Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of c...Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and metastasis.In order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal fibroblasts.We created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our theory.Moreover,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate secretion.These results were validated using the monoculture of each group separately as a control.In this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both cells.However,MCT4 and lactate stayed high after treatment with metformin.In conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal fibroblasts.Metformin,however,may change this state and affect fibroblasts'acquired phenotypes.Moreover,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.展开更多
Macrophages are innate immune cells that are ubiquitously distributed throughout the vertebrate body.Macrophages orchestrate sophisticated processes in development,homeostasis,immunity,and disease1.Macrophages residin...Macrophages are innate immune cells that are ubiquitously distributed throughout the vertebrate body.Macrophages orchestrate sophisticated processes in development,homeostasis,immunity,and disease1.Macrophages residing in tumor tissues are commonly known as tumor-associated macrophages(TAMs)and promote or inhibit tumor growth depending on the activation state2.展开更多
The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)inductio...The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.展开更多
Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according...Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according to a US report~1.展开更多
The markers of oocyte quality have remained a major controversy in the field of embryology due to the subjectivity of the different methods of oocyte assessment. Various scholars use oocyte quality and oocyte competen...The markers of oocyte quality have remained a major controversy in the field of embryology due to the subjectivity of the different methods of oocyte assessment. Various scholars use oocyte quality and oocyte competence interchangeably. Oocyte quality can be defined as the overall health of an oocyte whereas oocyte competence refers to the ability of an oocyte to be fertilized and develop into a healthy embryo. Diminished oocyte quality is believed to be a result of alterations in oocyte growth and maturation processes that stem from several pelvic and systemic factors before and after oocyte retrieval. In this review, we focus on the morphological and nonmorphological markers of oocyte quality. Strict restrictions that limit the number of oocytes fertilized in various countries have triggered researchers around the world to come up with the most appropriate and noninvasive markers that enhance oocyte selection and optimize IVF outcomes. PubMed, Google Scholar, and the Cochrane Library were used to search for peer-reviewed, original articles about oocyte quality markers. The review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Morphological markers are commonly used, but they are subjective, and no single marker can be used exclusively to predict oocyte competence and subsequent embryonic development potential. Furthermore, transcriptomics of differentially expressed genes in cumulus cells and assessment of metabolomics and other contents of follicular fluid have shown greater precision. However, their specificity to the different quality determinants needs further research.展开更多
Fewer than one million HIV infected individuals are currently receiving anti-retroviral therapy. Thelimitations of such treatment have underscored the need to develop more effective strategies to control thespread and...Fewer than one million HIV infected individuals are currently receiving anti-retroviral therapy. Thelimitations of such treatment have underscored the need to develop more effective strategies to control thespread and pathogenesis of HIV. Typically, naturally occurring protective immune responses provide theparadigm for such development. It is now clear however that HIV can utilise the millieu of an activatedimmune system to its own replicative advantage. Mobilisation of the immune response, intended to thwartof HIV contributes to lack of immune control and the development of progressive disease in the majority ofinfected, untreated individuals. Further delineation of the intimate interactions between the HIV and theimmune system will be critical and recent advances in this direction are discussed.展开更多
Diabetes and its complications reduce quality of life and are life-limiting.At present,diabetes treatment consists of hypoglycemic agents to control blood glucose and the use of insulin-sensitizing drugs to overcome i...Diabetes and its complications reduce quality of life and are life-limiting.At present,diabetes treatment consists of hypoglycemic agents to control blood glucose and the use of insulin-sensitizing drugs to overcome insulin resistance.In diabetes,autophagy is impaired and thus there is poor intracellular environment homeostasis.Pancreaticβ-cells and insulin target tissues are protected by enhancing autophagy.Autophagy decreasesβ-cell apoptosis,promotesβ-cell proliferation,and alleviates insulin resistance.Autophagy in diabetes is regulated by the mammalian target of rapamycin(mTOR)/adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)pathway and others.Autophagy enhancers can likely be used as a treatment for diabetes and its complications.This review examines the evidence linking autophagy to diabetes.展开更多
Immunological investigations provide useful information to guide diagnosis of several disorders. Many such tests are also commonly repeated at intervals, in an effort to facilitate disease monitoring. In general howev...Immunological investigations provide useful information to guide diagnosis of several disorders. Many such tests are also commonly repeated at intervals, in an effort to facilitate disease monitoring. In general however, immunology test results are often slow to alter. Furthermore, audit activity has indicated that repeated testing accounts for a substantial workload in many immunology services, which may waste resources and compromise the efficient completion of necessary tests. Consequently, the need and appropriate minimum interval between repeated testing requires critical evaluation. In this review, the clinical utility of repeated performance of several common immunology investigations has been evaluated, based upon published evidence. In some cases(e.g., paraprotein quantification, or measurement of anti-glomerular basement membrane antibodies), repeated testing provides vital clinical information and can be justified on a frequent and individualized basis. However, many other investigations provided by immunology services provide lessvaluable information when used to aid disease monitoring rather than diagnosis. It is hoped that the data summarized here will facilitate a more evidence-based approach to repeated testing. Such information may also assist with the local implementation of demand management strategies based upon setting of minimum retesting intervals for these investigations.展开更多
