BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,includi...BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determi展开更多
AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected b...AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected by immunohistochemistry in 185 specimens of gastric cancer, 20 gastric cancer specimens with lymphatic metastasis and 22 controls of normal gastric mucosa using four monoclonal antibodies. RESULTS: The expression of HLA class Ⅰ antigen (B/C locus) was significantly downregulated in gastric cancer and in lymphatic metastasis than that in normal gastric mucosa (x2=7.712, P<0.05). The expression of other HLA class Ⅰ antigens was also downregulated, but the change was slight. There was no relationship between the downregulation of HLA class Ⅰ antigen and that of β2m and LMP2. The expression of HLA class Ⅰ (B/C locus) was statistically correlated with pathologic stage in gastric adenocarcinoma (x2=4.164,P<0.05). CONCLUSION: The expression of HLA class Ⅰ antigen (B/C locus) was obviously downregulated in gastric cancer and in lymphatic metastasis. This abnormal expression would provide the tumor cells with a way to avoid immunological recognition.展开更多
BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotio...BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotion,and behavior.AIM To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments.METHODS This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period.The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy.The recognized cognitive battery tool,the MATRICS Consensus Cognitive Battery,was used to evaluate the scores for various dimensions of cognitive function.The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed.RESULTS Significant differences in GABA receptor subunit levels were found between the case and control groups(P<0.05).A significant difference was also found between the case and control groups in terms of cognitive function measures,including attention/alertness and learning ability(P<0.05).Specifically,as the expression levels of GABRA1(α1 subunit gene),GABRB2(β2 subunit gene),GABRD(δsubunit),and GABRE(εsubunit)decreased,the severity of the patients’condition increased gradually,indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia(P<0.05).However,the expression levels of GABRA5(α5 subunit gene)and GABRA6(α6 subunit gene)showed no significant correlation with schizophrenia(P>0.05).CONCLUSION Downregulation of the GABA receptor subunits is positively correlated with schizophrenia.In other words,when GABA receptor subunits are downregulated in patients,cognitive impairment becomes more severe.展开更多
In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excess...In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.展开更多
Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on t...Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on the definition of which parameters are the most sensitive for detecting CO2 acclimation. In order to investigate the most sensitive photosynthetic and molecular markers of CO2 acclimation, the effects of elevated CO2, and associated elevated temperature were analyzed in alfalfa plants inoculated with different Sinorhizobium meliloti strains. Plants （Medicago sativa L. cv. Aragon） were grown in summer or autumn in temperature gradient greenhouses （TGG）. At the end of the experiment, all plants showed acclimation in both seasons, especially under elevated summer temperatures. This was probably due to the lower nitrogen （N） availability caused by decreased N2-fixation under higher temperatures. Photosynthesis measured at growth CO2 concentration, rubisco in vitro activity and maximum rate of carboxylation were the most sensitive parameters for detecting downregulation. Severe acclimation was also related with decreases in leaf nitrogen content associated with declines in rubisco content （large and small subunits） and activity that resulted in a drop in photosynthesis. Despite the sensitivity of rubisco content as a marker of acclimation, it was not coordinated with gene expression, possibly due to a lag between gene transcription and protein translation.展开更多
Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihyd...Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.展开更多
In 1986, nuclear factor (NF)-κB was first discovered in the laboratory of Nobel Prize laureate David Baltimore via its interaction with a sequence (5′-GGGACTTTCC-3′) in the immunoglobulin light-chain enhancer in B
