Transducing thermal energy into mechanical movements via molecular reconfigurations offers a cutting-edge approach to thermal actuating materials,which could be applied to sensors,energy harvesting and storage devices...Transducing thermal energy into mechanical movements via molecular reconfigurations offers a cutting-edge approach to thermal actuating materials,which could be applied to sensors,energy harvesting and storage devices[1].Thermal expansion is a pivotal aspect in solid state chemistry,intricately intertwined with various factors such as crystal structure,chemical composition,electronic configuration,microstructure,and defects.Most materials undergo isotropic and positive thermal expansion(PTE)because of the disharmonic vibrational amplitudes of their chemical bonds.Moreover,anisotropic thermal expansion(ATE)and negative thermal expansion(NTE)are fascinating physical attributes of solids,which can originate from electronic or magnetic mechanisms,as well as through a transverse phonon mechanism in insulating lattice solids.展开更多
BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear f...BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.展开更多
Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell...Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.展开更多
Alpha-voltaic cell is a type of micro nuclear battery that provides several decades of reliable power in the nano watt to microwatt range,supplying for special applications where traditional chemical batteries or sola...Alpha-voltaic cell is a type of micro nuclear battery that provides several decades of reliable power in the nano watt to microwatt range,supplying for special applications where traditional chemical batteries or solar cells are difficult to operate.However,the power conversion efficiency of the alpha-voltaic cells reported are still far behind the theoretical limit,making the development of alpha-voltaic cell challenging.Developing advanced semiconductor transducers with higher efficiency in converting the energy of alpha particles into electric energy is proving to be necessary for realizing high-power conversion efficiency.Herein,we propose an alpha-voltaic cell based on SiC PIN transducer that includes a sensitive region with an area of 1 cm^(2),a width of 51.2μm,and a charge collection efficiency of 95.6%at 0 V bias.We find that optimizing the unintentional doping concentration and crystal quality of the SiC epitaxial layer can significantly increase the absorption and utilization of the energy of alpha particles,resulting in a 2.4-fold enhancement in power conversion efficiency compared with that of the previous study.Electrical properties of the SiC alpha-voltaic cell are measured using an He-ion accelerator as the equivalentα-radioisotopes,with the best power conversion efficiency of 2.10%and maximum output power density of 406.66 nW cm-2 is obtained.Our research makes a big leap in SiC alpha-voltaic cell,bridging the gap between micro nuclear batteries and practical applications in micro-electromechanical systems,micro aerial vehicles,and tiny satellites.展开更多
As an emerging multifunctional metal with the lowest melting point except for mercury,gallium combines a wide range of metallic and non-metallic elements to form advanced semiconductors critically important in cutting...As an emerging multifunctional metal with the lowest melting point except for mercury,gallium combines a wide range of metallic and non-metallic elements to form advanced semiconductors critically important in cutting-edge technologies.However,due to its low melting point and poor machinability,it is quite difficult to simultaneously characterize gallium’s elastic properties and damping characteristics using conventional methods,which is es-sential in designing and evaluating gallium-based structures.Therefore,developing effective methods to achieve accurate and efficient measurements of Young’s modulus and corresponding internal friction of gallium is of great significance.This letter studies simultaneous measurements of the variations in Young’s modulus and internal friction of gallium at varying temperatures by employing the modified piezoelectric ultrasonic composite oscil-lator technique.Combining the explicit theoretical formulas with the measured resonance and anti-resonance frequencies,it has been discovered that Young’s modulus undergoes an approximately linear decrease as the temperature rises,declining from 83.84 GPa at -70℃ to 79.37 GPa at 20℃.Moreover,like aluminum in the same Group ⅢA of the Periodic Table of Elements and exhibits a grain-boundary internal friction peak,gallium displays a longitudinal internal friction peak at approximately-12°C,with the peak value reaching 1.77×10^(-3).This basic research on gallium’s elastic properties and damping characteristics under low-temperature condi-tions will inspire further explorations of the mechanical properties of a diverse spectrum of low-melting-point functional materials and facilitate applications of gallium-based structures under complex conditions.展开更多
We theoretically investigate the feasibility of reconstructing the transverse structures of femtosecond laser filaments in air by photoacoustic tomography.To simulate the emission and transmission of filament-induced ...We theoretically investigate the feasibility of reconstructing the transverse structures of femtosecond laser filaments in air by photoacoustic tomography.To simulate the emission and transmission of filament-induced ultrasonic signals more truly,a series of experimentally recorded cross-sectional images are used to simulate the initial pressure rise from multiple filaments(MFs).The aperture size and sensitivity of the detector was incorporated into the reconstruction algorithm.The results show that frequency of acoustic signals induced by MFs with maximum volumetric energy density~100 k J/m^(3)is about 2 MHz below.The initial spatial distribution of optical filaments can be clearly reconstructed with the back projection based algorithm.We recommend a PAT system with transducers of a lower central frequency and a stronger apodization working at a longer scanning radius can be used in photoacoustic image reconstruction of femtosecond laser multifilaments.This study demonstrates the feasibility of using photoacoustic tomography to reconstruct femtosecond multifilament images,which is helpful for studying the complex dynamic processes of multifilament and multifilament manipulation and is also valuable for the remote applications of laser filaments.展开更多
