The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,whic...The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.展开更多
Background: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis. Methods: We created...Background: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis. Methods: We created three groups of K/BxN female mice that were positive for the anti‐glucose‐6‐phosphate isomerase (GPI) antibody: control diet (CD), high fat diet (HFD), and HFD with hydroxychloroquine (HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol (TCHO), low‐density lipoprotein cholesterol (LDL‐C), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), anti‐ GPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16sV4 sequencing. Results: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL‐C, TCHO, and TG, decreased serum levels of HDL‐C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL‐C, TCHO, and TG, increased serum levels of HDL‐C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA‐associated atherosclerosis and dyslipidemia. Conclusion: Our mouse model of RA indicated that HFD increased ankle width and aggravated a therosclerosis a nd d yslipidemia, a nd t hat H CQ a lleviated t he d yslipidemia and atherosclerosis, but had no effect on ankle width.展开更多
Background:Head and neck squamous cancer(HNSC)frequently occurs in the clinic.Revealing the role of the genes that correlate with cancer cell outgrowth will contribute to potential treatment target identification and ...Background:Head and neck squamous cancer(HNSC)frequently occurs in the clinic.Revealing the role of the genes that correlate with cancer cell outgrowth will contribute to potential treatment target identification and tumor inhibition.Methods:The gene expression profiles and gene ontology of the proton-sensing G-protein-coupled receptor OGR1 were analyzed using the TCGA(The Cancer Genome Atlas)database.The effects of sex,age,race,and degree of malignancy on HNSC were investigated,and the survival times of HNSC patients with high or low/medium expression levels of OGR1 were compared.Methylation of the OGR1 promoter CpG sites was also investigated and OGR1-related genes were analyzed using gene set enrichment analysis.Results:OGR1 is overexpressed in HNSC patients.However,compared with the low/median expression group,the high OGR1 expression group did not have different survival rates.The OGR1 expression level differed across sex,age,race,and degree of malignancy,while the methylation of the OGR1 promoter CpG sites was maintained at a similar level.Gene set enrichment analysis revealed that OGR1 was positively correlated with head and neck cancer,cisplatin resistance,hypoxia,angiogenesis,cell migration,and TGF-β.Conclusion:The expression of OGR1 correlated with HNSC progression and survival and thus can serve as a potential treatment target and prognostic marker.展开更多
SPR (Surface Plasmon Resonance) is an emerging optical biosensor which can monitor the processes at metal interface in real time without labeling requirements.Instrument SPR-2004 can sense two areas in one channel and...SPR (Surface Plasmon Resonance) is an emerging optical biosensor which can monitor the processes at metal interface in real time without labeling requirements.Instrument SPR-2004 can sense two areas in one channel and get two signals at same time in one test.One signal is the graph of the reaction;the other is the graph of reference.SPR biochip is modified with dextran,and only reaction area can be used to immobilize the protein.Two methods of antibody immobilization on chip were tested.One was to immobilize directly,the other was to immobilize protein A firstly and then the antibody was caught by immobilized protein A.The latter was chosen as suitable for retention of the native binding ability with virus of antibody.The latter chip was used to detect SARS-Cov.The signal of detection reached to 60 units within 40 min.It was 55 units even after reference.展开更多
Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induct...Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.展开更多
With the increasingly serious aging of the global population, dementia has already become a severe clinical challenge on a global scale. Dementia caused by Alzheimer’s disease(AD) is the most common form of dementia ...With the increasingly serious aging of the global population, dementia has already become a severe clinical challenge on a global scale. Dementia caused by Alzheimer’s disease(AD) is the most common form of dementia observed in the elderly, but its pathogenetic mechanism has still not been fully elucidated. Furthermore, no effective treatment strategy has been developed to date, despite considerable efforts. This can be mainly attributed to the paucity of animal models of AD that are sufficiently similar to humans. Among the presently established animal models, non-human primates share the closest relationship with humans, and their neural anatomy and neurobiology share highly similar characteristics with those of humans. Thus, there is no doubt that these play an irreplaceable role in AD research. Considering this, the present literature on non-human primate models of AD was reviewed to provide a theoretical basis for future research.展开更多
