Objective:To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal therapy.Methods: We predicted and characterized HQD patt...Objective:To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal therapy.Methods: We predicted and characterized HQD pattern genes using the new strategy,TCM-HIN2Vec,which involves heterogeneous network embedding and transcriptomic experiments.First,a heterogeneous network of traditional Chinese medicine(TCM)patterns was constructed using public databases.Next,we predicted HQD pattern genes using a heterogeneous network-embedding algorithm.We then analyzed the functional characteristics of HQD pattern genes using gene enrichment analysis and examined gene expression levels using RNA-seq.Finally,we identified TCM herbs that demonstrated enriched interactions with HQD pattern genes via herbal enrichment analysis.Results: Our TCM-HIN2Vec strategy revealed that candidate genes associated with HQD pattern were significantly enriched in energy metabolism,signal transduction pathways,and immune processes.Moreover,we found that these candidate genes were significantly differentially expressed in the transcriptional profile of mice model with heart failure with a qi deficiency pattern.Furthermore,herbal enrichment analysis identified TCM herbs that demonstrated enriched interactions with the top 10 candidate genes and could potentially serve as drug candidates for treating HQD.Conclusion: Our results suggested that TCM-HIN2Vec is capable of not only accurately identifying HQD pattern genes,but also deciphering the basis of HQD pattern.Furthermore our finding indicated that TCM-HIN2Vec may be further expanded to develop other patterns,leading to a new approach aimed at elucidating general TCM patterns and developing precision medicine.展开更多
Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and diffe...Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and different charge isomers(CIs)is of utmost importance,but is challenging.We intended to quantitatively characterize the posttranslational modification status of CIs of antibody drugs and explore the impact of posttranslational modifications on charge heterogeneity.The CIs of antibodies were fractionated by strong cation exchange chromatography and verified by capillary isoelectric focusing-whole column imaging detection,followed by stepwise structural characterization at three levels.First,the differences between CIs were explored at the intact protein level using a top-down mass spectrometry approach;this showed differences in glycoforms and deamidation status.Second,at the peptide level,common modifications of oxidation,deamidation,and glycosylation were identified.Peptide mapping showed nonuniform deamidation and glycoform distribution among CIs.In total,10 N-glycoforms were detected by peptide mapping.Finally,an in-depth analysis of glycan variants of CIs was performed through the detection of enriched glycopeptides.Qualitative and quantitative analyses demonstrated the dynamics of 24 N-glycoforms.The results revealed that sialic acid modification is a critical factor accounting for charge heterogeneity,which is otherwise missed in peptide mapping and intact molecular weight analyses.This study demonstrated the importance of the comprehensive analyses of antibody CIs and provides a reference method for the quality control of biopharmaceutical analysis.展开更多
Recombinant batroxobin(S3101)is a thrombin-like serine protease that binds to fibrinogen or is taken up by the reticuloendothelial system.A literature survey showed no adequate method that could determine sufficient c...Recombinant batroxobin(S3101)is a thrombin-like serine protease that binds to fibrinogen or is taken up by the reticuloendothelial system.A literature survey showed no adequate method that could determine sufficient concentrations to evaluate pharmacokinetic parameters for phase I clinical studies.Therefore,a sensitive method is urgently needed to support the clinical pharmacokinetic evaluation of S3101.In this study,a sensitive bioanalytical method was developed and validated,using a Quanterix single molecular array(Simoa)assay.Moreover,to thoroughly assess the platform,enzyme-linked immunosorbent assay and electrochemiluminescence assay were also developed,and their performance was compared with that of this novel technology platform.The assay was validated in compliance with the current guidelines.Measurements with the Simoa assay were precise and accurate,presenting a valid assay range from 6.55 to 4000 pg/mL.The intra-and inter-run accuracy and precision were within-19.3%to 15.3%and 5.5%to 17.0%,respectively.S3101 was stable in human serum for 280 days at-20℃and-70℃,for 2 h prior to pre-treatment and 24 h post pre-treatment at room temperature(22℃-28℃),respectively,and after five and two freeze-thaw cycles at-70℃and-20oC,respectively.The Simoa assay also demonstrated sufficient dilution linearity,assay sensitivity,and parallelism for quantifying S3101 in human serum.The Simoa assay is a sensitive and adequate method for evaluating the pharmacokinetic parameters of S3101 in human serum.展开更多
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
Salivary proteins serve multifaceted roles in maintaining oral health and hold significant potential for diagnosing and monitoring diseases due to the non-invasive nature of saliva sampling.However,the clinical utilit...Salivary proteins serve multifaceted roles in maintaining oral health and hold significant potential for diagnosing and monitoring diseases due to the non-invasive nature of saliva sampling.However,the clinical utility of current saliva biomarker studies is limited by the lack of reference intervals(RIs)to correctly interpret the testing result.Here,we developed a rapid and robust saliva proteome profiling workflow,obtaining coverage of>1,200 proteins from a 50-μL unstimulated salivary flow with 30 min gradients.With the workflow,we investigated protein variation in a cohort of 1,743 healthy individuals.The significant differences in non-linear saliva proteomes among age groups resulted in the establishment of age-related RIs covering 1,123 salivary protein variations.We then utilized a cohort of 30 epilepsy patients as a case study to illustrate the practical application of RIs in identifying disease-enriched outlier proteins,elucidating their cellular origins,determining disease diagnosis,and visualizing outlier proteins in each epilepsy patient.Our study showed the classification model based on the RI achieved PR-AUC of 0.815(95%CI:0.813–0.826).Additionally,we validated these results in an independent test set.Furthermore,the epilepsy cohort could be further stratified into 2 major subtypes,with one subtype characterized by disrupted metabolic proteins and containing mostly Focal Cortical Dysplasia(FCD)type III epilepsy patients.Overall,our study provided a proof-of-principle workflow for the use of salivary proteome for health monitoring,epilepsy diagnosis and subtyping.展开更多
