Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally lead...Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant(scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry(GC-MS) showed that the scd-/- mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike Scd-/ -mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body,especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis.Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis,acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.展开更多
Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Weste...Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.展开更多
Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD...Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.展开更多
Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 t...Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 to important sarbecoviruses,including SARS-CoV,SARS-CoV-2,and animal-origin SARS-CoV-2 related viruses.Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains(RBDs)of sarbecoviruses.We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV,SARS-CoV-2 prototype(PT),and Omicron BF.7.Through structural analysis,we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2,thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.In addition,the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-πinteraction with K353 in the fox ACE2 receptor.This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.These results indicate that foxes serve as potential hosts for numerous sarbecoviruses,highlighting the critical importance of surveillance efforts.展开更多
Gene mutations drive oncogene addiction in tumor cells,presenting opportunities for targeted gene therapy.Currently,targeted therapy is one of the most effective cancer treatment modalities.However,tumor cells demonst...Gene mutations drive oncogene addiction in tumor cells,presenting opportunities for targeted gene therapy.Currently,targeted therapy is one of the most effective cancer treatment modalities.However,tumor cells demonstrate remarkable plasticity,acquiring genetic mutations or activating alternative signaling pathways to evade targeted agents.Drug resistance frequently emerges,significantly diminishing the efficacy of targeted therapy.The precise causes of this resistance is unclear.The intricate interplay of immune and inflammatory pathways is integral to cancer development and response to treatment.Emerging evidence suggests that inflammatory pathways have pivotal roles in mediating resistance to targeted therapies across various cancer types,yet the exact mechanisms remain obscure.Herein we present an overview of the mechanisms underlying resistance to targeted therapies induced by inflammatory signaling,with a particular focus on inflammatory-driven resistance to EGFR-targeted therapies.展开更多
The global outbreak of coronavirus disease 19(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),has raised significant global apprehension.Developing a rapid,efficient,sensitive,and accu...The global outbreak of coronavirus disease 19(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),has raised significant global apprehension.Developing a rapid,efficient,sensitive,and accurate point-of-care detection method is imperative for curbing SARS-Co V-2 transmission.Here,we screened a sequence,designed a set of highly sensitive loopmediated isothermal amplification primers(LAMP)and g RNA,and developed a user-friendly detection platform combining CRISPRCas12a and RT-LAMP technology to specifically detect SARS-Co V-2 and its 5 variants.Bioinformatics analysis and Cas12a-g RNA identification ensured sequence specificity,allowing us to identify SARS-Co V-2 mutations.We developed a method for the detection of SARSCoV-2 using these primers in combination with LAMP amplification and CRISPR-Cas12a technology.This method is designed to detect SARS-CoV-2(NC_045512),Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),Delta(B.1.617.2)and Omicron(B.1.1.529).Additionally,it can differentiate SARS-CoV-2 from other coronaviruses.Quantitative analysis can be conducted by measuring fluorescence values,while qualitative analysis can be performed by observing fluorescence color point-of-care diagnosis changes with the naked eye.These results suggest that a set of novel sensitive LAMP primers and g RNA have been obtained to detect the extensive variants,and the RT-LAMPCRISPR-Cas12a platform significantly facilitates point-of-care diagnosis,thereby halting the spread of SARS-Co V-2,thus contributing to COVID-19 prevention and control.展开更多
Hepatocellular carcinoma(HCC) is one of the most lethal malignancies in the world. Several signaling pathways,including the wingless/int-1(Wnt) signaling pathway,have been shown to be commonly activated in HCC. The Wn...Hepatocellular carcinoma(HCC) is one of the most lethal malignancies in the world. Several signaling pathways,including the wingless/int-1(Wnt) signaling pathway,have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1(CTNNB1)-dependent(also known as "canonical") and CTNNB1-independent(often referred to as "non-canonical") pathways. Specifically,the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes(the cell-surface receptor complex,the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported,two main non-canonical pathways,Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway,participate in the regulation of hepatocarcinogenesis. Interestingly,the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover,other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore,crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.展开更多
Ficolins are serum complement lectins,with a structure similar to mannose-binding lectin （MBL） and lung surfactant protein （SP）-A and SP-D.Ficolins activate the lectin complement system and play important roles in...Ficolins are serum complement lectins,with a structure similar to mannose-binding lectin （MBL） and lung surfactant protein （SP）-A and SP-D.Ficolins activate the lectin complement system and play important roles in host innate immunity.Ficolins are members of the collectin family of proteins,which act as pattern recognition receptors （PRRs）.They are soluble oligomeric defense proteins with lectin-like activity,and are able to recognize pathogen-associated molecular patterns （PAMPs）,which are carbohydrate molecules on the surface of pathogens,and of apoptotic,necrotic,and malignant cells.Upon binding to their specific PAMPs,ficolins may trigger activation of the immune system either （1） by initiating activation of complement via the lectin pathway,（2） by a primitive type of opsonophagocytosis,or （3） by stimulating secretion of the inflammatory cytokines interferon （IFN）-γ,interleukin （IL）-17,IL-6,and tumor necrosis factor （TNF）-α,and production of nitric oxide （NO）by macrophages,thus limiting the infection and concurrently orchestrating the subsequent adaptive immune response.Recently,a number of reports have shown that dysfunction or abnormal expression of ficolins may play crucial roles in viral and bacterial diseases and in inflammation.This review summarizes the reports on the roles of ficolins in the infectious diseases,and provides insight into ficolins as novel innate immune therapeutic options to treat these diseases.展开更多
