Different types of pores ubiquitously form in cell membranes,leading to various types of cell death that profoundly influence the fate of inflammation and the disease status.However,these pores have never truly been v...Different types of pores ubiquitously form in cell membranes,leading to various types of cell death that profoundly influence the fate of inflammation and the disease status.However,these pores have never truly been visualized to date.Atomic force microscopy(AFM),which is emerging as a powerful tool to analyze the mechanical properties of biomolecules and cells,is actually an excellent imaging platform that allows biological samples to be visualized by probing surface roughness at the level of atomic resolution.Here,membrane pore structures were clearly visualized using AFM.This visualization not only describes the aperture and depth of the pore complexes but also highlights differences among the pores formed by perforin and gasdermins in tumor cell membranes and by complement in immune cell membranes.Additionally,this type of visualization also reveals the dynamic process of pore formation,fusion,and repair.展开更多
SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,com...SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed.Compared to normal controls,SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs,with drastic transcriptomic changes in cerebral cortex and right ventricle.Intriguingly,cerebral cortex exhibited a hyperinflammatory state evidenced by sig-nificant upregulation of inflammation response-related genes.Meanwhile,expressions of coagulation,angio-genesis and fibrosis factors were also up-regulated in cerebral cortex.Based on our findings,neuropilin 1(NRP1),a receptor of SARS-CoV-2,was significantly elevated in cerebral cortex post infection,accompanied by active immune response releasing inflammatory factors and signal transmission among tissues,which enhanced infection of the central nervous system(CNS)in a positive feedback way,leading to viral encephalitis.Overall,our study depicts a multi-tissue/organ tran-scriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2,and provides important insights into the mechanistic basis for COVID-19-asso-ciated clinical complications.展开更多
The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors...The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.展开更多
Objective: This study explores the correlation between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) by comparing the level of plasma Lp-PLA2 in the plasma of patients with ...Objective: This study explores the correlation between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) by comparing the level of plasma Lp-PLA2 in the plasma of patients with different types of CHD. Methods: Blood samples were collected from 56 patients diagnosed with CHD by the Department of Cardiology of the First People's Hospital of Foshan and 34 healthy subjects from February 2013 to January 2014. We measured the concentration of plasma Lp-PLA2 and determined the levels of total cholesterol (Tch), triglyceride (TG), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), lipoprotein a (Lp(a)), glucose (Glu), and high-sensitivity C-reactive protein (hs-CRP). The concentration of plasma Lp-PLA2 in the healthy control group and each subgroup of CHD patients were compared and analyzed for correlations of plasma Lp-PLA2 between the patients in different CHD subgroups and several laboratory indicators. Results: The concentration of plasma Lp-PLA2 in each subgroup of CHD was significantly higher than in the control group (P<0.05). The concentration of Lp-PLA2 in the unstable angina pectoris (UAP) group and acute myocardial infarction (AMI) group were significantly higher than in the stable angina pectoris (SAP) group (P<0.05), and the concentration of plasma Lp-PLA2 in the AMI group was significantly higher than in the UAP group (P<0.05). The concentration of plasma Lp-PLA2 in the CHD group merely showed a positive correlation (r ? 0.493, P<0.05) with the hs-CRP group, but the levels of Tch, TG, Apo-A1, Apo-B, HDL-c, LDL-c, Lp(a) and Glu did not. Conclusions: The concentration of plasma Lp-PLA2 in patients with CHD was higher than that in the control group. The concentration of plasma Lp-PLA2 in the subgroups of CHD patients varied greatly from each other. The inflammatory response of atherosclerosis might be resulted from the synergy of plasma Lp-PLA2 and hs-CRP. Copyright ? 2015, 展开更多
The poor salt tolerance,thermal stability,and environmental performance of petrochemicals can severely limit their applications in drilling engineering.In this study,cellulose nanofibril(CNF)hydrogels with improved sa...The poor salt tolerance,thermal stability,and environmental performance of petrochemicals can severely limit their applications in drilling engineering.In this study,cellulose nanofibril(CNF)hydrogels with improved salt tolerance and thermal stability were prepared,and their filtration performance was evaluated.The hydrogels were prepared through the simultaneous grafting of 2-acrylamido-2-methylpropane sulfonic acid(AMPS)and butyl acrylate(BA)onto the CNF surface through ceric ammoniumnitrate-induced radical polymerization.The modified and original CNF samples were characterized using Fourier Transform infrared spectroscopy(FT-IR)and rheological measurements.The FT-IR analysis results showed that both AMPS and BA were grafted onto the CNF backbone,affirming the successful preparation of the grafted CNFs.The rheological analysis results showed that the modified CNF hydrogels exhibited significantly improved salt tolerance,thermal stability,and“salt-thickening”effect.Moreover,the results of the fluid loss test showed that the modified CNF hydrogels exhibited a much better fluid loss control than the original CNF hydrogels.In addition,after adding 2%modified CNF hydrogels as a filtrate reducer in the drilling fluids prepared with a 6%combined salt solution,the filtrate loss was significantly reduced even after aging for 72 h at 160℃.展开更多