Hypocotyl formation during the epigeal germination of seedlings is under strict hormonal regulation. In a 3 d old Zinnia elegans seedling system, gibberellic acid （GA3） exerts an opposite effect to that exerted by l...Hypocotyl formation during the epigeal germination of seedlings is under strict hormonal regulation. In a 3 d old Zinnia elegans seedling system, gibberellic acid （GA3） exerts an opposite effect to that exerted by light on hypocotyl photomorphogenesis because GAz promotes an etiolated-like growth with an inhibition of radial （secondary） growth. For this reason, the effect of GA3 on the basic peroxidase isoenzyme from Z. elegans （ZePrx）, an enzyme involved in hypocotyl lignin biosynthesis, was studied. The results showed that GA3 reduces ZePrx activity, similarly to the way in which it reduces seedling secondary growth. This hormonal response is supported by the analysis of the ZePrx promoter, which contains four types of GA3-responsive cis.elements： the W Box/O2S; the Pyr Box; the GARE; and the Amy Box. Taken together, these results suggest that ZePrx is directly regulated by GA3, with this effect matching the inhibitory effect of GA on the hypocotyl secondary growth.展开更多
Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected ...Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.展开更多
Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that ...Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.展开更多
Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers;however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER...Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers;however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 afterneoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequentlyassociated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorlyunderstood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have beensuggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behindHER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples.The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of thisphenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specificallyaddressing HER2 loss are warranted.展开更多
基金Supported by Medicine and Health Science and Technology Plan Projects of Zhejiang Province,No.2018KY569Zhejiang Provincial Natural Science Foundation of China,No.LY17H030002
文摘BACKGROUND Liver cancer has a high mortality and morbidity rate throughout the world.In clinical practice,the prognosis of liver cancer patients is poor,and the complex reasons contribute to treatment failures,including fibrosis,hepatitis viral infection,drug resistance and metastasis.Thus,screening novel prognostic biomarkers is of great importance for guiding liver cancer therapy.Orosomucoid genes(ORMs)encode acute phase plasma proteins,including orosomucoid 1(ORM1)and ORM2.Previous studies showed their upregulation upon inflammation,but the specific function of ORMs has not yet been determined,especially in the development of liver cancer.AIM To determine the expression of ORMs and their potential function in liver cancer.METHODS Analysis of the expression of ORMs in different human tissues was performed on data from the HPA RNA-seq normal tissues project.The expression ratio of ORMs was determined using the HCCDB database,including the ratio between liver cancer and other cancers,normal liver and other normal tissues,liver cancer and adjacent normal liver tissues.Analysis of ORM expression in different cancer types was performed using The Cancer Genome Atlas and TIMER database.The expression of ORMs in liver tumor tissues and adjacent normal tissues were further confirmed using Gene Expression Omnibus data,including GSE36376 and GSE14520.The 10-year overall survival(OS),progression-free survival(PFS)and relapse-free survival(RFS)rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.Gene Set Enrichment Analysis(GSEA)was employed to explore the ORM2-associated signaling network.Correlations between ORM2 expression and tumor purity or the infiltration level of macrophages in liver tumor tissues were determined using the TIMER database.The correlation between ORM2 gene levels,tumor-associated macrophage(TAM)markers(including CD68 and TGFβ1)and T cell immunosuppression(including CTLA4 and PD-1)in liver tumor tissues and liver GTEx was determi
基金Supported by the Provincial Natural Science Fund of Jiangsu,No.BK2002055National Science Fund for Distinguished Young Scholars,No.30325017
文摘AIM:To discuss the expression of human leukocyte antigen (HLA) class Ⅰ antigens in gastric cancer and correlate these with pathologic type and TNM stage. METHODS: The expression of HLA class Ⅰ antigen was detected by immunohistochemistry in 185 specimens of gastric cancer, 20 gastric cancer specimens with lymphatic metastasis and 22 controls of normal gastric mucosa using four monoclonal antibodies. RESULTS: The expression of HLA class Ⅰ antigen (B/C locus) was significantly downregulated in gastric cancer and in lymphatic metastasis than that in normal gastric mucosa (x2=7.712, P<0.05). The expression of other HLA class Ⅰ antigens was also downregulated, but the change was slight. There was no relationship between the downregulation of HLA class Ⅰ antigen and that of β2m and LMP2. The expression of HLA class Ⅰ (B/C locus) was statistically correlated with pathologic stage in gastric adenocarcinoma (x2=4.164,P<0.05). CONCLUSION: The expression of HLA class Ⅰ antigen (B/C locus) was obviously downregulated in gastric cancer and in lymphatic metastasis. This abnormal expression would provide the tumor cells with a way to avoid immunological recognition.