The development of a massively producible vaccine against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),a novel coronavirus,is essential for stopping the current coronavirus disease(COVID-19)pandemic.A v...The development of a massively producible vaccine against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),a novel coronavirus,is essential for stopping the current coronavirus disease(COVID-19)pandemic.A vaccine must stimulate effective antibody and T cell responses in vivo to induce long-term protection.Scientific researchers have been developing vaccine candidates for the severe acute respiratory syndrome(SARS)and Middle East respiratory syndrome(MERS)since the outbreaks of these diseases.The prevalence of new biotechnologies such as genetic engineering has shed light on the generation of vaccines against novel viruses.In this review,we present the status of the development of coronavirus vaccines,focusing particularly on the biomimetic nanoparticle technology platform,which is likely to have a major role in future developments of personalized medicine.展开更多
BACKGROUND Liver cancer is the fourth most significant cause of cancer-related death.Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality.Exosomes,which co...BACKGROUND Liver cancer is the fourth most significant cause of cancer-related death.Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality.Exosomes,which contain various bioactive molecules,are characterized by high biocompatibility,low immunogenicity,and high transport efficiency.As a result,exosomes have become a research hotspot and present significant potential for cancer diagnosis biomarkers,biotherapeutics,therapy targets,drug carriers and therapeutic agents.AIM To explore the potential of exosomes in the diagnosis and treatment of liver cancer.METHODS We conducted a systematic literature search via PubMed and Web of Science.The following keywords were used:"exosomal biomarkers","exosomal therapy","exosomal therapy",and"liver cancer"or"HCC".The duplicate data were deleted by EndNote software.Literature search focused on full-texts and references of each article were carefully checked.One author(Xiao-Cui Wei)screened the literature that met the following inclusion criteria:(1)Detection of exosomes or their contents in clinical samples(body fluid or tissue);or(2)Exosomes served as drug carriers or therapeutic factors.Two authors(Xiao-Cui Wei and Li-Juan Liu)independently reviewed all retained literature and analyzed the information.RESULTS A total of 1295 studies were identified using the systematic literature search.Of these,835 duplicate studies were removed.A further 402 irrelevant studies were excluded due to being irrelevant,including other diseases,review articles,the literature containing neither clinical samples nor animal experiments,exosomeindependent studies,methods for detecting exosomes,or articles in Chinese.Finally,58 published papers were retained and analyzed in the study.It showed a list of potential exosomal biomarkers that were upregulated in the blood samples of patients with liver cancer.Those downregulated in exosomes might serve as possible biotherapeutics.Some exosomes derived from cells in vitro were used for cytology or animal experiments to explore the mechanism of these exosome contents in disease.These contents might serve as potential targets for liver cancer.Additionally,we also discussed that exosomes serve as drug carriers or therapeutic factors.CONCLUSION Exosomes might serve as potential biomarkers or therapeutic biotargets in liver cancer and have the potential to act as drug carriers and self-treatment factors for liver cancer patients.展开更多
Schizophrenia(SCZ)is a severe mental illness that affects several brain domains with relation to cognition and behaviour.SCZ symptoms are typically classified into three categories,namely,positive,negative,and cogniti...Schizophrenia(SCZ)is a severe mental illness that affects several brain domains with relation to cognition and behaviour.SCZ symptoms are typically classified into three categories,namely,positive,negative,and cognitive.The etiology of SCZ is thought to be multifactorial and poorly understood.Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ.Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ.Many factors,including synaptic structure changes,aberrant expression of plasticityrelated genes,and abnormal synaptic transmission,may influence synaptic plasticity and play vital roles in SCZ.In this article,we briefly summarize the morphology of the synapse,the neurobiology of synaptic plasticity,and the role of synaptic plasticity,and review potential mechanisms underlying abnormal synaptic plasticity in SCZ.These abnormalities involve dendritic spines,postsynaptic density,and long-term potentiation-like plasticity.We also focus on cognitive dysfunction,which reflects impaired connectivity in SCZ.Additionally,the potential targets for the treatment of SCZ are discussed in this article.Therefore,understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.展开更多
Dear Editor,Alternative splicing of eukaryotic transcripts refers to the posttranscriptional process in which the coding regions(exons)of a precursor transcript are joined in different combinations through the removal...Dear Editor,Alternative splicing of eukaryotic transcripts refers to the posttranscriptional process in which the coding regions(exons)of a precursor transcript are joined in different combinations through the removal or retention of non-coding intervening sequences(introns)to produce distinct mature messenger RNA(mRNA)transcripts and further generate one or more mature mRNAs(Lee and Rio,2015).Alternative splicing is revealed dysregulation in infectious diseases.Many pathogens hijack the splicing mechanism of host cells to complete their replications,accompanied by dysregulated innate immune response or cell damage,leading to the changes of alternative splicing landscape in host cells(Ashraf et al.,2019;Tomezsko et al.,2020;Kremsdorf et al.,2021).The regulation mechanism of alternative splicing by viral pathogens,such as hepatitis B virus(Duriez et al.,2017),human immunodeficiency virus 1(Tomezsko et al.,2020),Zika virus(Bonenfant et al.,2020)and enterovirus 71(Li et al.,2020),have been explored.展开更多