Solid tumor cells live in a highly dynamic mechanical microenvironment.How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma.Here,we show tha...Solid tumor cells live in a highly dynamic mechanical microenvironment.How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma.Here,we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells.Mechanistically,integrin?was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein(YAP).YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G(MAFG),allowing MAFG to transactivate the stemness genes NANOG,SOX2,and NESTIN.Inactivation also restoredβ8 expression,thereby forming a closed mechanical loop.Importantly,MAFG expression is correlated with worse prognosis.Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation,which has therapeutic implications for exploring innovative strategies to attack malignancies.展开更多
Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a...Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a large quantity of high-quality tissue-specific stem cells are needed for cartilage regeneration.Our previous report demonstrated that decellularized extracellular matrix(dECM)deposited by human synovium-derived stem cells(SDSCs),adipose-derived stem cells(ADSCs),urine-derived stem cells(UDSCs),or dermal fibroblasts(DFs)provided an ex vivo solution to rejuvenate human SDSCs in proliferation and chondrogenic potential,particularly for dECM deposited by UDSCs.To make the cell-derived dECM(C-dECM)approach applicable clinically,in this study,we evaluated ex vivo rejuvenation of rabbit infrapatellar fat pad-derived stem cells(IPFSCs),an easily accessible alternative for SDSCs,by the abovementioned C-dECMs,in vivo application for functional cartilage repair in a rabbit osteochondral defect model,and potential cellular and molecular mechanisms underlying this rejuvenation.We found that C-dECM rejuvenation promoted rabbit IPFSCs’cartilage engineering and functional regeneration in both ex vivo and in vivo models,particularly for the dECM deposited by UDSCs,which was further confirmed by proteomics data.RNA-Seq analysis indicated that both mesenchymal-epithelial transition(MET)and inflammation-mediated macrophage activation and polarization are potentially involved in the C-dECM-mediated promotion of IPFSCs’chondrogenic capacity,which needs further investigation.展开更多
Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidati...Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidation and reducing glutathione(GSH)levels,while it also inhibits ferroptosis by activating the expression of several ferroptosis repressors,such as FSP1 and iPLA2β,indicating the complexity of p53’s function in modulating ferroptosis in a cell-specific or context-specific manner(Liu and Gu,2022).展开更多
HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, ...HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.展开更多
Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a po...Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against SARS-CoV-2 infection.Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation.This pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal acidification.In addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects.These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.展开更多
Mammalian target of rapamycin(mTOR)controls cellular anabolism,and mTOR signaling is hyperactive in most cancer cells.As a result,inhibition of mTOR signaling benefits cancer patients.Rapamycin is a US Food and Drug A...Mammalian target of rapamycin(mTOR)controls cellular anabolism,and mTOR signaling is hyperactive in most cancer cells.As a result,inhibition of mTOR signaling benefits cancer patients.Rapamycin is a US Food and Drug Administration(FDA)-approved drug,a specific mTOR complex 1(mTORC1)inhibitor,for the treatment of several different types of cancer.However,rapamycin is reported to inhibit cancer growth rather than induce apoptosis.Pyruvate dehydrogenase complex(PDHc)is the gatekeeper for mitochondrial pyruvate oxidation.PDHc inactivation has been observed in a number of cancer cells,and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide(NAD^(+))exhaustion.In this paper,we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1(PDHA1)phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells.This inactivation reduces the sensitivity of cancer cells'response to rapamycin.As a result,rebooting PDHc activity with dichloroacetic acid(DCA),a pyruvate dehydrogenase kinase(PDK)inhibitor,promotes cancer cells'susceptibility to rapamycin treatment in vitro and in vivo.展开更多
Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Ac...Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.展开更多
It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the assoc...It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under env展开更多
Dear Editor,Alveolar macrophages(AMs)are among the first immune cells to encounter SARS-CoV-2 during an infection due to their abundant numbers and physical location in the lungs.Thus,the reaction of AMs to SARS-CoV-2...Dear Editor,Alveolar macrophages(AMs)are among the first immune cells to encounter SARS-CoV-2 during an infection due to their abundant numbers and physical location in the lungs.Thus,the reaction of AMs to SARS-CoV-2 has a profound impact on the outcome of the infection.In most cases,AMs can release cytokines and prime adaptive T-and B-cell immune responses to resolve the infection.展开更多
Dear Editor,Genetic variant Delta(B.1.617.2)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which possesses a remarkable ability to transmit and spread,is currently becoming predominant worldwide.Despit...Dear Editor,Genetic variant Delta(B.1.617.2)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which possesses a remarkable ability to transmit and spread,is currently becoming predominant worldwide.Despite its great harm to human beings,how the Delta variant with T478K,P681R and L452R mutations achieves its ultrafast spread remains elusive.Entry of SARS-CoV-2 into host cells is mediated by a rapid enzymatic hydrolysis.展开更多