Background: Lung cancer frequently occurs in the clinic, leading to poor prognosis and high mortality. Markers for early diagnosis of lung cancer are scarce, and further potential therapeutic targets are also urgently...Background: Lung cancer frequently occurs in the clinic, leading to poor prognosis and high mortality. Markers for early diagnosis of lung cancer are scarce, and further potential therapeutic targets are also urgently needed.Method: We established a new mouse model in which the specific gene HNRNPK(heterogeneous nuclear ribonucleoprotein K) was downregulated after administration of doxycycline. The lung metastatic nodules were investigated using bioluminescence imaging, micro-CT, and autopsy quantification.Results: Compared with the short hairpin negative control group, less lung metastatic nodules were formed in the short hairpin RNA group.Conclusion: Downregulation of HNRNPK in cancer cells can inhibit lung metastasis.展开更多
Background : Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self- renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling...Background : Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self- renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low- density lipoprotein, chylomicrons, and triglyceride- rich lipoproteins. Methods : The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence- activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL^(+/−) HSC microenvironment were detected by transplantation as- says using red fluorescent protein (RFP) transgenic mice. Results : To explore the function of LPL in HSC regulation, heterozygous LPL- knockout mice (LPL^(+/−)) were established and analyzed by FACS. LPL^(+/−) mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single- cell clono- genic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57^(KIP2) and p21^(WAF1)/ ^(CIP1) in LPL^(+/−) mice was upregulated. Conclusions : LPL^(+/−) mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.展开更多
Background: Nickel-induced allergic contact dermatitis (Ni-ACD) is a global health problem. More detailed knowledge on the skin uptake of haptens is required. This study aimed to investigate the penetration process an...Background: Nickel-induced allergic contact dermatitis (Ni-ACD) is a global health problem. More detailed knowledge on the skin uptake of haptens is required. This study aimed to investigate the penetration process and distribution of nickel in skin tissues with late phase and early phase of Ni-ACD to understand the mechanisms of metal allergy. Methods: Forty Hartley guinea pigs were divided into four groups according to the NiSO4 sensitizing concentration and the NiSO4 challenged concentration: the 5% NiSO4-group, 5% to 10%(sensitization-challenge;late phase group);10% NiSO4-group, 10% to 10%(sensitization-challenge;early-phase group);and the positive and negative controls. Pathological biopsies were performed on each group. The depth profile of nickel element concentration in the skin of guinea pigs was detected by synchrotron radiation micro X-ray fluorescence spectroscopy (SR-μ-XRF) and micro X-ray absorption near-edge spectroscopy (μ-XANES). Results: In each section, the nickel element concentration in both the 5% NiSO4-group and 10% NiSO4-group was significantly higher than that in the negative control group. In the upper 300-μm section of skin for the early phase group, the nickel element concentration was significantly higher than that in the lower section of skin. In deeper sections (>200 μm) of skin, the concentration of nickel in the early phase group was approximately equal to that in the late phase group. The curve of the late phase group was flat, which means that the nickel element concentration was distributed uniformly by SR-μ-XRF. According to the XANES data for the 10% NiSO4 metal salt solution, structural changes occurred in the skin model sample, indicating that nickel was not present in the Ni^2+ aqueous ionic state but in the nickel-binding protein. Conclusions: This study showed that the distribution of the nickel element concentration in ACD skin tissue was different between the early phase and late phase groups. The nickel element was not present in the Ni^2+ aqueous ionic state but bound with certain proteins to form a complex in the stratum corneum in ACD model tissue.展开更多
Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays...Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays a critical role in the pathogenesis of severe pneumonia and provides novel strategies for the treatment of severe influenza infection[1–3].The complement system plays critical roles in both innate and adaptive immunity by activating the classical,alternative and lectin pathways[4].展开更多
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-013)the National Key Research and Development Program of China(2021YFF0702801,2022YFF0710705)+1 种基金the Special Research Fund for Central Universities,Peking Union Medical College(No.3332022182)Seed Fund for Youth Talent Training Program of Beijing Tongren Hospital Affiliated to Capital Medical University(2020-YJJ-ZZL-034).