This paper proposes a method to generate Bessel-like collimated beams with suppressed side lobes using the flexural vibration modes of a fixed boundary circular plate,which is excited by a longitudinally vibrating tra...This paper proposes a method to generate Bessel-like collimated beams with suppressed side lobes using the flexural vibration modes of a fixed boundary circular plate,which is excited by a longitudinally vibrating transducer in a ring excitation manner.The factors affecting the generation of Bessel-like collimated beams are investigated by theoretical analysis,numerical simulation and experimental methods.The results indicate that Bessel-like wave can be generated by a thin circular plate with fixed boundaries.The third-order mode of the circular plate can be modified to generate a collimated beam with suppressing side lobes when it is excited in a ring excitation manner and the excitation position lies between the first two nodal circles of the plate.As the excitation radius increases,the main lobe width of the resulting Bessel-like collimated beam decreases,the extent of the focusing region increases,and the amplitude of the side lobes initially increases and then decreases.Based on the simulation results,a prototype Bessel-like collimated beam generation system is made and measured experimentally.The experimental results are in good agreement with the numerical results.The Bessel-like collimated beam can be generated by the proposed system,which has potential application in the fields of long-range detection,imaging of highly attenuated materials,and airflow acceleration.展开更多
Few-layer nanosheets(NSs)of hexagonal boron nitride(h-BN)and molybdenum disulfide(MoS_(2))display notable piezoelectric properties.Yet,their integration into polymers typically yields non-piezoelectric composites due ...Few-layer nanosheets(NSs)of hexagonal boron nitride(h-BN)and molybdenum disulfide(MoS_(2))display notable piezoelectric properties.Yet,their integration into polymers typically yields non-piezoelectric composites due to NSs’random distribution.We introduce a facile method for fabricating intrinsic piezoelectric composites incorporated with NSs without electric poling.Our innovative process aligns NSs within polyvinyl alcohol polymer,leveraging ice-water interfacial tension,water crystallization thrust,and directional cross-linking during freezing.The resulting PE composites exhibit a maximum piezoelectric coefficient of up to 25.5-28.4 pC N^(-1),comparable to polyvinylidene difluoride(PVDF),with significant costefficiency,safety,and scalability advantages over conventional materials.Using this composite,we develop highly sensitive wearable pressure and strain sensors,and an ultrasound energy harvester.These sensors detect finger bending and differentiate between walking and running,while the harvester generates1.18 V/2.31μA under 1Wcm^(-2)ultrasound input underwater.This universal method offers a novel manufacturing technique for piezoelectric composites,demonstrating remarkable effectiveness in synthesizing intrinsic piezoelectric composites based on 2D materials.Moreover,its potential extends to applications in wearable electronics and energy harvesting,promising significant advancements in these fields.展开更多
BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an a...BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an anti-VEGF agent,has shown promise in its treatment.Signal transducer and activator of transcription 3(STAT3)is involved in inflammatory processes and cellular signaling,while glial fibrillary acidic protein(GFAP)is a marker of glial cell activation,both contributing to retinal damage in DR.However,the mechanisms by which ranibizumab affect early-stage DR through the VEGF/STAT3/GFAP pathway are not fully understood.AIM To investigate the role of ranibizumab in early DR via the VEGF/STAT3/GFAP pathway.METHODS Adult retinal pigment epithelial 19(ARPE-19)cells and human retinal microvascular endothelial cells(HRMECs)were cultured under high-glucose conditions to simulate a diabetic environment.The effects of ranibizumab on cytokine mRNA and protein expression were analyzed by quantitative polymerase chain reaction and Western blot analysis.A diabetic rat model was induced with streptozotocin(60 mg/kg).Retinal changes,including retinal ganglion cell(RGC)apoptosis,vascular alterations,and cytokine expression,were evaluated using fundus fluorescein angiography,hematoxylin and eosin and periodic acid Schiff staining,immunofluorescence,confocal imaging,and Western blot analysis.RESULTS High-glucose conditions significantly increased the mRNA and protein levels of VEGF,STAT3,GFAP,and other cytokines in ARPE-19 and HRMECs.However,these levels were partially suppressed by ranibizumab.RGC apoptosis,vascular leakage,and elevated cytokine expression were observed during early-stage DR in diabetic rats.Ranibizumab treatment in diabetic rats reduced cytokine expression,restored RGCs,and repaired vascular networks.CONCLUSION Intravitreal ranibizumab modulates the VEGF/STAT3/GFAP pathway,suppresses cytokine expression,and promotes retinal repair,effectively delaying or preventing early DR progression.展开更多
Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in st...Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.展开更多
Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver str...Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver structure,cell apoptosis,and the modulation of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway,employing a combination of network pharmacology and experimental approaches.Methods:A DEN-induced rat model of liver cirrhosis was established to assess the formula’s effectiveness.Parameters such as overall health,liver morphology,and survival were monitored.Network pharmacology was employed to decipher the active compounds and key targets of the formula in addressing liver cirrhosis.Predictions made via network pharmacology were substantiated through experimental validation in the animal model.Results:Administration of the Yigan Xiaozheng formula led to noticeable improvements in clinical symptoms of liver cirrhosis in rats,marked by enhanced body weight,lessened liver pathology,and higher survival rates.Network pharmacological analysis unveiled intricate interactions between active ingredients of the formula and cirrhosis-related targets.Protein-protein interaction(PPI)networks pinpointed crucial proteins and regulatory modules.Enrichment analysis underscored a significant involvement of the JAK2/STAT3 signaling pathway.On a molecular scale,the formula was observed to reduce the expression of BCL-2 associated X protein(Bax)and cytochrome C(Cyt-C),diminish the Bax/B-cell lymphoma 2(Bcl-2)ratio,and impede JAK2/STAT3 pathway activation,thereby curtailing liver fibrosis and cellular apoptosis.Conclusion:The study demonstrates the Yigan Xiaozheng formula’s capacity to ameliorate liver cirrhosis in a DEN-induced model,primarily through its active ingredients’interactions with cirrhosis targets and modulation of the JAK2/STAT3 pathway.These findings endorse the potential of this traditional Chinese medicinal formula as a viable treatment option for liver cirrhosis.展开更多