The coronavirus disease 2019(COVID-19)pandemic has caused more than 6.3 million deaths to date.Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),vaccines and neutr...The coronavirus disease 2019(COVID-19)pandemic has caused more than 6.3 million deaths to date.Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),vaccines and neutralizing antibodies are in the gloom due to persistent viral mutations and antiviral compounds face challenges of specificity and safety.In addition,vaccines are unable to treat already-infected individuals,and antiviral drugs cannot be used prophylactically.Therefore,exploration of unconventional strategies to curb the current pandemic is highly urgent.Alveolar macrophages(AMs)residing on the surface of alveoli are the first immune cells that dispose of alveoli-invading viruses.Our findings demonstrate that M1 AMs have an acidic endosomal pH,thus favoring SARS-CoV-2 to leave endosomes and release into the cytosol where the virus initiates replication;in contrast,M2 AMs have an increased endosomal pH,which dampens the viral escape and facilitates delivery of the virus for lysosomal degradation.In this review,we propose that AMs are the Achilles’heel of SARS-CoV-2 infection and that modulation of the endosomal pH of AMs has the potential to eliminate invaded SARS-CoV-2;the same strategy might also be suitable for other lethal respiratory viruses.展开更多
Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.Th...Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.Methods:The biological functions of YB1 in hepatocellular carcinoma(HCC)cells were investigated by cell proliferation,wound healing,and transwell invasion assays.The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines.The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR,dual-luciferase reporter assay,RNA immunoprecipitation,and pull-down assay.The relationships of YB1,DGCR8,Dicer,TUT4,and TUT1 were identified by pull-down and coimmunoprecipitation experiments.The cellular co-localization of YB1,DGCR8,and Dicer were detected by immunofluorescent staining.The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice.The expression levels of epithelial tomesenchymal transition markerswere detected by immunoblotting and immunohistochemistry assays.Results:YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b‒ZEB1 axis partially in a Snail-independent manner.YB1 suppressedmiR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain.Subsequently,the downregulation of miR-205 and miR-200b enhanced ZEB1 expression,thus leading to increased cell migration and invasion.Furthermore,statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.Conclusion:This study reveals a previously undescribed mechanism展开更多
Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,in...Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,including internal genetic alterations and external inflammation-related stimuli.Overflow of exocrine pancreatic enzymes caused by PDAC obstruction inevitably results in autolysis of surrounding normal cells and extracellular matrix,generating tissue damage-related inflammation;however,this process does not cause autolysis of PDAC cells.How tumor cells acquire resistance to pancreatic enzymatic digestion has been ignored for a long time.In this review,we discuss how PDAC cells mobilize gasdermin E,a pore-forming protein,to achieve resistance to autolysis by pancreatic digestive enzymes.展开更多
The pandemic of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is sweeping across the world and has caused the loss of more than 3.3 million lives.Before clearance by virus-specific T and B cell-mediated a...The pandemic of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is sweeping across the world and has caused the loss of more than 3.3 million lives.Before clearance by virus-specific T and B cell-mediated adaptive immunity,excessive inflammation by innate immune cells might cause severe lung and even multiorganic pathologies,thus interfering with antiviral immunity.To curb infection and subsequent organic damage,a deep understanding of the pathogenetic process is highly desirable.Recently,we found that IFN-driven mucin expression in type Ⅱ alveolar epithelial cells is crucial in initiating hypoxia and early lung pathology1,and SARS-CoV-2 is disposed of by M1 and M2 alveolar macrophages(AMs)in distinct manners2.In this correspondence,we propose that(1)following the invasion of the alveoli and uptake by local alveolar macrophages,SARS-CoV-2 may stimulate macrophages to produce proinflammatory cytokines,including type Ⅰ interferon;(2)type I interferon acts on neighboring alveolar type Ⅱ pneumocytes and activates the cytoplasmic transcription factor aryl hydrocarbon receptor(AhR);(3)subsequently,AhR is translocated to the nucleus,where it promotes the expression of mucin genes,leading to mucus production;and(4)mucus begins to accumulate in the alveoli and gradually impairs the exchange of O2 and CO2,initially causing hypoxia and then dampening CO2 exhalation,leading to a critical illness.Here,we dissect these early pathogenic events,which might provide clues to interfering with SARS-CoV-2 infection at an early stage.展开更多
Cellular mechanics,a major regulating factor of cellular architecture and biological functions,responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the microenviro...Cellular mechanics,a major regulating factor of cellular architecture and biological functions,responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the microenvironment.Cellular mechanics also acts as a fundamental mediator in complicated immune responses,such as cell migration,immune cell activation,and pathogen clearance.The principle of atomic force microscopy(AFM)and its three running modes are introduced for the mechanical characterization of living cells.The peak force tapping mode provides the most delicate and desirable virtues to collect high-resolution images of morphology and force curves.For a concrete description of AFM capabilities,three AFM applications are discussed.These applications include the dynamic progress of a neutrophil-extracellular-trap release by neutrophils,the immunological functions of macrophages,and the membrane pore formation mediated by perforin,streptolysin O,gasdermin D,or membrane attack complex.展开更多
基金supported by grants from Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(CAMS-I2M)2017-I2M-1-001,the National Natural Science Foundation of China(81788101,81661128007,81530080,and 81773062)the CAMS Initiative for Innovative Medicine(2016-I2M-1–007).
