Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the pa...Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the past decades,their invasiveness and limited spatial resolution hinder the characterization of fibroblasts in a single cell.Here,taking mouse embryonic fibroblasts(MEFs)as an example,we propose a novel noninvasive approach to investigate the compositional distribution of MEFs at the single-cell scale via terahertz(THz)nanos⁃copy.Compared to the topological morphology,THz nano-imaging enables the component-based visualization of MEFs,such as the membrane,cytoplasm,nucleus,and extracellular vesicles(EVs).Notably,we demonstrate the real-space observation of the influence of rapamycin treatment on the increase of EVs in MEFs.Moreover,the line-cut and area-statistical analysis establishes the relationship between the topological morphology and the THz near-field amplitudes for different cellular components of MEFs.This work provides a new pathway to char⁃acterize the effects of pharmaceutical treatments,with potential applications in disease diagnosis and drug devel⁃opment.展开更多
Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a d...Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.展开更多
Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown rem...Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.展开更多
Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer prog...Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer progression,therapy resistance,and metastasis.The TME is a complex ecosystem consisting of stromal and immune cells,extracellular matrix(ECM),and various signaling molecules that dynamically interact with tumor cells.Cancer-associated fibro-blasts remodel the ECM and secrete growth factors that promote tumor growth and invasion.Immune cells,such as tumor-associated macrophages,regulatory T cells,and myeloid-derived suppressor cells,often contribute to an immunosup-pressive environment that hinders anti-tumor immune responses.The ECM pro-vides structural support and acts as a reservoir for signaling molecules that in-fluence cancer cell behavior.These components evolve together with tumor cells,facilitating immune evasion,therapy resistance,and epithelial-to-mesenchymal transition,which promotes metastasis.Understanding these interactions is nece-ssary to develop novel therapeutic strategies that target both tumor and micro-environmental components.This minireview highlights the key stromal and immune elements within the breast cancer microenvironment,discussing their individual and collective roles in tumor progression and clinical outcomes,while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.展开更多
Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor pro...Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor progression and therapy resistance.Senescent CAFs,which exhibit a senescence-associated secretory phenotype(SASP),further exacerbate cancer growth through inflammatory cytokine secretion.This editorial highlights a study by Jiang et al,which investigates the potential of resveratrol,a natural polyphenolic compound,in targeting senescent CAFs to inhibit pancreatic cancer progression.The study demonstrates that resveratrol reduces senescent CAFs and downregulates SASP factors,thereby disrupting the pro-tumorigenic activities of these cells.Resveratrol’s ability to modulate the TME,induce apoptosis in pancreatic cancer cells,and inhibit metastasis underscores its potential as an adjunctive therapy.This research offers promising insights into novel strategies for improving therapeutic outcomes in pancreatic cancer by targeting the TME and senescent CAFs.展开更多
The resistance to cancer treatment is a major clinical obstacle,being strongly influenced by the tumor microen-vironment(TME).Cancer-associated fibroblasts(CAFs)are critical elements of the TME.CAFs are heterogeneous ...The resistance to cancer treatment is a major clinical obstacle,being strongly influenced by the tumor microen-vironment(TME).Cancer-associated fibroblasts(CAFs)are critical elements of the TME.CAFs are heterogeneous and are activated through diverse pathways.These CAFs engage in reciprocal interactions with tumor cells,driv-ing tumor progression and therapeutic resistance.In this review,we discuss the role of CAFs in the development of tumor resistance to chemotherapy,radiotherapy,targeted therapy,and immunotherapy.Besides,we sum-marize recent clinical trials in CAF-targeted therapies.The development of resistance involves physical barrier formation,metabolic reprogramming,exosome release,DNA repair,bypass pathway activation,multidrug resis-tance protein upregulation,and immune checkpoint inhibition.Challenges remain in addressing drug resistance despite the therapeutic potential of targeting CAFs:the cellular origins of CAFs need to be clarified,and their limited clinical applications need to be increased.Future studies should focus on elucidating the reasons for CAF heterogeneity,developing precise targeting strategies,and validating the clinical safety and efficacy of CAF-based therapies to overcome treatment resistance and improve patient outcomes.展开更多
Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,p...Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,pyruvate dehydrogenase kinase 1(PDK1),hexokinase 2(HK2),and glucose transporter 1(GLUT1)in normal human skin fibroblasts(NFs)and KFs were analyzed using RT-qPCR analyses and western blotting.Cellular proliferation,invasion,and migration were evaluated using Transwell,wound healing,5-ethynyl-2′-deoxyuridine(EdU),and cell counting kit-8(CCK-8)assays.The extracellular acidification rate(ECAR)was measured using the XF96 Extracellular Flux Analyzer.Glucose uptake and ATP production were measured using specific assay kits.The expression ofα-smooth muscle actin(α-SMA)was determined by immunofluorescence assays.The expression levels of collagen I,α-smooth muscle actin(α-SMA),fibronectin(FN),and components of the phosphoinositide-3-kinase/protein kinase B(PI3K/AKT)signaling pathway were quantified by western blotting.Results:The expression of TRIM32 and glycolysis-related proteins was significantly elevated in KFs compared to that in NFs.TRIM32 overex-pression enhanced the proliferation,invasion,and migration of KFs,as well as extracellular matrix(ECM)deposition,glucose uptake,and ATP production,while TRIM32 silencing produced the opposite effects.The glycolysis inhibitor,2-deoxy-glucose(2-DG),significantly suppressed the biological functions of KFs;however,TRIM32 overexpression effectively counteracted the inhibitory effects of 2-DG.TRIM32 activated the PI3K/AKT signaling pathway in KFs.The PI3K inhibitor LY294002 decreased cellular glycolysis,with TRIM32 overexpression mitigated these inhibitory effects.Conclusion:This study demonstrated that TRIM32 enhances the viability of KFs by regulating glycolytic activity,potentially mediated via the PI3K/AKT signaling pathway,thereby suggesting novel therapeutic approaches for the treatment of keloids.展开更多
Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous ...Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous system,and we have focused on cancer-associated fibroblasts(CAFs)for decades,it’s imperative to elucidate the impact of CAFs on SCs in PNI+OSCCs.We describe a disease progression-driven shift of PNI−towards PNI+during the progression of early-stage OSCC(31%,n=125)to late-stage OSCC(53%,n=97),characterized by abundant CAFs and nerve demyelination.CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro,and this involved up-regulated ER stress and decreased MAPK signals.Moreover,CAFs also aggravated the paralysis of the hind limb and PNI in vivo.Unexpectedly,leukemia inhibitory factor(LIF)was exclusively expressed on CAFs and up-regulated in metastatic OSCC.The LIF inhibitor EC330 restored CAF-induced SC inactivation.Thus,OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.展开更多
Objectives:Recently,pre-/post-operative Local Estrogen Therapy(LET)has shown effectiveness in alleviating Pelvic Organ Prolapse(POP)symptoms in clinical therapy.However,there is a lack of scientific evidence to suppor...Objectives:Recently,pre-/post-operative Local Estrogen Therapy(LET)has shown effectiveness in alleviating Pelvic Organ Prolapse(POP)symptoms in clinical therapy.However,there is a lack of scientific evidence to support these claims.Therefore,we aimed to explore the anti-senescence effects and mechanisms of 17β-estradiol(E2)on POP-derived fibroblasts.Methods:The primary fibroblast cells were isolated and cultured fromthe surgical samples of postmenopausal women clinically diagnosed with pelvic organ prolapse(POP)at stages III-IV(quantified using the POP-Q system)and without any other treatment within 6 months.(n=12,age 50–75).Colorimetric Cell Counting Kit(CCK-8)assay and Senescence-Associated-β-Galactosidase(SA-β-Gal)staining were used to test the cell proliferative capacity and the senescence rate.Western blotting(WB)was used to detect the expression of Collagen Type I(COL-I),Collagen Type III(COL-III),Cyclin-dependent kinase 4 inhibitor A(p16INK4a),Cyclin-dependent kinase inhibitor 1A(p21),Tumor Protein 53(p53),Sirtuin 1(SIRT-1)and Microtubule-associated protein 1A/1B-light chain 3-I/II(LC3-I/II)protein.A transmission ElectronMicroscope(TEM)was used to observe the ultrastructure of fibroblasts.Results:The results showed that E2 significantly promoted the proliferation of fibroblasts derived from POP and reduced the staining rate of SA-β-Gal.It markedly enhanced the extracellular matrix proteins COL-I and COL-III,accompanied by inhibition of the senescent maker p16INK4a.Additionally,our results improved the cells’autophagy and metabolic activity.Additionally,our results indicate the anti-senescence mechanism of E2 through the mediated SIRT-1/p53/p21 axis pathway.Conclusion:We provide preliminary evidence for the anti-aging effects and mechanisms of E2 on POP,hoping to provide a theoretical basis for estrogen against POP senescence and guide the clinical application and local administration of estrogen in POP treatment.展开更多
Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CA...Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.展开更多
AIM:To explore the effect of co-host non-coding RNA(ncRNA)MIR503HG/miR-503-5p on the angiogenesis of pterygium.METHODS:MIR503HG/miR-503-5p/fibroblast growth factor 2(FGF2)expression levels in pterygium tissues,control...AIM:To explore the effect of co-host non-coding RNA(ncRNA)MIR503HG/miR-503-5p on the angiogenesis of pterygium.METHODS:MIR503HG/miR-503-5p/fibroblast growth factor 2(FGF2)expression levels in pterygium tissues,control conjunctival tissues,and human pterygium fibroblasts(HPF)were examined by reverse transcription-polymerase chain reaction(qRT-PCR)and immunohistochemical methods.Effects of MIR503HG/miR-503-5p on low molecular weight FGF2(LWM FGF2),migration and angiogenesis of human retinal microvascular endothelial cells(HRMEC)were determined in an HPF and HRMEC co-culture model using Western blots,wound healing assay,Matrigel-based tube formation assay,and Transwell assay.RESULTS:MIR503HG/miR-503-5p/FGF2 pathway was actively increased in pterygium tissue and there was a negative correlation between the expression of the two ncRNAs.FGF2 expression level was positively correlated with MIR503HG and negatively correlated with miR-503-5p.Overexpressed MIR503HG/miR-503-5p did not affect the migration and angiogenesis of HRMECs cultured separately,but significantly affected migration and angiogenesis of HRMEC in HPF and HRMEC co-culture models.Western blotting revealed that MIR503HG/miR-503-5p overexpression significantly increased LMW FGF2 expression in HPF.CONCLUSION:MIR503HG/miR-503-5p inhibits HRMEC migration and angiogenic function by interfering with the interaction between HPF and endothelial cells via reducing LMW FGF2 in HPF.展开更多
BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogen...BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.展开更多
BACKGROUND Pelvic organ prolapse(POP)involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity,and vaginal structure is an essential factor.In POP,the vaginal walls exhibit abnormal collagen d...BACKGROUND Pelvic organ prolapse(POP)involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity,and vaginal structure is an essential factor.In POP,the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions.The intricate etiology of POP and the prohibition of trans-vaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development.Human umbilical cord mesenchymal stromal cells(hucMSCs)present limitations,but their exosomes(hucMSC-Exo)are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.suppressed inflammation in POP group fibroblasts,stimulated primary fibroblast growth,and elevated collagen I(Col1)production in vitro.High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11(MMP11)expression.CONCLUSION HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro.Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression.HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.展开更多
Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is ...Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.展开更多
Background:A differential gene,triggering receptor expressed on myeloid cells 1(TREM1),was identified in blood sequencing datasets from myocardial infarction patients and healthy controls.Myocardialfibrosis following my...Background:A differential gene,triggering receptor expressed on myeloid cells 1(TREM1),was identified in blood sequencing datasets from myocardial infarction patients and healthy controls.Myocardialfibrosis following myocardial infarction significantly contributes to cardiac dysfunction.Objectives:This study aimed to unveil the intrinsic regulatory mechanism of TREM1 in myocardialfibrosis.Methods:Mimicking pathology by angiotensin II(Ang II)treatment of human cardiacfibroblasts(HCFs),the impacts of TREM1 knockdown on its proliferation,migration,and secretion of the pro-fibrotic matrix were identified.Using the Human Transcription Factor Database(HumanTFDB)website,lysine-specific demethylase 5B(KDM5B)was found to bind to the TREM1 promoter,which was further validated through luciferase reporter and chromatin immunoprecipitation(ChIP).By promoting KDM5B overexpression,its effect on the regulation of TREM1 was examined.Results:TREM1 knockdown suppressed the proliferation,migration,and secretion of the pro-fibrotic matrix in HCFs upon Ang II treatment.KDM5B bound to the TREM1 promoter and upregulated its transcriptional expression.Furthermore,KDM5B overexpression reversed the regulation of the above cellular phenotypes by TREM1 knockdown.Conclusion:This study sheds light on the positive regulation of TREM1 by KDM5B,demonstrating their role in promoting myocardialfibrosis.Thisfinding provides a theoretical foundation for understanding disease pathology and potentially advancing the development of new targeted therapies.展开更多
Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the ...Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.展开更多
Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associ...Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.展开更多
Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and ...Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.展开更多
Objective:Long-term effects of chronic skin ulcers(CSU)include diminished physical and emotional well-being,an increased risk of cancer in more severe cases,and significant social costs due to inadequate treatment.Pin...Objective:Long-term effects of chronic skin ulcers(CSU)include diminished physical and emotional well-being,an increased risk of cancer in more severe cases,and significant social costs due to inadequate treatment.Pinian powder is a topical Chinese medicine created by the late renowned traditional Chinese medicine(TCM)master WEN Zhuozhi,with a long history of clinical use,and has been proven effective in treating various CSU.However,its exact mechanism of action is unknown.This study aims to investigate the effects and mechanisms of Pinian powder on chronic skin ulcers.Methods:A mouse model with skin defects and foreign body implantation was developed.Mice were divided into five groups:Control group,model control group,Pinian powder(PNP)group,inhibitor(MSAB)group,and PNP with inhibitor group.Treatments included saline washes,daily PNP application,intraperitoneal MSAB injection,and combined treatment.Wound healing was assessed on day 1,day 3,day 7,and day 14 using photography and software.Histological and Western blotting assays evaluated epidermal repair and protein expression related to wound healing.Immunofluorescence staining detected specific protein localization and expression.Statistical analysis was conducted using GraphPad Prism software,with significance set at P<0.05.Results:Clinical cases have demonstrated that Pinian powder can influence epidermal migration,reduce wound secretion,and stimulate granulation tissue formation in chronic skin ulcers.In vivo experiments,Pinian powder is applied externally to total skin defects and added to foreign body implantation in a mouse model of CSU.It activates the Wnt4/β-catenin signaling pathway,increases the expression of crucial proteins of fibroblast proliferation and keratinocyte proliferation,such asα-smooth muscle actin(α-SMA),Ki-67,K10,and K14,promotes wound healing.After the action ofβ-catenin inhibitor MSAB,the effect of Pinian powder was reversed.Conclusions:Pinian powder can promote the proliferation of keratinocytes and fibroblasts by activating the Wnt4/β-catenin signaling pathway and accelerating the wound healing of CSU.展开更多
