BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary...BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary sites between lncRNA SRA1,miRNA-363-5p,and phospholysine phosphohistidine inorganic pyrophosphate phosphatase(LHPP)predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression.AIM To investigate the molecular events of SRA1 in the malignant behavior in ESCC.METHODS Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired.SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction.Cell counting Kit-8 assay,transwell invasion assay,glycolysis assay,and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1.The t-test and theχ2 test were used for comparison between groups.Survival curve analysis was performed using the Kaplan-Meier method.RESULTS SRA1 downregulation was identified in ESCC.ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression.The introduction of SRA1 inhibited cell proliferation,glucose uptake,and lactate production in ESCC.In vivo,the growth of ESCC was hindered by SRA1 overexpression.Then,SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p.Lastly,the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1.CONCLUSION SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis.The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.展开更多
AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic seq...AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically signifi cant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.展开更多
Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider t...Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, theiruse of corepressors and coactivators to modify chromatinstructure and the implications for transcriptional control.The assembly of specific nucleoprotein architectures andtargeted histone modification emerge as central controlling elements for gene expression.展开更多
Background: While the role of adipocyte-derived hormones in breast cancer pathogenesis well studied, it is speculated that there is a crosstalk between adipocytokines and Esterogen receptor(ER) signaling. To test this...Background: While the role of adipocyte-derived hormones in breast cancer pathogenesis well studied, it is speculated that there is a crosstalk between adipocytokines and Esterogen receptor(ER) signaling. To test this hypothesis we evaluate the possible correlation between serum levels of adipocytokins with steroid hormone receptors gene expression in breast cancer patients. Methods: In this case-control study, 70 women with breast cancer participated with different grades of obesity (36 none obese, BMI 0.05). In case of leptin, we observed a positive correlation between leptin and ERα and PR mRNA. (r = 0.553, n = 64, p < 0.001, r = 0.359, n = 64, p = 0.002 and a reverse significant correlation between leptin and ERβ (r= –0.506, n = 64 and p < 0.001). We also observed a significant correlation between TNFα and IL6 with steroid receptors gene expression in samples (P < 0.05). Conclusion: As the presence of steroid receptors are used as the most common prognostic markers in breast cancer patients, so targeting adipocytokines as potential regulators of steroid receptorsgene expression can be a new approach in treatment of obese breast cancer subjects.展开更多
Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- yea...Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- year survival rate through stratification and multivariatc analysis. The results showed that histologic tumor type and grading, lymphnode status, ER value and patient age took more important role in patient survival, and SR, especially, conferred survival advantage in advanced cases with tumor size larger than 2 cm, node involved, or TNM Stage Ⅱ-Ⅲ.展开更多
Breast cancer(BC)is the most common cancer among women,and current available therapies often have high success rates.Nevertheless,BC might acquire drug resistance and sometimes relapse.Current knowledge about the most...Breast cancer(BC)is the most common cancer among women,and current available therapies often have high success rates.Nevertheless,BC might acquire drug resistance and sometimes relapse.Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC,the so-called“BC stem cells”(BCSCs).The role of BCSCs in cancer formation,growth,invasiveness,therapy resistance and tumor recurrence is becoming increasingly clear.The growth and metastatic properties of BCSCs are regulated by different pathways,which are only partially known.Sex steroid receptors(SSRs),which are involved in BC etiology and progression,promote BCSC proliferation,dedifferentiation and migration.However,in the literature,there is incomplete information about their roles.Particularly,there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers,such as estrogen receptor alpha(ERα),together with scant,albeit promising information concerning ER beta(ERβ)and androgen receptor(AR)properties that control different transduction pathways in BCSCs.In this review,we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.展开更多