Osteoarthritis(OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are ...Osteoarthritis(OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are unclear. In this study, we found activated Akt signaling in human OA cartilage as well as in a mouse OA model with surgical destabilization of the medial meniscus.Genetic mouse models mimicking sustained Akt signaling in articular chondrocytes via PTEN deficiency driven by either Col2a1-Cre or Col2a1-Cre^(ERT2) developed OA, whereas restriction of Akt signaling reversed the OA phenotypes in PTEN-deficient mice.Mechanistically, prolonged activation of Akt signaling caused an accumulation of reactive oxygen species and triggered chondrocyte senescence as well as a senescence-associated secretory phenotype, whereas chronic administration of the antioxidant N-acetylcysteine suppressed chondrocyte senescence and mitigated OA progression in PTEN-deficient mice. Therefore,inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage. Disrupted Akt signaling in articular chondrocytes triggers oxidative stress-induced chondrocyte senescence and causes OA.展开更多
Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in e...Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in experimental models of liver regeneration has not been reported.This study aimed to investigate the role of TLR5 in partial hepatectomy(PHx)-induced liver regeneration.Methods:We performed 2/3 PHx in wild-type(WT)mice,TLR5 knockout mice,or TLR5 agonist CBLB502 treated mice,as a model of liver regeneration.Bacterial flagellin content was measured with ELISA,and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry.To study the effects of TLR5 on hepatocyte proliferation,we analyzed bromodeoxyuridine(BrdU)incorporation and proliferating cell nuclear antigen(PCNA)expression with immunohistochemistry(IHC)staining.The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels,and with Western blotting analysis of hepatic NF-κB and STAT3 activation.Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array(CBA)assays.Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.Results:The bacterial flagellin content in the serum and liver increased,and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx.TLR5-deficient mice exhibited diminished numbers of BrdU-and PCNA-positive cells,suppressed immediate early gene expression,and decreased cytokine and growth factor production.Moreover,PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5–/–mice,as compared with WT mice.Consistently,the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation,which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver.Furthermore,Tlr5–/–mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.Conclusions:We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx.Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.展开更多
The rapid development of genome editing technology has brought major breakthroughs in the fields of life science and medicine. In recent years, the clustered regularly interspaced short palindromic repeats(CRISPR)-bas...The rapid development of genome editing technology has brought major breakthroughs in the fields of life science and medicine. In recent years, the clustered regularly interspaced short palindromic repeats(CRISPR)-based genome editing toolbox has been greatly expanded, not only with emerging CRISPR-associated protein(Cas) nucleases, but also novel applications through combination with diverse effectors. Recently, transposon-associated programmable RNA-guided genome editing systems have been uncovered, adding myriads of potential new tools to the genome editing toolbox. CRISPR-based genome editing technology has also revolutionized cardiovascular research. Here we first summarize the advances involving newly identified Cas orthologs, engineered variants and novel genome editing systems, and then discuss the applications of the CRISPR-Cas systems in precise genome editing, such as base editing and prime editing. We also highlight recent progress in cardiovascular research using CRISPR-based genome editing technologies, including the generation of genetically modified in vitro and animal models of cardiovascular diseases(CVD) as well as the applications in treating different types of CVD. Finally, the current limitations and future prospects of genome editing technologies are discussed.展开更多
Lung cancer is one of the most common malignancies and has the highest number of deaths among all cancers.Despite continuous advances in medical strategies,the overall survival of lung cancer patients is still low,pro...Lung cancer is one of the most common malignancies and has the highest number of deaths among all cancers.Despite continuous advances in medical strategies,the overall survival of lung cancer patients is still low,probably due to disease progression or drug resistance.Ferroptosis is an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides,and its dysregulation is implicated in cancer development.Preclinical evidence has shown that targeting the ferroptosis pathway could be a potential strategy for improving lung cancer treatment outcomes.In this review,we summarize the underlying mechanisms and regulatory networks of ferroptosis in lung cancer and highlight ferroptosis-targeting preclinical attempts to provide new insights for lung cancer treatment.展开更多
Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical re...Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy responses.The proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging methods.The subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy samples.The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy.Differentially overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical trials.Finally,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy.Collectively,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.展开更多