[Objective] The aim of this study was to establish the in vitro culture system of chicken fibroblasts.[Method] Tissue explant method and enzymatic digestion method were used to separate and culture chicken skin fibrob...[Objective] The aim of this study was to establish the in vitro culture system of chicken fibroblasts.[Method] Tissue explant method and enzymatic digestion method were used to separate and culture chicken skin fibroblasts respectively.The rate of cell growth,cryopreservation and recovery were compared.[Result] The primary chicken fibroblasts prepared by enzymatic digestion grew faster and converged together to form monolayer on 5 d post preparation;the passage cells prepared by these 2 methods grew at similar speed and formed monolayer within 2-3 d;homogeneous fibroblasts could be obtained by trypsin digestion and repeated attachment for 3-4 passages;there were 75%-80% of cells survived after cryopreservation and recovery;the growth curves of embryonic fibroblasts and skin fibroblasts were all normal and the two kind of cells still retained the normal number of chromosomes even at the twelfth passage.[Conclusion] The feeder layer cells needed for establishing ES cell lines could be obtained by culturing chicken fibroblasts through both tissue explant method and enzymatic digestion method.This study provided a basis for the successful establishment of ES cell lines.展开更多
基金Supported by the National Natural Science Foundation of China(61988102,62401113,92463308)the National Safety Academic Fund(U2130113)+2 种基金the Sichuan Science and Technology Program(2022JDJQ0065)the Chengdu Science and Technology Program(2024-YF05-01803-SN)the Sichuan Provincial Administration of Traditional Chinese Medicine(2024MS512)and the from Key Laboratory of THz Technology,Ministry of Education.
文摘Fibroblasts support a broad range of essential organ functions via microarchitectural,biomechanical,and biochemical cues.Despite great advances in fluorescence,photoacoustic conversion,and Raman scattering over the past decades,their invasiveness and limited spatial resolution hinder the characterization of fibroblasts in a single cell.Here,taking mouse embryonic fibroblasts(MEFs)as an example,we propose a novel noninvasive approach to investigate the compositional distribution of MEFs at the single-cell scale via terahertz(THz)nanos⁃copy.Compared to the topological morphology,THz nano-imaging enables the component-based visualization of MEFs,such as the membrane,cytoplasm,nucleus,and extracellular vesicles(EVs).Notably,we demonstrate the real-space observation of the influence of rapamycin treatment on the increase of EVs in MEFs.Moreover,the line-cut and area-statistical analysis establishes the relationship between the topological morphology and the THz near-field amplitudes for different cellular components of MEFs.This work provides a new pathway to char⁃acterize the effects of pharmaceutical treatments,with potential applications in disease diagnosis and drug devel⁃opment.
基金Supported by National Key Research and Development Program Project,No.2017YFC1700601Shaanxi Provincial Key Research and Development Program Project,No.2018SF-350Leading Talents in Scientific and Technological Innovation of the Shaanxi Province Special Support Plan,No.00518。
文摘Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival rate.This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease progression.In particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies.This study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens.Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.
基金supported by the grants provided by Zhuhai People's Hospital,China(Grant No.:2021KYQD-03)the National Natural Science Foundation of China(Grant No.:22176016).
文摘Fibroblast activation protein(FAP)is overexpressed in cancer-associated fibroblasts across various cancer types.Numerous radiolabeled FAP inhibitors(FAPIs)(Fig.S1A)currently under clinical investigation have shown remarkable potential in cancer theranostics.
文摘Breast cancer is one of the most common malignancies worldwide and is a major cause of cancer-related mortality among women.Beyond tumor cells,the tumor microenvironment(TME)also plays an important role in cancer progression,therapy resistance,and metastasis.The TME is a complex ecosystem consisting of stromal and immune cells,extracellular matrix(ECM),and various signaling molecules that dynamically interact with tumor cells.Cancer-associated fibro-blasts remodel the ECM and secrete growth factors that promote tumor growth and invasion.Immune cells,such as tumor-associated macrophages,regulatory T cells,and myeloid-derived suppressor cells,often contribute to an immunosup-pressive environment that hinders anti-tumor immune responses.The ECM pro-vides structural support and acts as a reservoir for signaling molecules that in-fluence cancer cell behavior.These components evolve together with tumor cells,facilitating immune evasion,therapy resistance,and epithelial-to-mesenchymal transition,which promotes metastasis.Understanding these interactions is nece-ssary to develop novel therapeutic strategies that target both tumor and micro-environmental components.This minireview highlights the key stromal and immune elements within the breast cancer microenvironment,discussing their individual and collective roles in tumor progression and clinical outcomes,while emphasizing emerging therapeutic approaches aiming to reprogram the TME to improve treatment efficacy.