Microplastics(MPs)have become a significant concern for their potential toxicity.However,the correlation between the size of plastic particles and their toxicity remains inconclusive.Here,we investigate the toxic effe...Microplastics(MPs)have become a significant concern for their potential toxicity.However,the correlation between the size of plastic particles and their toxicity remains inconclusive.Here,we investigate the toxic effects of different sizes(80 nm,800 nm,8μm and 80μm)polystyrene MPs(PS-MPs)on the model organism Nile tilapia(Oreochromis niloticus).The results of bioluminescent imaging indicate that the 80 nm PS-MPs are more likely to invade the body.H&E staining shows severe damage on the intestinal villi and distinct hepatic steatosis in the 80 nm group.Ed U labeling shows that the proliferation activity of intestinal and liver cells reduces significantly in the 80 nm group.The gut microbiome analysis shows a severe imbalance of gut microbiota homeostasis in the 80 nm group.The analysis of liver transcriptomics and metabolomics shows that the liver lipid metabolism is disordered in the 80 nm group.In conclusion,this study confirms that the 80 nm PS-MPs are more likely to induce intestinal and liver toxicity.All the above lay the foundation for further study on the pathological damage of MPs to other organisms.展开更多
Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis,allergic asthma,atopic dermatitis,and chronic rhinosinusitis with nasal polyps.It...Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis,allergic asthma,atopic dermatitis,and chronic rhinosinusitis with nasal polyps.It is the predominant type of immune response against helminths to prevent their tissue infiltration and induce their expulsion.Recent studies suggest that epithelial barrier dysfunction contributes to the development of type 2 inflammation in asthma,which may partly explain the increasing prevalence of asthma in China and around the globe.The epithelial barrier hypothesis has recently been proposed and has received great interest from the scientific community.The development of leaky epithelial barriers leads to microbial dysbiosis and the translocation of bacteria to inter-and sub-epithelial areas and the development of epithelial tissue inflammation.Accordingly,preventing the impairment and promoting the restoration of a deteriorated airway epithelial barrier represents a promising strategy for the treatment of asthma.This review introduces the interaction between type 2 inflammation and the airway epithelial barrier in asthma,the structure and molecular composition of the airway epithelial barrier,and the assessment of epithelial barrier integrity.The role of airway epithelial barrier disruption in the pathogenesis of asthma will be discussed.In addition,the possible mechanisms underlying the airway epithelial barrier dysfunction induced by allergens and environmental pollutants,and current treatments to restore the airway epithelial barrier are reviewed.展开更多
Dear Editor,Coronavirus disease 2019(COVID-19)is a global pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).SARS-Co V-2 infection was first detected in Wuhan,China in late December 2019.T...Dear Editor,Coronavirus disease 2019(COVID-19)is a global pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).SARS-Co V-2 infection was first detected in Wuhan,China in late December 2019.The virus was spreading rapidly to other cities of China and accumulating cases had been reported(Li et al.2020).展开更多
The detection and analysis of circulating tumor cells （CTCs） from patients＇ blood is important to assess tumor status; however, it remains a challenge. In the present study, we developed a programmable DNA-responsi...The detection and analysis of circulating tumor cells （CTCs） from patients＇ blood is important to assess tumor status; however, it remains a challenge. In the present study, we developed a programmable DNA-responsive microchip for the highly efficient capture and nondestructive release of CTCs via nucleic acid hybridization. Transparent and patternable substrates with hierarchical architectures were integrated into the microchip with herringbone grooves, resulting in greatly enhanced cell-surface interaction via herringbone micromixers, more binding sites, and better matched topographical interactions. In combination with a high-affinity aptamer, target cancer cells were specifically and efficiently captured on the chip. Captured cancer cells were gently released from the chip under physiological conditions using toehold-mediated strand displacement, without any destructive factors for cells or substrates. More importantly, aptamercontaining DNA sequences on the surface of the retrieved cancer cells could be further amplified by polymerase chain reaction （PCR）, facilitating the detection of cell surface biomarkers and characterization of the CTCs. Furthermore, this system was extensively applied to the capture and release of CTCs from patients＇ blood samples, demonstrating a promising high-performance platform for CTC enrichment, release, and characterization.展开更多
The human myxovirus resistance 2(Mx2/Mx B)protein,a member of interferon(IFN)-inducible dynamin-like large GTPases,restricts a number of virus infections.Inhibition of these viruses occurs at poorly-defined steps afte...The human myxovirus resistance 2(Mx2/Mx B)protein,a member of interferon(IFN)-inducible dynamin-like large GTPases,restricts a number of virus infections.Inhibition of these viruses occurs at poorly-defined steps after viral entry and has a common requirement for Mx B oligomerization.However,the GTPase activity is essential for the anti-viral effects of Mx B against herpesviruses and HBV but not HIV-1.To understand the role of Mx B GTPase activity,including GTP binding and GTP hydrolysis,in restriction of HIV-1 infection,we genetically separated these two functions and evaluated their contributions to restriction.We found that both the GTP binding and hydrolysis function of Mx B involved in the restriction of HIV-1 replication.The GTPase activity of Mx B contributed to its nuclear location,interaction with nucleoporins(NUPs)and HIV-1 capsids.Furthermore,Mx B disrupted the association between NUPs and HIV-1 cores dependently upon its GTPase activity.The function of GTPase activity was therefore multi-faceted,led to fundamentally distinct mechanisms employed by wild-type Mx B and GTPase activity defective Mx B mutations to restrict HIV-1 replication.