocrinology and Metabolism Huashan HospitalShanghai Medical SchoolFudan UniversityShanghaiChina

To the Editor:Primary generalized glucocorticoid hypersensitivity is a rare condition characterized by generalized,partial target-tissue hypersensitivity to ***,low concentration of glucocorticoids is sufficient to effectively maintain the patient’s cell physiological effects and to suppress the hypothalamic-pituitary-adrenal *** study aims to provide some insight into when glucocorticoid hypersensitivity should be considered and how to diagnose *** also propose a diagnostic flow chart for glucocorticoid hypersensitivity for the first time based on our experience and previous literature *** study was reviewed and approved by the Institutional Review Board of Huashan Hospital,Fudan University(***2020-049).

关键词： glucocorticoid hypersensitivity patient

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Morphological and behavioral consequences of recurrent seizures in neo-natal rats are associated with glucocorticoid levels

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Neuroscience Bulletin 2007年第2期23卷 83-91页

作者：石秀玉王纪文雷格非孙若鹏山东大学齐鲁医院儿科济南250012

Objective It is well documented that epilepsy can increase neurogenesis in certain brain regions and cause behavioral alternations in patients and different epileptic animal models. A series of experimental studies have demonstrated that neurogenesis is regulated by various factors including glucocorticoid （CORT）, which can reduce neurogenesis. Most of studies in animal have been focused on adulthood stage, while the effect of recurrent seizures to immature brain in neonatal period has not been well established. This study was designed to investigate how the recurrent seizures occurred in the neonatal period affected the immature brain and how CORT regulated neurogenesis in immature animals. Methods Neonatal rats were subjected to 3 pilocarpine-induced seizures from postnatal day 1 to day 7. Then neurogenesis at different postnatal ages （i.e. P8, P12, P22, P50） was observed. Behavioral performance was tested when the rats were mature （P40）, and plasma CORT levels following recurrent seizures were simultaneously monitored. Results Rats with neonatal seizures had a significant reduction in the number of Bromodeoxyuridine （BrdU） labeled cells in the dentate gyrus compared with the control groups when the animals were euthanized on P8 or P12 （P 〈 0.05）; whereas there was no difference between the two groups on P22. Until P50, rats with neonatal seizures had increased number of BrdU-labeled cells compared with the control group （P 〈 0.05）. In Morris water maze task, pilocarpine-treated rats were significantly slower than the control rats at the first and second day, and there were no differences at other days. In probe trial, there was no significant difference in time spent in the goal quadrant between the two groups. Endocrine studies showed a correla- tion between the number of BrdU positive cells and the CORT level. Sustained increase in circulating CORT levels was observed following neonatal seizures on P8 and P12. Conclusion Neonatal recurrent seizures can biphasel

关键词： epilepsy development cell proliferation learning memory glucocorticoid

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Study of the Effects of glucocorticoid on Growth and Adult Final Height in Children with Primary Nephrotic Syndrome

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Open Journal of Nephrology 2024年第1期14卷 1-9页

作者： Fazhan Zhong Miao Zhang Yan Gao Department of Pediatric Nephrology Guangzhou Women and Children’s Medical Center Guangzhou Medical University Guangzhou China

Objective: To analyze the epidemiological characteristics of growth, as well as factors associated with growth retardation in children with primary nephrotic syndrome (PNS), and to investigate the effect of glucocorticoid (GC) use duration on growth retardation in these children. Methods: Clinical and laboratory data of 353 PNS children treated at our hospital from July 2014 to June 2015 were collected through the medical record management system. Height, weight, and GC usage were recorded. Follow-up assessments were conducted in August 2022 for the original group, recording height, weight, and GC usage. Height and weight were evaluated using standard deviation scores (SDS). Categorical data were analyzed using chi-square test while continuous measurement data were analyzed using t-test or rank-sum test. Linear regression was used to assess the association between two single independent variables, and logistic regression analysis was used to screen for risk factors related to growth retardation in children with PNS. Results: Among the 353 PNS children enrolled in this study, male-to-female ratio of 2.64:1 (256 males vs 97 females). A total of 119 children exhibited growth retardation, incidence rate of 33.71%. The duration of GC usage among those with growth retardation was significantly longer compared to those without it (762.81 ± 934.50 days vs 263.77 ± 420.49 days;p Conclusion: PNS children treated with GC have a high incidence of growth retardation, and a high proportion of short stature in adulthood, especially in children with growth retardation in childhood, most of them have short stature after grown up. Time of GC usage is a risk factor for growth retardation in children with PNS.

关键词： Primary Nephrotic Syndrome glucocorticoid Children Growth Retardation Adult Height

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Traditional Chinese medicine combined with low-dose glucocorticoid for treating nephrotic syndrome: A case report

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Drug Combination Therapy 2020年第1期2卷 34-44页

作者： Shu-Ting Huang Si-Chao Ding Gan-Feng Xu Heilongjiang Academy of Traditional Chinese Medicine Harbin 150036China Heitongjiang Provincial Hospital of Traditional Chinese Medicine Harbin 150036China

Nephrotic syndrome(NS)is a common refractory clinical disease that can develop into end-stage renal disease(ESRD)if cannot be *** present,in Western medicine,glucocorticoid or immunosuppressant drugs with heavy dose and long course are used for the therapy of *** are still few reports on the combined treatment of traditional Chinese medicine and low-dose glucocorticoid for ***,we reported a case of a 48-year-old man diagnosed with NS,accompanied by severe pulmonary infection,abundant proteinuria,and pleural *** traditional Chinese and Western medicine was used as the therapeutic regimen of this *** Chinese medicine(TCM)mainly focused on invigorating spleen and kidney,promoting blood circulation,removing blood stasis and promoting diuresis,and Chinese patent medicines or TCM immunosuppressants were given to consolidate the *** Western medicine,small dose and short course glucocorticoids combined with symptomatic treatment were ***,proteinuria subsided after 5 months treatment with integrated TCM and Western medicine and all laboratory reports were negative after 10 months,which has been normal so far(July 2019).This case report indicates that the combination of TCM and low-dose glucocorticoid is effective in curing NS,with low recurrence rate and few side effects.

