BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals...BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.展开更多
BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells...BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation(H/R)-induced oxidative iniury are still unclear.METHODS: The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid(9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA-pretreated group(100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group(2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential(ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signif icant when P was <0.05.RESULTS: Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531.CONCLUSION: The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.展开更多
Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphol...Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.展开更多
Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in art...Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in artificial breeding.However,reproductive behavior at the level of genes is rarely reported,thus,the research on the genetic basis of behavior,reproduction,and artificial breeding was limited.We applied RNA-seq in different stages of reproduction to investigate the reason of rapid aging after spawning,pre-maturity,pre-spawning after maturity,and post-spawning.The retinoid X receptor(RXR)gene family in S.japonica was identified,and 1343–1452 differentially expressed genes(DEGs)in all 3 stages of reproductive life were identified from pairwise m RNA comparisons.Furthermore,through the GO term and KEGG analysis,S.japonica could handle neuronal development and network formation before maturity and have a functional degradation of neural communication,signal transduction,vision,and gene expression after spawning.Eight Sj RXRαs have been identified and they played different roles in growth development or reproduction.Therefore,the regulation of several channels and receptors is the intrinsic molecular mechanism of rapid aging after spawning in S.japonica.This study revealed the survival strategy and provided fundamental data on the level of genes for understanding the reproductive behavior and the reproduction of S.japonica.展开更多
BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases(IBDs)and that the P2X7 receptor triggers neuronal death.However,the mechanism by which enteric neurons are...BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases(IBDs)and that the P2X7 receptor triggers neuronal death.However,the mechanism by which enteric neurons are lost in IBDs is unknown.AIM To study the role of the caspase-3 and nuclear factor kappa B(NF-κB)pathways in myenteric neurons in a P2X7 receptor knockout(KO)mouse model of IBDs.METHODS Forty male wild-type(WT)C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid(colitis group).Mice in the sham groups were injected with vehicle.The mice were divided into eight groups(n=5):The WT sham 24 h and 4 d groups,the WT colitis 24 h and 4 d groups,the KO sham 24 h and 4 d groups,and the KO colitis 24 h and 4 d groups.The disease activity index(DAI)was analyzed,the distal colon was collected for immunohistochemistry analyses,and immunofluorescence was performed to identify neurons immunoreactive(ir)for calretinin,P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,and total NF-κB.We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion,the neuronal profile area(μm^(2)),and corrected total cell fluorescence(CTCF).RESULTS Cells double labeled for calretinin and P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,or total NF-κB were observed in the WT colitis 24 h and 4 d groups.The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(2.10±0.13 vs 3.33±0.17,P<0.001;2.92±0.12 vs 3.70±0.11,P<0.05),but was not significantly different between the KO groups.The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group(312.60±7.85 vs 278.41±6.65,P<0.05),and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group(104.63±2.49 vs 117.41±1.14,P<0.01).The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(19.49±0.35 vs 22.21±0.18,P<0.001;20.35±0.14 vs 22.75±0.51,P<0.001),and no P2X7 receptor-ir neurons were observed in the KO groups.Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group.The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(485949±14140 vs 371371±16426,P<0.001;480381±11336 vs 378365±4053,P<0.001),but was not significantly different between the KO groups.The total caspase-3 CTCF,phospho-NF-κB CTCF,and total NF-κB CTCF were not significantly different among the groups.The DAI was recovered in the KO groups.Furthermore,we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration,tissue damage,collagen deposition,and the decrease in the number of goblet cells in the distal colon.CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice,and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation.The P2X7 receptor can be a therapeutic target for IBDs.展开更多
Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,...Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PXR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PXR.PXR plays an important role in drug metabolism and clearance,and PXR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.展开更多