Endothelial cells(ECs)form a single cell layer that lines the inner surface of all blood and lymphatic vessels,acting as the barrier between vessels and underlying tissues.ECs are not only responsible for the flow of ...Endothelial cells(ECs)form a single cell layer that lines the inner surface of all blood and lymphatic vessels,acting as the barrier between vessels and underlying tissues.ECs are not only responsible for the flow of substances and fluid into and out of tissues but are also involved in many processes,such as coagulation,fibrinolysis,and regulation of vascular tone and inflammation.展开更多
Hepatocellular carcinoma(HCC)is a highly heterogeneous tumor,with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment(TIME).1 Elegant research has ind...Hepatocellular carcinoma(HCC)is a highly heterogeneous tumor,with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment(TIME).1 Elegant research has indicated that cancer stem cells,a small subset of neoplastic cells confined within dedicated niches,display stem cell-like properties and interact with cells in TIME,thereby imparting an indelible impact on stemness regulation,tumor heterogeneity,and cancer cell plasticity.2 Previous taxonomies solely from the perspective of stemness or TIME may introduce some degree of bias in the comprehension of HCC carcinogenesis,3,4 and thus it is of paramount importance to systematically consider tumor stemness and TIME as a whole to truly portray the biological landscape of HCC.展开更多
Gastric cancer(GC)ranks fifth for cancer incidence and fourth for mortality globally.1 Clinical outcomes have varied among patients receiving similar treatments at the same stage,suggesting the current prognostic tool...Gastric cancer(GC)ranks fifth for cancer incidence and fourth for mortality globally.1 Clinical outcomes have varied among patients receiving similar treatments at the same stage,suggesting the current prognostic tools remain somewhat flawed.2,3 single-cell analysis of GC data allowed us to dissect transcriptional programs underlying lymphocyte residency and exhaustion.展开更多
The human microbiota,a diverse community of microorganisms living on or within their hosts,play an irreplaceable role in maintaining human health.Dysbiosis of the microbiota is associated with the pathogenesis of dive...The human microbiota,a diverse community of microorganisms living on or within their hosts,play an irreplaceable role in maintaining human health.Dysbiosis of the microbiota is associated with the pathogenesis of diverse human dis-eases.In recent years,growing evidence has been presented to support the substantial effect of human microbiota on the progression of infectious diseases.In this review,we describe the functional role of human microbiota in infec-tious diseases by highlighting their Janus-faced effects in the regulation of acute and chronic infections as well as their related co-morbidities.Thereafter,we review the latest advances elucidating the mechanisms underlying tri-directional interactions between the microbiota,hosts,and invading pathogens,with a further discussion on external environ-mental factors that shape this interconnected regulatory network.A better understanding of the regulatory functions and mechanisms of human microbiota in infectious diseases will facilitate the development of new diagnostic,preven-tive,and therapeutic approaches for infectious diseases.展开更多
Hydrogen sulfide(H2S)is a signaling molecule that regulates plant hormone and stress responses.The phytohormone abscisic acid(ABA)plays an important role in plant adaptation to unfavorable environmental conditions and...Hydrogen sulfide(H2S)is a signaling molecule that regulates plant hormone and stress responses.The phytohormone abscisic acid(ABA)plays an important role in plant adaptation to unfavorable environmental conditions and induces the persulfidation of L-CYSTEINE DESULFHYDRASE1(DES1)and the production of H2S in guard cells.However,it remains largely unclear how H2S and protein persulfidation participate in the relay of ABA signals.In this study,we discovered that ABSCISIC ACID INSENSITIVE 4(ABI4)acts downstream of DES1 in the control of ABA responses in Arabidopsis.ABI4 undergoes persulfidation at Cys250 that is triggered in a time-dependent manner by ABA,and loss of DES1 function impairs this process.Cys250 and its persulfidation are essential for ABI4 function in the regulation of plant responses to ABA and the H2S donor NaHS during germination,seedling establishment,and stomatal closure,which are abolished in the ABI4Cys250Ala mutated variant.Introduction of the ABI4Cys250Ala variant into the abi4 des1 mutant did not rescue its hyposensitivity to ABA.Cys250 is critical for the binding of ABI4 to its cognate motif in the promoter of Mitogen-Activated Protein Kinase Kinase Kinase 18(MAPKKK18),which propagates the MAPK signaling cascade induced by ABA.Furthermore,the DES1-mediated persulfidation of ABI4 enhances the transactivation activity of ABI4 toward MAPKKK18,and ABI4 can bind the DES1 promoter,forming a regulatory loop.Taken together,these findings advance our understanding of a post-translational regulatory mechanism and suggest that ABI4 functions as an integrator of ABA and MAPK signals through a process in which DES1-produced H2S persulfidates ABI4 at Cys250.展开更多
Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes,including cell division,immune responses,and apoptosis.Ubiquitin-mediated control over these processes can be rev...Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes,including cell division,immune responses,and apoptosis.Ubiquitin-mediated control over these processes can be reversed by deubiquitinases(DUBs),which remove ubiquitin from target proteins and depolymerize polyubiquitin chains.Recently,much progress has been made in the DUBs.In humans,the ovarian tumor protease(OTU)subfamily of DUBs includes 16 members,most of which mediate cell signaling cascades.These OTUs show great variation in structure and function,which display a series of mechanistic features.In this review,we provide a comprehensive analysis of current progress in character,structure and function of OTUs,such as the substrate specificity and catalytic activity regulation.Then we discuss the relationship between some diseases and OTUs.Finally,we summarize the structure of viral OTUs and their function in immune escape and viral survival.Despite the challenges,OTUs might provide new therapeutic targets,due to their involvement in key regulatory processes.展开更多