文摘BACKGROUND The expression pattern of gamma aminobutyric acid(GABA)receptor subunits are commonly altered in patients with schizophrenia,which may lead to nerve excitation/inhibition problems,affecting cognition,emotion,and behavior.AIM To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments.METHODS This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period.The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy.The recognized cognitive battery tool,the MATRICS Consensus Cognitive Battery,was used to evaluate the scores for various dimensions of cognitive function.The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed.RESULTS Significant differences in GABA receptor subunit levels were found between the case and control groups(P<0.05).A significant difference was also found between the case and control groups in terms of cognitive function measures,including attention/alertness and learning ability(P<0.05).Specifically,as the expression levels of GABRA1(α1 subunit gene),GABRB2(β2 subunit gene),GABRD(δsubunit),and GABRE(εsubunit)decreased,the severity of the patients’condition increased gradually,indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia(P<0.05).However,the expression levels of GABRA5(α5 subunit gene)and GABRA6(α6 subunit gene)showed no significant correlation with schizophrenia(P>0.05).CONCLUSION Downregulation of the GABA receptor subunits is positively correlated with schizophrenia.In other words,when GABA receptor subunits are downregulated in patients,cognitive impairment becomes more severe.
基金Yunnan Fundamental Research Projects(202201AU070167,202301AT070258)Yunnan Key Laboratory of Formulated Granules(202105AG070014).
文摘In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.
基金supported by Ministerio de Ciencia e Innovación (MICINN BFU2008-01405)Ministerio de Economia y Competitividad (BFU2011-26989)+1 种基金Fundación Universitaria de Navarra (PIUNA-2008)Fundación Caja Navarra
文摘Elevated CO2 leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on the definition of which parameters are the most sensitive for detecting CO2 acclimation. In order to investigate the most sensitive photosynthetic and molecular markers of CO2 acclimation, the effects of elevated CO2, and associated elevated temperature were analyzed in alfalfa plants inoculated with different Sinorhizobium meliloti strains. Plants （Medicago sativa L. cv. Aragon） were grown in summer or autumn in temperature gradient greenhouses （TGG）. At the end of the experiment, all plants showed acclimation in both seasons, especially under elevated summer temperatures. This was probably due to the lower nitrogen （N） availability caused by decreased N2-fixation under higher temperatures. Photosynthesis measured at growth CO2 concentration, rubisco in vitro activity and maximum rate of carboxylation were the most sensitive parameters for detecting downregulation. Severe acclimation was also related with decreases in leaf nitrogen content associated with declines in rubisco content （large and small subunits） and activity that resulted in a drop in photosynthesis. Despite the sensitivity of rubisco content as a marker of acclimation, it was not coordinated with gene expression, possibly due to a lag between gene transcription and protein translation.
基金supported by Cancer Institute NSW CDF fellowship (YZ)Cure Cancer Foundation of Australia (YZ)+3 种基金Cancer Council New South Wales (MJS, YZ, HZ, and CRD)Prostate Cancer Foundation of Australia (MJS, YZ, HZ, and CRD)NH and MRC Early Career Fellowship 596870 (YZ)German Research Foundation HO 5109/2-1 and HO 5109/2-2 (KH)
文摘Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.
文摘In 1986, nuclear factor (NF)-κB was first discovered in the laboratory of Nobel Prize laureate David Baltimore via its interaction with a sequence (5′-GGGACTTTCC-3′) in the immunoglobulin light-chain enhancer in B
基金supported by grants from the MEC (BFU2006-11577/BFI)-FEDERCARM (Programa de Generación de Conocimiento Científico de Excelencia de la Fundación Sneca,Agencia de Ciencia y Tecnología de la Región de Murcia en el Marco del Ⅱ PCTRM 2007–2010,project 08610/PI/08)
文摘Hypocotyl formation during the epigeal germination of seedlings is under strict hormonal regulation. In a 3 d old Zinnia elegans seedling system, gibberellic acid （GA3） exerts an opposite effect to that exerted by light on hypocotyl photomorphogenesis because GAz promotes an etiolated-like growth with an inhibition of radial （secondary） growth. For this reason, the effect of GA3 on the basic peroxidase isoenzyme from Z. elegans （ZePrx）, an enzyme involved in hypocotyl lignin biosynthesis, was studied. The results showed that GA3 reduces ZePrx activity, similarly to the way in which it reduces seedling secondary growth. This hormonal response is supported by the analysis of the ZePrx promoter, which contains four types of GA3-responsive cis.elements： the W Box/O2S; the Pyr Box; the GARE; and the Amy Box. Taken together, these results suggest that ZePrx is directly regulated by GA3, with this effect matching the inhibitory effect of GA on the hypocotyl secondary growth.