This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is ...This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is effective against human breast cancer BT-20 and MCF-7 cell lines. At the same time, compound L2 exerts its effect on human prostate cancer PC-3 and human breast cancer MDA-MB-231 and MCF-7 cell lines respectively. The retinoid ligands exert their pleiotropic action toward retinoic acid receptors (RARs) than their metal complexes but all compounds exhibit concentration-dependent.展开更多
All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodim...All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.展开更多
Nogo-B受体(Nogo-B receptor,NgBR)参与脂肪肝和胰岛素敏感性的形成,但是并不清楚肝X受体(liver X receptor,LXR)激动剂是否能够调控NgBR的表达。文章使用人工合成的LXR激动剂(T0901317和GW3965)分析其对肝源细胞系中NgBR表达的影响,构...Nogo-B受体(Nogo-B receptor,NgBR)参与脂肪肝和胰岛素敏感性的形成,但是并不清楚肝X受体(liver X receptor,LXR)激动剂是否能够调控NgBR的表达。文章使用人工合成的LXR激动剂(T0901317和GW3965)分析其对肝源细胞系中NgBR表达的影响,构建正常或突变NgBR启动子,通过双荧光素酶报告基因系统检测LXR激动剂对启动子活性的影响;采用CRISPR-CAS9方法建立LXRα或LXRβ基因敲除的HepG2细胞系,通过Western Blot检测相关基因的表达变化;向ApoE-/-小鼠腹腔注射LXR激动剂T0901317,分析小鼠肝脏中NgBR的表达变化。结果发现,LXR激动剂能够通过激活LXR促进NgBR蛋白的表达,该诱导作用是以LXRE依赖的方式进行的,并且LXR的表达发挥着重要作用。在体内实验中,也证明了LXR激动剂T0901317上调NgBR蛋白表达。结果表明,NgBR是LXR的靶蛋白,LXR通过结合NgBR启动子LXRE序列促进其转录和翻译。展开更多
基金Supported by the Major Basic Research Project of Natural Science Foundation of Shandong Province,No.ZR2020ZD15.
文摘BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.
基金supported by grants from the National Natural Science Foundation of China(81270282,81070176,30600242,81170192,81200163)Wenzhou Science Technology Bureau Foundation(Y20100010)Education Foundation of Zhejiang Province(Y200906376)
文摘BACKGROUND: Retinoid X receptor(RXR) plays a central role in the regulation of intracellular receptor signaling pathways. The activation of RXR has protective effect on H2O2-induced apoptosis of H9c2 ventricular cells in rats. But the protective effect and mechanism of activating RXR in cardiomyocytes against hypoxia/reoxygenation(H/R)-induced oxidative iniury are still unclear.METHODS: The model of H/R injury was established through hypoxia for 2 hours and reoxygenation for 4 hours in H9c2 cardiomyocytes of rats. 9-cis-retinoic acid(9-cis RA) was obtained as an RXR agonist, and HX531 as an RXR antagonist. Cultured cardiomyocytes were randomly divided into four groups: sham group, H/R group, H/R+9-cis RA-pretreated group(100 nmol/L 9-cis RA), and H/R+9-cis RA+HX531-pretreated group(2.5 μmol/L HX531). The cell viability was measured by MTT, apoptosis rate of cardiomyocytes by flow cytometry analysis, and mitochondrial membrane potential(ΔΨm) by JC-1 fluorescent probe, and protein expressions of Bcl-2, Bax and cleaved caspase-9 with Western blotting. All measurement data were expressed as mean±standard deviation, and analyzed using one-way ANOVA and the Dunnett test. Differences were considered signif icant when P was <0.05.RESULTS: Pretreatment with RXR agonist enhanced cell viability, reduced apoptosis ratio, and stabled ΔΨm. Dot blotting experiments showed that under H/R stress conditions, Bcl-2 protein level decreased, while Bax and cleaved caspase-9 were increased. 9-cis RA administration before H/R stress prevented these effects, but the protective effects of activating RXR on cardiomyocytes against H/R induced oxidative injury were abolished when pretreated with RXR pan-antagonist HX531.CONCLUSION: The activation of RXR has protective effects against H/R injury in H9c2 cardiomyocytes of rats through attenuating signaling pathway of mitochondria apoptosis.
基金supported by Natural Sciences and Engineering Council of Canada Discovery Grant to RLC and GES
文摘Some adult vertebrate species,such as newts,axolotls and zebrafish,have the ability to regenerate their central nervous system（CNS）.However,the factors that establish a permissive CNS environment for correct morphological and functional regeneration in these species are not well understood.Recent evidence supports a role for retinoid signaling in the intrinsic ability of neurons,in these regeneration-competent species,to regrow after CNS injury.Previously,we demonstrated that a specific retinoic acid receptor（RAR）subtype,RARβ,mediates the effects of endogenous retinoic acid（RA）on neuronal growth and guidance in the adult newt CNS after injury.Here,we now examine the expression of the retinoid X receptor RXRα（a potential heterodimeric transcriptional regulator with RARβ）,in newt tail and spinal cord regeneration.We show that at 21 days post-amputation（dpa）,RXRαis expressed at temporally distinct periods and in non-overlapping spatial domains compared to RARβ.Whereas RARβprotein levels increase,RXRαproteins level decrease by 21 dpa.A selective agonist for RXR,SR11237,prevents both this downregulation of RXRαand upregulation of RARβand inhibits tail and caudal spinal cord regeneration.Moreover,treatment with a selective antagonist for RARβ,LE135,inhibits regeneration with the same morphological consequences as treatment with SR11237.Interestingly,LE135 treatment also inhibits the normal downregulation of RXRαin tail and spinal cord tissues at 21 dpa.These results reveal a previously unidentified,indirect regulatory feedback loop between these two receptor subtypes in regulating the regeneration of tail and spinal cord tissues in this regeneration-competent newt.