Osmotic stress caused by drought and high salinity is a significant environmental threat that limits plant growth and agricultural yield. Redox regulation plays an important role in plant stress responses, but the mec...Osmotic stress caused by drought and high salinity is a significant environmental threat that limits plant growth and agricultural yield. Redox regulation plays an important role in plant stress responses, but the mechanisms by which plants perceive and transduce redox signals are still underexplored. Here, we report a critical function for the thiol peroxidase GPX1 in osmotic stress response in rice, where it serves as a redox sensor and transducer. GPX1 is quickly oxidized upon exposure to osmotic stress and forms an intramolecular disulfide bond, which is required for the activation of bZIP68, a VRE-like basic leucine zipper (bZIP) transcription factor involved in the ABA-independent osmotic stress response pathway. The disulfide exchange between GPX1 and bZIP68 induces homo-tetramerization of bZIP68 and thus positively regulates osmotic stress response by regulating osmotic-responsive gene expression. Furthermore, we discovered that the nuclear translocation of GPX1 is regulated by its acetylation under osmotic stress. Taken together, our findings not only uncover the redox regulation of the GPX1-bZIP68 module during osmotic stress but also highlight the coordination of protein acetylation and redox signaling in plant osmotic stress responses.展开更多
Dear editor,Mycosis fungoides(MF),the most common subtype of cutaneous T cell lymphoma,is a rare disease[1,2].Patients with early-stageMF have a 5-year overall survival between 88%and 100%[3].In patients with advanced...Dear editor,Mycosis fungoides(MF),the most common subtype of cutaneous T cell lymphoma,is a rare disease[1,2].Patients with early-stageMF have a 5-year overall survival between 88%and 100%[3].In patients with advanced MF,the skin may present with tumors and erythroderma,and the median survival of patients with lymph node and visceral metastasis is 13 months[4].Therefore,it is important to achieve an early diagnosis to improve prognosis[5].展开更多
Signaling pathway alterations in COVID-19 of living humans as well as therapeutic targets of the host proteins are not clear.We analyzed 317 urine proteomes,including 86 COVID-19,55 pneumonia and 176 healthy controls,...Signaling pathway alterations in COVID-19 of living humans as well as therapeutic targets of the host proteins are not clear.We analyzed 317 urine proteomes,including 86 COVID-19,55 pneumonia and 176 healthy controls,and identified specific RNA virus detector protein DDX58/RIG-I only in COVID-19 samples.Comparison of the COVID-19 urinary proteomes with controls revealed major pathway alterations in immunity,metabolism and protein localization.Biomarkers that may stratify severe symptoms from moderate ones suggested that macrophage induced inflammation and thrombolysis may play a critical role in worsening the disease.Hyper activation of the TCA cycle is evident and a macrophage enriched enzyme CLYBL is up regulated in COVID-19 patients.As CLYBL converts the immune modulatory TCA cycle metabolite itaconate through the citramalyl-CoA intermediate to acetyl-CoA,an increase in CLYBL may lead to the depletion of itaconate,limiting its anti-inflammatory function.These observations suggest that supplementation of itaconate and inhibition of CLYBL are possible therapeutic options for treating COVID-19,opening an avenue of modulating host defense as a means of combating SARS-CoV-2 viruses.展开更多
A comprehensive analysis of the humoral immune response to the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is essential in understanding COVID-19 pathogenesis and developing antibody-based diagnostics a...A comprehensive analysis of the humoral immune response to the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is essential in understanding COVID-19 pathogenesis and developing antibody-based diagnostics and therapy.In this work,we performed a longitudinal analysis of antibody responses to SARS-CoV-2 proteins in 104 serum samples from 49 critical COVID-19 patients using a peptide-based SARS-CoV-2 proteome microarray.Our data show that the binding epitopes of IgM and IgG antibodies differ across SARS-CoV-2 proteins and even within the same protein.展开更多
基金supported by the National Natural Science Foundation of China(32088101)National key Research and Development Program of China(2017YFC1700105,2021YFA1301603).
文摘Objective:To elucidate the biological basis of the heart qi deficiency(HQD)pattern,an in-depth understanding of which is essential for improving clinical herbal therapy.Methods: We predicted and characterized HQD pattern genes using the new strategy,TCM-HIN2Vec,which involves heterogeneous network embedding and transcriptomic experiments.First,a heterogeneous network of traditional Chinese medicine(TCM)patterns was constructed using public databases.Next,we predicted HQD pattern genes using a heterogeneous network-embedding algorithm.We then analyzed the functional characteristics of HQD pattern genes using gene enrichment analysis and examined gene expression levels using RNA-seq.Finally,we identified TCM herbs that demonstrated enriched interactions with HQD pattern genes via herbal enrichment analysis.Results: Our TCM-HIN2Vec strategy revealed that candidate genes associated with HQD pattern were significantly enriched in energy metabolism,signal transduction pathways,and immune processes.Moreover,we found that these candidate genes were significantly differentially expressed in the transcriptional profile of mice model with heart failure with a qi deficiency pattern.Furthermore,herbal enrichment analysis identified TCM herbs that demonstrated enriched interactions with the top 10 candidate genes and could potentially serve as drug candidates for treating HQD.Conclusion: Our results suggested that TCM-HIN2Vec is capable of not only accurately identifying HQD pattern genes,but also deciphering the basis of HQD pattern.Furthermore our finding indicated that TCM-HIN2Vec may be further expanded to develop other patterns,leading to a new approach aimed at elucidating general TCM patterns and developing precision medicine.
