Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that gene...Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.展开更多
Background:Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes.Their dysregulation has been closely associated with tumorigenesis.LINC00265 is upreg...Background:Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes.Their dysregulation has been closely associated with tumorigenesis.LINC00265 is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer.However,the mechanism underlying its function in cancer progression remains poorly understood.Methods:Here,the regulatory role of LINC00265 in lung adenocarcinoma was examined using lung cancer cell lines,clinical samples,and xenografts.Results:We found that high levels of LINC00265 expression were associated with shorter overall survival rate of patients,whereas knockdown of LINC00265 inhibited proliferation of cancer cell lines and tumor growth in xenografts.Western blot andflow cytometry analyses indicated that silencing of LINC00265 induced autophagy and apoptosis.Moreover,we showed that LINC00265 interacted with and stabilized the transcriptional co-repressor Switch-independent 3a(SIN3A),which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner.Silencing of SIN3A also reduced proliferation of lung cancer cells,which was correlated with the induction of autophagy.These observations raise the possibility that LINC00265 functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma.Conclusions:Ourfindings thus identify SIN3A as a LINC00265-associated protein and should help to understand the mechanism underlying LINC00265-mediated oncogenesis.展开更多
Extracellular vesicles from skin-derived precursor Schwann cells(SKP-SC-EVs)promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats.This study aimed at expanding the application of SKPSC...Extracellular vesicles from skin-derived precursor Schwann cells(SKP-SC-EVs)promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats.This study aimed at expanding the application of SKPSC-EVs in nerve grafting by creating a chitosan/PLGA-based,SKP-SC-EVs-containing tissue engineered nerve graft(TENG)to bridge a 40-mm long sciatic nerve defect in dogs.SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions,supported the outgrowth and myelination of regenerated axons,and alleviated the denervation-induced atrophy of target muscles in dogs.To clarify the underlying molecular mechanism,we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons,and miR-30b-5p was the most important among others.We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK,STAT3 or CREB.Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.展开更多
Lysine-specific demethylase 1 （LSD1） was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcrip...Lysine-specific demethylase 1 （LSD1） was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex. Transcriptional target analysis using ChIP-on-chip technology revealed that the LSD1/SIN3A/HDAC complex targets several cellular signalling pathways that are critically involved in cell proliferation, survival, metastasis, and apoptosis, especially the p53 signalling pathway. We have demonstrated that LSD1 coordinates with the SIN3A/HDAC complex in inhibiting a series of genes such as CASP7, TGFB2, CDKN1A（p21）, HIF1A, TERT, and MDM2, some of which are oncogenic. Our experiments also found that LSD1 and SIN3A are required for optimal survival and growth of breast cancer cells while also essential for the maintenance of epithelial homoeostasis and chemosensitivity. Our data indicate that LSD1 is a functional alternative subunit of the SIN3A/HDAC complex, providing a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodelling, and suggest that the LSD1/SIN3A/HDAC complex could be a target for breast cancer therapeutic strategies.展开更多