文摘Different types of pores ubiquitously form in cell membranes,leading to various types of cell death that profoundly influence the fate of inflammation and the disease status.However,these pores have never truly been visualized to date.Atomic force microscopy(AFM),which is emerging as a powerful tool to analyze the mechanical properties of biomolecules and cells,is actually an excellent imaging platform that allows biological samples to be visualized by probing surface roughness at the level of atomic resolution.Here,membrane pore structures were clearly visualized using AFM.This visualization not only describes the aperture and depth of the pore complexes but also highlights differences among the pores formed by perforin and gasdermins in tumor cell membranes and by complement in immune cell membranes.Additionally,this type of visualization also reveals the dynamic process of pore formation,fusion,and repair.
基金supported by grants from National Key R&D Program of China(2020YFC0848900)CAS Key Research Projects of the Frontier Science(QYZDY-SSW-SMC027)+5 种基金National Natural Science Foundation of China(31625016 and 81788101)K.C.Wong Education Foundation(GJTD-2019-08)Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(2016-I2M-2-001,2017-I2M-2-006,2020-I2M-CoV19-003,2020-I2M-CoV19-007)the Youth Innovation Promotion Association,CAS(2018133)China National Postdoctoral Program for Innovative Talents(BX2021291)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01).
文摘SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed.Compared to normal controls,SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs,with drastic transcriptomic changes in cerebral cortex and right ventricle.Intriguingly,cerebral cortex exhibited a hyperinflammatory state evidenced by sig-nificant upregulation of inflammation response-related genes.Meanwhile,expressions of coagulation,angio-genesis and fibrosis factors were also up-regulated in cerebral cortex.Based on our findings,neuropilin 1(NRP1),a receptor of SARS-CoV-2,was significantly elevated in cerebral cortex post infection,accompanied by active immune response releasing inflammatory factors and signal transmission among tissues,which enhanced infection of the central nervous system(CNS)in a positive feedback way,leading to viral encephalitis.Overall,our study depicts a multi-tissue/organ tran-scriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2,and provides important insights into the mechanistic basis for COVID-19-asso-ciated clinical complications.
基金National Natural Science Foundation of China(Nos.81788101,82271775,and 81972875)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Nos.2021-I2M-1-021,2021-I2M-1-061,and 2022-I2M-1-047)+1 种基金Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00009)Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(Nos.BK20220049 and BK20211505)
文摘The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.