基金the financial support from the National Key Program for Basic Research of China(Grant Nos.:2018YFC0910302 and 2017YFF0205400)the National Natural Science Foundation of China(Grant No.:81530021)Innovation Foundation of Medicine(Grant Nos.:BWS14J052 and 16CXZ027)
文摘Posttranslational modifications of antibody products affect their stability,charge distribution,and drug activity and are thus a critical quality attribute.The comprehensive mapping of antibody modifications and different charge isomers(CIs)is of utmost importance,but is challenging.We intended to quantitatively characterize the posttranslational modification status of CIs of antibody drugs and explore the impact of posttranslational modifications on charge heterogeneity.The CIs of antibodies were fractionated by strong cation exchange chromatography and verified by capillary isoelectric focusing-whole column imaging detection,followed by stepwise structural characterization at three levels.First,the differences between CIs were explored at the intact protein level using a top-down mass spectrometry approach;this showed differences in glycoforms and deamidation status.Second,at the peptide level,common modifications of oxidation,deamidation,and glycosylation were identified.Peptide mapping showed nonuniform deamidation and glycoform distribution among CIs.In total,10 N-glycoforms were detected by peptide mapping.Finally,an in-depth analysis of glycan variants of CIs was performed through the detection of enriched glycopeptides.Qualitative and quantitative analyses demonstrated the dynamics of 24 N-glycoforms.The results revealed that sialic acid modification is a critical factor accounting for charge heterogeneity,which is otherwise missed in peptide mapping and intact molecular weight analyses.This study demonstrated the importance of the comprehensive analyses of antibody CIs and provides a reference method for the quality control of biopharmaceutical analysis.
文摘Recombinant batroxobin(S3101)is a thrombin-like serine protease that binds to fibrinogen or is taken up by the reticuloendothelial system.A literature survey showed no adequate method that could determine sufficient concentrations to evaluate pharmacokinetic parameters for phase I clinical studies.Therefore,a sensitive method is urgently needed to support the clinical pharmacokinetic evaluation of S3101.In this study,a sensitive bioanalytical method was developed and validated,using a Quanterix single molecular array(Simoa)assay.Moreover,to thoroughly assess the platform,enzyme-linked immunosorbent assay and electrochemiluminescence assay were also developed,and their performance was compared with that of this novel technology platform.The assay was validated in compliance with the current guidelines.Measurements with the Simoa assay were precise and accurate,presenting a valid assay range from 6.55 to 4000 pg/mL.The intra-and inter-run accuracy and precision were within-19.3%to 15.3%and 5.5%to 17.0%,respectively.S3101 was stable in human serum for 280 days at-20℃and-70℃,for 2 h prior to pre-treatment and 24 h post pre-treatment at room temperature(22℃-28℃),respectively,and after five and two freeze-thaw cycles at-70℃and-20oC,respectively.The Simoa assay also demonstrated sufficient dilution linearity,assay sensitivity,and parallelism for quantifying S3101 in human serum.The Simoa assay is a sensitive and adequate method for evaluating the pharmacokinetic parameters of S3101 in human serum.
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 by the National Natural Science Foundation of China(32088101,32271498)the National Key Research and Development Program of China(2022YFA1303200)+3 种基金State Key Laboratory of Proteomics(SKLP-K202002)State Key Laboratory of Dampness Syndrome of Chinese Medicine,The Second Affiliated Hospital of Guangzhou University of Chinese Medicine(SZ2021ZZ06,SZ2021ZZ3205)Key-Area Research and Development Program of Guangdong Province(2020B1111100009)Guangzhou Science and Technology Plan Project(202102010275,202201020499).
文摘Salivary proteins serve multifaceted roles in maintaining oral health and hold significant potential for diagnosing and monitoring diseases due to the non-invasive nature of saliva sampling.However,the clinical utility of current saliva biomarker studies is limited by the lack of reference intervals(RIs)to correctly interpret the testing result.Here,we developed a rapid and robust saliva proteome profiling workflow,obtaining coverage of>1,200 proteins from a 50-μL unstimulated salivary flow with 30 min gradients.With the workflow,we investigated protein variation in a cohort of 1,743 healthy individuals.The significant differences in non-linear saliva proteomes among age groups resulted in the establishment of age-related RIs covering 1,123 salivary protein variations.We then utilized a cohort of 30 epilepsy patients as a case study to illustrate the practical application of RIs in identifying disease-enriched outlier proteins,elucidating their cellular origins,determining disease diagnosis,and visualizing outlier proteins in each epilepsy patient.Our study showed the classification model based on the RI achieved PR-AUC of 0.815(95%CI:0.813–0.826).Additionally,we validated these results in an independent test set.Furthermore,the epilepsy cohort could be further stratified into 2 major subtypes,with one subtype characterized by disrupted metabolic proteins and containing mostly Focal Cortical Dysplasia(FCD)type III epilepsy patients.Overall,our study provided a proof-of-principle workflow for the use of salivary proteome for health monitoring,epilepsy diagnosis and subtyping.
基金supported by grants from the State Key Program of National Natural Science of China (31630093)the National Natural Science Foundation of China (31571512, 31871476, and 81241062)+1 种基金the Beijing Nova Program (Z161100004916146)the National Basic Research Program of China (2012CB966904)
文摘Osteoarthritis(OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are unclear. In this study, we found activated Akt signaling in human OA cartilage as well as in a mouse OA model with surgical destabilization of the medial meniscus.Genetic mouse models mimicking sustained Akt signaling in articular chondrocytes via PTEN deficiency driven by either Col2a1-Cre or Col2a1-Cre^(ERT2) developed OA, whereas restriction of Akt signaling reversed the OA phenotypes in PTEN-deficient mice.Mechanistically, prolonged activation of Akt signaling caused an accumulation of reactive oxygen species and triggered chondrocyte senescence as well as a senescence-associated secretory phenotype, whereas chronic administration of the antioxidant N-acetylcysteine suppressed chondrocyte senescence and mitigated OA progression in PTEN-deficient mice. Therefore,inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage. Disrupted Akt signaling in articular chondrocytes triggers oxidative stress-induced chondrocyte senescence and causes OA.