关键词： Nephrotic syndrome Traditional Chinese medicine Integrated Chinese and Western medicine Treatment based on syndrome differentiation glucocorticoid

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Effect of moxibustion at Shenshu(BL 23) on the ethology,corticosterone and glucocorticoid receptor in aging rats

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Journal of Acupuncture and Tuina Science 2016年第4期14卷 250-256页

作者：雷菲沈文宾崔云华吴焕淦吴璐一刘慧荣包春辉赵继梦周次利赵琛杨燕萍(译) Shanghai R.esearch Institute of Acupuncture and Meridian Shanghai 200630China Shanghai University of Traditional Chinese Medicine Shanghai 201203China Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Shanghai University of Traditional Chinese MedicineShanghai 200437China Shanghai Qigong Research Institute Shanghai 200030China 不详

Objective：To observe the effect of moxibustion on learning and memory abilities,corticosterone and glucocorticoid receptor（GR） in subacute aging ***：Twenty four Sprague-Dawley（SD） rats were randomly divided into a normal group,a model group and a moxibustion group,8 rats in each *** in the model group and the moxibustion group were subcutaneously injected with 25% D-galactose [125 mg/（kg·bw）] for 40 d continuous;rats in the normal group were injected with saline at the same position for 40 d *** in the moxibustion group were given mild moxibustion at bilateral Shenshu（BL 23） at the same time of modeling;rats in the normal group and the model group were only identically grabbed without moxibustion for 40 *** learning and memory abilities of rats were observed using the Morris water maze at the end of the *** aorta blood and thymus were collected after water maze ***-linked immunosorbent assay（ELISA） was used to detect serum corticosterone level,and immunohistochemical method was used to detect the expression of thymus ***：Compared with the normal group,rats in the model group showed that a significantly longer escape latency time（P〈0.01） on the third and the fourth days;number of times crossing the platform in 70 s significantly reduced（P〈0.01）;activity times in the fourth quadrant significantly decreased（P〈0.05）;serum corticosterone levels increased（P〈0.01）;thymus GR expression decreased（P〈0.05）.Compared with the model group,rats in the moxibustion group showed that the escape latency times were significantly shorter on the third,the fourth and the fifth days（P〈0.01,P〈0.05）;number of times crossing the platform in 70 s significantly increased（P〈0.05）;activity times in the fourth quadrant significantly increased（P〈0.05）;serum corticosterone levels decreased（P〈0.05）;thymus GR expression increased（P〈0.05）.Conclusion：Moxibustion could improve the learning and memory abilities of subacute aging rats,down

关键词： Moxibustion Therapy Mild Moxibustion Point Shenshu(BL 23) Aging Corticosterone Receptors glucocorticoid

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Odd couple: The unexpected partnership of glucocorticoid hormones and cysteinyl-leukotrienes in the extrinsic regulation of murine bone-marrow eosinopoiesis

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World Journal of Experimental Medicine 2017年第1期7卷 11-24页

作者： Pedro Xavier-Elsas Daniela Masid-de-Brito Bruno Marques Vieira Maria Ignez C Gaspar-Elsas Department Immu-nology Instituto de Microbiologia Paulo de GóesUniversidade Federal do Rio de Janeiro Department Pediatrics Instituto Nacional de Saúde da Mulherda Crian?a e do Adolescente Fernandes FigueiraFIOCRUZ

Granulopoiesis in murine bone-marrow is regulated by both intrinsic and extrinsic factors(including hormones, drugs, inflammatory mediators and cytokines). Eosinophils, a minor subpopulation of circulating leukocytes, which remains better understood in its contributions to tissue injury in allergic disease than in its presumably beneficial actions in host defense, provide a striking example of joint regulation of granulopoiesis within murine bone-marrow by all of these classes of extrinsic factors. We first described the upregulation of eosinopoiesis in bone-marrow of allergen-sensitized mice following airway allergen challenge. Over the last decade, we were able to show a critical role for endogenous glucocorticoid hormones and cytokines in mediating this phenomenon through modification of cytokine effects, thereby supporting a positive association between stress hormones and allergic reactions. We have further shown that cysteinylleukotrienes(Cys LT), a major proinflammatory class of lipid mediators, generated through the 5-lipoxygenase pathway, upregulate bone-marrow eosinopoiesis in vivo and in vitro. Cys LT mediate the positive effects of drugs(indomethacin and aspirin) and of proallergic cytokines(eotaxin/CCL11 and interleukin-13) on in vitro eosinopoiesis. While these actions of endogenous GC and Cys LT might seem unrelated and even antagonistic, we demonstrated a critical partnership of these mediators in vivo, shedding light on mechanisms linking stress to allergy: GC are required for Cys LT-mediated upregulation of bone-marrow eosinopoiesis in vivo, but also attenuate subsequent ex vivo responses to Cys LT. GC and Cys LT therefore work together to induce eosinophilia, but through subtle regulatory mechanisms also limit the magnitude of subsequent bone-marrow responses to allergen.

关键词： Bone marrow Leukotriene Eosinophil Stress glucocorticoid

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