文摘Objective: This study explores the correlation between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) and coronary heart disease (CHD) by comparing the level of plasma Lp-PLA2 in the plasma of patients with different types of CHD. Methods: Blood samples were collected from 56 patients diagnosed with CHD by the Department of Cardiology of the First People's Hospital of Foshan and 34 healthy subjects from February 2013 to January 2014. We measured the concentration of plasma Lp-PLA2 and determined the levels of total cholesterol (Tch), triglyceride (TG), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), lipoprotein a (Lp(a)), glucose (Glu), and high-sensitivity C-reactive protein (hs-CRP). The concentration of plasma Lp-PLA2 in the healthy control group and each subgroup of CHD patients were compared and analyzed for correlations of plasma Lp-PLA2 between the patients in different CHD subgroups and several laboratory indicators. Results: The concentration of plasma Lp-PLA2 in each subgroup of CHD was significantly higher than in the control group (P<0.05). The concentration of Lp-PLA2 in the unstable angina pectoris (UAP) group and acute myocardial infarction (AMI) group were significantly higher than in the stable angina pectoris (SAP) group (P<0.05), and the concentration of plasma Lp-PLA2 in the AMI group was significantly higher than in the UAP group (P<0.05). The concentration of plasma Lp-PLA2 in the CHD group merely showed a positive correlation (r ? 0.493, P<0.05) with the hs-CRP group, but the levels of Tch, TG, Apo-A1, Apo-B, HDL-c, LDL-c, Lp(a) and Glu did not. Conclusions: The concentration of plasma Lp-PLA2 in patients with CHD was higher than that in the control group. The concentration of plasma Lp-PLA2 in the subgroups of CHD patients varied greatly from each other. The inflammatory response of atherosclerosis might be resulted from the synergy of plasma Lp-PLA2 and hs-CRP. Copyright ? 2015,
基金the National Natural Science Foundation of China(Grant No.31700514)the Natural Science Foundation of Tianjin,China(Grant No.18JCYBJC86500)for their financial supports
文摘The poor salt tolerance,thermal stability,and environmental performance of petrochemicals can severely limit their applications in drilling engineering.In this study,cellulose nanofibril(CNF)hydrogels with improved salt tolerance and thermal stability were prepared,and their filtration performance was evaluated.The hydrogels were prepared through the simultaneous grafting of 2-acrylamido-2-methylpropane sulfonic acid(AMPS)and butyl acrylate(BA)onto the CNF surface through ceric ammoniumnitrate-induced radical polymerization.The modified and original CNF samples were characterized using Fourier Transform infrared spectroscopy(FT-IR)and rheological measurements.The FT-IR analysis results showed that both AMPS and BA were grafted onto the CNF backbone,affirming the successful preparation of the grafted CNFs.The rheological analysis results showed that the modified CNF hydrogels exhibited significantly improved salt tolerance,thermal stability,and“salt-thickening”effect.Moreover,the results of the fluid loss test showed that the modified CNF hydrogels exhibited a much better fluid loss control than the original CNF hydrogels.In addition,after adding 2%modified CNF hydrogels as a filtrate reducer in the drilling fluids prepared with a 6%combined salt solution,the filtrate loss was significantly reduced even after aging for 72 h at 160℃.
基金supported by National Natural Science Foundation of China grant nos.82388201 to B.H.and 82003145 to J.L.Haihe Laboratory of Cell Ecosystem Innovation Fund grant no.22HHXBSS00009 to B.H.+1 种基金National Key Research and Development Program of China grant no.2022YFA1206000CAMS Innovation Fund for Medical Sciences(CIFMS)grant nos.2021-I2M-1-021 and 2022-I2M-JB-008 to B.H.
文摘Solid tumor cells live in a highly dynamic mechanical microenvironment.How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma.Here,we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells.Mechanistically,integrin?was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein(YAP).YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G(MAFG),allowing MAFG to transactivate the stemness genes NANOG,SOX2,and NESTIN.Inactivation also restoredβ8 expression,thereby forming a closed mechanical loop.Importantly,MAFG expression is correlated with worse prognosis.Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation,which has therapeutic implications for exploring innovative strategies to attack malignancies.
文摘Articular cartilage has a limited capacity to self-heal once damaged.Tissue-specific stem cells are a solution for cartilage regeneration;however,ex vivo expansion resulting in cell senescence remains a challenge as a large quantity of high-quality tissue-specific stem cells are needed for cartilage regeneration.Our previous report demonstrated that decellularized extracellular matrix(dECM)deposited by human synovium-derived stem cells(SDSCs),adipose-derived stem cells(ADSCs),urine-derived stem cells(UDSCs),or dermal fibroblasts(DFs)provided an ex vivo solution to rejuvenate human SDSCs in proliferation and chondrogenic potential,particularly for dECM deposited by UDSCs.To make the cell-derived dECM(C-dECM)approach applicable clinically,in this study,we evaluated ex vivo rejuvenation of rabbit infrapatellar fat pad-derived stem cells(IPFSCs),an easily accessible alternative for SDSCs,by the abovementioned C-dECMs,in vivo application for functional cartilage repair in a rabbit osteochondral defect model,and potential cellular and molecular mechanisms underlying this rejuvenation.We found that C-dECM rejuvenation promoted rabbit IPFSCs’cartilage engineering and functional regeneration in both ex vivo and in vivo models,particularly for the dECM deposited by UDSCs,which was further confirmed by proteomics data.RNA-Seq analysis indicated that both mesenchymal-epithelial transition(MET)and inflammation-mediated macrophage activation and polarization are potentially involved in the C-dECM-mediated promotion of IPFSCs’chondrogenic capacity,which needs further investigation.