基金the National Natural Science Foundation of China(81800561)the State Key Laboratory of Proteomics(SKLP-K201404).
文摘Background:Toll-like receptor 5(TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases.However,the role of TLR5 in experimental models of liver regeneration has not been reported.This study aimed to investigate the role of TLR5 in partial hepatectomy(PHx)-induced liver regeneration.Methods:We performed 2/3 PHx in wild-type(WT)mice,TLR5 knockout mice,or TLR5 agonist CBLB502 treated mice,as a model of liver regeneration.Bacterial flagellin content was measured with ELISA,and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry.To study the effects of TLR5 on hepatocyte proliferation,we analyzed bromodeoxyuridine(BrdU)incorporation and proliferating cell nuclear antigen(PCNA)expression with immunohistochemistry(IHC)staining.The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels,and with Western blotting analysis of hepatic NF-κB and STAT3 activation.Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array(CBA)assays.Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx.Results:The bacterial flagellin content in the serum and liver increased,and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx.TLR5-deficient mice exhibited diminished numbers of BrdU-and PCNA-positive cells,suppressed immediate early gene expression,and decreased cytokine and growth factor production.Moreover,PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5–/–mice,as compared with WT mice.Consistently,the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation,which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver.Furthermore,Tlr5–/–mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx.Conclusions:We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx.Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.
基金supported by the National Natural Science Foundation of China (82270355, 82270354, 81970134, 82030011, 31630093)the National Key Research and Development Program of China (2019YFA0801601, 2021YFA1101801)。
文摘The rapid development of genome editing technology has brought major breakthroughs in the fields of life science and medicine. In recent years, the clustered regularly interspaced short palindromic repeats(CRISPR)-based genome editing toolbox has been greatly expanded, not only with emerging CRISPR-associated protein(Cas) nucleases, but also novel applications through combination with diverse effectors. Recently, transposon-associated programmable RNA-guided genome editing systems have been uncovered, adding myriads of potential new tools to the genome editing toolbox. CRISPR-based genome editing technology has also revolutionized cardiovascular research. Here we first summarize the advances involving newly identified Cas orthologs, engineered variants and novel genome editing systems, and then discuss the applications of the CRISPR-Cas systems in precise genome editing, such as base editing and prime editing. We also highlight recent progress in cardiovascular research using CRISPR-based genome editing technologies, including the generation of genetically modified in vitro and animal models of cardiovascular diseases(CVD) as well as the applications in treating different types of CVD. Finally, the current limitations and future prospects of genome editing technologies are discussed.
基金National Natural Science Foundation of China(No.82073108)
文摘Lung cancer is one of the most common malignancies and has the highest number of deaths among all cancers.Despite continuous advances in medical strategies,the overall survival of lung cancer patients is still low,probably due to disease progression or drug resistance.Ferroptosis is an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides,and its dysregulation is implicated in cancer development.Preclinical evidence has shown that targeting the ferroptosis pathway could be a potential strategy for improving lung cancer treatment outcomes.In this review,we summarize the underlying mechanisms and regulatory networks of ferroptosis in lung cancer and highlight ferroptosis-targeting preclinical attempts to provide new insights for lung cancer treatment.
基金supported by the National Key R&D Program of China(Grant Nos.2018YFA0507503,2017YFA0505102,2017YFA0505103,and 2017YFA0505104)the National Natural Science Foundation of China(Grant Nos.82072597,62131009,31770892,31970725,31870828,81874237,and 81974016)+2 种基金the Beijing Municipal Natural Science Foundation(Grant No.7192199)the State Key Laboratory of Proteomics(Grant No.SKLP-K202002)the Kaifeng Science and Technology Development Plan Project(Grant No.1806005),China.
文摘Small cell lung cancer(SCLC)is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models.Here,we analyzed formalin-fixed,paraffin-embedded(FFPE)samples of surgical resections by proteomic profiling,and stratified SCLC into three proteomic subtypes(S-I,S-II,and S-III)with distinct clinical outcomes and chemotherapy responses.The proteomic subtyping was an independent prognostic factor and performed better than current tumor–node–metastasis or Veterans Administration Lung Study Group staging methods.The subtyping results could be further validated using FFPE biopsy samples from an independent cohort,extending the analysis to both surgical and biopsy samples.The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy.Differentially overexpressed proteins in S-III,the worst prognostic subtype,allowed us to nominate potential therapeutic targets,indicating that patient selection may bring new hope for previously failed clinical trials.Finally,analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy.Collectively,our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.
基金This work was supported by the National Key Research and Development Program of China(2018YFA0801104 and 2021YFA1301604)the National Natural Science Foundation of China(82372721,31630093,and 82394443)Independent Research Program of the State Key Laboratory of Proteomics(SKLP-K202004).
文摘Endothelial cells(ECs)form a single cell layer that lines the inner surface of all blood and lymphatic vessels,acting as the barrier between vessels and underlying tissues.ECs are not only responsible for the flow of substances and fluid into and out of tissues but are also involved in many processes,such as coagulation,fibrinolysis,and regulation of vascular tone and inflammation.