基金supported by National Natural Science Foundation of China(11932012,81870790 and 31801233)Science and Technology Commission of Shanghai Municipality(18441903600)+1 种基金Clinical Research Plan of SHDC(No.SHDC2020CR3009A)Innovative Research Team of High-level Local Universities in Shanghai(SSMU-ZDCX20180902)。
文摘Osteoarthritis(OA)is a prevalent joint disease with no effective treatment strategies.Aberrant mechanical stimuli was demonstrated to be an essential factor for OA pathogenesis.Although multiple studies have detected potential regulatory mechanisms underlying OA and have concentrated on developing novel treatment strategies,the epigenetic control of OA remains unclear.Histone demethylase JMJD3 has been reported to mediate multiple physiological and pathological processes,including cell differentiation,proliferation,autophagy,and apoptosis.However,the regulation of JMJD3 in aberrant force-related OA and its mediatory effect on disease progression are still unknown.In this work,we confirmed the upregulation of JMJD3 in aberrant forceinduced cartilage injury in vitro and in vivo.Functionally,inhibition of JMJD3 by its inhibitor,GSK-J4,or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 could alleviate the aberrant force-induced chondrocyte injury.Mechanistic investigation illustrated that aberrant force induces JMJD3 expression and then demethylates H3K27me3 at the NR4A1 promoter to promote its expression.Further experiments indicated that NR4A1 can regulate chondrocyte apoptosis,cartilage degeneration,extracellular matrix degradation,and inflammatory responses.In vivo,anterior cruciate ligament transection(ACLT)was performed to construct an OA model,and the therapeutic effect of GSK-J4 was validated.More importantly,we adopted a peptide-si RNA nanoplatform to deliver si-JMJD3 into articular cartilage,and the severity of joint degeneration was remarkably mitigated.Taken together,our findings demonstrated that JMJD3 is flow-responsive and epigenetically regulates OA progression.Our work provides evidences for JMJD3 inhibition as an innovative epigenetic therapy approach for joint diseases by utilizing p5RHH-si RNA nanocomplexes.
文摘Natural killer T （NKT） cells are a unique T cell population that have important immunoregulatory functions and have been shown to be involved in host immunity against a range of microorganisms. It also emerges that they might play a role in HIV-1 infection, and therefore be selectively depleted during the early stages of infection. Recent studies are reviewed regarding the dynamics of NKT depletion during HIV-1 infection and their recovery under highly active antiretroviral treatment （HAART）. Possible mechanisms for these changes are proposed based on the recent developments in HIV pathogenesis. Further discussions are focused on HIV＇s disruption of NKT activation by downregulating CDld expression on antigen presentation cells （APC）. HIV-1 protein Nefis found to play the major role by interrupting the intracellular trafficking of nascent and recycling CDld molecules.
文摘Loss of HER2 in previously HER2-positive breast tumors is not rare, occurring in up to 50% of breast cancers;however, clinical research and practice underestimate this issue. Many studies have reported the loss of HER2 afterneoadjuvant therapy and at metastatic relapse and identified clinicopathological variables more frequentlyassociated with this event. Nevertheless, the biological mechanisms underlying HER2 loss are still poorlyunderstood. HER2 downregulation, intratumoral heterogeneity, clonal selection, and true subtype switch have beensuggested as potential causes of HER2 loss, but translational studies specifically investigating the biology behindHER2 loss are virtually absent. On the other side, technical pitfalls may justify HER2 loss in some of these samples.The best treatment strategy for patients with HER2 loss is currently unknown. Considering the prevalence of thisphenomenon and its apparent correlation with worse outcomes, we believe that correlative studies specificallyaddressing HER2 loss are warranted.