基金Supported by National Natural Science Foundation of China,No.82304151.
文摘Pancreatic cancer is a highly aggressive malignancy with a poor prognosis and limited therapeutic options.The tumor microenvironment(TME),including cancer-associated fibroblasts(CAFs),plays a pivotal role in tumor progression and therapy resistance.Senescent CAFs,which exhibit a senescence-associated secretory phenotype(SASP),further exacerbate cancer growth through inflammatory cytokine secretion.This editorial highlights a study by Jiang et al,which investigates the potential of resveratrol,a natural polyphenolic compound,in targeting senescent CAFs to inhibit pancreatic cancer progression.The study demonstrates that resveratrol reduces senescent CAFs and downregulates SASP factors,thereby disrupting the pro-tumorigenic activities of these cells.Resveratrol’s ability to modulate the TME,induce apoptosis in pancreatic cancer cells,and inhibit metastasis underscores its potential as an adjunctive therapy.This research offers promising insights into novel strategies for improving therapeutic outcomes in pancreatic cancer by targeting the TME and senescent CAFs.
文摘The resistance to cancer treatment is a major clinical obstacle,being strongly influenced by the tumor microen-vironment(TME).Cancer-associated fibroblasts(CAFs)are critical elements of the TME.CAFs are heterogeneous and are activated through diverse pathways.These CAFs engage in reciprocal interactions with tumor cells,driv-ing tumor progression and therapeutic resistance.In this review,we discuss the role of CAFs in the development of tumor resistance to chemotherapy,radiotherapy,targeted therapy,and immunotherapy.Besides,we sum-marize recent clinical trials in CAF-targeted therapies.The development of resistance involves physical barrier formation,metabolic reprogramming,exosome release,DNA repair,bypass pathway activation,multidrug resis-tance protein upregulation,and immune checkpoint inhibition.Challenges remain in addressing drug resistance despite the therapeutic potential of targeting CAFs:the cellular origins of CAFs need to be clarified,and their limited clinical applications need to be increased.Future studies should focus on elucidating the reasons for CAF heterogeneity,developing precise targeting strategies,and validating the clinical safety and efficacy of CAF-based therapies to overcome treatment resistance and improve patient outcomes.
文摘Objectives:The present study investigated whether Tripartite Motif-Containing Protein 32(TRIM32)contributes to the aberrant activation of keloid fibroblasts(KFs)via glycolysis.Methods:The expression levels of TRIM32,pyruvate dehydrogenase kinase 1(PDK1),hexokinase 2(HK2),and glucose transporter 1(GLUT1)in normal human skin fibroblasts(NFs)and KFs were analyzed using RT-qPCR analyses and western blotting.Cellular proliferation,invasion,and migration were evaluated using Transwell,wound healing,5-ethynyl-2′-deoxyuridine(EdU),and cell counting kit-8(CCK-8)assays.The extracellular acidification rate(ECAR)was measured using the XF96 Extracellular Flux Analyzer.Glucose uptake and ATP production were measured using specific assay kits.The expression ofα-smooth muscle actin(α-SMA)was determined by immunofluorescence assays.The expression levels of collagen I,α-smooth muscle actin(α-SMA),fibronectin(FN),and components of the phosphoinositide-3-kinase/protein kinase B(PI3K/AKT)signaling pathway were quantified by western blotting.Results:The expression of TRIM32 and glycolysis-related proteins was significantly elevated in KFs compared to that in NFs.TRIM32 overex-pression enhanced the proliferation,invasion,and migration of KFs,as well as extracellular matrix(ECM)deposition,glucose uptake,and ATP production,while TRIM32 silencing produced the opposite effects.The glycolysis inhibitor,2-deoxy-glucose(2-DG),significantly suppressed the biological functions of KFs;however,TRIM32 overexpression effectively counteracted the inhibitory effects of 2-DG.TRIM32 activated the PI3K/AKT signaling pathway in KFs.The PI3K inhibitor LY294002 decreased cellular glycolysis,with TRIM32 overexpression mitigated these inhibitory effects.Conclusion:This study demonstrated that TRIM32 enhances the viability of KFs by regulating glycolytic activity,potentially mediated via the PI3K/AKT signaling pathway,thereby suggesting novel therapeutic approaches for the treatment of keloids.
基金supported by the National Natural Science Foundation of China(82373037 and 82403486)the Natural Science Foundation of Jiangsu Province(BK20230054 and BK20230161)+1 种基金the China Postdoctoral Science Foundation(2023M741766)the Nanjing Medical Science and Technology Development Foundation,Nanjing Department of Health(YKK21182 and JQX23010).