The morphological complexity of cells and tissues,whether normal or pathological,is characterized by two primary attributes:Irregularity and self-similarity across different scales.When an object exhibits self-similar...The morphological complexity of cells and tissues,whether normal or pathological,is characterized by two primary attributes:Irregularity and self-similarity across different scales.When an object exhibits self-similarity,its shape remains unchanged as the scales of measurement vary because any part of it resembles the whole.On the other hand,the size and geometric characteristics of an irregular object vary as the resolution increases,revealing more intricate details.Despite numerous attempts,a reliable and accurate method for quantifying the morphological features of gastrointestinal organs,tissues,cells,their dynamic changes,and pathological disorders has not yet been established.However,fractal geometry,which studies shapes and patterns that exhibit self-similarity,holds promise in providing a quantitative measure of the irregularly shaped morphologies and their underlying self-similar temporal behaviors.In this context,we explore the fractal nature of the gastrointestinal system and the potential of fractal geometry as a robust descriptor of its complex forms and functions.Additionally,we examine the practical applications of fractal geometry in clinical gastroenterology and hepatology practice.展开更多
In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms o...In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms of substance P in epidural fibrosis remain unclear.In this study,we established a mouse model of L1–L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids.In vitro experiments revealed that type 1 macrophages secreted substance P,which promoted differentiation of type 1 macrophages towards a type 2 phenotype.High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P.Specifically,sphingomyelin synthase 2,a component of the sphingolipid metabolic pathway,promoted M2 differentiation in substance P-treated macrophages,while treating the macrophages with LY93,a sphingomyelin synthase 2 inhibitor,suppressed M2 differentiation.In addition,substance P promoted the formation of neutrophil extracellular traps,which further boosted M2 differentiation.Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis,as evidenced by decreased fibronectin,α-smooth muscle actin,and collagen I in the scar tissue.These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps.These findings provide a novel strategy for the treatment of epidural fibrosis.展开更多
BACKGROUND F-box and leucine-rich repeat 6(FBXL6)have reportedly been associated with several cancer types.However,the role and mechanisms of FBXL6 in gastric cancer(GC)require further elucidation.AIM To investigate t...BACKGROUND F-box and leucine-rich repeat 6(FBXL6)have reportedly been associated with several cancer types.However,the role and mechanisms of FBXL6 in gastric cancer(GC)require further elucidation.AIM To investigate the effect of FBXL6 in GC tissues and cells and the underlying mechanisms.METHODS TCGA and GEO database analysis was performed to evaluate the expression of FBXL6 in GC tissues and adjacent normal tissues.Reverse transcription-quantitative polymerase chain reaction,immunofluorescence,and western blotting were used to detect the expression of FBXL6 in GC tissue and cell lines.Cell clone formation,5-ethynyl-2’-deoxyuridine(EdU)assays,CCK-8,transwell migration assay,and wound healing assays were performed to evaluate the malignant biological behavior in GC cell lines after transfection with FBXL6-shRNA and the overexpression of FBXL6 plasmids.Furthermore,in vivo tumor assays were performed to prove whether FBXL6 promoted cell proliferation in vivo.RESULTS FBXL6 expression was upregulated more in tumor tissues than in adjacent normal tissues and positively associated with clinicopathological characteristics.The outcomes of CCK-8,clone formation,and Edu assays demonstrated that FBXL6 knockdown inhibited cell proliferation,whereas upregulation of FBXL6 promoted proliferation in GC cells.Additionally,the transwell migration assay revealed that FBXL6 knockdown suppressed migration and invasion,whereas the overex pression of FBXL6 showed the opposite results.Through the subcutaneous tumor implantation assay,it was evident that the knockdown of FBXL6 inhibited GC graft tumor growth in vivo.Western blotting showed that the effects of FBXL6 on the expression of the proteins associated with the epithelial-mesenchymal transition-associated proteins in GC cells.CONCLUSION Silencing of FBXL6 inactivated the EMT pathway to suppress GC malignancy in vitro.FBXL6 can potentially be used for the diagnosis and targeted therapy of patients with GC.展开更多
Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"...Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"in the AGS cells wound healing assay was incorrectly inserted during the preparation of the submission;the correct figure is provided in this correction.展开更多
Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accura...Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.展开更多
T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regula...T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.展开更多