This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation...This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.展开更多
BACKGROUND At present,the incidence of diabetic nephropathy is increasing year by year,and there are many studies on the pathogenesis of diabetic nephropathy,but it is still not completely clear.The final pathological...BACKGROUND At present,the incidence of diabetic nephropathy is increasing year by year,and there are many studies on the pathogenesis of diabetic nephropathy,but it is still not completely clear.The final pathological result of diabetic nephropathy is mainly glomerular cell fibrosis,and the roles of micro-RNA(miRNA)-29 and DNA methyl transferase(DNMTs)in cell fibrosis have been confirmed in other studies,but there is a lack of relevant research in the kidney at present.AIM To study the potential involvement of miRNA-29a-3p in fibrosis related to diabetic kidney disease(DKD).METHODS The expression of miR-29a-3p,DNMT3A/3B,fibrosis-related molecules,Wnt3a,β-catenin,Janus kinase 2,and signal transducer and activator of transcription 3 was assessed in SV40MES13 cells and diabetic mice using quantitative real-time PCR and western blotting.Furthermore,the expression changes of fibrosis-related molecules were further analyzed using immunofluorescence and immunohistochemical blotting.The renal pathological changes of DKD in each group were also studied using hematoxylin-eosin and periodate-Schiff reaction staining.RESULTS In both the in vivo and in vitro experiments,it was observed that high glucose induction significantly decreased miR-29a-3p expression.As a result of this downregulation,DKD-related fibrosis was found to be promoted,as confirmed by elevated expression levels ofα-smooth muscle actin,collagen type I,and fibronectin.MiR-29a-3p targets the 3’non-coding regions of DNMT3A and DNMT3B and inhibits their expression.Inhibition of DNMT3A and DNMT3B can reverse the effect of miR-29a-3p downregulation on DKD-related fibrosis.CONCLUSION MiR-29a-3p can regulate Wnt/β-catenin and Janus kinase/signal transducer and activator of transcription signal pathways by regulating and inhibiting the expression of DNMT3A/3B and thus participate in the inhibition of DKD-related fibrosis.展开更多
This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the ...This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.展开更多
Exosomes derived from hypoxic endometrial epithelial cells are pivotal in cellular communication and tissue repair,offering new perspectives on reproductive health.This manuscript highlights the study by Zhang et al,w...Exosomes derived from hypoxic endometrial epithelial cells are pivotal in cellular communication and tissue repair,offering new perspectives on reproductive health.This manuscript highlights the study by Zhang et al,which investigates the effects of miR-214-5p and miR-21-5p in hypoxic cell-derived exosomes on human umbilical cord mesenchymal stem cells.The study reveals that low levels of these microRNAs activate the signal transducer and activator of transcription 3 signaling pathway,enhancing human umbilical cord mesenchymal stem cell migration and differentiation.These findings provide novel insights into therapeutic strategies for improving endometrial health and addressing infertility linked to thin endometrium.展开更多
BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium...BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.展开更多
Objective Th17 cell-mediated immune injury is a crucial factor contributing to tubulointerstitial fibrosis in patients with IgA nephropathy(IgAN).However,the exact mechanisms by which Th17 cells induce tubulointerstit...Objective Th17 cell-mediated immune injury is a crucial factor contributing to tubulointerstitial fibrosis in patients with IgA nephropathy(IgAN).However,the exact mechanisms by which Th17 cells induce tubulointerstitial fibrosis remain to be fully elucidated.Methods An IgAN mouse model was established and validated.Transcriptome sequencing,combined with bioinformatics analysis,was carried out to explore the immune injury pathways in renal tissues and the activation pathways in Th17 cells that were co-cultured with tubular epithelial cells.In subsequent experiments,small interfering RNA(siRNA)and overexpression plasmids were used to manipulate cellular targets.Validation was conducted through quantitative real-time polymerase chain reaction(qPCR),Western blotting,and immunofluorescence assays.Results Compared with the control mice,IgAN mice exhibited elevated serum creatinine levels and increased urine protein-to-creatinine ratios.Renal pathological examination revealed the characteristic features of IgAN.Transcriptomic analysis of the kidney tissues from the model mice showed the activation of Th17 differentiation pathways,which was further confirmed by immunofluorescence analysis showing increased expression of interleukin-17A(IL-17A).These findings indicate an increased abundance of Th17 cells with potential pathogenic significance.When Th17 cells were co-cultured with tubular epithelial cells,the level of interleukin-9(IL-9)in the system increased.This increase in IL-9 activated the Janus kinase 1-signal transducer and activator of transcription 3(JAK1-STAT3)pathway through the IL-9 receptor(IL-9R)and upregulated the signature transcription factor retinoic acid-related orphan receptor gamma(ROR-γ),thus promoting Th17 cell differentiation.When IL-9R was silenced using siRNA or when the activity of STAT3 was inhibited,both the levels of phosphorylated STAT3(p-STAT3)and ROR-γdecreased.Moreover,IL-17A secreted by Th17 cells promoted the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)in tubular epithelial cells by activating the IL-17 receptor A(IL-17RA)–adaptor protein Act1–tumor necrosis factor receptor-associated factor 6(TRAF6)complex.This process regulated the production of inflammatory cytokines and drove the initiation and progression of fibrosis.Treatment with a STAT3 inhibitor in IgAN mice led to a reduction in the number of renal Th17 cells and alleviated the fibrotic phenotype.Conclusion This study demonstrated that the interaction between Th17 cells and tubular epithelial cells triggers excessive extracellular matrix deposition in the tubulointerstitium,thereby exacerbating the fibrotic phenotype and accelerating the progression of IgAN.展开更多
Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging ther...Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.展开更多
Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a...Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.展开更多
Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(...Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.展开更多
基金supported by the National Natural Science Foundation of China(22171155)Natural Science Foundation of Shandong Province(ZR2022YQ07)Taishan Scholar Program(tsqn202306166).