文摘Perineural invasion(PNI)by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma(OSCC).Since Schwann cells(SCs)and fibroblasts maintain the physiological homeostasis of the peripheral nervous system,and we have focused on cancer-associated fibroblasts(CAFs)for decades,it’s imperative to elucidate the impact of CAFs on SCs in PNI+OSCCs.We describe a disease progression-driven shift of PNI−towards PNI+during the progression of early-stage OSCC(31%,n=125)to late-stage OSCC(53%,n=97),characterized by abundant CAFs and nerve demyelination.CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro,and this involved up-regulated ER stress and decreased MAPK signals.Moreover,CAFs also aggravated the paralysis of the hind limb and PNI in vivo.Unexpectedly,leukemia inhibitory factor(LIF)was exclusively expressed on CAFs and up-regulated in metastatic OSCC.The LIF inhibitor EC330 restored CAF-induced SC inactivation.Thus,OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
基金supported by 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21048)Foundation of Sichuan Provincial Science and Technology Program(2022JDR0091,2023NSFSC0004,2023NSFSC0639,2023NSFSC1742)+5 种基金Cooperation Project for Academician&Expert Workstation(HXYS20001)Sichuan University Education Foundation(0040206107011)National Natural Science Foundation of China(Nos.82371883,82402191)China Postdoctoral Science Foundation(2023M732456)Postdoctor Research Fund of West China Hospital(2024HXBH142)Sichuan University“From 0 to 1”Innovation Research Project(2023SCUH0056).
文摘Objectives:Recently,pre-/post-operative Local Estrogen Therapy(LET)has shown effectiveness in alleviating Pelvic Organ Prolapse(POP)symptoms in clinical therapy.However,there is a lack of scientific evidence to support these claims.Therefore,we aimed to explore the anti-senescence effects and mechanisms of 17β-estradiol(E2)on POP-derived fibroblasts.Methods:The primary fibroblast cells were isolated and cultured fromthe surgical samples of postmenopausal women clinically diagnosed with pelvic organ prolapse(POP)at stages III-IV(quantified using the POP-Q system)and without any other treatment within 6 months.(n=12,age 50–75).Colorimetric Cell Counting Kit(CCK-8)assay and Senescence-Associated-β-Galactosidase(SA-β-Gal)staining were used to test the cell proliferative capacity and the senescence rate.Western blotting(WB)was used to detect the expression of Collagen Type I(COL-I),Collagen Type III(COL-III),Cyclin-dependent kinase 4 inhibitor A(p16INK4a),Cyclin-dependent kinase inhibitor 1A(p21),Tumor Protein 53(p53),Sirtuin 1(SIRT-1)and Microtubule-associated protein 1A/1B-light chain 3-I/II(LC3-I/II)protein.A transmission ElectronMicroscope(TEM)was used to observe the ultrastructure of fibroblasts.Results:The results showed that E2 significantly promoted the proliferation of fibroblasts derived from POP and reduced the staining rate of SA-β-Gal.It markedly enhanced the extracellular matrix proteins COL-I and COL-III,accompanied by inhibition of the senescent maker p16INK4a.Additionally,our results improved the cells’autophagy and metabolic activity.Additionally,our results indicate the anti-senescence mechanism of E2 through the mediated SIRT-1/p53/p21 axis pathway.Conclusion:We provide preliminary evidence for the anti-aging effects and mechanisms of E2 on POP,hoping to provide a theoretical basis for estrogen against POP senescence and guide the clinical application and local administration of estrogen in POP treatment.
基金supported by the National Natural Science Foundation of China(grant number 81773285)Beijing Chao-Yang Hospital Golden Seeds Foundation(grant number CYJZ202341).
文摘Osteosarcoma(OS)is a prevalent primary bone malignancy with limited treatment options.Therefore,it is imperative to investigate and understand the mechanisms underlying OS pathogenesis.Cancer-associated fibroblasts(CAFs)are markedly abundant in tumor stromal cells and are essentially involved in the modulation of tumor occurrence and development.In recent years,CAFs have become a hotspot as researchers aim to elucidate CAF mechanisms that regulate tumor progression.However,most studies on CAFs are limited to a few common cancers,and their association with OS remains elusive.This review describes the role and current knowledge of CAFs in OS,focusing on their potential cellular origin,classification,and diverse functionality.It was found that CAFs influenced OS tumor cell signaling,proliferation,invasion,metastasis,epithelial-mesenchymal transition,stemness maintenance,angiogenesis,and the ability to modify immune system components.Furthermore,findings on other common cancers indicated that effective therapeutic strategies included the manipulation of CAF activation,targeting CAF-derived components,and depletion of CAFs by biomarkers.This review provides new insights and a theoretical basis for OS research.
基金Supported by the National Natural Science Foundation of China(No.81770898).