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.The association of hepatitis B virus(HBV)infection with HCC is hitherto documented.Exosomal miRNAs contribute to cancer progression an...BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.The association of hepatitis B virus(HBV)infection with HCC is hitherto documented.Exosomal miRNAs contribute to cancer progression and chemoresistance.HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis.However,there has been no report on hepatitis B core antigen(HBc)regulating exosomal miRNAs to induce drug resistance of HCC cells.AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride(Dox)resistance in HCC.METHODS Exosomes were isolated by ultracentrifugation.The morphology and size of exosomes were evaluated by Dynamic Light Scattering(DLS)and transmission electron microscopy(TEM).The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas(TCGA)database.The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction.TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p.Finally,we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry,Cell counting kit 8(CCK-8)assay and western blot.RESULTS We found that HBc increased the expression of exosomal miR-135a-5p.Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues.Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2(VAMP2)as a novel target gene of miR-135a-5p.Functional assays showed that exosomal miR-135a-5p induced apoptosis protection,cell proliferation,and chemotherapy resistance in HCC.In addition,the rescue experiment demonstrated that VAMP2 reversed apoptosis protection,cell growth,and drug resistance by miR-135a-5p.Finally,HBc promoted HCC anti-apoptosis,proliferation,and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis.CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis,cell proliferation,and chemical resistance through miR-135a-5p/VAMP2.Thus,our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.展开更多
Human endogenous retrovirus W env(HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis(MS). These diseases are accompanied by immunological reactions in th...Human endogenous retrovirus W env(HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis(MS). These diseases are accompanied by immunological reactions in the central nervous system(CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter – nitric oxide(NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase(hi NOS) and enhanced the promoter activity of hi NOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.展开更多
An efficient synthesis of chromeno[4,3-b]quinoline derivatives via one-pot,four-component reaction of 4-hydroxycoumarin, formaldehyde,cyclohexanedione,ammonium ceric nitrate under microwave irradiation was accomplishe...An efficient synthesis of chromeno[4,3-b]quinoline derivatives via one-pot,four-component reaction of 4-hydroxycoumarin, formaldehyde,cyclohexanedione,ammonium ceric nitrate under microwave irradiation was accomplished.The structures of these compounds were unambiguously confirmed by single crystal X-ray diffraction.Furthermore,the anti-AChE activities of these compounds in vitro were investigated at concentrations of 20μM and 50μM by using a standard Ellman's method.The relationship of inhibitory activities and structures of these chromeno [4,3-b]quinolines was also systematically studied.Of all the compounds investigated,4ag emerged as the most potent AChE inhibitor with IC50 values of 5.63μM,and it might be used as potent lead for the development anti-AChE agents.Moreover,molecular modelling was conducted to understand the optimal interaction of AChE with these types of compounds.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA24010108)National Natural Science Foundation of China(31872554,32172952)Project from the State Key Laboratory of Freshwater Ecology and Biotechnology(2019FBZ05)。
文摘Stearyl coenzyme A desaturase(SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids.In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant(scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry(GC-MS) showed that the scd-/- mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike Scd-/ -mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body,especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis.Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis,acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.
基金supported by the Shenzhen Science and Technology Program (Grant no. JCYJ20230807090459001)the Joint Research Fund of the National Science Fund of China Science and Technology Development Fund of Macao SAR (No. 32161160303 for NSFC and No. 0010/2021/AFJ for FDCT)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University (Grant no. ZNJC202330)。
文摘Objective: Abnormal metabolism is the underlying reason for breast cancer progression. Decreased lactate dehydrogenase B(LDHB) has been detected in breast cancer but the function of LDHB remains unknown.Methods: Western blot was used to analyze LDHB expression in breast cancer cells. The impact of LDHB on tumor cell migration and invasion was determined using Transwell assays, wound healing assays, and a mouse lung metastasis model. Subcutaneous tumor formation, a natural killer(NK) cell cytotoxicity assay, and flow cytometry evaluated NK cell activation. Immunofluorescence and quantitative real-time PCR detected NK cell activation markers. Kaplan-Meier analysis evaluated the effect of immune cell infiltration on prognosis. Single-sample gene set enrichment analysis determined NK cell activation scores. A support vector machine predicted the role of LDHB in NK cell activation.Results: In this study we showed that LDHB inhibits the breast cancer cell metastasis and orchestrates metabolic reprogramming within tumor cells. Our results revealed that LDHB-mediated lactic acid clearance in breast cancer cells triggers NK cell activation within the tumor microenvironment. Our findings, which were confirmed in a murine model, demonstrated that LDHB in tumor cells promotes NK cell activation and ultimately results in the eradication of malignant cells. Clinically, our study further validated that LDHB affects immune cell infiltration and function. Specifically, its expression has been linked to enhanced NK cell-mediated cytotoxicity and improved patient survival. Furthermore, we identified LDHB expression in tumors as an important predictor of NK cell activation, with strong predictive ability in some cancers.Conclusions: Our results suggest that LDHB is a promising target for activating the tumor immune microenvironment in breast cancer, where LDHB-associated lactic acid clearance leads to increased NK cell activity. This study highlights the critical role of LDHB in regulating immune responses and its potential as a therapeutic target for breast cancer.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81670531)Hubei Key Laboratory of Edible Wild Plants Conservation and Utilization(Grant No.EWPL201804).