AIM:To investigate the role of autophagy inhibitor 3-methyladenine(3-MA)on a diabetic mice model(DM)and the potential mechanism.METHODS:Male C57BL/6J mice were randomly divided into a normal control group(NC group)and...AIM:To investigate the role of autophagy inhibitor 3-methyladenine(3-MA)on a diabetic mice model(DM)and the potential mechanism.METHODS:Male C57BL/6J mice were randomly divided into a normal control group(NC group)and an DM group.DM were induced by multiple low-dose intraperitoneal injection of streptozotocin(STZ)60 mg/kgd for 5 consecutive days.DM mice were randomly subdivided into untreated group(DM group),3-MA(10 mg/kgd by gavage)treated group(DM+3-MA group)and chloroquine(CQ;50 mg/kg by intraperitoneal injection)treated group(DM+CQ group).The fasting blood glucose(FBG)levels were recorded every week.At the end of experiment,retinal samples were collected.The expression levels of pro-apoptotic proteins cleaved caspase-3,cleaved poly ADP-ribose polymerase 1(PARP1)and Bax,anti-apoptotic protein Bcl-2,fibrosisassociated proteins Fibronectin and type 1 collagenα1 chain(COL1A1),vascular endothelial growth factor(VEGF),inflammatory factors interleukin(IL)-1βand tumor necrosis factor(TNF)-α,as well as autophagy related proteins LC3,Beclin-1 and P62 were determined by Western blotting.The oxidative stress indicators 8-hydroxydeoxyguanosine(8-OHdG)and malondialdehyde(MDA)were detected by commercial kits.RESULTS:Both 3-MA and CQ had shor t-term hypoglycemic effect on FBG and reduced the expression of VEGF and inflammatory factors IL-1βand TNF-αin DM mice.3-MA also significantly alleviated oxidative stress indicators 8-OHdG and MDA,decreased the expression of fibrosisrelated proteins Fibronectin and COL1A1,pro-apoptotic proteins cleaved caspase-3,cleaved PARP1,as well as the ratio of Bax/Bcl-2.CQ had no significant impact on the oxidative stress indicators,fibrosis,and apoptosis related proteins.The results of Western blotting for autophagy related proteins showed that the ratio of LC3 II/LC3 I and the expression of Beclin-1 in the retina of DM mice were decreased by 3-MA treatment,and the expression of P62 was further increased by CQ treatment.CONCLUSION:3-MA has anti-apoptotic and anti-fibrotic effects on the retina of DM mice,and can attenuate retinal oxidative stress,VEGF expression and the production of inflammatory factors in the retina of DM mice.The underlying mechanism of the above effects of 3-MA may be related to its inhibition of early autophagy and hypoglycemic effect.展开更多
BACKGROUND Tocilizumab is a humanized monoclonal antibody against the interleukin-6(IL-6)receptor that is commonly used to treat large vessel vasculitis and antineutrophil cytoplasmic antibody-related small vessel vas...BACKGROUND Tocilizumab is a humanized monoclonal antibody against the interleukin-6(IL-6)receptor that is commonly used to treat large vessel vasculitis and antineutrophil cytoplasmic antibody-related small vessel vasculitis.However,tocilizumab in combination with glucocorticoids for successfully treating granulomatosis with polyangiitis(GPA)has rarely been reported.CASE SUMMARY Here,we report a 40-year-old male patient who suffered GPA for 4 years.He was treated with multiple rounds of drugs,including cyclophosphamide,Tripterygium wilfordii,mycophenolate mofetil,and belimumab,with no improvement.In addition,he exhibited persistently high IL-6 levels.After tocilizumab treatment,his symptoms improved,and his inflammatory marker levels returned to normal.CONCLUSION Tocilizumab may be effective for treating GPA.展开更多
Background:Amarogentin(AMA)is a secoiridoid glycoside extracted from Swertia and Gentiana roots and exhibits many biological effects such as antioxidative,antiinflammatory,and antitumor activities.Atopic dermatitis(AD...Background:Amarogentin(AMA)is a secoiridoid glycoside extracted from Swertia and Gentiana roots and exhibits many biological effects such as antioxidative,antiinflammatory,and antitumor activities.Atopic dermatitis(AD)is a chronic inflammatory skin disease caused by disorders in the regulation of multiple inflammatory cytokines.No effective cure has been found for AD now.Methods:We constructed the HaCat and splenocyte model and tested the inhibitory effect of AMA on IL-4,IL-6,and IL-13 secretions using enzyme-linked immunosorbent assay(ELISA).The AD mouse model was constructed and treated with AMA,the severity of skin lesions was observed,epidermal tissue was collected,and epidermal thickness and mast cell infiltration were observed using hematoxylin and eosin and toluidine blue staining,respectively.The expression of kallikrein-related peptidase 7(KLK7)and filaggrin(FLG)was detected using immunostaining and Western blot analysis.The mRNA expression of KLK7 and FLG was detected using quantitative polymerase chain reaction(qPCR).Blood immunoglobulin E(IgE)secretion was detected.Results:AMA inhibited IL-6 secreted by tumor necrosis factor(TNF)-α-induced HaCaT cells and reduced IL-4 and IL-13 secreted by phytohemagglutinin(PHA)-induced primary cells in the mice spleen.It was found that the treatment of AMA with 2,4-din itrochlorobenzene-induced AD-like mice could promote the recovery of dermatitis,reduce the score of dermatitis severity and the scratching frequency,treat the skin lesions,reduce the epidermal thickness,decrease the infiltration of mast cells,reduce the IgE level in serum,decrease the expression levels of AD-related cytokines,increase protein and mRNA expression of FLG,and reduce the protein and mRNA expression of KLK7 in the skin tissues of AD-like mice.Conclusion:In conclusion,AMA inhibits inflammatory response at the cellular level,and AMA reduces the validation response of specific dermatitis mice,relieves pruritus,and repairs the damaged skin barrier.展开更多
Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because ne...Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because neutrophils are short-lived,terminally differentiated,and do not proliferate.Although traditionally considered anti-bacterial cells,research has demonstrated the multifaceted roles of neutrophils in cancer.Studies have suggested that neutrophils with normal functions co-exist with pathologically activated neutrophils that support tumorprogression and metastasis in the context of cancer.展开更多
The bony skeleton is continuously renewed throughout adult life by the bone remodeling process,in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms.Osteocytes regulate bone remodeling ...The bony skeleton is continuously renewed throughout adult life by the bone remodeling process,in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms.Osteocytes regulate bone remodeling by producing the osteoclast differentiation factor RANKL(encoded by the TNFSF11 gene).However,the precise mechanisms underlying RANKL expression in osteocytes are still elusive.Here,we explored the epigenomic landscape of osteocytic cells and identified a hitherto-undescribed osteocytic cell-specific intronic enhancer in the TNFSF11 gene locus.Bioinformatics analyses showed that transcription factors involved in cell death and senescence act on this intronic enhancer region.Single-cell transcriptomic data analysis demonstrated that cell death signaling increased RANKL expression in osteocytic cells.Genetic deletion of the intronic enhancer led to a high-bone-mass phenotype with decreased levels of RANKL in osteocytic cells and osteoclastogenesis in the adult stage,while RANKL expression was not affected in osteoblasts or lymphocytes.These data suggest that osteocytes may utilize a specialized regulatory element to facilitate osteoclast formation at the bone surface to be resorbed by linking signals from cellular senescence/death and RANKL expression.展开更多
Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, the...Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, therefore, novel strategies to reverse chemoresistance by regulating autophagy are desperately needed. Methods: The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) between A549 and A549/DDP cell lines were identified using the limma package in R, after gene expression profiles were obtained from Gene Expression Omnibus (GEO) database. By combining Autophagy-Related Genes (ARGs) from Human Autophagy Database (HADb), the interactions lncRNA-miRNAs and the interactions miRNAs-mRNAs respectively predicted by miRcode and miRDB/Targetscan database, the autophagy-related ceRNA network was constructed. Then, extraction of ceRNA subnetwork and Cox regression analyses were performed. A prognosis-related ceRNA subnetwork was constructed, and the upstream Transcription Factors (TFs) regulating lncRNAs were predicted by the JASPAR database. Finally, the expression patterns of candidate genes were further verified by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Results: A total of 3179 DEmRNAs, 180 DEmiRNAs, and 160 DElncRNAs were identified, and 35 DEmRNAs were contained in the HADb. Based on the ceRNA hypothesis, we established a ceRNA network, including 10 autophagy-related DEmRNAs, 9 DEmiRNAs, and 14 DElncRNAs. Then, LINC00520, miR-181d, and BCL2 were identified to construct a risk score model, which was confirmed to be a well-predicting prognostic factor. Furthermore, 5 TF ZNF family members were predicted to regulate LINC00520, whereas the RT-PCR results showed that the 5 ZNFs were consistent with the bioinformatics analysis. Finally, a ZNF regulatory LINC00520/miR-181d/BCL2 ceRNA subnetwork was constructed. Conclusions: An ZNFs/LINC00520/miR-181d/BCL2 axis as a novel network in DDP-resistant LUAD has been constructed successfully, which may provide potential therapeutic targets for LUAD.展开更多
基金the National Institute for Medical Research Development(NIMADGrant No.995813).
文摘Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy resitance.The hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and metastasis.In order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal fibroblasts.We created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our theory.Moreover,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate secretion.These results were validated using the monoculture of each group separately as a control.In this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both cells.However,MCT4 and lactate stayed high after treatment with metformin.In conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal fibroblasts.Metformin,however,may change this state and affect fibroblasts'acquired phenotypes.Moreover,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.
基金the National Key R&D Program of China(Grant Nos.2020YFA0509400 and 2019YFA0110300 to JC)the National Natural Science Foundation of China(Grant Nos.82150117 and 82071745 to JC and 31900570 to GJ)+2 种基金the Nanshan Scholarship of Guangzhou Medical University start-up fund(to GJ)the Science and Technology Program of Guangzhou(Grant No.202002030069 to JC)the Guangdong Project(Grant No.2019QN01Y212 to JC)。
文摘Macrophages are innate immune cells that are ubiquitously distributed throughout the vertebrate body.Macrophages orchestrate sophisticated processes in development,homeostasis,immunity,and disease1.Macrophages residing in tumor tissues are commonly known as tumor-associated macrophages(TAMs)and promote or inhibit tumor growth depending on the activation state2.
基金National Natural Science Foundation of China(Grants Numbers 81902878 and 81971468).
文摘The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
基金supported by the Construction Project of Cancer Precision Diagnosis and Drug Treatment Technology(Grant No. ZLJZZDYYWZL04)the Clinical Oncology Research Fund of CSCO(Grant No. Y-SY2021MS-0240)+2 种基金the Haihe Yingcai(Tianjin)Project(Grant No. TJSJMYXYC-D2-039)the Tianjin Key Medical Discipline(Specialty)Construction Project grant(Grant No. TJYXZDXK-009A)the CACA-BeiGene Lymphoma Research Foundation(Grant No.CORP-117)。
文摘Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according to a US report~1.
文摘The markers of oocyte quality have remained a major controversy in the field of embryology due to the subjectivity of the different methods of oocyte assessment. Various scholars use oocyte quality and oocyte competence interchangeably. Oocyte quality can be defined as the overall health of an oocyte whereas oocyte competence refers to the ability of an oocyte to be fertilized and develop into a healthy embryo. Diminished oocyte quality is believed to be a result of alterations in oocyte growth and maturation processes that stem from several pelvic and systemic factors before and after oocyte retrieval. In this review, we focus on the morphological and nonmorphological markers of oocyte quality. Strict restrictions that limit the number of oocytes fertilized in various countries have triggered researchers around the world to come up with the most appropriate and noninvasive markers that enhance oocyte selection and optimize IVF outcomes. PubMed, Google Scholar, and the Cochrane Library were used to search for peer-reviewed, original articles about oocyte quality markers. The review was written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Morphological markers are commonly used, but they are subjective, and no single marker can be used exclusively to predict oocyte competence and subsequent embryonic development potential. Furthermore, transcriptomics of differentially expressed genes in cumulus cells and assessment of metabolomics and other contents of follicular fluid have shown greater precision. However, their specificity to the different quality determinants needs further research.