文摘AIM:To explore the effect of co-host non-coding RNA(ncRNA)MIR503HG/miR-503-5p on the angiogenesis of pterygium.METHODS:MIR503HG/miR-503-5p/fibroblast growth factor 2(FGF2)expression levels in pterygium tissues,control conjunctival tissues,and human pterygium fibroblasts(HPF)were examined by reverse transcription-polymerase chain reaction(qRT-PCR)and immunohistochemical methods.Effects of MIR503HG/miR-503-5p on low molecular weight FGF2(LWM FGF2),migration and angiogenesis of human retinal microvascular endothelial cells(HRMEC)were determined in an HPF and HRMEC co-culture model using Western blots,wound healing assay,Matrigel-based tube formation assay,and Transwell assay.RESULTS:MIR503HG/miR-503-5p/FGF2 pathway was actively increased in pterygium tissue and there was a negative correlation between the expression of the two ncRNAs.FGF2 expression level was positively correlated with MIR503HG and negatively correlated with miR-503-5p.Overexpressed MIR503HG/miR-503-5p did not affect the migration and angiogenesis of HRMECs cultured separately,but significantly affected migration and angiogenesis of HRMEC in HPF and HRMEC co-culture models.Western blotting revealed that MIR503HG/miR-503-5p overexpression significantly increased LMW FGF2 expression in HPF.CONCLUSION:MIR503HG/miR-503-5p inhibits HRMEC migration and angiogenic function by interfering with the interaction between HPF and endothelial cells via reducing LMW FGF2 in HPF.
文摘BACKGROUND Pancreatic cancer,a formidable gastrointestinal neoplasm,is characterized by its insidious onset,rapid progression,and resistance to treatment,which often lead to a grim prognosis.While the complex pathogenesis of pancreatic cancer is well recognized,recent attention has focused on the oncogenic roles of senescent tumor-associated fibroblasts.However,their precise role in pancreatic cancer remains unknown.Resveratrol is a natural polyphenol known for its multifaceted biological actions,including antioxidative and neuroprotective properties,as well as its potential to inhibit tumor proliferation and migration.Our current investigation builds on prior research and reveals the remarkable ability of resveratrol to inhibit pancreatic cancer proliferation and metastasis.AIM To explore the potential of resveratrol in inhibiting pancreatic cancer by targeting senescent tumor-associated fibroblasts.METHODS Immunofluorescence staining of pancreatic cancer tissues revealed prominent coexpression ofα-SMA and p16.HP-1 expression was determined using immunohistochemistry.Cells were treated with the senescence-inducing factors known as 3CKs.Long-term growth assays confirmed that 3CKs significantly decreased the CAF growth rate.Western blotting was conducted to assess the expression levels of p16 and p21.Immunofluorescence was performed to assess LaminB1 expression.Quantitative real-time polymerase chain reaction was used to measure the levels of several senescence-associated secretory phenotype factors,including IL-4,IL-6,IL-8,IL-13,MMP-2,MMP-9,CXCL1,and CXCL12.A scratch assay was used to assess the migratory capacity of the cells,whereas Transwell assays were used to evaluate their invasive potential.RESULTS Specifically,we identified the presence of senescent tumor-associated fibroblasts within pancreatic cancer tissues,linking their abundance to cancer progression.Intriguingly,Resveratrol effectively eradicated these fibroblasts and hindered their senescence,which consequently impeded pancreatic cancer progression.CONCLUSION This groundbreaking discovery reinforces Resveratrol's stature as a potential antitumor agent and positions senescent tumor-associated fibroblasts as pivotal contenders in future therapeutic strategies against pancreatic cancer.
基金Supported by the National Natural Science Foundation of China,No.81671439the Science and Technology Commission of Shanghai Municipality,No.21Y11906700 and No.20Y11907300the Medical Innovation Research Project of the Science and Technology Commission of Shanghai Municipality,No.22Y11906500。
文摘BACKGROUND Pelvic organ prolapse(POP)involves pelvic organ herniation into the vagina due to pelvic floor tissue laxity,and vaginal structure is an essential factor.In POP,the vaginal walls exhibit abnormal collagen distribution and decreased fibroblast levels and functions.The intricate etiology of POP and the prohibition of trans-vaginal meshes in pelvic reconstruction surgery present challenges in targeted therapy development.Human umbilical cord mesenchymal stromal cells(hucMSCs)present limitations,but their exosomes(hucMSC-Exo)are promising therapeutic tools for promoting fibroblast proliferation and extracellular matrix remodeling.suppressed inflammation in POP group fibroblasts,stimulated primary fibroblast growth,and elevated collagen I(Col1)production in vitro.High-throughput RNA-seq of fibroblasts treated with hucMSC-Exo and miRNA sequencing of hucMSC-Exo revealed that abundant exosomal miRNAs downregulated matrix metalloproteinase 11(MMP11)expression.CONCLUSION HucMSC-Exo normalized the growth and function of primary fibroblasts from patients with POP by promoting cell growth and Col1 expression in vitro.Abundant miRNAs in hucMSC-Exo targeted and downregulated MMP11 expression.HucMSC-Exo-based therapy may be ideal for safely and effectively treating POP.
基金supported by grants from the Natural Science Foundation of Hunan Province(2022JJ80044)the Youth Science Foundation of Xiangya Hospital(2019Q13).