Objective Idiopathic nephrotic syndrome(INS)is the most common glomerular disease in children.Toll-like receptors(TLRs)have been reported to be associated with response to steroid treatment in children with INS.Nevert...Objective Idiopathic nephrotic syndrome(INS)is the most common glomerular disease in children.Toll-like receptors(TLRs)have been reported to be associated with response to steroid treatment in children with INS.Nevertheless,the correlation between TLR genes and the progression of INS has not yet been clarified.The present study aimed to investigate the association of single-nucleotide polymorphisms(SNPs)in TLR2,TLR4,and TLR9 with susceptibility to INS as well as the clinical phenotyping of steroid responsiveness in Chinese children with INS.Methods A total of 183 pediatric inpatients with INS were included and given standard steroid therapy.Based on their clinical response to steroids,the patients were classified into three groups:steroid-sensitive nephrotic syndrome(SSNS),steroid-dependent nephrotic syndrome(SDNS),and steroid-resistant nephrotic syndrome(SRNS).A total of 100 healthy children were employed as controls.The blood genome DNA was extracted from each participant.Six SNPs(rs11536889,rs1927914,rs7869402,rs11536891,rs352140,and rs3804099)in TLR2,TLR4,and TLR9 were selected and detected by multiplex polymerase chain reaction with next-generation sequencing to assess TLR gene polymorphisms.Results Among the 183 patients with INS,89(48.6%)had SSNS,73(39.9%)had SDNS,and 21(11.5%)had SRNS.No significant difference was found in the genotype distribution between healthy children and patients with INS.However,the genotype and allele frequencies of TLR4 rs7869402 were significantly different between SRNS and SSNS.Compared with patients with the C allele and CC genotype,patients with the T allele and CT genotype had an increased risk of SRNS.Conclusion TLR4 rs7869402 affected the steroid response in Chinese children with INS.It might be a predictor for the early detection of SRNS in this population.展开更多
In this editorial,we comment on the article by Meng et al published in the World Journal of Clinical Cases.We comprehensively review immunoglobulin A nephro-pathy(IgAN),including epidemiology,clinical presentation,dia...In this editorial,we comment on the article by Meng et al published in the World Journal of Clinical Cases.We comprehensively review immunoglobulin A nephro-pathy(IgAN),including epidemiology,clinical presentation,diagnosis,and management.IgAN,also known as Berger's disease,is the most frequent type of primary glomerulonephritis(GN)globally.It is mostly found among the Asian population.The presentation can be variable,from microscopic hematuria to a rapidly progressive GN.Around 50%of patients present with single or recurring episodes of gross hematuria.An upper respiratory infection and tonsillitis often precede these episodes.Around 30%of patients present microscopic hematuria with or without proteinuria,usually detected on routine examination.The diagnosis relies on having a renal biopsy for pathology and immunofluorescence microscopy.We focus on risk stratification and management of IgAN.We provide a review of all the landmark studies to date.According to the 2021 KDIGO(kidney disease:Improving Global Outcomes)guidelines,patients with non-variant form IgAN are first treated conservatively for three to six months.This approach consists of adequate blood pressure control,reduction of proteinuria with renin-angiotensin system blockade,treatment of dyslipidemia,and lifestyle modifications(weight loss,exercise,smoking cessation,and dietary sodium restrictions).Following three to six months of conservative therapy,patients are further classified as high or low risk for disease progression.High-risk patients have proteinuria≥1 g/d or<1 g/d with significant microscopic hematuria and active inflammation on kidney biopsy.Some experts consider proteinuria≥2 g/d to be very high risk.Patients with high and very high-risk profiles are treated with immunosuppressive therapy.A proteinuria level of<1 g/d and stable/im-proved renal function indicates a good treatment response for patients on immu-nosuppressive therapy.展开更多