文摘Transducing thermal energy into mechanical movements via molecular reconfigurations offers a cutting-edge approach to thermal actuating materials,which could be applied to sensors,energy harvesting and storage devices[1].Thermal expansion is a pivotal aspect in solid state chemistry,intricately intertwined with various factors such as crystal structure,chemical composition,electronic configuration,microstructure,and defects.Most materials undergo isotropic and positive thermal expansion(PTE)because of the disharmonic vibrational amplitudes of their chemical bonds.Moreover,anisotropic thermal expansion(ATE)and negative thermal expansion(NTE)are fascinating physical attributes of solids,which can originate from electronic or magnetic mechanisms,as well as through a transverse phonon mechanism in insulating lattice solids.
基金Supported by Xi’an Science and Technology Plan Project,No.23YXYJ0162Shaanxi Province Traditional Chinese Medicine Research and Innovation Talent Plan Project,No.TZKN-CXRC-16+2 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.SZYKJCYC-2025-JC-010Shaanxi Province Key Research and Development Plan Project-Social Development Field,No.S2025-YF-YBSF-0391the Science and Technology Innovation Cultivation Program of Longhua Hospital affiliated to Shanghai University of Chinese Medicine,No.YD202220。
文摘BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
基金Mechanistic Investigation into the Extraction,Purification,and Anti-Esophageal Cancer Effects of Gallic Acid Derived from Rhodiola crenulata(YLUKLM2023001).
文摘Background:Gallic acid(GA),a plant-derived polyphenol,possesses diverse biological functions such as reducing inflammation and against tumors.Currently,the influence of GA on the resistance of esophageal squamous cell carcinoma(ESCC)cells to cisplatin(DDP)is not well understood.Methods:Cell counting kit-8 assay examined how GA affected KYSE30 and TE-1 cell viability.5-Ethynyl-2′-deoxyuridine and TdT-mediated dUTP Nick-End labeling staining detected cell proliferation and apoptosis.Clone formation assay,flow cytometry,Carboxyfluorescein diacetate succinimidyl ester fluorescent probes,and Transwell assay determined cell biological properties,and 2′,7′-Dichlorofluorescin diacetate(DCFH-DA)fluorescent probes detected oxidative stress levels.Signal transducer and activator of transcription 3(STAT3)/Notch pathway protein levels after GA and/or Interleukin-6(IL-6)intervention were examined through Western blot.Furthermore,a model for subcutaneous graft tumors was established in nude mice.Results:GA exerted suppressive effects on cell proliferation,and caused apoptosis of KYSE30 and TE-1 cells.IL-6 intervention activated the STAT3/Notch pathway and promoted the malignant biological properties of ESCC cells.In contrast,GA attenuated the effects of IL-6,while STAT3 or Notch inhibitor further enhanced the effects of GA,suggesting that GA inhibited the IL-6/STAT3/Notch pathway.Not only that,GA promoted oxidative stress and enhanced cell sensitivity to DDP both in vitro and in vivo.Conclusion:GA suppresses the malignant progression of ESCC and enhances cell sensitivity to DDP by hindering the IL-6/STAT3/Notch pathway.