基金supported by the National Natural Science Foundation of China(82072879,82273098,81874053,82173022)General Program of Open Science Foundation of Jiangxi Cancer Hospital(2021J04)HL was in part funded by the Reynolds and Ryan Families Chair fund in Transitional Cancer at Tulane.
文摘Dear Editor,Ferroptosis is a non-apoptotic form of regulated cell death driven by iron-dependent phospholipid peroxidation(Chen et al.,2021).The tumor suppressor p53 promotes ferroptosis by increasing lipid peroxidation and reducing glutathione(GSH)levels,while it also inhibits ferroptosis by activating the expression of several ferroptosis repressors,such as FSP1 and iPLA2β,indicating the complexity of p53’s function in modulating ferroptosis in a cell-specific or context-specific manner(Liu and Gu,2022).
基金financial support from the National Natural Science Foundation of China(NSFC,Nos.82173677,81773574)the Key Project of NSFC for International Cooperation(No.81420108027)+2 种基金the Shandong Provincial Key Research and Development Project(No.2019JZZY021011)the Science Foundation for Outstanding Young Scholars of Shandong Province(No.ZR2020JQ31)NIH/NIAID grant(No.R01AI150491,Cocklin,PI,Salvino,Co-I)。
文摘HIV-1 capsid protein(CA) has emerged as a promising target for antiviral treatment considering its structural and regulatory roles in HIV-1 replication. Here, we disclose the design, synthesis, biological assessment, and mechanism investigation of a novel series of phenylalanine derivatives gained by further structural modification of PF74. The newly synthesized compounds demonstrated potent anti-HIV activity, represented by 7n displayed anti-HIV-1 activity 6.25-fold better than PF74, and 7h showed anti-HIV-2activity with nearly 139 times improved efficacy over PF74. Surface plasmon resonance(SPR) studies of representative compounds proved that HIV-1 CA was the binding target. Competitive SPR studies using CPSF6 and NUP153 peptides identified that 7n binds to a vital CA assembly interface between the Nterminal and C-terminal domain(NTD-CTD interface). Action stage determination assay revealed that the newly synthesized compounds were antiviral with a dual-stage inhibitory profile. Molecular dynamics(MD) simulations offered the crucial foundation for the hopeful antiviral potency of 7n. Besides, 7m and7n modestly increased metabolic stabilities in human liver microsome(HLM) and human plasma compared to PF74. Overall, these studies offer valuable insights and can regard as the beginning for succedent medicinal chemistry endeavors to discover promising HIV capsid inhibitors with improved efficacy and better drug-like characteristics.
基金supported by the National Natural Science Foundation of China(81788101,91942314)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-021).
文摘Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against SARS-CoV-2 infection.Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation.This pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal acidification.In addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects.These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.
基金supported by the National Key Research and Development Program of China(No.2022YFA0806503)the National Natural Science Foundation of China(No.81972625)+1 种基金the Dalian Science and Technology Innovation Funding(No.2019J12SN52)the Liaoning Revitalization Talents Program(No.XLYC2002035),China。
文摘Mammalian target of rapamycin(mTOR)controls cellular anabolism,and mTOR signaling is hyperactive in most cancer cells.As a result,inhibition of mTOR signaling benefits cancer patients.Rapamycin is a US Food and Drug Administration(FDA)-approved drug,a specific mTOR complex 1(mTORC1)inhibitor,for the treatment of several different types of cancer.However,rapamycin is reported to inhibit cancer growth rather than induce apoptosis.Pyruvate dehydrogenase complex(PDHc)is the gatekeeper for mitochondrial pyruvate oxidation.PDHc inactivation has been observed in a number of cancer cells,and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide(NAD^(+))exhaustion.In this paper,we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1(PDHA1)phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells.This inactivation reduces the sensitivity of cancer cells'response to rapamycin.As a result,rebooting PDHc activity with dichloroacetic acid(DCA),a pyruvate dehydrogenase kinase(PDK)inhibitor,promotes cancer cells'susceptibility to rapamycin treatment in vitro and in vivo.