文摘Hepatocellular carcinoma(HCC)is a highly heterogeneous tumor,with dynamic equilibrium and complex interplay between its intricate tumor nature and ambient tumor immune microenvironment(TIME).1 Elegant research has indicated that cancer stem cells,a small subset of neoplastic cells confined within dedicated niches,display stem cell-like properties and interact with cells in TIME,thereby imparting an indelible impact on stemness regulation,tumor heterogeneity,and cancer cell plasticity.2 Previous taxonomies solely from the perspective of stemness or TIME may introduce some degree of bias in the comprehension of HCC carcinogenesis,3,4 and thus it is of paramount importance to systematically consider tumor stemness and TIME as a whole to truly portray the biological landscape of HCC.
基金supported by the Major Science and Technologyprojectsof Henan Province,China(No.221100310100).
文摘Gastric cancer(GC)ranks fifth for cancer incidence and fourth for mortality globally.1 Clinical outcomes have varied among patients receiving similar treatments at the same stage,suggesting the current prognostic tools remain somewhat flawed.2,3 single-cell analysis of GC data allowed us to dissect transcriptional programs underlying lymphocyte residency and exhaustion.
基金supported by the National Key Research and Development Program of China(2022YFC2302900 to C.H.L.,2021YFA1300200 to C.H.L.and L.Z.,and 2022YFC2303201 to Q.C.)the National Natural Science Foundation of China(82330069,81825014,and 31830003 to C.H.L.and 82171744 to Q.C.)the State Key Laboratory of Proteomics(SKLP-K202001 to C.H.L.and L.Z.).
文摘The human microbiota,a diverse community of microorganisms living on or within their hosts,play an irreplaceable role in maintaining human health.Dysbiosis of the microbiota is associated with the pathogenesis of diverse human dis-eases.In recent years,growing evidence has been presented to support the substantial effect of human microbiota on the progression of infectious diseases.In this review,we describe the functional role of human microbiota in infec-tious diseases by highlighting their Janus-faced effects in the regulation of acute and chronic infections as well as their related co-morbidities.Thereafter,we review the latest advances elucidating the mechanisms underlying tri-directional interactions between the microbiota,hosts,and invading pathogens,with a further discussion on external environ-mental factors that shape this interconnected regulatory network.A better understanding of the regulatory functions and mechanisms of human microbiota in infectious diseases will facilitate the development of new diagnostic,preven-tive,and therapeutic approaches for infectious diseases.
基金supported by grants from the National Natural Science Foundation of China(31670255)the National Natural Science Foundation of China of Jiangsu Province(BK20200561,BK20200282,BK20161447)+3 种基金the National Science Fund for Outstanding Young Scholars(21922702)the China Postdoctoral Science Foundation(2019M661860)the Fundamental Research Funds for the Central Universities(KYZ201859)the European Regional Development Fund through the Agenda Estatal de Investigacion(grant no.PID2019-109785GB-IOO).
文摘Hydrogen sulfide(H2S)is a signaling molecule that regulates plant hormone and stress responses.The phytohormone abscisic acid(ABA)plays an important role in plant adaptation to unfavorable environmental conditions and induces the persulfidation of L-CYSTEINE DESULFHYDRASE1(DES1)and the production of H2S in guard cells.However,it remains largely unclear how H2S and protein persulfidation participate in the relay of ABA signals.In this study,we discovered that ABSCISIC ACID INSENSITIVE 4(ABI4)acts downstream of DES1 in the control of ABA responses in Arabidopsis.ABI4 undergoes persulfidation at Cys250 that is triggered in a time-dependent manner by ABA,and loss of DES1 function impairs this process.Cys250 and its persulfidation are essential for ABI4 function in the regulation of plant responses to ABA and the H2S donor NaHS during germination,seedling establishment,and stomatal closure,which are abolished in the ABI4Cys250Ala mutated variant.Introduction of the ABI4Cys250Ala variant into the abi4 des1 mutant did not rescue its hyposensitivity to ABA.Cys250 is critical for the binding of ABI4 to its cognate motif in the promoter of Mitogen-Activated Protein Kinase Kinase Kinase 18(MAPKKK18),which propagates the MAPK signaling cascade induced by ABA.Furthermore,the DES1-mediated persulfidation of ABI4 enhances the transactivation activity of ABI4 toward MAPKKK18,and ABI4 can bind the DES1 promoter,forming a regulatory loop.Taken together,these findings advance our understanding of a post-translational regulatory mechanism and suggest that ABI4 functions as an integrator of ABA and MAPK signals through a process in which DES1-produced H2S persulfidates ABI4 at Cys250.
文摘Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes,including cell division,immune responses,and apoptosis.Ubiquitin-mediated control over these processes can be reversed by deubiquitinases(DUBs),which remove ubiquitin from target proteins and depolymerize polyubiquitin chains.Recently,much progress has been made in the DUBs.In humans,the ovarian tumor protease(OTU)subfamily of DUBs includes 16 members,most of which mediate cell signaling cascades.These OTUs show great variation in structure and function,which display a series of mechanistic features.In this review,we provide a comprehensive analysis of current progress in character,structure and function of OTUs,such as the substrate specificity and catalytic activity regulation.Then we discuss the relationship between some diseases and OTUs.Finally,we summarize the structure of viral OTUs and their function in immune escape and viral survival.Despite the challenges,OTUs might provide new therapeutic targets,due to their involvement in key regulatory processes.