基金financially supported by the National Natural Science Foundation of China(Nos.12050005,11922507,and 12205016)supported by Major State Basic Research Development Program of China(No.2021YFB3201000)。
文摘Alpha-voltaic cell is a type of micro nuclear battery that provides several decades of reliable power in the nano watt to microwatt range,supplying for special applications where traditional chemical batteries or solar cells are difficult to operate.However,the power conversion efficiency of the alpha-voltaic cells reported are still far behind the theoretical limit,making the development of alpha-voltaic cell challenging.Developing advanced semiconductor transducers with higher efficiency in converting the energy of alpha particles into electric energy is proving to be necessary for realizing high-power conversion efficiency.Herein,we propose an alpha-voltaic cell based on SiC PIN transducer that includes a sensitive region with an area of 1 cm^(2),a width of 51.2μm,and a charge collection efficiency of 95.6%at 0 V bias.We find that optimizing the unintentional doping concentration and crystal quality of the SiC epitaxial layer can significantly increase the absorption and utilization of the energy of alpha particles,resulting in a 2.4-fold enhancement in power conversion efficiency compared with that of the previous study.Electrical properties of the SiC alpha-voltaic cell are measured using an He-ion accelerator as the equivalentα-radioisotopes,with the best power conversion efficiency of 2.10%and maximum output power density of 406.66 nW cm-2 is obtained.Our research makes a big leap in SiC alpha-voltaic cell,bridging the gap between micro nuclear batteries and practical applications in micro-electromechanical systems,micro aerial vehicles,and tiny satellites.
基金financially supported by the National Key R&D Program of China(Grant No.2023YFF0716800)the National Natural Science Foundation of China(Grant No.12074160)the Natural Science Foundation of Liaoning Province of China(Grant No.2024-MS-181).
文摘As an emerging multifunctional metal with the lowest melting point except for mercury,gallium combines a wide range of metallic and non-metallic elements to form advanced semiconductors critically important in cutting-edge technologies.However,due to its low melting point and poor machinability,it is quite difficult to simultaneously characterize gallium’s elastic properties and damping characteristics using conventional methods,which is es-sential in designing and evaluating gallium-based structures.Therefore,developing effective methods to achieve accurate and efficient measurements of Young’s modulus and corresponding internal friction of gallium is of great significance.This letter studies simultaneous measurements of the variations in Young’s modulus and internal friction of gallium at varying temperatures by employing the modified piezoelectric ultrasonic composite oscil-lator technique.Combining the explicit theoretical formulas with the measured resonance and anti-resonance frequencies,it has been discovered that Young’s modulus undergoes an approximately linear decrease as the temperature rises,declining from 83.84 GPa at -70℃ to 79.37 GPa at 20℃.Moreover,like aluminum in the same Group ⅢA of the Periodic Table of Elements and exhibits a grain-boundary internal friction peak,gallium displays a longitudinal internal friction peak at approximately-12°C,with the peak value reaching 1.77×10^(-3).This basic research on gallium’s elastic properties and damping characteristics under low-temperature condi-tions will inspire further explorations of the mechanical properties of a diverse spectrum of low-melting-point functional materials and facilitate applications of gallium-based structures under complex conditions.
基金Project supported by the National Natural Science Foundation of China(Grant No.42105176)the National University of Defense Technology Independent Research Project(Grant No.ZK21-40)。
文摘We theoretically investigate the feasibility of reconstructing the transverse structures of femtosecond laser filaments in air by photoacoustic tomography.To simulate the emission and transmission of filament-induced ultrasonic signals more truly,a series of experimentally recorded cross-sectional images are used to simulate the initial pressure rise from multiple filaments(MFs).The aperture size and sensitivity of the detector was incorporated into the reconstruction algorithm.The results show that frequency of acoustic signals induced by MFs with maximum volumetric energy density~100 k J/m^(3)is about 2 MHz below.The initial spatial distribution of optical filaments can be clearly reconstructed with the back projection based algorithm.We recommend a PAT system with transducers of a lower central frequency and a stronger apodization working at a longer scanning radius can be used in photoacoustic image reconstruction of femtosecond laser multifilaments.This study demonstrates the feasibility of using photoacoustic tomography to reconstruct femtosecond multifilament images,which is helpful for studying the complex dynamic processes of multifilament and multifilament manipulation and is also valuable for the remote applications of laser filaments.
基金Project supported by the National Natural Science Foundation of China(Grant No.12474440).
文摘This paper proposes a method to generate Bessel-like collimated beams with suppressed side lobes using the flexural vibration modes of a fixed boundary circular plate,which is excited by a longitudinally vibrating transducer in a ring excitation manner.The factors affecting the generation of Bessel-like collimated beams are investigated by theoretical analysis,numerical simulation and experimental methods.The results indicate that Bessel-like wave can be generated by a thin circular plate with fixed boundaries.The third-order mode of the circular plate can be modified to generate a collimated beam with suppressing side lobes when it is excited in a ring excitation manner and the excitation position lies between the first two nodal circles of the plate.As the excitation radius increases,the main lobe width of the resulting Bessel-like collimated beam decreases,the extent of the focusing region increases,and the amplitude of the side lobes initially increases and then decreases.Based on the simulation results,a prototype Bessel-like collimated beam generation system is made and measured experimentally.The experimental results are in good agreement with the numerical results.The Bessel-like collimated beam can be generated by the proposed system,which has potential application in the fields of long-range detection,imaging of highly attenuated materials,and airflow acceleration.
基金funded by the Key Research Project of Zhejiang(LD22E030007)the“Leading Goose”R&D Program of Zhejiang Province(No.2022C01136)+2 种基金National Science Foundation of China(NSFC No.61974037,No.61904042,No.62274049)Zhejiang University Education Foundation Global Partnership Fund(No.100000-11320)the support of the Micro-nano Fabrication Center of International campus of Zhejiang University.