文摘Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.
基金supported by the National Key R&D Program of China(2022YFC2303401,2021YFA1300803)National Natural Science Foundation of China(32122008)+2 种基金supported by Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)fellowships from the China Postdoctoral Science Foundation(2022T150688)the Postdoctoral Science Foundation of China(2021M700161).
文摘Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 to important sarbecoviruses,including SARS-CoV,SARS-CoV-2,and animal-origin SARS-CoV-2 related viruses.Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains(RBDs)of sarbecoviruses.We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV,SARS-CoV-2 prototype(PT),and Omicron BF.7.Through structural analysis,we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2,thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.In addition,the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-πinteraction with K353 in the fox ACE2 receptor.This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.These results indicate that foxes serve as potential hosts for numerous sarbecoviruses,highlighting the critical importance of surveillance efforts.
基金supported by the National Natural Science Foundation of China(Grant No.82372854)for Excellent Young Scholars,the Fundamental Research Funds for the Central Universities,and the National Science Foundation of Hubei Province(Grant No.2022CFA008).
文摘Gene mutations drive oncogene addiction in tumor cells,presenting opportunities for targeted gene therapy.Currently,targeted therapy is one of the most effective cancer treatment modalities.However,tumor cells demonstrate remarkable plasticity,acquiring genetic mutations or activating alternative signaling pathways to evade targeted agents.Drug resistance frequently emerges,significantly diminishing the efficacy of targeted therapy.The precise causes of this resistance is unclear.The intricate interplay of immune and inflammatory pathways is integral to cancer development and response to treatment.Emerging evidence suggests that inflammatory pathways have pivotal roles in mediating resistance to targeted therapies across various cancer types,yet the exact mechanisms remain obscure.Herein we present an overview of the mechanisms underlying resistance to targeted therapies induced by inflammatory signaling,with a particular focus on inflammatory-driven resistance to EGFR-targeted therapies.
基金Supported by the National Natural Sciences Foundation of China(52073022)the Fundamental Research Funds for the Central Universities of China and the Translational Medical Research Fund of Wuhan University Taikang Medical School(School of Basic Medical Sciences)the Key Laboratory of Environmental Pollution Monitoring and Disease Control(Guizhou Medical University)Ministry of Education(GMU-2022-HJZ)。
文摘The global outbreak of coronavirus disease 19(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),has raised significant global apprehension.Developing a rapid,efficient,sensitive,and accurate point-of-care detection method is imperative for curbing SARS-Co V-2 transmission.Here,we screened a sequence,designed a set of highly sensitive loopmediated isothermal amplification primers(LAMP)and g RNA,and developed a user-friendly detection platform combining CRISPRCas12a and RT-LAMP technology to specifically detect SARS-Co V-2 and its 5 variants.Bioinformatics analysis and Cas12a-g RNA identification ensured sequence specificity,allowing us to identify SARS-Co V-2 mutations.We developed a method for the detection of SARSCoV-2 using these primers in combination with LAMP amplification and CRISPR-Cas12a technology.This method is designed to detect SARS-CoV-2(NC_045512),Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),Delta(B.1.617.2)and Omicron(B.1.1.529).Additionally,it can differentiate SARS-CoV-2 from other coronaviruses.Quantitative analysis can be conducted by measuring fluorescence values,while qualitative analysis can be performed by observing fluorescence color point-of-care diagnosis changes with the naked eye.These results suggest that a set of novel sensitive LAMP primers and g RNA have been obtained to detect the extensive variants,and the RT-LAMPCRISPR-Cas12a platform significantly facilitates point-of-care diagnosis,thereby halting the spread of SARS-Co V-2,thus contributing to COVID-19 prevention and control.
基金Supported by National Natural Science Foundation of China,No.31470264 and No.81502418the Key Program of Natural Science Foundation of Hubei Province of China,No.2014CFA078+7 种基金the Hubei Provincial Natural Science Foundation of China,No.2015CFB168 and No.2012FFB04304the Scientific research Innovation Team in Hubei,No.2015CFA009the General Financial Grant from the China Postdoctoral Science Foundation,No.2014M550411the Fundamental research Funds for the Central Universities,No.2042014kf0029the Tianqing Liver Disease research Fund of the China Foundation for Hepatitis Prevention and Control,No.TQGB20140250the Innovation Seed Fund of Wuhan University School of Medicinethe Science and Technology Department Supported Program of Jiangxi Province of China,No.2010BSA13500the Science and Technology Project of Education Department of Jiangxi Province of China,No.GJJ11570
文摘Hepatocellular carcinoma(HCC) is one of the most lethal malignancies in the world. Several signaling pathways,including the wingless/int-1(Wnt) signaling pathway,have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1(CTNNB1)-dependent(also known as "canonical") and CTNNB1-independent(often referred to as "non-canonical") pathways. Specifically,the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes(the cell-surface receptor complex,the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported,two main non-canonical pathways,Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway,participate in the regulation of hepatocarcinogenesis. Interestingly,the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover,other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore,crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.