文摘Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.
文摘Background:A differential gene,triggering receptor expressed on myeloid cells 1(TREM1),was identified in blood sequencing datasets from myocardial infarction patients and healthy controls.Myocardialfibrosis following myocardial infarction significantly contributes to cardiac dysfunction.Objectives:This study aimed to unveil the intrinsic regulatory mechanism of TREM1 in myocardialfibrosis.Methods:Mimicking pathology by angiotensin II(Ang II)treatment of human cardiacfibroblasts(HCFs),the impacts of TREM1 knockdown on its proliferation,migration,and secretion of the pro-fibrotic matrix were identified.Using the Human Transcription Factor Database(HumanTFDB)website,lysine-specific demethylase 5B(KDM5B)was found to bind to the TREM1 promoter,which was further validated through luciferase reporter and chromatin immunoprecipitation(ChIP).By promoting KDM5B overexpression,its effect on the regulation of TREM1 was examined.Results:TREM1 knockdown suppressed the proliferation,migration,and secretion of the pro-fibrotic matrix in HCFs upon Ang II treatment.KDM5B bound to the TREM1 promoter and upregulated its transcriptional expression.Furthermore,KDM5B overexpression reversed the regulation of the above cellular phenotypes by TREM1 knockdown.Conclusion:This study sheds light on the positive regulation of TREM1 by KDM5B,demonstrating their role in promoting myocardialfibrosis.Thisfinding provides a theoretical foundation for understanding disease pathology and potentially advancing the development of new targeted therapies.
文摘Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.
基金Supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT)de la Dirección General de Asuntos de Personal Académico,No.IN212722 and No.IA208424Consejo Mexiquense de Ciencia y Tecnología,No.CS000132Consejo Nacional de Humanidades,Ciencia y Tecnología,No.CF-2023-I-563.
文摘Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.
文摘Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.
基金supported by the National Natural Science Foundation of China(No.82004380).
文摘Objective:Long-term effects of chronic skin ulcers(CSU)include diminished physical and emotional well-being,an increased risk of cancer in more severe cases,and significant social costs due to inadequate treatment.Pinian powder is a topical Chinese medicine created by the late renowned traditional Chinese medicine(TCM)master WEN Zhuozhi,with a long history of clinical use,and has been proven effective in treating various CSU.However,its exact mechanism of action is unknown.This study aims to investigate the effects and mechanisms of Pinian powder on chronic skin ulcers.Methods:A mouse model with skin defects and foreign body implantation was developed.Mice were divided into five groups:Control group,model control group,Pinian powder(PNP)group,inhibitor(MSAB)group,and PNP with inhibitor group.Treatments included saline washes,daily PNP application,intraperitoneal MSAB injection,and combined treatment.Wound healing was assessed on day 1,day 3,day 7,and day 14 using photography and software.Histological and Western blotting assays evaluated epidermal repair and protein expression related to wound healing.Immunofluorescence staining detected specific protein localization and expression.Statistical analysis was conducted using GraphPad Prism software,with significance set at P<0.05.Results:Clinical cases have demonstrated that Pinian powder can influence epidermal migration,reduce wound secretion,and stimulate granulation tissue formation in chronic skin ulcers.In vivo experiments,Pinian powder is applied externally to total skin defects and added to foreign body implantation in a mouse model of CSU.It activates the Wnt4/β-catenin signaling pathway,increases the expression of crucial proteins of fibroblast proliferation and keratinocyte proliferation,such asα-smooth muscle actin(α-SMA),Ki-67,K10,and K14,promotes wound healing.After the action ofβ-catenin inhibitor MSAB,the effect of Pinian powder was reversed.Conclusions:Pinian powder can promote the proliferation of keratinocytes and fibroblasts by activating the Wnt4/β-catenin signaling pathway and accelerating the wound healing of CSU.
基金Supported by National Natural Science Foundation of China(30801353)Shandong Education Department Foundation Project(G08LG53)~~
文摘[Objective] The aim of this study was to establish the in vitro culture system of chicken fibroblasts.[Method] Tissue explant method and enzymatic digestion method were used to separate and culture chicken skin fibroblasts respectively.The rate of cell growth,cryopreservation and recovery were compared.[Result] The primary chicken fibroblasts prepared by enzymatic digestion grew faster and converged together to form monolayer on 5 d post preparation;the passage cells prepared by these 2 methods grew at similar speed and formed monolayer within 2-3 d;homogeneous fibroblasts could be obtained by trypsin digestion and repeated attachment for 3-4 passages;there were 75%-80% of cells survived after cryopreservation and recovery;the growth curves of embryonic fibroblasts and skin fibroblasts were all normal and the two kind of cells still retained the normal number of chromosomes even at the twelfth passage.[Conclusion] The feeder layer cells needed for establishing ES cell lines could be obtained by culturing chicken fibroblasts through both tissue explant method and enzymatic digestion method.This study provided a basis for the successful establishment of ES cell lines.