BACKGROUND Chronic inflammatory pain is associated with increased expression of interleukin(IL)-1,an inflammatory cytokine,and activity on its receptor(IL-1R).In response,the body produces IL-1R antagonist(IL-1Ra)to r...BACKGROUND Chronic inflammatory pain is associated with increased expression of interleukin(IL)-1,an inflammatory cytokine,and activity on its receptor(IL-1R).In response,the body produces IL-1R antagonist(IL-1Ra)to reduce this signaling.Autologous conditioned serum(ACS)is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms.This systematic review investigates the effectiveness of ACS in treating pain and dis-ability caused by spinal pathologies.AIM To evaluate the use of ACS as a conservative management option for spinal path-ology.METHODS A systematic review of PubMed/Medline was performed to identify studies inve-stigating administration of ACS for treatment of any spinal pathology.RESULTS Six articles were included,comprising 684 patients treated with epidural(n=133)or transforaminal(n=551)ACS injections.Patients had an average age of 54.0 years with slight female predominance(53.2%).The lumbar spine was most com-monly treated,with 567 patients(82.9%)receiving injections for lumbar radicu-lopathy(n=67),degenerative disc disease(DDD)(n=372),or spinal stenosis(n=128);cervical injections were performed in 109 patients(15.9%).Mean(SD)follow-up was 21.7(4.8)weeks from first ACS injection.All studies investigating mecha-nical lumbar and lumbar or cervical radicular pain reported significant pain re-duction at final follow-up compared to baseline.ACS achieved comparable or su-perior results to lumbar epidural steroid injections.Adverse events were reported in 21 patients(3.1%),with no serious adverse events.CONCLUSION ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies,including cervical and lumbar radiculopathies.展开更多
Objective To investigate the variation of sex hormone and its receptor level in elderly male patients with coronary heart disease (CHD) and to evaluate the correlations between CHD and sex hormone as well as sex hormo...Objective To investigate the variation of sex hormone and its receptor level in elderly male patients with coronary heart disease (CHD) and to evaluate the correlations between CHD and sex hormone as well as sex hormone receptor. Methods Altogether 139 male CHD patients (CHD group) aged 60-92 years and 400 healthy men (control group) aged 60-90 years were included in this cross sectional study. The plasma concentrations of dehydroepiandrosterone sulfate (DHEAS),total testosterone (TT),free testosterone (FT),estradiol (E2),sex hormone binding globulin (SHBG),luteinizing hormone (LH),and follicle-stimulating hormone (FSH) were measured. The androgen receptor (AR) was tested by flow cytometry. Correlations between CHD and levels of sex hormones and AR were analyzed. Results Compared with the control group,the levels of DHEAS,TT,FT,SHBG,and the fluorescence intensity of AR in the CHD group significantly reduced (P<0.05),while the levels of FSH and E2 significantly increased (P<0.01). Age was negatively correlated with TT (r=-0.28,P=0.00) and FT (r=-0.17,P=0.01),while it was positively correlated with SHBG (r=0.14,P=0.04) and E2 (r=0.33,P=0.00). AR fluorescence intensity was negatively correlated with systolic blood pressure (r=-0.12,P=0.01). Binary logistic regression analysis showed that TT,SHBG,and AR were all negatively correlated with CHD (P<0.05). Conclusions Elderly male patients with CHD are found to have low levels of DHEAS,TT,FT,SHBG,and AR,while high concentrations of E2 and FSH. Low levels of TT and SHBG may be the potential risk factors of CHD in elderly men.展开更多
Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvul...Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids adminis- tration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute prom- ising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3ct-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions.展开更多
Hormone replacement therapy is necessary for patients with adrenal and gonadal failure.Steroid hormone treatment is also employed in aging people for sex hormone deficiency.These patients undergo such therapies,which ...Hormone replacement therapy is necessary for patients with adrenal and gonadal failure.Steroid hormone treatment is also employed in aging people for sex hormone deficiency.These patients undergo such therapies,which have associated risks,for their entire life.Stem cells represent an innovative tool for tissue regeneration and the possibility of solving these problems.Among various stem cell types,mesenchymal stem cells have the potential to differentiate into steroidogenic cells both in vivo and in vitro.In particular,they can effectively be differentiated into steroidogenic cells by expressing nuclear receptor 5A subfamily proteins(steroidogenic factor-1 and liver receptor homolog-1)with the aid of cAMP.This approach will provide a source of cells for future regenerative medicine for the treatment of diseases caused by steroidogenesis deficiencies.It can also represent a useful tool for studying the molecular mechanisms of steroidogenesis and its related diseases.展开更多