基金supported by grants of 81530093 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of China+23 种基金supported by grants of 31390431 from the National Natural Science Foundation of Chinasupported by grants of Natural Sciences Foundation of China(31301007 and 81272525)supported by grants of 81622010 from the National Natural Science Foundation of Chinasupported by grants of 81472717 and 81673474 from the National Natural Science Foundation of China81661128007, 81472653 and 81530080 from National Natural Science Foundation of Chinasupported by grants of 81400286 and 81530093 from the National Natural Science Foundation of Chinasupported by grants of 81400140 from the National Natural Science Foundation of Chinasupported by grants of 81503128 from the National Natural Science Foundation of China2016I2M-1-008 from Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciencessupported by grants of 2014CB542103 from National Basic Research Program of China81502473 from National Natural Science Fund for Young Scholars of Chinasupported by US National Institutes of Health grants (CA217510, CA123088, CA099985, CA193136 and CA152470)supported by grants from the Canadian Institutes of Health Research(FRN 123516 and 152954)the Ontario Institute for Cancer Research(ORBiT)supported by NIH grant GM072744Ministry of Science and Technology of China grant 2016YFA0101100the Fundamental Research Fund for the Central University(No. 2017KFQWJX002) from Huazhong University of Science and TechnologyCore fund (Wang2016) for Development of Cell and Gene Therapy Centre of Academy of Medical Sciences,Zhengzhou UniversityThe MRC (MR/M015696/1)2017YFA0205400 from Ministry of Science and Technology of China2016ZX310190 and 2016ZX320014 from Central Public-interest Scientific Institution Basal Research Fund7162133 from Beijing Natural Science Foundation2016-I2M-4-001 from CAMS Innovation Fund for Medical Sciences2016-I2M-1-007 from the
文摘Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.
基金the National Natural Science Foundation of China,No.81572010,No.81671399,No.81721002 and No.81971329the Capital Health Research and Development of Special Fund Program,No.2016-2-5032and the Beijing Natural Science Foundation No.7172206.
文摘It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen(HBsAg)are associated with nucleoside/nucleotide analog resistance.AIM To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations.METHODS In total,19440 patients with chronic hepatitis B virus infection,who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017,were enrolled.As determined by sequence analysis,6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations.Phenotypic analyses were performed to evaluate HBsAg production,replication capacity,and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V.RESULTS The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations.In particular,these mutations were sQ101H/K/R,sS114A/L/T,sT118A/K/M/R/S/V,sP120A/L/Q/S/T,sT/I126A/N/P/S,sM133I/L/T,sC137W/Y,sG145A/R,and sA159G/V.Among these,sA159V was detected in 1.95%(136/6982)of patients with resistance mutations and 1.08%(134/12,458)of patients lacking resistance mutations(P<0.05).The coexistence of sA159V with lamivudine(LAM)and entecavir(ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance.HBsAg production was significantly lower and the replication capacity was significantly higher,without a significant difference in LAM/ETV susceptibility,in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts.CONCLUSION In summary,we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations.sA159V might increase the fitness of LAM/ETV-resistant mutants under env
基金This work was supported by the National Natural Science Foundation of China(81788101)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-021).
文摘Dear Editor,Alveolar macrophages(AMs)are among the first immune cells to encounter SARS-CoV-2 during an infection due to their abundant numbers and physical location in the lungs.Thus,the reaction of AMs to SARS-CoV-2 has a profound impact on the outcome of the infection.In most cases,AMs can release cytokines and prime adaptive T-and B-cell immune responses to resolve the infection.
基金This work was supported by the National Natural Science Foundation of China(81788101,82041008)Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(2021-I2M-1-021).
文摘Dear Editor,Genetic variant Delta(B.1.617.2)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which possesses a remarkable ability to transmit and spread,is currently becoming predominant worldwide.Despite its great harm to human beings,how the Delta variant with T478K,P681R and L452R mutations achieves its ultrafast spread remains elusive.Entry of SARS-CoV-2 into host cells is mediated by a rapid enzymatic hydrolysis.
基金supported by the National Natural Science Foundation of China(81788101)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-021).
文摘The coronavirus disease 2019(COVID-19)pandemic has caused more than 6.3 million deaths to date.Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),vaccines and neutralizing antibodies are in the gloom due to persistent viral mutations and antiviral compounds face challenges of specificity and safety.In addition,vaccines are unable to treat already-infected individuals,and antiviral drugs cannot be used prophylactically.Therefore,exploration of unconventional strategies to curb the current pandemic is highly urgent.Alveolar macrophages(AMs)residing on the surface of alveoli are the first immune cells that dispose of alveoli-invading viruses.Our findings demonstrate that M1 AMs have an acidic endosomal pH,thus favoring SARS-CoV-2 to leave endosomes and release into the cytosol where the virus initiates replication;in contrast,M2 AMs have an increased endosomal pH,which dampens the viral escape and facilitates delivery of the virus for lysosomal degradation.In this review,we propose that AMs are the Achilles’heel of SARS-CoV-2 infection and that modulation of the endosomal pH of AMs has the potential to eliminate invaded SARS-CoV-2;the same strategy might also be suitable for other lethal respiratory viruses.