基金supported by grants from the National Outstanding Youth Foundation of China(81025008)973 Program of China(2012CB720604)+4 种基金National Natural Science Foundation of China(31221061,31370197)National Grand Program on Key Infectious Disease(2012ZX10003002-015)the Hubei Province's Outstanding Medical Academic Leader Program,Changjiang Scholars and Innovative Research Team,the 211 program(303-581045)the Science and Technology Program of Wuhan(301274075)the FundamentalResearch Funds for the Central Universities
文摘Ficolins are serum complement lectins,with a structure similar to mannose-binding lectin （MBL） and lung surfactant protein （SP）-A and SP-D.Ficolins activate the lectin complement system and play important roles in host innate immunity.Ficolins are members of the collectin family of proteins,which act as pattern recognition receptors （PRRs）.They are soluble oligomeric defense proteins with lectin-like activity,and are able to recognize pathogen-associated molecular patterns （PAMPs）,which are carbohydrate molecules on the surface of pathogens,and of apoptotic,necrotic,and malignant cells.Upon binding to their specific PAMPs,ficolins may trigger activation of the immune system either （1） by initiating activation of complement via the lectin pathway,（2） by a primitive type of opsonophagocytosis,or （3） by stimulating secretion of the inflammatory cytokines interferon （IFN）-γ,interleukin （IL）-17,IL-6,and tumor necrosis factor （TNF）-α,and production of nitric oxide （NO）by macrophages,thus limiting the infection and concurrently orchestrating the subsequent adaptive immune response.Recently,a number of reports have shown that dysfunction or abnormal expression of ficolins may play crucial roles in viral and bacterial diseases and in inflammation.This review summarizes the reports on the roles of ficolins in the infectious diseases,and provides insight into ficolins as novel innate immune therapeutic options to treat these diseases.
基金This work was supported by the Fundamental Research Funds for the Central Universities(No.2042020kf1015)National Natural Science Foundation of China(No.81672114,81702627)the Medical talented youth development project in the Health Commission of Hubei Province(No.WJ2019Q049).
文摘The development of a massively producible vaccine against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),a novel coronavirus,is essential for stopping the current coronavirus disease(COVID-19)pandemic.A vaccine must stimulate effective antibody and T cell responses in vivo to induce long-term protection.Scientific researchers have been developing vaccine candidates for the severe acute respiratory syndrome(SARS)and Middle East respiratory syndrome(MERS)since the outbreaks of these diseases.The prevalence of new biotechnologies such as genetic engineering has shed light on the generation of vaccines against novel viruses.In this review,we present the status of the development of coronavirus vaccines,focusing particularly on the biomimetic nanoparticle technology platform,which is likely to have a major role in future developments of personalized medicine.
基金National Natural Science Foundation of China,No.81971943 and No.81772196the Medical Science Advancement Program(Clinical Medicine)of Wuhan University,No.TFLC 2018003.
文摘BACKGROUND Liver cancer is the fourth most significant cause of cancer-related death.Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality.Exosomes,which contain various bioactive molecules,are characterized by high biocompatibility,low immunogenicity,and high transport efficiency.As a result,exosomes have become a research hotspot and present significant potential for cancer diagnosis biomarkers,biotherapeutics,therapy targets,drug carriers and therapeutic agents.AIM To explore the potential of exosomes in the diagnosis and treatment of liver cancer.METHODS We conducted a systematic literature search via PubMed and Web of Science.The following keywords were used:"exosomal biomarkers","exosomal therapy","exosomal therapy",and"liver cancer"or"HCC".The duplicate data were deleted by EndNote software.Literature search focused on full-texts and references of each article were carefully checked.One author(Xiao-Cui Wei)screened the literature that met the following inclusion criteria:(1)Detection of exosomes or their contents in clinical samples(body fluid or tissue);or(2)Exosomes served as drug carriers or therapeutic factors.Two authors(Xiao-Cui Wei and Li-Juan Liu)independently reviewed all retained literature and analyzed the information.RESULTS A total of 1295 studies were identified using the systematic literature search.Of these,835 duplicate studies were removed.A further 402 irrelevant studies were excluded due to being irrelevant,including other diseases,review articles,the literature containing neither clinical samples nor animal experiments,exosomeindependent studies,methods for detecting exosomes,or articles in Chinese.Finally,58 published papers were retained and analyzed in the study.It showed a list of potential exosomal biomarkers that were upregulated in the blood samples of patients with liver cancer.Those downregulated in exosomes might serve as possible biotherapeutics.Some exosomes derived from cells in vitro were used for cytology or animal experiments to explore the mechanism of these exosome contents in disease.These contents might serve as potential targets for liver cancer.Additionally,we also discussed that exosomes serve as drug carriers or therapeutic factors.CONCLUSION Exosomes might serve as potential biomarkers or therapeutic biotargets in liver cancer and have the potential to act as drug carriers and self-treatment factors for liver cancer patients.