The anti-inflammatory effects of the new ster-oidal antedrug, 21-acetyloxy-9α-fluoro-11β-hy-droxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8)...The anti-inflammatory effects of the new ster-oidal antedrug, 21-acetyloxy-9α-fluoro-11β-hy-droxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8) production, were inves-tigated together with its parent steroid predni-solone (PRED). PRED is one of the anti-in-flammatory steroids but has systemic side ef-fects which limit the use of it. PRED was modi-fied with ‘antedrug concept’ to create safer drugs that attack problems such as inflamma-tion, then quickly become inactive before they can cause systemic side effect. We had a test about the effect of the modified anti-inflamma-tory steroidal antedrug on anti-inflammatory activity. The present study evaluated their ability to inhibit cytokine-induced NO and IL-8 produc-tion in human alveolar epithelial cells. We also investigated their ability to enhance the expres-sion of inhibitory cytokine receptor, interleukin 22 receptor (IL-22R) in human alveolar epithelial cells. Our results showed that FP-ISO-21AC sh- owed higher ability to inhibit the cytokine - in-duced production of NO than PRED. Exogenous IL-22 was added to the media of both human alveolar epithelial cells (A549) and human lung fibroblast (HLF-1). In the presence of the ex-ogenous inhibitory cytokine IL-22, further re-duction of NO production was observed in A549 cells, which express IL-22R, but not in HLF1, which does not express IL-22R. These data suggested that the steroidal antedrugs en-hanced the expression of IL-22R. FP-ISO- 21AC showed higher potency than PRED to restore the expression of IL-22R. FP-ISO-21AC further reduced NO production to 27% and PRED further reduced NO production to 39%. In con-clusion, a synthesized steroidal antedrug FP- ISO-21AC showed higher anti-inflammatory ef-fects than PRED by inhibiting the expression of pro-inflammatory mediator NO and stimulating the expression of IL-22R.展开更多
Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism a...Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism and elimination. To further explore the role of PXR in body’s homeostatic mechanisms, we for the first time, report successful prokary- otic expression and purification of full-length PXR and preparation of polyclonal antibody against the whole protein. The full-length cDNA encoding a 434 amino acids protein was sub-cloned into prokaryotic expression vector, pET-30b and transformed into E. coli BL21(DE3) cells for efficient over expression. The inclusion body fraction, containing the expressed recombinant protein, was purified first by solubilizing in sarcosine extraction buffer and then by affinity column chromatography using Ni-NTA His-Bind matrix. The efficacy of anti-PXR antibody was confirmed by immunocytology, Western blot analysis, EMSA and immunohistochemistry. The antibody obtained was capable of detecting human and mouse PXR with high specificity and sensitivity. Immunofluorescence staining of COS-1 cells transfected with human or mouse PXR showed a clear nuclear localization. Results from immunohistochemistry showed that level of PXR in liver sections is immunologically detectable in the nuclei. Similar to exogenously transfected PXR, Western blot analysis of cell extract from HepG2 and COLO320DM cells revealed a major protein band for endogenous PXR having the expected molecular weight of 50 kDa. Relevance of other immunodetectable bands with reference to PXR isoforms and current testimony are evaluated. Advantages of antibody raised against full-length PXR protein for functional characterization of receptor is discussed and its application for clinical purposes is envisaged.展开更多
AIM: We studied the estrogen receptor (ER) and progesterone receptor (PR) isoforms expression in gastric antrum and corpus of female gerbils and their regulation by estradiol (E2) and progesterone (P4). METHODS: Ovari...AIM: We studied the estrogen receptor (ER) and progesterone receptor (PR) isoforms expression in gastric antrum and corpus of female gerbils and their regulation by estradiol (E2) and progesterone (P4). METHODS: Ovariectomized adult female gerbils were subcutaneously treated with E2, and E2 + P4. Uteri and stomachs were removed, the latter were cut along the greater curvature, and antrum and corpus were excised. Proteins were immunoblotted using antibodies that recognize ER-alpha, ER-beta, and PR-A and PR-B receptor isoforms. Tissues from rats treated in the same way were used as controls. RESULTS: Specific bands were detected for ER-alpha (68 KDa), and PR isoforms (85 and 120 KDa for PR-A and PR-B isoforms, respectively) in uteri, gastric antrum and corpus. We could not detect ER-beta isoform. PR isoforms were not regulated by E2 or P4 in uterus and gastric tissues of gerbils. ER-alpha isoform content was significantly down-regulated by E2 in the corpus, but not affected by hormones in uterus and gastric antrum. CONCLUSION: The presence of ER-alpha and PR isoforms in gerbils stomach suggests that E2 and P4 actions in this organ are in part mediated by their nuclear receptors.展开更多
基金Supported by Innovative Team of Jiangsu Province,No.CXTDA2017042Jiangsu Provincial Medical Youth Talent,No.QNRC2016508In-Hospital Project of Taizhou People's Hospital,No.ZL201930.