目的研究miR-145-3p能否调控人牙周膜成纤维细胞(HPDLFs)的自噬及其可能存在的作用机制。方法收集12~18岁因正畸需要减数而拔除的健康前磨牙,采集和培养HPDLFs,并进行鉴定。将miR-145-3p类似物(miR-145-3p-mimics组)、miR-145-3p抑制物(...目的研究miR-145-3p能否调控人牙周膜成纤维细胞(HPDLFs)的自噬及其可能存在的作用机制。方法收集12~18岁因正畸需要减数而拔除的健康前磨牙,采集和培养HPDLFs,并进行鉴定。将miR-145-3p类似物(miR-145-3p-mimics组)、miR-145-3p抑制物(miR-145-3p-inhibitor组)、阴性对照(miR-145-3p normal control,miR-145-3p-NC组)以及带有GFP-LC3的质粒转染至HPDLFs,24 h后荧光显微镜观察荧光发生情况。双荧光素酶报告实验验证miR-145-3p与HDAC4的靶向关系,Western Blot检测各转染组细胞内HDAC4、Beclin-1、P62和LC3的蛋白表达。结果免疫组化结果表明,波形蛋白为阳性染色而角蛋白呈阴性染色,证明其为无混杂细胞的HPDLFs。转染结果显示,miR-145-3p-mimics组的细胞内荧光强度最高,有大量自噬体形成,而miR-145-3p-inhibitor组荧光最弱。双荧光素酶报告实验证实miR-145-3p靶向抑制HPDLFs细胞中HDAC4的表达。4组细胞中miR-145-3p-inhibitor组P62蛋白表达最高(P<0.05),而其他3组差异无统计学意义(P>0.05);miR-145-3p-mimics组细胞内Beclin-1和LC3蛋白表达最高(P<0.05),其他3组差异无统计学意义(P>0.05)。结论miR-145-3p在HPDLFs中可调控自噬,这种作用可能是通过靶向抑制HDAC4表达实现的。展开更多
基金supported by the National Natural Science Foundation Council of China(82172386 and 81922081 to C.L.,82100943 to X.F.,82104216 to J.L.,and 82230081,82250710175 and 8226116039 to G.X.)the Department of Education of Guangdong Province(2021KTSCX104 to C.L.)+5 种基金the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab)(2020B1212030006 to A.L.)the Guangdong Provincial Science and Technology Innovation Council Grant(2017B030301018 to G.X.)the Guangdong Basic and Applied Basic Research Foundation(2022A1515012164 to C.L.,and 2023A1515012000 to X.F.)the Science,Technology and Innovation Commission of Shenzhen(JCYJ20210324104201005 to C.L.,JCYJ20220530115006014 to X.F.,JCYJ20230807095118035 to J.L.,and JCYJ20220818100617036 to G.X.)the Hong Kong General Research Fund(12102722 to A.L.)the Hong Kong RGC Themebased Research Scheme(T12-201/20-R to A.L.).
文摘Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies.
基金supported in part by the National Natural Science Foundation of China(NSFC)(82073388 to SWM)the Natural Outstanding Youth Fund of Guangdong Province(2022B1515020090 to SWM)+1 种基金Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases(2022B1212030003 to SWM)the Affiliated Hospital of Guangdong Medical University Clinical Research Program(LCYJ2020B005 to SWM).
文摘Background:Long non-coding RNAs are important regulators in cancer biology and function either as tumor suppressors or as oncogenes.Their dysregulation has been closely associated with tumorigenesis.LINC00265 is upregulated in lung adenocarcinoma and is a prognostic biomarker of this cancer.However,the mechanism underlying its function in cancer progression remains poorly understood.Methods:Here,the regulatory role of LINC00265 in lung adenocarcinoma was examined using lung cancer cell lines,clinical samples,and xenografts.Results:We found that high levels of LINC00265 expression were associated with shorter overall survival rate of patients,whereas knockdown of LINC00265 inhibited proliferation of cancer cell lines and tumor growth in xenografts.Western blot andflow cytometry analyses indicated that silencing of LINC00265 induced autophagy and apoptosis.Moreover,we showed that LINC00265 interacted with and stabilized the transcriptional co-repressor Switch-independent 3a(SIN3A),which is a scaffold protein functioning either as a tumor repressor or as an oncogene in a context-dependent manner.Silencing of SIN3A also reduced proliferation of lung cancer cells,which was correlated with the induction of autophagy.These observations raise the possibility that LINC00265 functions to promote the oncogenic activity of SIN3A in lung adenocarcinoma.Conclusions:Ourfindings thus identify SIN3A as a LINC00265-associated protein and should help to understand the mechanism underlying LINC00265-mediated oncogenesis.