文摘Few-layer nanosheets(NSs)of hexagonal boron nitride(h-BN)and molybdenum disulfide(MoS_(2))display notable piezoelectric properties.Yet,their integration into polymers typically yields non-piezoelectric composites due to NSs’random distribution.We introduce a facile method for fabricating intrinsic piezoelectric composites incorporated with NSs without electric poling.Our innovative process aligns NSs within polyvinyl alcohol polymer,leveraging ice-water interfacial tension,water crystallization thrust,and directional cross-linking during freezing.The resulting PE composites exhibit a maximum piezoelectric coefficient of up to 25.5-28.4 pC N^(-1),comparable to polyvinylidene difluoride(PVDF),with significant costefficiency,safety,and scalability advantages over conventional materials.Using this composite,we develop highly sensitive wearable pressure and strain sensors,and an ultrasound energy harvester.These sensors detect finger bending and differentiate between walking and running,while the harvester generates1.18 V/2.31μA under 1Wcm^(-2)ultrasound input underwater.This universal method offers a novel manufacturing technique for piezoelectric composites,demonstrating remarkable effectiveness in synthesizing intrinsic piezoelectric composites based on 2D materials.Moreover,its potential extends to applications in wearable electronics and energy harvesting,promising significant advancements in these fields.
基金Supported by the Natural Science Foundation of Jiangxi Province,No.20242BAB25489National Natural Science Foundation of China,No.82260211 and No.81460092+1 种基金Key Research and Development Project in Jiangxi Province,No.20203BBG73058Chinese Medicine Science and Technology Project in Jiangxi Province,No.2020A0166。
文摘BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an anti-VEGF agent,has shown promise in its treatment.Signal transducer and activator of transcription 3(STAT3)is involved in inflammatory processes and cellular signaling,while glial fibrillary acidic protein(GFAP)is a marker of glial cell activation,both contributing to retinal damage in DR.However,the mechanisms by which ranibizumab affect early-stage DR through the VEGF/STAT3/GFAP pathway are not fully understood.AIM To investigate the role of ranibizumab in early DR via the VEGF/STAT3/GFAP pathway.METHODS Adult retinal pigment epithelial 19(ARPE-19)cells and human retinal microvascular endothelial cells(HRMECs)were cultured under high-glucose conditions to simulate a diabetic environment.The effects of ranibizumab on cytokine mRNA and protein expression were analyzed by quantitative polymerase chain reaction and Western blot analysis.A diabetic rat model was induced with streptozotocin(60 mg/kg).Retinal changes,including retinal ganglion cell(RGC)apoptosis,vascular alterations,and cytokine expression,were evaluated using fundus fluorescein angiography,hematoxylin and eosin and periodic acid Schiff staining,immunofluorescence,confocal imaging,and Western blot analysis.RESULTS High-glucose conditions significantly increased the mRNA and protein levels of VEGF,STAT3,GFAP,and other cytokines in ARPE-19 and HRMECs.However,these levels were partially suppressed by ranibizumab.RGC apoptosis,vascular leakage,and elevated cytokine expression were observed during early-stage DR in diabetic rats.Ranibizumab treatment in diabetic rats reduced cytokine expression,restored RGCs,and repaired vascular networks.CONCLUSION Intravitreal ranibizumab modulates the VEGF/STAT3/GFAP pathway,suppresses cytokine expression,and promotes retinal repair,effectively delaying or preventing early DR progression.
基金Supported by the National Natural Science Foundation of China,No.81270465the Sichuan Science and Technology Program,No.2024NSFSC0631,No.2023JDRC0088,and No.MZGC20240097+4 种基金the Basic Research Cultivation Support Program of Fundamental Research Funds for the Central Universities,No.2682023ZTPY071the Baiqiuen Public Welfare Foundation Program,No.BCF-LX-XH-20221014-12the Third People’s Hospital of Chengdu Clinical Research Program,No.CSY-YN-01-2023-012the Yibin Science and Technology Program,No.2021ZYY009and the Chengdu Medical Research Project Foundation,No.2022284.
文摘Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.
基金supported by National Natural Science Foundation of China Grant Program(No.81603555).
文摘Background:This investigation aimed to evaluate the therapeutic impact of the Yigan Xiaozheng formula on liver cirrhosis in rats,particularly induced by diethylnitrosamine(DEN).The study focused on analyzing liver structure,cell apoptosis,and the modulation of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway,employing a combination of network pharmacology and experimental approaches.Methods:A DEN-induced rat model of liver cirrhosis was established to assess the formula’s effectiveness.Parameters such as overall health,liver morphology,and survival were monitored.Network pharmacology was employed to decipher the active compounds and key targets of the formula in addressing liver cirrhosis.Predictions made via network pharmacology were substantiated through experimental validation in the animal model.Results:Administration of the Yigan Xiaozheng formula led to noticeable improvements in clinical symptoms of liver cirrhosis in rats,marked by enhanced body weight,lessened liver pathology,and higher survival rates.Network pharmacological analysis unveiled intricate interactions between active ingredients of the formula and cirrhosis-related targets.Protein-protein interaction(PPI)networks pinpointed crucial proteins and regulatory modules.Enrichment analysis underscored a significant involvement of the JAK2/STAT3 signaling pathway.On a molecular scale,the formula was observed to reduce the expression of BCL-2 associated X protein(Bax)and cytochrome C(Cyt-C),diminish the Bax/B-cell lymphoma 2(Bcl-2)ratio,and impede JAK2/STAT3 pathway activation,thereby curtailing liver fibrosis and cellular apoptosis.Conclusion:The study demonstrates the Yigan Xiaozheng formula’s capacity to ameliorate liver cirrhosis in a DEN-induced model,primarily through its active ingredients’interactions with cirrhosis targets and modulation of the JAK2/STAT3 pathway.These findings endorse the potential of this traditional Chinese medicinal formula as a viable treatment option for liver cirrhosis.