基金the National Key R&D Program of China(No.2019YFD0901204)the Hong Kong,Macao and Taiwan Science and Technology Cooperation Project(No.2014DFT30120)+2 种基金the Zhejiang Provincial Natural Science Foundation of China(No.Y14C190008)the National Natural Science Foundation of China(Nos.31101937,31872547)the Science Foundation of Donghai Laboratory(No.DH-2022KF0209)。
文摘Sepiella japonica is a worldwide marine cuttlefish species of high economic value.S.japonica routinely modifying behaviors in reproductive life,such as rapid aging until death after spawning,has been recognized in artificial breeding.However,reproductive behavior at the level of genes is rarely reported,thus,the research on the genetic basis of behavior,reproduction,and artificial breeding was limited.We applied RNA-seq in different stages of reproduction to investigate the reason of rapid aging after spawning,pre-maturity,pre-spawning after maturity,and post-spawning.The retinoid X receptor(RXR)gene family in S.japonica was identified,and 1343–1452 differentially expressed genes(DEGs)in all 3 stages of reproductive life were identified from pairwise m RNA comparisons.Furthermore,through the GO term and KEGG analysis,S.japonica could handle neuronal development and network formation before maturity and have a functional degradation of neural communication,signal transduction,vision,and gene expression after spawning.Eight Sj RXRαs have been identified and they played different roles in growth development or reproduction.Therefore,the regulation of several channels and receptors is the intrinsic molecular mechanism of rapid aging after spawning in S.japonica.This study revealed the survival strategy and provided fundamental data on the level of genes for understanding the reproductive behavior and the reproduction of S.japonica.
基金Supported by the National Council for Scientific and Technological Development,No.168015/2018-8the São Paulo Research Foundation,No.2014/25927-2 and No.2018/07862-1.
文摘BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases(IBDs)and that the P2X7 receptor triggers neuronal death.However,the mechanism by which enteric neurons are lost in IBDs is unknown.AIM To study the role of the caspase-3 and nuclear factor kappa B(NF-κB)pathways in myenteric neurons in a P2X7 receptor knockout(KO)mouse model of IBDs.METHODS Forty male wild-type(WT)C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid(colitis group).Mice in the sham groups were injected with vehicle.The mice were divided into eight groups(n=5):The WT sham 24 h and 4 d groups,the WT colitis 24 h and 4 d groups,the KO sham 24 h and 4 d groups,and the KO colitis 24 h and 4 d groups.The disease activity index(DAI)was analyzed,the distal colon was collected for immunohistochemistry analyses,and immunofluorescence was performed to identify neurons immunoreactive(ir)for calretinin,P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,and total NF-κB.We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion,the neuronal profile area(μm^(2)),and corrected total cell fluorescence(CTCF).RESULTS Cells double labeled for calretinin and P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,or total NF-κB were observed in the WT colitis 24 h and 4 d groups.The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(2.10±0.13 vs 3.33±0.17,P<0.001;2.92±0.12 vs 3.70±0.11,P<0.05),but was not significantly different between the KO groups.The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group(312.60±7.85 vs 278.41±6.65,P<0.05),and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group(104.63±2.49 vs 117.41±1.14,P<0.01).The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(19.49±0.35 vs 22.21±0.18,P<0.001;20.35±0.14 vs 22.75±0.51,P<0.001),and no P2X7 receptor-ir neurons were observed in the KO groups.Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group.The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(485949±14140 vs 371371±16426,P<0.001;480381±11336 vs 378365±4053,P<0.001),but was not significantly different between the KO groups.The total caspase-3 CTCF,phospho-NF-κB CTCF,and total NF-κB CTCF were not significantly different among the groups.The DAI was recovered in the KO groups.Furthermore,we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration,tissue damage,collagen deposition,and the decrease in the number of goblet cells in the distal colon.CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice,and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation.The P2X7 receptor can be a therapeutic target for IBDs.