基金Supported by National Natural Science Foundation of China,No. 81971943, No. 81772196, No. 31470264, No. 81271820, No. 30870789 and No. 30300117Stanley Foundation from the Stanley Medical Research Institute (SMRI),United States,No. 06R-1366 (to Dr. Zhu F)Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University,No. TFJC 2018002
文摘Schizophrenia(SCZ)is a severe mental illness that affects several brain domains with relation to cognition and behaviour.SCZ symptoms are typically classified into three categories,namely,positive,negative,and cognitive.The etiology of SCZ is thought to be multifactorial and poorly understood.Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ.Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ.Many factors,including synaptic structure changes,aberrant expression of plasticityrelated genes,and abnormal synaptic transmission,may influence synaptic plasticity and play vital roles in SCZ.In this article,we briefly summarize the morphology of the synapse,the neurobiology of synaptic plasticity,and the role of synaptic plasticity,and review potential mechanisms underlying abnormal synaptic plasticity in SCZ.These abnormalities involve dendritic spines,postsynaptic density,and long-term potentiation-like plasticity.We also focus on cognitive dysfunction,which reflects impaired connectivity in SCZ.Additionally,the potential targets for the treatment of SCZ are discussed in this article.Therefore,understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.
基金supported by the National Key Research and Development Plan of China(Grant No.2021YFC2300700).
文摘Dear Editor,Alternative splicing of eukaryotic transcripts refers to the posttranscriptional process in which the coding regions(exons)of a precursor transcript are joined in different combinations through the removal or retention of non-coding intervening sequences(introns)to produce distinct mature messenger RNA(mRNA)transcripts and further generate one or more mature mRNAs(Lee and Rio,2015).Alternative splicing is revealed dysregulation in infectious diseases.Many pathogens hijack the splicing mechanism of host cells to complete their replications,accompanied by dysregulated innate immune response or cell damage,leading to the changes of alternative splicing landscape in host cells(Ashraf et al.,2019;Tomezsko et al.,2020;Kremsdorf et al.,2021).The regulation mechanism of alternative splicing by viral pathogens,such as hepatitis B virus(Duriez et al.,2017),human immunodeficiency virus 1(Tomezsko et al.,2020),Zika virus(Bonenfant et al.,2020)and enterovirus 71(Li et al.,2020),have been explored.
基金supported by China Agriculture Research System (No.CARS-46)the Central Public-interest Scienti?c Institution Basal Research Fund,CAFS (No.YFI202208)the National Natural Science Foundation of China (Nos.31872554and 32172952)
文摘Microplastics(MPs)have become a significant concern for their potential toxicity.However,the correlation between the size of plastic particles and their toxicity remains inconclusive.Here,we investigate the toxic effects of different sizes(80 nm,800 nm,8μm and 80μm)polystyrene MPs(PS-MPs)on the model organism Nile tilapia(Oreochromis niloticus).The results of bioluminescent imaging indicate that the 80 nm PS-MPs are more likely to invade the body.H&E staining shows severe damage on the intestinal villi and distinct hepatic steatosis in the 80 nm group.Ed U labeling shows that the proliferation activity of intestinal and liver cells reduces significantly in the 80 nm group.The gut microbiome analysis shows a severe imbalance of gut microbiota homeostasis in the 80 nm group.The analysis of liver transcriptomics and metabolomics shows that the liver lipid metabolism is disordered in the 80 nm group.In conclusion,this study confirms that the 80 nm PS-MPs are more likely to induce intestinal and liver toxicity.All the above lay the foundation for further study on the pathological damage of MPs to other organisms.
文摘Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis,allergic asthma,atopic dermatitis,and chronic rhinosinusitis with nasal polyps.It is the predominant type of immune response against helminths to prevent their tissue infiltration and induce their expulsion.Recent studies suggest that epithelial barrier dysfunction contributes to the development of type 2 inflammation in asthma,which may partly explain the increasing prevalence of asthma in China and around the globe.The epithelial barrier hypothesis has recently been proposed and has received great interest from the scientific community.The development of leaky epithelial barriers leads to microbial dysbiosis and the translocation of bacteria to inter-and sub-epithelial areas and the development of epithelial tissue inflammation.Accordingly,preventing the impairment and promoting the restoration of a deteriorated airway epithelial barrier represents a promising strategy for the treatment of asthma.This review introduces the interaction between type 2 inflammation and the airway epithelial barrier in asthma,the structure and molecular composition of the airway epithelial barrier,and the assessment of epithelial barrier integrity.The role of airway epithelial barrier disruption in the pathogenesis of asthma will be discussed.In addition,the possible mechanisms underlying the airway epithelial barrier dysfunction induced by allergens and environmental pollutants,and current treatments to restore the airway epithelial barrier are reviewed.
基金funded by the Zhongnan Hospital of Wuhan University Science,Technology and Innovation Seed Fund(Grant No.znpy2018007)。
文摘Dear Editor,Coronavirus disease 2019(COVID-19)is a global pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2).SARS-Co V-2 infection was first detected in Wuhan,China in late December 2019.The virus was spreading rapidly to other cities of China and accumulating cases had been reported(Li et al.2020).
基金This work was supported by the National Natural Science Foundation of China （NSFC） （Nos. 21432008, 91413109 and 21575110）. China Postdoctoral Innovative Talent Support Program of China （No. BX201700176）.