文摘The premetastatic niches(PMN)formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization.Targeted PMN therapy may prevent tumor metastasis in the early stages,which is becoming increasingly important.At present,there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN.Here,we summarize current research advances on the cellular and molecular characteristics of the PMN.We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis,which provides a promising basis for future research and clinical application.
基金supported by CAMS Initiative for Innovative Medicine of China,Grant/Award Number:No.2016-12M-1-006National Key R&D Program of China,Grant/Award Number:No.2017YFC1103603
文摘Background: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis. Methods: We created three groups of K/BxN female mice that were positive for the anti‐glucose‐6‐phosphate isomerase (GPI) antibody: control diet (CD), high fat diet (HFD), and HFD with hydroxychloroquine (HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol (TCHO), low‐density lipoprotein cholesterol (LDL‐C), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), anti‐ GPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16sV4 sequencing. Results: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL‐C, TCHO, and TG, decreased serum levels of HDL‐C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL‐C, TCHO, and TG, increased serum levels of HDL‐C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA‐associated atherosclerosis and dyslipidemia. Conclusion: Our mouse model of RA indicated that HFD increased ankle width and aggravated a therosclerosis a nd d yslipidemia, a nd t hat H CQ a lleviated t he d yslipidemia and atherosclerosis, but had no effect on ankle width.
基金This work was supported by grants from the National Natural Science Foundation of China(no.81372253)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2016-I2M-3-019).
文摘Background:Head and neck squamous cancer(HNSC)frequently occurs in the clinic.Revealing the role of the genes that correlate with cancer cell outgrowth will contribute to potential treatment target identification and tumor inhibition.Methods:The gene expression profiles and gene ontology of the proton-sensing G-protein-coupled receptor OGR1 were analyzed using the TCGA(The Cancer Genome Atlas)database.The effects of sex,age,race,and degree of malignancy on HNSC were investigated,and the survival times of HNSC patients with high or low/medium expression levels of OGR1 were compared.Methylation of the OGR1 promoter CpG sites was also investigated and OGR1-related genes were analyzed using gene set enrichment analysis.Results:OGR1 is overexpressed in HNSC patients.However,compared with the low/median expression group,the high OGR1 expression group did not have different survival rates.The OGR1 expression level differed across sex,age,race,and degree of malignancy,while the methylation of the OGR1 promoter CpG sites was maintained at a similar level.Gene set enrichment analysis revealed that OGR1 was positively correlated with head and neck cancer,cisplatin resistance,hypoxia,angiogenesis,cell migration,and TGF-β.Conclusion:The expression of OGR1 correlated with HNSC progression and survival and thus can serve as a potential treatment target and prognostic marker.
基金This work was supported by the National Natural Science Foundation of China (No. 60341005 and No. 60427001).
文摘SPR (Surface Plasmon Resonance) is an emerging optical biosensor which can monitor the processes at metal interface in real time without labeling requirements.Instrument SPR-2004 can sense two areas in one channel and get two signals at same time in one test.One signal is the graph of the reaction;the other is the graph of reference.SPR biochip is modified with dextran,and only reaction area can be used to immobilize the protein.Two methods of antibody immobilization on chip were tested.One was to immobilize directly,the other was to immobilize protein A firstly and then the antibody was caught by immobilized protein A.The latter was chosen as suitable for retention of the native binding ability with virus of antibody.The latter chip was used to detect SARS-Cov.The signal of detection reached to 60 units within 40 min.It was 55 units even after reference.
文摘Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
基金The CAMS Innovation Fund for Medical Science(2016-12M-2-006 and 2016-12M-1-10)the PUMC Innovation Fund for Graduate Students(Grant/Award number:2017-1001-07)
文摘With the increasingly serious aging of the global population, dementia has already become a severe clinical challenge on a global scale. Dementia caused by Alzheimer’s disease(AD) is the most common form of dementia observed in the elderly, but its pathogenetic mechanism has still not been fully elucidated. Furthermore, no effective treatment strategy has been developed to date, despite considerable efforts. This can be mainly attributed to the paucity of animal models of AD that are sufficiently similar to humans. Among the presently established animal models, non-human primates share the closest relationship with humans, and their neural anatomy and neurobiology share highly similar characteristics with those of humans. Thus, there is no doubt that these play an irreplaceable role in AD research. Considering this, the present literature on non-human primate models of AD was reviewed to provide a theoretical basis for future research.