文摘Fewer than one million HIV infected individuals are currently receiving anti-retroviral therapy. Thelimitations of such treatment have underscored the need to develop more effective strategies to control thespread and pathogenesis of HIV. Typically, naturally occurring protective immune responses provide theparadigm for such development. It is now clear however that HIV can utilise the millieu of an activatedimmune system to its own replicative advantage. Mobilisation of the immune response, intended to thwartof HIV contributes to lack of immune control and the development of progressive disease in the majority ofinfected, untreated individuals. Further delineation of the intimate interactions between the HIV and theimmune system will be critical and recent advances in this direction are discussed.
基金This work was supported by grants from the Hubei Province Scientific Research Project of Health Commission(No.WJ2021Q015)the Yangtze Fund for Youth Teams of Science and Technology Innovation(No.2016cqt04)+1 种基金Central Funds Guiding the Local Science and Technology Development of Hubei Province(No.2019ZYYD066)Joint Foundation of the Health Commission of Hubei Province(No.WJ2018H173).
文摘Diabetes and its complications reduce quality of life and are life-limiting.At present,diabetes treatment consists of hypoglycemic agents to control blood glucose and the use of insulin-sensitizing drugs to overcome insulin resistance.In diabetes,autophagy is impaired and thus there is poor intracellular environment homeostasis.Pancreaticβ-cells and insulin target tissues are protected by enhancing autophagy.Autophagy decreasesβ-cell apoptosis,promotesβ-cell proliferation,and alleviates insulin resistance.Autophagy in diabetes is regulated by the mammalian target of rapamycin(mTOR)/adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK)pathway and others.Autophagy enhancers can likely be used as a treatment for diabetes and its complications.This review examines the evidence linking autophagy to diabetes.
文摘Immunological investigations provide useful information to guide diagnosis of several disorders. Many such tests are also commonly repeated at intervals, in an effort to facilitate disease monitoring. In general however, immunology test results are often slow to alter. Furthermore, audit activity has indicated that repeated testing accounts for a substantial workload in many immunology services, which may waste resources and compromise the efficient completion of necessary tests. Consequently, the need and appropriate minimum interval between repeated testing requires critical evaluation. In this review, the clinical utility of repeated performance of several common immunology investigations has been evaluated, based upon published evidence. In some cases(e.g., paraprotein quantification, or measurement of anti-glomerular basement membrane antibodies), repeated testing provides vital clinical information and can be justified on a frequent and individualized basis. However, many other investigations provided by immunology services provide lessvaluable information when used to aid disease monitoring rather than diagnosis. It is hoped that the data summarized here will facilitate a more evidence-based approach to repeated testing. Such information may also assist with the local implementation of demand management strategies based upon setting of minimum retesting intervals for these investigations.
文摘The morphological complexity of cells and tissues,whether normal or pathological,is characterized by two primary attributes:Irregularity and self-similarity across different scales.When an object exhibits self-similarity,its shape remains unchanged as the scales of measurement vary because any part of it resembles the whole.On the other hand,the size and geometric characteristics of an irregular object vary as the resolution increases,revealing more intricate details.Despite numerous attempts,a reliable and accurate method for quantifying the morphological features of gastrointestinal organs,tissues,cells,their dynamic changes,and pathological disorders has not yet been established.However,fractal geometry,which studies shapes and patterns that exhibit self-similarity,holds promise in providing a quantitative measure of the irregularly shaped morphologies and their underlying self-similar temporal behaviors.In this context,we explore the fractal nature of the gastrointestinal system and the potential of fractal geometry as a robust descriptor of its complex forms and functions.Additionally,we examine the practical applications of fractal geometry in clinical gastroenterology and hepatology practice.
基金supported by the National Natural Science Foundation of China,Nos.82172486(to JL),82171738(to MSZ),81671563(to MSZ)Jiangsu Provincial Commission of Health and Family Planning,No.JSWST-028(to JL)+1 种基金"Six One"Project of Jiangsu Province,No.LGY2016018(to JL)Jiangsu Provincial Personnel Department"the Great of Six Talented Man Peak"Project,No.WSW-040(to JL)。
文摘In response to spinal surgery,neurons secrete a large amount of substance P into the epidural area.Substance P is involved in macrophage differentiation and fibrotic disease.However,the specific roles and mechanisms of substance P in epidural fibrosis remain unclear.In this study,we established a mouse model of L1–L3 laminectomy and found that dorsal root ganglion neurons and the macrophages infiltrating into the wound area released sphingolipids.In vitro experiments revealed that type 1 macrophages secreted substance P,which promoted differentiation of type 1 macrophages towards a type 2 phenotype.High-throughput mRNA-seq analysis revealed that the sphingolipid metabolic pathway may be involved in the regulation of type 2 macrophages by substance P.Specifically,sphingomyelin synthase 2,a component of the sphingolipid metabolic pathway,promoted M2 differentiation in substance P-treated macrophages,while treating the macrophages with LY93,a sphingomyelin synthase 2 inhibitor,suppressed M2 differentiation.In addition,substance P promoted the formation of neutrophil extracellular traps,which further boosted M2 differentiation.Blocking substance P with the neurokinin receptor 1 inhibitor RP67580 decreased the number of M2 macrophages in the wound area after spinal surgery and alleviated epidural fibrosis,as evidenced by decreased fibronectin,α-smooth muscle actin,and collagen I in the scar tissue.These results demonstrated that substance P promotes M2 macrophage differentiation in epidural fibrosis via sphingomyelin synthase 2 and neutrophil extracellular traps.These findings provide a novel strategy for the treatment of epidural fibrosis.