基金NationalNatural Science Foundation of China,Grant/Award Numbers:81672440,31701156,81972625DICP,Grant/Award Number:ZZBS201803The Construction of Liaoning CancerResearch Center,Grant/Award Number:1564992449013。
文摘Background:Y-box binding protein 1(YB1 or YBX1)plays a critical role in tumorigenesis and cancer progression.However,whether YB1 affects malignant transformation by modulating non-codingRNAs remains largely unknown.This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network.Methods:The biological functions of YB1 in hepatocellular carcinoma(HCC)cells were investigated by cell proliferation,wound healing,and transwell invasion assays.The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines.The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR,dual-luciferase reporter assay,RNA immunoprecipitation,and pull-down assay.The relationships of YB1,DGCR8,Dicer,TUT4,and TUT1 were identified by pull-down and coimmunoprecipitation experiments.The cellular co-localization of YB1,DGCR8,and Dicer were detected by immunofluorescent staining.The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice.The expression levels of epithelial tomesenchymal transition markerswere detected by immunoblotting and immunohistochemistry assays.Results:YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b‒ZEB1 axis partially in a Snail-independent manner.YB1 suppressedmiR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain.Subsequently,the downregulation of miR-205 and miR-200b enhanced ZEB1 expression,thus leading to increased cell migration and invasion.Furthermore,statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis.Conclusion:This study reveals a previously undescribed mechanism
基金National Natural Science Foundation of China(81788101)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-021)
文摘Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,including internal genetic alterations and external inflammation-related stimuli.Overflow of exocrine pancreatic enzymes caused by PDAC obstruction inevitably results in autolysis of surrounding normal cells and extracellular matrix,generating tissue damage-related inflammation;however,this process does not cause autolysis of PDAC cells.How tumor cells acquire resistance to pancreatic enzymatic digestion has been ignored for a long time.In this review,we discuss how PDAC cells mobilize gasdermin E,a pore-forming protein,to achieve resistance to autolysis by pancreatic digestive enzymes.
基金supported by the National Natural Science Foundation of China(81788101)Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(2020-l2M-CoV19-007).
文摘The pandemic of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is sweeping across the world and has caused the loss of more than 3.3 million lives.Before clearance by virus-specific T and B cell-mediated adaptive immunity,excessive inflammation by innate immune cells might cause severe lung and even multiorganic pathologies,thus interfering with antiviral immunity.To curb infection and subsequent organic damage,a deep understanding of the pathogenetic process is highly desirable.Recently,we found that IFN-driven mucin expression in type Ⅱ alveolar epithelial cells is crucial in initiating hypoxia and early lung pathology1,and SARS-CoV-2 is disposed of by M1 and M2 alveolar macrophages(AMs)in distinct manners2.In this correspondence,we propose that(1)following the invasion of the alveoli and uptake by local alveolar macrophages,SARS-CoV-2 may stimulate macrophages to produce proinflammatory cytokines,including type Ⅰ interferon;(2)type I interferon acts on neighboring alveolar type Ⅱ pneumocytes and activates the cytoplasmic transcription factor aryl hydrocarbon receptor(AhR);(3)subsequently,AhR is translocated to the nucleus,where it promotes the expression of mucin genes,leading to mucus production;and(4)mucus begins to accumulate in the alveoli and gradually impairs the exchange of O2 and CO2,initially causing hypoxia and then dampening CO2 exhalation,leading to a critical illness.Here,we dissect these early pathogenic events,which might provide clues to interfering with SARS-CoV-2 infection at an early stage.
基金supported by the National Natural Science Foundation of China(No.81788101)the Chinese Academy of Medical Sciences Initiative for Innovative Medicine(CAMS-I2M)(No.2016-I2M-1-007)supported by the project of“Research on the Passive Micro Sensor Components and Systems Applied in SF6 Detection”(No.54681618002400k0000000).
文摘Cellular mechanics,a major regulating factor of cellular architecture and biological functions,responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the microenvironment.Cellular mechanics also acts as a fundamental mediator in complicated immune responses,such as cell migration,immune cell activation,and pathogen clearance.The principle of atomic force microscopy(AFM)and its three running modes are introduced for the mechanical characterization of living cells.The peak force tapping mode provides the most delicate and desirable virtues to collect high-resolution images of morphology and force curves.For a concrete description of AFM capabilities,three AFM applications are discussed.These applications include the dynamic progress of a neutrophil-extracellular-trap release by neutrophils,the immunological functions of macrophages,and the membrane pore formation mediated by perforin,streptolysin O,gasdermin D,or membrane attack complex.