文摘BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary sites between lncRNA SRA1,miRNA-363-5p,and phospholysine phosphohistidine inorganic pyrophosphate phosphatase(LHPP)predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression.AIM To investigate the molecular events of SRA1 in the malignant behavior in ESCC.METHODS Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired.SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction.Cell counting Kit-8 assay,transwell invasion assay,glycolysis assay,and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1.The t-test and theχ2 test were used for comparison between groups.Survival curve analysis was performed using the Kaplan-Meier method.RESULTS SRA1 downregulation was identified in ESCC.ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression.The introduction of SRA1 inhibited cell proliferation,glucose uptake,and lactate production in ESCC.In vivo,the growth of ESCC was hindered by SRA1 overexpression.Then,SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p.Lastly,the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1.CONCLUSION SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis.The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.
基金Supported by The Swiss IBD Cohort Study (SNF Grant 33CSC0-108792)the Swiss National Science Foundation (Grant 32-120463/1)+2 种基金the Zurich University Research Priority Pro-gramme "Integrative Human Physiology" (ZIHP)the Center of Clinical Research at the University Hospital Zurichthe Novartis Foundation for Biomedical Research
文摘AIM: To study whether the glucocorticoid receptor (GR/ NR3C1) gene haplotypes influence the steroid therapy outcome in inflammatory bowel disease (IBD). METHODS: We sequenced all coding exons and flanking intronic sequences of the NR3C1 gene in 181 IBD patients, determined the single nucleotide polymorphisms, and predicted the NR3C1 haplotypes. Furthermore, we investigated whether certain NR3C1 haplotypes are significantly associated with steroid therapy outcomes. RESULTS: We detected 13 NR3C1 variants, which led to the formation of 17 different haplotypes with a certainty of > 95% in 173 individuals. The three most commonly occurring haplotypes were included in the association analysis of the influence of haplotype on steroid therapy outcome or IBD activity. None of the NR3C1 haplotypes showed statistically signifi cant association with glucocorticoid therapy success. CONCLUSION: NR3C1 haplotypes are not related to steroid therapy outcome.
文摘Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, theiruse of corepressors and coactivators to modify chromatinstructure and the implications for transcriptional control.The assembly of specific nucleoprotein architectures andtargeted histone modification emerge as central controlling elements for gene expression.
文摘Background: While the role of adipocyte-derived hormones in breast cancer pathogenesis well studied, it is speculated that there is a crosstalk between adipocytokines and Esterogen receptor(ER) signaling. To test this hypothesis we evaluate the possible correlation between serum levels of adipocytokins with steroid hormone receptors gene expression in breast cancer patients. Methods: In this case-control study, 70 women with breast cancer participated with different grades of obesity (36 none obese, BMI 0.05). In case of leptin, we observed a positive correlation between leptin and ERα and PR mRNA. (r = 0.553, n = 64, p < 0.001, r = 0.359, n = 64, p = 0.002 and a reverse significant correlation between leptin and ERβ (r= –0.506, n = 64 and p < 0.001). We also observed a significant correlation between TNFα and IL6 with steroid receptors gene expression in samples (P < 0.05). Conclusion: As the presence of steroid receptors are used as the most common prognostic markers in breast cancer patients, so targeting adipocytokines as potential regulators of steroid receptorsgene expression can be a new approach in treatment of obese breast cancer subjects.
文摘Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- year survival rate through stratification and multivariatc analysis. The results showed that histologic tumor type and grading, lymphnode status, ER value and patient age took more important role in patient survival, and SR, especially, conferred survival advantage in advanced cases with tumor size larger than 2 cm, node involved, or TNM Stage Ⅱ-Ⅲ.
基金Supported by the National Ministry of University and Research,Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale,No.2017EKMFTN_002,No.2015B7M39T_003Umberto Veronesi Foundation Post-doctoral Fellowship 2019Program VALERE(Vanvitelli per la RicercaUniversity of Campania"L.Vanvitelli")
文摘Breast cancer(BC)is the most common cancer among women,and current available therapies often have high success rates.Nevertheless,BC might acquire drug resistance and sometimes relapse.Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC,the so-called“BC stem cells”(BCSCs).The role of BCSCs in cancer formation,growth,invasiveness,therapy resistance and tumor recurrence is becoming increasingly clear.The growth and metastatic properties of BCSCs are regulated by different pathways,which are only partially known.Sex steroid receptors(SSRs),which are involved in BC etiology and progression,promote BCSC proliferation,dedifferentiation and migration.However,in the literature,there is incomplete information about their roles.Particularly,there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers,such as estrogen receptor alpha(ERα),together with scant,albeit promising information concerning ER beta(ERβ)and androgen receptor(AR)properties that control different transduction pathways in BCSCs.In this review,we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.