基金Supported by the Key Research and Development Program of Anhui Province,No.202104J07020029.
文摘BACKGROUND F-box and leucine-rich repeat 6(FBXL6)have reportedly been associated with several cancer types.However,the role and mechanisms of FBXL6 in gastric cancer(GC)require further elucidation.AIM To investigate the effect of FBXL6 in GC tissues and cells and the underlying mechanisms.METHODS TCGA and GEO database analysis was performed to evaluate the expression of FBXL6 in GC tissues and adjacent normal tissues.Reverse transcription-quantitative polymerase chain reaction,immunofluorescence,and western blotting were used to detect the expression of FBXL6 in GC tissue and cell lines.Cell clone formation,5-ethynyl-2’-deoxyuridine(EdU)assays,CCK-8,transwell migration assay,and wound healing assays were performed to evaluate the malignant biological behavior in GC cell lines after transfection with FBXL6-shRNA and the overexpression of FBXL6 plasmids.Furthermore,in vivo tumor assays were performed to prove whether FBXL6 promoted cell proliferation in vivo.RESULTS FBXL6 expression was upregulated more in tumor tissues than in adjacent normal tissues and positively associated with clinicopathological characteristics.The outcomes of CCK-8,clone formation,and Edu assays demonstrated that FBXL6 knockdown inhibited cell proliferation,whereas upregulation of FBXL6 promoted proliferation in GC cells.Additionally,the transwell migration assay revealed that FBXL6 knockdown suppressed migration and invasion,whereas the overex pression of FBXL6 showed the opposite results.Through the subcutaneous tumor implantation assay,it was evident that the knockdown of FBXL6 inhibited GC graft tumor growth in vivo.Western blotting showed that the effects of FBXL6 on the expression of the proteins associated with the epithelial-mesenchymal transition-associated proteins in GC cells.CONCLUSION Silencing of FBXL6 inactivated the EMT pathway to suppress GC malignancy in vitro.FBXL6 can potentially be used for the diagnosis and targeted therapy of patients with GC.
文摘Correction to“Interleukin-34 promotes the proliferation and epithelialmesenchymal transition of gastric cancer cells”.In this article,we found the following error in Figure 3A:The panel image"24 h,sh-RNA1"in the AGS cells wound healing assay was incorrectly inserted during the preparation of the submission;the correct figure is provided in this correction.
基金This work was supported by the National Natural Science Foundation of China(No.82171986).
文摘Objective Fibroblast activation protein(FAP)has been widely studied and exploited for its clinical applications.One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls,making the results less specific and less confirmative.This study aimed to establish a pair of cell lines,in which one highly expresses FAP(HT1080-hFAP)and the other has no detectable FAP(HT1080-vec)as control,to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo.Methods The cell lines of the experimental group(HT1080-hFAP)and no-load group(HT1080-vec)were obtained by molecular construction of the recombinant plasmid pIRES-hFAP.The expression of hFAP in HT1080 cells was detected by PCR,Western blotting and flow cytometry.CCK-8,Matrigel transwell invasion assay,scratch test,flow cytometry and immunofluorescence were used to verify the physiological function of FAP.The activities of human dipeptidyl peptidase(DPP)and human endopeptidase(EP)were detected by ELISA in HT1080-hFAP cells.PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP.Results RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells.Flow cytometry confirmed that nearly 95%of the HT1080-hFAP cells were FAP positive.The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions,including internalization,proliferation-,migration-,and invasion-promoting activities.The HT1080-hFAP xenografted tumors in nude mice bound and took up^(68)GA-FAPI-04 with superior selectivity.High image contrast and tumor-organ ratio were obtained by PET imaging.The HT1080-hFAP tumor retained the radiotracer for at least 60 min.Conclusion This pair of HT1080 cell lines was successfully established,making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.
文摘T lymphocytes,the main participants of cellular immunity,can express a variety of surface molecules and form different lymphocyte subsets under the induction of different factors to play the functions of immune regulation and immune killing.Studies have shown that platelets play a crucial role in maintaining the stable differentiation of lymphocytes and the balance in immunomodulation.Therefore,it is necessary to study the effect of platelets on lymphocytes in vitro to better understand the role of platelets in the immune system and broaden the application of adoptive immunotherapy.Methods:Cell counting and microscopic observation were used to detect the effect of activated platelets on lymphocyte proliferation in vitro;Flow cytometry was used to detect whether changes in platelet activity affect the proportion of lymphocyte subpopulations in vitro,and to detect differences in the expression of granzyme B;lactate dehydrogenase assay(LDH)was used to determine the difference in lymphocyte killing activity caused by platelet activity in vitro.Results:This was the first to promote lymphocyte proliferation through the expression or release of certain molecules in vitro,demonstrating that platelet activation is one of the key factors.Secondly,activated platelets or inactivated platelets promoted lymphocyte subset differentiation by enhancing the proportion of CD3+CD8+T lymphocytes(CTL cells)but had a slight effect on the proportion of CD3+CD4+T(Th cells)and CD4+CD25+T lymphocytes(Treg cells).Then,it was found that either activated platelets or inactivated platelets down-regulated the proportion of natural killer(NK)T lymphocytes,while activated platelets significantly enhance the proportion of NK lymphocytes.Therefore,by further detecting the killing activity of PBMCs treated with platelets,it was found that activated platelets promoted the extensive anti-tumor activity of lymphocytes and significantly increased the expression of granzyme B.Conclusion:Our results suggest that activated platelets promote lymphocyte proliferation,optimize lymphocyte subpopulation ratio,and promote cytotoxic effect of lymphocytes in vitro,which may provide a new strategy for optimizing the adoptive immunotherapy culture system and improving its efficacy.