基金Supported by the General Program of the Natural Science Foundation of Guangdong Province,No.2025A1515011163.
文摘This article comments on the study by Zhang et al,which proposed that exosomes derived from hypoxia-injured endometrial epithelial cells promote human umbilical cord mesenchymal stem cell migration and differentiation into endo-metrial epithelial cells via exosomal miR-137-3p.The authors demonstrated that miR-137-3p targets ubiquitin protein ligase E3C and activates signal transducer and activator of transcription 3 signaling,thereby driving epithelial lineage transition.While this study expands our understanding of exosome-mediated intercellular communication in endometrial repair,several key gaps remain.Notably,microRNA(miRNA)profiling was performed in human umbilical cord mesenchymal stem cells post-exosome treatment,not in the exosomes derived from hypoxia-injured endometrial epithelial cell themselves,leaving open whether miR-137-3p is directly transferred or indirectly induced.In addition,data on exosome characterization were unavailable,and the rationale for selecting miR-137-3p over other differentially expressed miRNAs was not well justified.Future studies should include direct exosomal miRNA content analysis,in vivo validation,and deeper mechanistic exploration of the ubiquitin protein ligase E3C-signal transducer and activator of transcription 3 ubiquitination axis to establish the clinical and biological relevance of this pathway.
基金Supported by the Chongqing Basic Research and Frontier Exploration Project,No.cstc2018jcyjAX0834.
文摘BACKGROUND At present,the incidence of diabetic nephropathy is increasing year by year,and there are many studies on the pathogenesis of diabetic nephropathy,but it is still not completely clear.The final pathological result of diabetic nephropathy is mainly glomerular cell fibrosis,and the roles of micro-RNA(miRNA)-29 and DNA methyl transferase(DNMTs)in cell fibrosis have been confirmed in other studies,but there is a lack of relevant research in the kidney at present.AIM To study the potential involvement of miRNA-29a-3p in fibrosis related to diabetic kidney disease(DKD).METHODS The expression of miR-29a-3p,DNMT3A/3B,fibrosis-related molecules,Wnt3a,β-catenin,Janus kinase 2,and signal transducer and activator of transcription 3 was assessed in SV40MES13 cells and diabetic mice using quantitative real-time PCR and western blotting.Furthermore,the expression changes of fibrosis-related molecules were further analyzed using immunofluorescence and immunohistochemical blotting.The renal pathological changes of DKD in each group were also studied using hematoxylin-eosin and periodate-Schiff reaction staining.RESULTS In both the in vivo and in vitro experiments,it was observed that high glucose induction significantly decreased miR-29a-3p expression.As a result of this downregulation,DKD-related fibrosis was found to be promoted,as confirmed by elevated expression levels ofα-smooth muscle actin,collagen type I,and fibronectin.MiR-29a-3p targets the 3’non-coding regions of DNMT3A and DNMT3B and inhibits their expression.Inhibition of DNMT3A and DNMT3B can reverse the effect of miR-29a-3p downregulation on DKD-related fibrosis.CONCLUSION MiR-29a-3p can regulate Wnt/β-catenin and Janus kinase/signal transducer and activator of transcription signal pathways by regulating and inhibiting the expression of DNMT3A/3B and thus participate in the inhibition of DKD-related fibrosis.
文摘This study by Zhang et al elucidates the role of exosome miR-137-3p targeting ubiquitin protein ligase E3C to activate signal transducer and activator of transcription 3 under hypoxia conditions,thereby promoting the migration and differentiation of human umbilical cord mesenchymal stem cells to endometrial epithelial cells.It emphasizes that exosomal miR-137-3p/ubiquitin protein ligase E3C/signal transducer and activator of transcription 3 axis is a promising pathway for endometrial regeneration.This article introduced the therapeutic potential of exosomal microRNAs in regenerative medicine while underscoring the need for standardized protocols in optimizing exosome delivery and validating molecular pathways for clinical translation.
基金the National Natural Science Foundation of China,No.82170406 and No.81970238the Royal Society United Kingdom,No.IEC\NSFC\201094.
文摘Exosomes derived from hypoxic endometrial epithelial cells are pivotal in cellular communication and tissue repair,offering new perspectives on reproductive health.This manuscript highlights the study by Zhang et al,which investigates the effects of miR-214-5p and miR-21-5p in hypoxic cell-derived exosomes on human umbilical cord mesenchymal stem cells.The study reveals that low levels of these microRNAs activate the signal transducer and activator of transcription 3 signaling pathway,enhancing human umbilical cord mesenchymal stem cell migration and differentiation.These findings provide novel insights into therapeutic strategies for improving endometrial health and addressing infertility linked to thin endometrium.