基金This study was funded by the Science and Technology Projects of Zhejiang Province(No.LGC21H200004)the Key Research and Development Plan of Zhejiang Province(No.2019C03028)the Medical Scientific Projects from Health Department of Zhejiang Province(No.2018KY455)。
文摘Objective Idiopathic nephrotic syndrome(INS)is the most common glomerular disease in children.Toll-like receptors(TLRs)have been reported to be associated with response to steroid treatment in children with INS.Nevertheless,the correlation between TLR genes and the progression of INS has not yet been clarified.The present study aimed to investigate the association of single-nucleotide polymorphisms(SNPs)in TLR2,TLR4,and TLR9 with susceptibility to INS as well as the clinical phenotyping of steroid responsiveness in Chinese children with INS.Methods A total of 183 pediatric inpatients with INS were included and given standard steroid therapy.Based on their clinical response to steroids,the patients were classified into three groups:steroid-sensitive nephrotic syndrome(SSNS),steroid-dependent nephrotic syndrome(SDNS),and steroid-resistant nephrotic syndrome(SRNS).A total of 100 healthy children were employed as controls.The blood genome DNA was extracted from each participant.Six SNPs(rs11536889,rs1927914,rs7869402,rs11536891,rs352140,and rs3804099)in TLR2,TLR4,and TLR9 were selected and detected by multiplex polymerase chain reaction with next-generation sequencing to assess TLR gene polymorphisms.Results Among the 183 patients with INS,89(48.6%)had SSNS,73(39.9%)had SDNS,and 21(11.5%)had SRNS.No significant difference was found in the genotype distribution between healthy children and patients with INS.However,the genotype and allele frequencies of TLR4 rs7869402 were significantly different between SRNS and SSNS.Compared with patients with the C allele and CC genotype,patients with the T allele and CT genotype had an increased risk of SRNS.Conclusion TLR4 rs7869402 affected the steroid response in Chinese children with INS.It might be a predictor for the early detection of SRNS in this population.
文摘In this editorial,we comment on the article by Meng et al published in the World Journal of Clinical Cases.We comprehensively review immunoglobulin A nephro-pathy(IgAN),including epidemiology,clinical presentation,diagnosis,and management.IgAN,also known as Berger's disease,is the most frequent type of primary glomerulonephritis(GN)globally.It is mostly found among the Asian population.The presentation can be variable,from microscopic hematuria to a rapidly progressive GN.Around 50%of patients present with single or recurring episodes of gross hematuria.An upper respiratory infection and tonsillitis often precede these episodes.Around 30%of patients present microscopic hematuria with or without proteinuria,usually detected on routine examination.The diagnosis relies on having a renal biopsy for pathology and immunofluorescence microscopy.We focus on risk stratification and management of IgAN.We provide a review of all the landmark studies to date.According to the 2021 KDIGO(kidney disease:Improving Global Outcomes)guidelines,patients with non-variant form IgAN are first treated conservatively for three to six months.This approach consists of adequate blood pressure control,reduction of proteinuria with renin-angiotensin system blockade,treatment of dyslipidemia,and lifestyle modifications(weight loss,exercise,smoking cessation,and dietary sodium restrictions).Following three to six months of conservative therapy,patients are further classified as high or low risk for disease progression.High-risk patients have proteinuria≥1 g/d or<1 g/d with significant microscopic hematuria and active inflammation on kidney biopsy.Some experts consider proteinuria≥2 g/d to be very high risk.Patients with high and very high-risk profiles are treated with immunosuppressive therapy.A proteinuria level of<1 g/d and stable/im-proved renal function indicates a good treatment response for patients on immu-nosuppressive therapy.