基金Supported by the National Natural Science Foundation of China(No.82270893)Joint Fund of Health Committee of Hubei Province(No.WJ2019-16).
文摘AIM:To investigate the role of autophagy inhibitor 3-methyladenine(3-MA)on a diabetic mice model(DM)and the potential mechanism.METHODS:Male C57BL/6J mice were randomly divided into a normal control group(NC group)and an DM group.DM were induced by multiple low-dose intraperitoneal injection of streptozotocin(STZ)60 mg/kgd for 5 consecutive days.DM mice were randomly subdivided into untreated group(DM group),3-MA(10 mg/kgd by gavage)treated group(DM+3-MA group)and chloroquine(CQ;50 mg/kg by intraperitoneal injection)treated group(DM+CQ group).The fasting blood glucose(FBG)levels were recorded every week.At the end of experiment,retinal samples were collected.The expression levels of pro-apoptotic proteins cleaved caspase-3,cleaved poly ADP-ribose polymerase 1(PARP1)and Bax,anti-apoptotic protein Bcl-2,fibrosisassociated proteins Fibronectin and type 1 collagenα1 chain(COL1A1),vascular endothelial growth factor(VEGF),inflammatory factors interleukin(IL)-1βand tumor necrosis factor(TNF)-α,as well as autophagy related proteins LC3,Beclin-1 and P62 were determined by Western blotting.The oxidative stress indicators 8-hydroxydeoxyguanosine(8-OHdG)and malondialdehyde(MDA)were detected by commercial kits.RESULTS:Both 3-MA and CQ had shor t-term hypoglycemic effect on FBG and reduced the expression of VEGF and inflammatory factors IL-1βand TNF-αin DM mice.3-MA also significantly alleviated oxidative stress indicators 8-OHdG and MDA,decreased the expression of fibrosisrelated proteins Fibronectin and COL1A1,pro-apoptotic proteins cleaved caspase-3,cleaved PARP1,as well as the ratio of Bax/Bcl-2.CQ had no significant impact on the oxidative stress indicators,fibrosis,and apoptosis related proteins.The results of Western blotting for autophagy related proteins showed that the ratio of LC3 II/LC3 I and the expression of Beclin-1 in the retina of DM mice were decreased by 3-MA treatment,and the expression of P62 was further increased by CQ treatment.CONCLUSION:3-MA has anti-apoptotic and anti-fibrotic effects on the retina of DM mice,and can attenuate retinal oxidative stress,VEGF expression and the production of inflammatory factors in the retina of DM mice.The underlying mechanism of the above effects of 3-MA may be related to its inhibition of early autophagy and hypoglycemic effect.
文摘BACKGROUND Tocilizumab is a humanized monoclonal antibody against the interleukin-6(IL-6)receptor that is commonly used to treat large vessel vasculitis and antineutrophil cytoplasmic antibody-related small vessel vasculitis.However,tocilizumab in combination with glucocorticoids for successfully treating granulomatosis with polyangiitis(GPA)has rarely been reported.CASE SUMMARY Here,we report a 40-year-old male patient who suffered GPA for 4 years.He was treated with multiple rounds of drugs,including cyclophosphamide,Tripterygium wilfordii,mycophenolate mofetil,and belimumab,with no improvement.In addition,he exhibited persistently high IL-6 levels.After tocilizumab treatment,his symptoms improved,and his inflammatory marker levels returned to normal.CONCLUSION Tocilizumab may be effective for treating GPA.
基金The present study was supported by the National Natural Science Foundation of China(grant numbers:81902067 and 82078189)the Medical Scientific Research Foundation of Guangdong Province(grant number:A2019502)+2 种基金the Shenzhen Science and Technology Innovation Committee(grant numbers:JCY20180305124849781 and 20200812211704001)the SZU Top Ranking Project(grant number:86000000210)the Hospital Project of Huazhong University of Science and Technology Union Shenzhen Hospital(grant number:2021042).