基金Supported by the National High Level Hospital Clinical Research Funding,No.2022-PUMCH-B-080 and No.2022-PUMCH-C-064.
文摘BACKGROUND Thin endometrium,leading cause of recurrent implantation failure and infertility,has been found to respond to exosomes.AIM To investigate the efficacy of exosomes in addressing the issue of thin endometrium.METHODS RNA sequencing and reverse transcription-quantitative polymerase chain reaction were employed to identify differentially expressed microRNAs(miRNAs)in human umbilical cord mesenchymal stem cell(hucMSC)treated with exosomes enriched with endometrial cell-derived components.Additionally,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to highlight significant enrichment in specific biological pathways,molecular functions,and cellular components.Transwell and wound healing assays were performed to assess migratory potential,and western blotting was detected protein level.RESULTS A total of 53 differentially expressed miRNAs were identified in hucMSC treated with exosomes enriched with endometrial cell-derived components,comprising 27 upregulated and 26 downregulated miRNAs,which includes miR-137-3p.Enhanced migratory potential was observed in the Transwell and wound healing assays,and western blotting confirmed the epithelial differentiation of hucMSC and the increased p-signal transducer and activator of transcription 3.These effects were attributed to the upregulation of miR-137-3p.CONCLUSION miR-137-3p in exosomes from hypoxia-affected endometrial epithelial cell stimulates the signal transducer and activator of transcription 3 signaling pathway,enhancing the migration and differentiation of hucMSC into endometrial epithelial cell.
基金supported by grants from the Open Grant from the Pingyuan Laboratory(No.2023PYOP-0203)Young Elite Scientists Sponsorship Program by China Association for Science and Technology(No.2023QNRC001)+1 种基金Beijing Natural Science Foundation(No.7244407)National Natural Science Foundation of China(Nos.82400846 and 82274327).
文摘Objective Th17 cell-mediated immune injury is a crucial factor contributing to tubulointerstitial fibrosis in patients with IgA nephropathy(IgAN).However,the exact mechanisms by which Th17 cells induce tubulointerstitial fibrosis remain to be fully elucidated.Methods An IgAN mouse model was established and validated.Transcriptome sequencing,combined with bioinformatics analysis,was carried out to explore the immune injury pathways in renal tissues and the activation pathways in Th17 cells that were co-cultured with tubular epithelial cells.In subsequent experiments,small interfering RNA(siRNA)and overexpression plasmids were used to manipulate cellular targets.Validation was conducted through quantitative real-time polymerase chain reaction(qPCR),Western blotting,and immunofluorescence assays.Results Compared with the control mice,IgAN mice exhibited elevated serum creatinine levels and increased urine protein-to-creatinine ratios.Renal pathological examination revealed the characteristic features of IgAN.Transcriptomic analysis of the kidney tissues from the model mice showed the activation of Th17 differentiation pathways,which was further confirmed by immunofluorescence analysis showing increased expression of interleukin-17A(IL-17A).These findings indicate an increased abundance of Th17 cells with potential pathogenic significance.When Th17 cells were co-cultured with tubular epithelial cells,the level of interleukin-9(IL-9)in the system increased.This increase in IL-9 activated the Janus kinase 1-signal transducer and activator of transcription 3(JAK1-STAT3)pathway through the IL-9 receptor(IL-9R)and upregulated the signature transcription factor retinoic acid-related orphan receptor gamma(ROR-γ),thus promoting Th17 cell differentiation.When IL-9R was silenced using siRNA or when the activity of STAT3 was inhibited,both the levels of phosphorylated STAT3(p-STAT3)and ROR-γdecreased.Moreover,IL-17A secreted by Th17 cells promoted the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)in tubular epithelial cells by activating the IL-17 receptor A(IL-17RA)–adaptor protein Act1–tumor necrosis factor receptor-associated factor 6(TRAF6)complex.This process regulated the production of inflammatory cytokines and drove the initiation and progression of fibrosis.Treatment with a STAT3 inhibitor in IgAN mice led to a reduction in the number of renal Th17 cells and alleviated the fibrotic phenotype.Conclusion This study demonstrated that the interaction between Th17 cells and tubular epithelial cells triggers excessive extracellular matrix deposition in the tubulointerstitium,thereby exacerbating the fibrotic phenotype and accelerating the progression of IgAN.
基金supported by Health Education England/National Institute for Health Research(NIHR)(Clinical Lectureship CL-2020-18-009 for C.H.).
文摘Introduction Late age-related macular degeneration(AMD)is one of the leading causes of blindness globally(1).In their recent study published in JAMA Ophthalmology,Hallak et al.explore the potential of an emerging therapeutic opportunity of Janus kinase inhibitor(JAKi)in the role of systemic inflammation in AMD pathogenesis(2).This study offers a real-world examination of the relationship between JAKi and AMD,comparing the incidence of AMD in patients treated with JAKi and those receiving other immunotherapies for existing autoimmune diseases.
基金supported by grants from Jazz Pharmaceuticals Inc.the Texas A&M University of School of Medicine to AKS
文摘Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
基金The Sixth Batch of Special Support Plans in Anhui Province(No.dlPtzjh20200050)Key Natural Science Research Project of Higher Education Institutions in Anhui Province(No.KJ2020A0426)。
文摘Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.