文摘BACKGROUND Chronic inflammatory pain is associated with increased expression of interleukin(IL)-1,an inflammatory cytokine,and activity on its receptor(IL-1R).In response,the body produces IL-1R antagonist(IL-1Ra)to reduce this signaling.Autologous conditioned serum(ACS)is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms.This systematic review investigates the effectiveness of ACS in treating pain and dis-ability caused by spinal pathologies.AIM To evaluate the use of ACS as a conservative management option for spinal path-ology.METHODS A systematic review of PubMed/Medline was performed to identify studies inve-stigating administration of ACS for treatment of any spinal pathology.RESULTS Six articles were included,comprising 684 patients treated with epidural(n=133)or transforaminal(n=551)ACS injections.Patients had an average age of 54.0 years with slight female predominance(53.2%).The lumbar spine was most com-monly treated,with 567 patients(82.9%)receiving injections for lumbar radicu-lopathy(n=67),degenerative disc disease(DDD)(n=372),or spinal stenosis(n=128);cervical injections were performed in 109 patients(15.9%).Mean(SD)follow-up was 21.7(4.8)weeks from first ACS injection.All studies investigating mecha-nical lumbar and lumbar or cervical radicular pain reported significant pain re-duction at final follow-up compared to baseline.ACS achieved comparable or su-perior results to lumbar epidural steroid injections.Adverse events were reported in 21 patients(3.1%),with no serious adverse events.CONCLUSION ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies,including cervical and lumbar radiculopathies.
基金Supported by the Military Health Care Grant (01AM301, 06G105)
文摘Objective To investigate the variation of sex hormone and its receptor level in elderly male patients with coronary heart disease (CHD) and to evaluate the correlations between CHD and sex hormone as well as sex hormone receptor. Methods Altogether 139 male CHD patients (CHD group) aged 60-92 years and 400 healthy men (control group) aged 60-90 years were included in this cross sectional study. The plasma concentrations of dehydroepiandrosterone sulfate (DHEAS),total testosterone (TT),free testosterone (FT),estradiol (E2),sex hormone binding globulin (SHBG),luteinizing hormone (LH),and follicle-stimulating hormone (FSH) were measured. The androgen receptor (AR) was tested by flow cytometry. Correlations between CHD and levels of sex hormones and AR were analyzed. Results Compared with the control group,the levels of DHEAS,TT,FT,SHBG,and the fluorescence intensity of AR in the CHD group significantly reduced (P<0.05),while the levels of FSH and E2 significantly increased (P<0.01). Age was negatively correlated with TT (r=-0.28,P=0.00) and FT (r=-0.17,P=0.01),while it was positively correlated with SHBG (r=0.14,P=0.04) and E2 (r=0.33,P=0.00). AR fluorescence intensity was negatively correlated with systolic blood pressure (r=-0.12,P=0.01). Binary logistic regression analysis showed that TT,SHBG,and AR were all negatively correlated with CHD (P<0.05). Conclusions Elderly male patients with CHD are found to have low levels of DHEAS,TT,FT,SHBG,and AR,while high concentrations of E2 and FSH. Low levels of TT and SHBG may be the potential risk factors of CHD in elderly men.
基金supported by grants from Agencia Nacional de Promocion Cientifica y Tecnologica(ANPCYT,PICT-2006-727)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET,PIP-860)
文摘Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids adminis- tration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute prom- ising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3ct-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions.
基金Supported by Ministry of Education,Culture,Sports,Science and Technology of Japan,No.23590329the Terumo Life Science Foundationthe Smoking Research Foundation
文摘Hormone replacement therapy is necessary for patients with adrenal and gonadal failure.Steroid hormone treatment is also employed in aging people for sex hormone deficiency.These patients undergo such therapies,which have associated risks,for their entire life.Stem cells represent an innovative tool for tissue regeneration and the possibility of solving these problems.Among various stem cell types,mesenchymal stem cells have the potential to differentiate into steroidogenic cells both in vivo and in vitro.In particular,they can effectively be differentiated into steroidogenic cells by expressing nuclear receptor 5A subfamily proteins(steroidogenic factor-1 and liver receptor homolog-1)with the aid of cAMP.This approach will provide a source of cells for future regenerative medicine for the treatment of diseases caused by steroidogenesis deficiencies.It can also represent a useful tool for studying the molecular mechanisms of steroidogenesis and its related diseases.