文摘Background:Amarogentin(AMA)is a secoiridoid glycoside extracted from Swertia and Gentiana roots and exhibits many biological effects such as antioxidative,antiinflammatory,and antitumor activities.Atopic dermatitis(AD)is a chronic inflammatory skin disease caused by disorders in the regulation of multiple inflammatory cytokines.No effective cure has been found for AD now.Methods:We constructed the HaCat and splenocyte model and tested the inhibitory effect of AMA on IL-4,IL-6,and IL-13 secretions using enzyme-linked immunosorbent assay(ELISA).The AD mouse model was constructed and treated with AMA,the severity of skin lesions was observed,epidermal tissue was collected,and epidermal thickness and mast cell infiltration were observed using hematoxylin and eosin and toluidine blue staining,respectively.The expression of kallikrein-related peptidase 7(KLK7)and filaggrin(FLG)was detected using immunostaining and Western blot analysis.The mRNA expression of KLK7 and FLG was detected using quantitative polymerase chain reaction(qPCR).Blood immunoglobulin E(IgE)secretion was detected.Results:AMA inhibited IL-6 secreted by tumor necrosis factor(TNF)-α-induced HaCaT cells and reduced IL-4 and IL-13 secreted by phytohemagglutinin(PHA)-induced primary cells in the mice spleen.It was found that the treatment of AMA with 2,4-din itrochlorobenzene-induced AD-like mice could promote the recovery of dermatitis,reduce the score of dermatitis severity and the scratching frequency,treat the skin lesions,reduce the epidermal thickness,decrease the infiltration of mast cells,reduce the IgE level in serum,decrease the expression levels of AD-related cytokines,increase protein and mRNA expression of FLG,and reduce the protein and mRNA expression of KLK7 in the skin tissues of AD-like mice.Conclusion:In conclusion,AMA inhibits inflammatory response at the cellular level,and AMA reduces the validation response of specific dermatitis mice,relieves pruritus,and repairs the damaged skin barrier.
基金supported by the National Natural Science Foundation of China (U20A20375,82372779,82373279,and 82373283)the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A)。
文摘Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because neutrophils are short-lived,terminally differentiated,and do not proliferate.Although traditionally considered anti-bacterial cells,research has demonstrated the multifaceted roles of neutrophils in cancer.Studies have suggested that neutrophils with normal functions co-exist with pathologically activated neutrophils that support tumorprogression and metastasis in the context of cancer.
基金supported in part by the Japan Agency for Medical Research and Development (AMED) (JP22ek0410073 and JP23ek0410108h0001)AMED-CREST (JP22gm1210008)+7 种基金AMED-PRIME (JP22gm6310029h0001)the AMED Japan Initiative for Worldleading Vaccine Research and Development Centers (233fa627001h0002)Grants-in-Aid for Scientific Research S (21H05046)Scientific Research B (21H03104,22H03195,and 22H02844)Challenging Research (21K18254)the JST FOREST Program (JPMJFR205Z)supported by a JSPS Research Fellowship for Young Scientists (19J21942)a JSPS Postdoctoral Fellowships for Overseas Researchers (22F22108)。
文摘The bony skeleton is continuously renewed throughout adult life by the bone remodeling process,in which old or damaged bone is removed by osteoclasts via largely unknown mechanisms.Osteocytes regulate bone remodeling by producing the osteoclast differentiation factor RANKL(encoded by the TNFSF11 gene).However,the precise mechanisms underlying RANKL expression in osteocytes are still elusive.Here,we explored the epigenomic landscape of osteocytic cells and identified a hitherto-undescribed osteocytic cell-specific intronic enhancer in the TNFSF11 gene locus.Bioinformatics analyses showed that transcription factors involved in cell death and senescence act on this intronic enhancer region.Single-cell transcriptomic data analysis demonstrated that cell death signaling increased RANKL expression in osteocytic cells.Genetic deletion of the intronic enhancer led to a high-bone-mass phenotype with decreased levels of RANKL in osteocytic cells and osteoclastogenesis in the adult stage,while RANKL expression was not affected in osteoblasts or lymphocytes.These data suggest that osteocytes may utilize a specialized regulatory element to facilitate osteoclast formation at the bone surface to be resorbed by linking signals from cellular senescence/death and RANKL expression.
文摘Background: Resistance to cisplatin (DDP) leads to poor prognosis in patients with Lung Adenocarcinoma (LUAD) and limits its clinical application. It has been confirmed that autophagy promotes chemoresistance and, therefore, novel strategies to reverse chemoresistance by regulating autophagy are desperately needed. Methods: The differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) between A549 and A549/DDP cell lines were identified using the limma package in R, after gene expression profiles were obtained from Gene Expression Omnibus (GEO) database. By combining Autophagy-Related Genes (ARGs) from Human Autophagy Database (HADb), the interactions lncRNA-miRNAs and the interactions miRNAs-mRNAs respectively predicted by miRcode and miRDB/Targetscan database, the autophagy-related ceRNA network was constructed. Then, extraction of ceRNA subnetwork and Cox regression analyses were performed. A prognosis-related ceRNA subnetwork was constructed, and the upstream Transcription Factors (TFs) regulating lncRNAs were predicted by the JASPAR database. Finally, the expression patterns of candidate genes were further verified by quantitative real-time polymerase chain reaction (qRT-PCR) experiments. Results: A total of 3179 DEmRNAs, 180 DEmiRNAs, and 160 DElncRNAs were identified, and 35 DEmRNAs were contained in the HADb. Based on the ceRNA hypothesis, we established a ceRNA network, including 10 autophagy-related DEmRNAs, 9 DEmiRNAs, and 14 DElncRNAs. Then, LINC00520, miR-181d, and BCL2 were identified to construct a risk score model, which was confirmed to be a well-predicting prognostic factor. Furthermore, 5 TF ZNF family members were predicted to regulate LINC00520, whereas the RT-PCR results showed that the 5 ZNFs were consistent with the bioinformatics analysis. Finally, a ZNF regulatory LINC00520/miR-181d/BCL2 ceRNA subnetwork was constructed. Conclusions: An ZNFs/LINC00520/miR-181d/BCL2 axis as a novel network in DDP-resistant LUAD has been constructed successfully, which may provide potential therapeutic targets for LUAD.