基金National Natural Science Foundation of China,Grant/Award Number:81602460
文摘Background: Lung cancer frequently occurs in the clinic, leading to poor prognosis and high mortality. Markers for early diagnosis of lung cancer are scarce, and further potential therapeutic targets are also urgently needed.Method: We established a new mouse model in which the specific gene HNRNPK(heterogeneous nuclear ribonucleoprotein K) was downregulated after administration of doxycycline. The lung metastatic nodules were investigated using bioluminescence imaging, micro-CT, and autopsy quantification.Results: Compared with the short hairpin negative control group, less lung metastatic nodules were formed in the short hairpin RNA group.Conclusion: Downregulation of HNRNPK in cancer cells can inhibit lung metastasis.
基金The Beijing Natural Science Foundation,Grant/Award Number:5202024The National Science Foundation of China,Grant/Award Number:31672374CAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2019-I2M-1-006.
文摘Background : Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self- renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low- density lipoprotein, chylomicrons, and triglyceride- rich lipoproteins. Methods : The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence- activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL^(+/−) HSC microenvironment were detected by transplantation as- says using red fluorescent protein (RFP) transgenic mice. Results : To explore the function of LPL in HSC regulation, heterozygous LPL- knockout mice (LPL^(+/−)) were established and analyzed by FACS. LPL^(+/−) mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single- cell clono- genic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57^(KIP2) and p21^(WAF1)/ ^(CIP1) in LPL^(+/−) mice was upregulated. Conclusions : LPL^(+/−) mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.
基金the grants from National Natural Science Foundation of China (No.81373175)CAMS Innovation Fund for Medical Sciences (No.2016-I2M-1003).
文摘Background: Nickel-induced allergic contact dermatitis (Ni-ACD) is a global health problem. More detailed knowledge on the skin uptake of haptens is required. This study aimed to investigate the penetration process and distribution of nickel in skin tissues with late phase and early phase of Ni-ACD to understand the mechanisms of metal allergy. Methods: Forty Hartley guinea pigs were divided into four groups according to the NiSO4 sensitizing concentration and the NiSO4 challenged concentration: the 5% NiSO4-group, 5% to 10%(sensitization-challenge;late phase group);10% NiSO4-group, 10% to 10%(sensitization-challenge;early-phase group);and the positive and negative controls. Pathological biopsies were performed on each group. The depth profile of nickel element concentration in the skin of guinea pigs was detected by synchrotron radiation micro X-ray fluorescence spectroscopy (SR-μ-XRF) and micro X-ray absorption near-edge spectroscopy (μ-XANES). Results: In each section, the nickel element concentration in both the 5% NiSO4-group and 10% NiSO4-group was significantly higher than that in the negative control group. In the upper 300-μm section of skin for the early phase group, the nickel element concentration was significantly higher than that in the lower section of skin. In deeper sections (>200 μm) of skin, the concentration of nickel in the early phase group was approximately equal to that in the late phase group. The curve of the late phase group was flat, which means that the nickel element concentration was distributed uniformly by SR-μ-XRF. According to the XANES data for the 10% NiSO4 metal salt solution, structural changes occurred in the skin model sample, indicating that nickel was not present in the Ni^2+ aqueous ionic state but in the nickel-binding protein. Conclusions: This study showed that the distribution of the nickel element concentration in ACD skin tissue was different between the early phase and late phase groups. The nickel element was not present in the Ni^2+ aqueous ionic state but bound with certain proteins to form a complex in the stratum corneum in ACD model tissue.
基金This work was supported by grants from National Natural Science Foundation of China(82071747,81373114)Beijing Municipal Natural Science Foundation,China(7182013).
文摘Severe pandemic influenza A(H1N1)2009 virus(pH1N1)infection causes significant morbidity and mortality.We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays a critical role in the pathogenesis of severe pneumonia and provides novel strategies for the treatment of severe influenza infection[1–3].The complement system plays critical roles in both innate and adaptive immunity by activating the classical,alternative and lectin pathways[4].