文摘The anti-inflammatory effects of the new ster-oidal antedrug, 21-acetyloxy-9α-fluoro-11β-hy-droxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8) production, were inves-tigated together with its parent steroid predni-solone (PRED). PRED is one of the anti-in-flammatory steroids but has systemic side ef-fects which limit the use of it. PRED was modi-fied with ‘antedrug concept’ to create safer drugs that attack problems such as inflamma-tion, then quickly become inactive before they can cause systemic side effect. We had a test about the effect of the modified anti-inflamma-tory steroidal antedrug on anti-inflammatory activity. The present study evaluated their ability to inhibit cytokine-induced NO and IL-8 produc-tion in human alveolar epithelial cells. We also investigated their ability to enhance the expres-sion of inhibitory cytokine receptor, interleukin 22 receptor (IL-22R) in human alveolar epithelial cells. Our results showed that FP-ISO-21AC sh- owed higher ability to inhibit the cytokine - in-duced production of NO than PRED. Exogenous IL-22 was added to the media of both human alveolar epithelial cells (A549) and human lung fibroblast (HLF-1). In the presence of the ex-ogenous inhibitory cytokine IL-22, further re-duction of NO production was observed in A549 cells, which express IL-22R, but not in HLF1, which does not express IL-22R. These data suggested that the steroidal antedrugs en-hanced the expression of IL-22R. FP-ISO- 21AC showed higher potency than PRED to restore the expression of IL-22R. FP-ISO-21AC further reduced NO production to 27% and PRED further reduced NO production to 39%. In con-clusion, a synthesized steroidal antedrug FP- ISO-21AC showed higher anti-inflammatory ef-fects than PRED by inhibiting the expression of pro-inflammatory mediator NO and stimulating the expression of IL-22R.
文摘Pregnane and Xenobiotic Receptor (PXR; or Steroid and Xenobiotic Receptor, SXR), a new member of the nuclear receptor superfamily, is thought to modulate a network of genes that are involved in xenobiotic metabolism and elimination. To further explore the role of PXR in body’s homeostatic mechanisms, we for the first time, report successful prokary- otic expression and purification of full-length PXR and preparation of polyclonal antibody against the whole protein. The full-length cDNA encoding a 434 amino acids protein was sub-cloned into prokaryotic expression vector, pET-30b and transformed into E. coli BL21(DE3) cells for efficient over expression. The inclusion body fraction, containing the expressed recombinant protein, was purified first by solubilizing in sarcosine extraction buffer and then by affinity column chromatography using Ni-NTA His-Bind matrix. The efficacy of anti-PXR antibody was confirmed by immunocytology, Western blot analysis, EMSA and immunohistochemistry. The antibody obtained was capable of detecting human and mouse PXR with high specificity and sensitivity. Immunofluorescence staining of COS-1 cells transfected with human or mouse PXR showed a clear nuclear localization. Results from immunohistochemistry showed that level of PXR in liver sections is immunologically detectable in the nuclei. Similar to exogenously transfected PXR, Western blot analysis of cell extract from HepG2 and COLO320DM cells revealed a major protein band for endogenous PXR having the expected molecular weight of 50 kDa. Relevance of other immunodetectable bands with reference to PXR isoforms and current testimony are evaluated. Advantages of antibody raised against full-length PXR protein for functional characterization of receptor is discussed and its application for clinical purposes is envisaged.
文摘AIM: We studied the estrogen receptor (ER) and progesterone receptor (PR) isoforms expression in gastric antrum and corpus of female gerbils and their regulation by estradiol (E2) and progesterone (P4). METHODS: Ovariectomized adult female gerbils were subcutaneously treated with E2, and E2 + P4. Uteri and stomachs were removed, the latter were cut along the greater curvature, and antrum and corpus were excised. Proteins were immunoblotted using antibodies that recognize ER-alpha, ER-beta, and PR-A and PR-B receptor isoforms. Tissues from rats treated in the same way were used as controls. RESULTS: Specific bands were detected for ER-alpha (68 KDa), and PR isoforms (85 and 120 KDa for PR-A and PR-B isoforms, respectively) in uteri, gastric antrum and corpus. We could not detect ER-beta isoform. PR isoforms were not regulated by E2 or P4 in uterus and gastric tissues of gerbils. ER-alpha isoform content was significantly down-regulated by E2 in the corpus, but not affected by hormones in uterus and gastric antrum. CONCLUSION: The presence of ER-alpha and PR isoforms in gerbils stomach suggests that E2 and P4 actions in this organ are in part mediated by their nuclear receptors.