基金supported by the Major Research Plan of the National Natural Science Foundation of China(92068112)the National Key Research and Development Program of China(2017YFA0104700)+1 种基金the National Natural Science Foundation of China(82201509)the National Major Project of Research and Development(2022YFA1105500).
文摘Extracellular vesicles from skin-derived precursor Schwann cells(SKP-SC-EVs)promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats.This study aimed at expanding the application of SKPSC-EVs in nerve grafting by creating a chitosan/PLGA-based,SKP-SC-EVs-containing tissue engineered nerve graft(TENG)to bridge a 40-mm long sciatic nerve defect in dogs.SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions,supported the outgrowth and myelination of regenerated axons,and alleviated the denervation-induced atrophy of target muscles in dogs.To clarify the underlying molecular mechanism,we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons,and miR-30b-5p was the most important among others.We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK,STAT3 or CREB.Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.
基金This work was supported by grants from the Major State Basic Research Development Program of China （2016YFA0102400 to Y.W.）, the National Natural Science Foundation of China （81773017 and 81472733 to Y.W., 81402334 to Y.Y., and 81502446 to R.Q.）, China Postdoctoral Science Foundation （2014M561192 and 2015T80224 to Y.Y.）, the Tianjin Municipal Science and Technology Commission （15JCQNJC11900 to Y.Y.）, and the Science ＆ Technology Development Fund of Tianjin Education Commission for Higher Education （20140105 to R.Q.）.
文摘Lysine-specific demethylase 1 （LSD1） was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex. Transcriptional target analysis using ChIP-on-chip technology revealed that the LSD1/SIN3A/HDAC complex targets several cellular signalling pathways that are critically involved in cell proliferation, survival, metastasis, and apoptosis, especially the p53 signalling pathway. We have demonstrated that LSD1 coordinates with the SIN3A/HDAC complex in inhibiting a series of genes such as CASP7, TGFB2, CDKN1A（p21）, HIF1A, TERT, and MDM2, some of which are oncogenic. Our experiments also found that LSD1 and SIN3A are required for optimal survival and growth of breast cancer cells while also essential for the maintenance of epithelial homoeostasis and chemosensitivity. Our data indicate that LSD1 is a functional alternative subunit of the SIN3A/HDAC complex, providing a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodelling, and suggest that the LSD1/SIN3A/HDAC complex could be a target for breast cancer therapeutic strategies.
文摘目的研究miR-145-3p能否调控人牙周膜成纤维细胞(HPDLFs)的自噬及其可能存在的作用机制。方法收集12~18岁因正畸需要减数而拔除的健康前磨牙,采集和培养HPDLFs,并进行鉴定。将miR-145-3p类似物(miR-145-3p-mimics组)、miR-145-3p抑制物(miR-145-3p-inhibitor组)、阴性对照(miR-145-3p normal control,miR-145-3p-NC组)以及带有GFP-LC3的质粒转染至HPDLFs,24 h后荧光显微镜观察荧光发生情况。双荧光素酶报告实验验证miR-145-3p与HDAC4的靶向关系,Western Blot检测各转染组细胞内HDAC4、Beclin-1、P62和LC3的蛋白表达。结果免疫组化结果表明,波形蛋白为阳性染色而角蛋白呈阴性染色,证明其为无混杂细胞的HPDLFs。转染结果显示,miR-145-3p-mimics组的细胞内荧光强度最高,有大量自噬体形成,而miR-145-3p-inhibitor组荧光最弱。双荧光素酶报告实验证实miR-145-3p靶向抑制HPDLFs细胞中HDAC4的表达。4组细胞中miR-145-3p-inhibitor组P62蛋白表达最高(P<0.05),而其他3组差异无统计学意义(P>0.05);miR-145-3p-mimics组细胞内Beclin-1和LC3蛋白表达最高(P<0.05),其他3组差异无统计学意义(P>0.05)。结论miR-145-3p在HPDLFs中可调控自噬,这种作用可能是通过靶向抑制HDAC4表达实现的。