基金Supported by Science project of Hunan Provincial Health Commission,No.B202304089304.
文摘Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PXR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PXR.PXR plays an important role in drug metabolism and clearance,and PXR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.
文摘【目的】研究连翘叶提取物(Forsythia suspensa leaves extract,FSLE)对孕马血清促性腺激素(pregnant mare serum gonadotropin,PMSG)在肝脏中代谢的影响,改善在畜牧生产中因PMSG代谢缓慢而造成的氧化应激。【方法】采用半仿生酶醇法提取连翘叶有效成分,给予昆明雌鼠不同含量的FSLE进行动物体内试验;收集小鼠血清,进行酶联免疫吸附试验,检测各组小鼠血清中PMSG的质量浓度;采集小鼠肝脏组织,检测氧化应激指标谷胱甘肽、超氧化物歧化酶、丙二醛和过氧化氢的水平;采用Western-blot检测小鼠肝脏组织孕烷X受体(pregnane X receptor,PXR)和细胞色素酶P45017A1(cytochrome P45017A1,CYP17A1)蛋白的表达水平。【结果】FSLE可显著降低小鼠血清中PMSG的质量浓度,且可以减缓PMSG代谢引起的氧化应激。Western-blot结果显示:FSLE可显著下调小鼠肝组织中PXR和CYP17A1蛋白的表达。【结论】连翘叶提取物可能是通过下调肝脏中PXR和CYP17A1的表达减缓PMSG代谢引起的氧化应激。
文摘This work deals with the synthesis and physicochemical characterizations of a new group of novel retinoidal ligands and their metal complexes. Their in vitro anti-proliferative activities have shown that ligand L1 is effective against human breast cancer BT-20 and MCF-7 cell lines. At the same time, compound L2 exerts its effect on human prostate cancer PC-3 and human breast cancer MDA-MB-231 and MCF-7 cell lines respectively. The retinoid ligands exert their pleiotropic action toward retinoic acid receptors (RARs) than their metal complexes but all compounds exhibit concentration-dependent.
文摘All-trans retinoic acid (ATRA) triggers a wide range of effects on vertebrate development by regulating cell proliferation, differentiation, and apoptosis. ATRA activates retinoic acid receptors (RARs) which heterodimerize with retinoid X receptors (RXRs). RAR/RXR heterodimers function as ATRA-dependent transcriptional regulators by binding to retinoic acid response elements (RAREs). To identify RAR/RXR heterodimer-binding sites in the human genome, we performed a modified yeast one-hybrid assays and identified 193 RAR/RXR heterodimer-binding fragments in the human genome. The putative target genes included genes involved in development process and cell differentiation. Gel mobility shift assays indicated that 160 putative RAREs could directly interact with the RAR/RXR heterodimer. Moreover, 19 functional regulatory single nucleotide polymorphisms (rSNPs) on the RAR/RXR-binding sequences were identified by analyzing the difference in the DNA-binding affinities. These results provide insights into the molecular mechanisms underlying the physiological and pathological actions of RAR/RXR heterodimers.
文摘Nogo-B受体(Nogo-B receptor,NgBR)参与脂肪肝和胰岛素敏感性的形成,但是并不清楚肝X受体(liver X receptor,LXR)激动剂是否能够调控NgBR的表达。文章使用人工合成的LXR激动剂(T0901317和GW3965)分析其对肝源细胞系中NgBR表达的影响,构建正常或突变NgBR启动子,通过双荧光素酶报告基因系统检测LXR激动剂对启动子活性的影响;采用CRISPR-CAS9方法建立LXRα或LXRβ基因敲除的HepG2细胞系,通过Western Blot检测相关基因的表达变化;向ApoE-/-小鼠腹腔注射LXR激动剂T0901317,分析小鼠肝脏中NgBR的表达变化。结果发现,LXR激动剂能够通过激活LXR促进NgBR蛋白的表达,该诱导作用是以LXRE依赖的方式进行的,并且LXR的表达发挥着重要作用。在体内实验中,也证明了LXR激动剂T0901317上调NgBR蛋白表达。结果表明,NgBR是LXR的靶蛋白,LXR通过结合NgBR启动子LXRE序列促进其转录和翻译。