基金supported by grants from the National Natural Science Foundation of Jiangsu Province(BK20200561)the National Natural Science Foundation of China(32101671 and 31670255)+3 种基金the National Natural Science Foundation of Jiangsu Province(BK20200282 and BK20161447)the National Science Fund for Outstanding Young Scholars(21922702)the China Postdoctoral Science Foundation(2019M661860)the Fundamental Research Funds for the Central Universities(KYZ201859).
文摘Osmotic stress caused by drought and high salinity is a significant environmental threat that limits plant growth and agricultural yield. Redox regulation plays an important role in plant stress responses, but the mechanisms by which plants perceive and transduce redox signals are still underexplored. Here, we report a critical function for the thiol peroxidase GPX1 in osmotic stress response in rice, where it serves as a redox sensor and transducer. GPX1 is quickly oxidized upon exposure to osmotic stress and forms an intramolecular disulfide bond, which is required for the activation of bZIP68, a VRE-like basic leucine zipper (bZIP) transcription factor involved in the ABA-independent osmotic stress response pathway. The disulfide exchange between GPX1 and bZIP68 induces homo-tetramerization of bZIP68 and thus positively regulates osmotic stress response by regulating osmotic-responsive gene expression. Furthermore, we discovered that the nuclear translocation of GPX1 is regulated by its acetylation under osmotic stress. Taken together, our findings not only uncover the redox regulation of the GPX1-bZIP68 module during osmotic stress but also highlight the coordination of protein acetylation and redox signaling in plant osmotic stress responses.
基金This work was supported by the National Natural Science Foundation of China(No.82173449)the Beijing Nature Science Foundation(No.7182127),the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019XK320024)+1 种基金the National Key Research and Development Program of China(No.2016YFC0901500)the Medical and Health Science and Technology Innovation Project of Chinese Academy of Medical Sciences(2019-I2M-1-001).
文摘Dear editor,Mycosis fungoides(MF),the most common subtype of cutaneous T cell lymphoma,is a rare disease[1,2].Patients with early-stageMF have a 5-year overall survival between 88%and 100%[3].In patients with advanced MF,the skin may present with tumors and erythroderma,and the median survival of patients with lymph node and visceral metastasis is 13 months[4].Therefore,it is important to achieve an early diagnosis to improve prognosis[5].
基金This work was supported by the National Key Research and Development Program of China(2017YFA0505102,2017YFA0505103,2017YFA0505104,2017YFC0908404,2018YFA0507503,2020YFA0708001)the National Natural Science Foundation of China(81874237,31870828)+4 种基金Major National Science and technology projects(2017ZX10305501-006)National Administration of Traditional Chinese Medicine:2019 Project of Building Evidence Based Practice Capacity for TCM(2019XZZX-LG003)Guangdong Key-Area Research and Development Program(2019B020229002,2020B1111300005)Guangzhou Science and Technology Program(201902020009)Guangdong Provincial Key Laboratory of Research on Emergency in TCM(2017B030314176).
文摘Signaling pathway alterations in COVID-19 of living humans as well as therapeutic targets of the host proteins are not clear.We analyzed 317 urine proteomes,including 86 COVID-19,55 pneumonia and 176 healthy controls,and identified specific RNA virus detector protein DDX58/RIG-I only in COVID-19 samples.Comparison of the COVID-19 urinary proteomes with controls revealed major pathway alterations in immunity,metabolism and protein localization.Biomarkers that may stratify severe symptoms from moderate ones suggested that macrophage induced inflammation and thrombolysis may play a critical role in worsening the disease.Hyper activation of the TCA cycle is evident and a macrophage enriched enzyme CLYBL is up regulated in COVID-19 patients.As CLYBL converts the immune modulatory TCA cycle metabolite itaconate through the citramalyl-CoA intermediate to acetyl-CoA,an increase in CLYBL may lead to the depletion of itaconate,limiting its anti-inflammatory function.These observations suggest that supplementation of itaconate and inhibition of CLYBL are possible therapeutic options for treating COVID-19,opening an avenue of modulating host defense as a means of combating SARS-CoV-2 viruses.
基金This research was supported by grants from the National Key R&D Program of China(2020YFC0861000,2020YFE0202200,2018YFE0207300)Beijing Municipal Science&Technology Commission(Z211100002521021)+4 种基金National Natural Science Foundation of China Grants(81671618,81871302,81673040,31870823)CAMS Innovation Fund for Medical Sciences(CIFMS)(2020-I2M-COV19-001,2017-I2M-3-001,2017-I2M-B&R-01,2019-I2M-5-063)the State Key Laboratory of Proteomics(SKLP-C202001,SKLP-0201703,SKLP-K201505)the Beijing Municipal Education Commission and the National Program on Key Basic Research Project(2018YFA0507503,2017YFC0906703,2018ZX09733003)This work is supported by Beijing Key Clinical Specialty for Laboratory Medicine-Excellent Project(No.ZK201000)。
文摘A comprehensive analysis of the humoral immune response to the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is essential in understanding COVID-19 pathogenesis and developing antibody-based diagnostics and therapy.In this work,we performed a longitudinal analysis of antibody responses to SARS-CoV-2 proteins in 104 serum samples from 49 critical COVID-19 patients using a peptide-based SARS-CoV-2 proteome microarray.Our data show that the binding epitopes of IgM and IgG antibodies differ across SARS-CoV-2 proteins and even within the same protein.