文摘The detection and analysis of circulating tumor cells （CTCs） from patients＇ blood is important to assess tumor status; however, it remains a challenge. In the present study, we developed a programmable DNA-responsive microchip for the highly efficient capture and nondestructive release of CTCs via nucleic acid hybridization. Transparent and patternable substrates with hierarchical architectures were integrated into the microchip with herringbone grooves, resulting in greatly enhanced cell-surface interaction via herringbone micromixers, more binding sites, and better matched topographical interactions. In combination with a high-affinity aptamer, target cancer cells were specifically and efficiently captured on the chip. Captured cancer cells were gently released from the chip under physiological conditions using toehold-mediated strand displacement, without any destructive factors for cells or substrates. More importantly, aptamercontaining DNA sequences on the surface of the retrieved cancer cells could be further amplified by polymerase chain reaction （PCR）, facilitating the detection of cell surface biomarkers and characterization of the CTCs. Furthermore, this system was extensively applied to the capture and release of CTCs from patients＇ blood samples, demonstrating a promising high-performance platform for CTC enrichment, release, and characterization.
基金supported by the National Science Foundation of China(81271818 and 81471940 to YF,and 81471941,81871659 and 81828005 to WH)
文摘The human myxovirus resistance 2(Mx2/Mx B)protein,a member of interferon(IFN)-inducible dynamin-like large GTPases,restricts a number of virus infections.Inhibition of these viruses occurs at poorly-defined steps after viral entry and has a common requirement for Mx B oligomerization.However,the GTPase activity is essential for the anti-viral effects of Mx B against herpesviruses and HBV but not HIV-1.To understand the role of Mx B GTPase activity,including GTP binding and GTP hydrolysis,in restriction of HIV-1 infection,we genetically separated these two functions and evaluated their contributions to restriction.We found that both the GTP binding and hydrolysis function of Mx B involved in the restriction of HIV-1 replication.The GTPase activity of Mx B contributed to its nuclear location,interaction with nucleoporins(NUPs)and HIV-1 capsids.Furthermore,Mx B disrupted the association between NUPs and HIV-1 cores dependently upon its GTPase activity.The function of GTPase activity was therefore multi-faceted,led to fundamentally distinct mechanisms employed by wild-type Mx B and GTPase activity defective Mx B mutations to restrict HIV-1 replication.
基金National Natural Science Foundation of China,No.81971943 and 81772196the Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University,No.TFJC 2018002.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.The association of hepatitis B virus(HBV)infection with HCC is hitherto documented.Exosomal miRNAs contribute to cancer progression and chemoresistance.HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis.However,there has been no report on hepatitis B core antigen(HBc)regulating exosomal miRNAs to induce drug resistance of HCC cells.AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride(Dox)resistance in HCC.METHODS Exosomes were isolated by ultracentrifugation.The morphology and size of exosomes were evaluated by Dynamic Light Scattering(DLS)and transmission electron microscopy(TEM).The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas(TCGA)database.The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction.TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p.Finally,we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry,Cell counting kit 8(CCK-8)assay and western blot.RESULTS We found that HBc increased the expression of exosomal miR-135a-5p.Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues.Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2(VAMP2)as a novel target gene of miR-135a-5p.Functional assays showed that exosomal miR-135a-5p induced apoptosis protection,cell proliferation,and chemotherapy resistance in HCC.In addition,the rescue experiment demonstrated that VAMP2 reversed apoptosis protection,cell growth,and drug resistance by miR-135a-5p.Finally,HBc promoted HCC anti-apoptosis,proliferation,and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis.CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis,cell proliferation,and chemical resistance through miR-135a-5p/VAMP2.Thus,our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.
基金supported by grants from the National Natural Sciences Foundation of China(No.31470264,No.81271820,No.30870789,and No.30300117)the Key Program of Natural Science Foundation of Hubei Province of China(No.2014CFA078)+1 种基金the Stanley Foundation from the Stanley Medical Research Institute(SMRI),USA(No.06R-1366),to Dr.Fan Zhuthe Scientific Innovation Team Project of Hubei Province of China(No.2015CFA009)
文摘Human endogenous retrovirus W env(HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis(MS). These diseases are accompanied by immunological reactions in the central nervous system(CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter – nitric oxide(NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase(hi NOS) and enhanced the promoter activity of hi NOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.
基金NSFC(Grant No.81773557,81573279,81373255)Major Project of Technology Innovation Program of Hubei Province(Grant No.2016ACA126)+1 种基金NSFHP(Grant No.2017CFA024)and the Fun damental Research Funds for the Central Universities of China(Grant No.2042017kf0288)
文摘An efficient synthesis of chromeno[4,3-b]quinoline derivatives via one-pot,four-component reaction of 4-hydroxycoumarin, formaldehyde,cyclohexanedione,ammonium ceric nitrate under microwave irradiation was accomplished.The structures of these compounds were unambiguously confirmed by single crystal X-ray diffraction.Furthermore,the anti-AChE activities of these compounds in vitro were investigated at concentrations of 20μM and 50μM by using a standard Ellman's method.The relationship of inhibitory activities and structures of these chromeno [4,3-b]quinolines was also systematically studied.Of all the compounds investigated,4ag emerged as the most potent AChE inhibitor with IC50 values of 5.63μM,and it might be used as potent lead for the development anti-AChE agents.Moreover,molecular modelling was conducted to understand the optimal interaction of AChE with these types of compounds.
