Objective:Diagnosis of immunoglobulin A nephropathy(IgAN)requires the evaluation of renal biopsy specimens.However,renal biopsy is an invasive procedure and is not frequently performed for various reasons.Thus,recogni...Objective:Diagnosis of immunoglobulin A nephropathy(IgAN)requires the evaluation of renal biopsy specimens.However,renal biopsy is an invasive procedure and is not frequently performed for various reasons.Thus,recognized noninvasive biomarkers for predicting IgAN progression are urgently needed.Methods:In the present study,we included 86 IgAN patients with renal biopsy from June 2015 to May 2016 and had their plasma interleukin-7(IL-7)level measured with ELISA.The association between the plasma IL-7 level and clinico-pathological characteristics was analyzed.Immunohistochemical staining was used to assay the in situ expression of IL-7 in vivo.Western blotting was perfonned to examine the production of extracellular matrix,p-mTOR and the markers of autophagy under the treatment of IL-7 after TGF-β1 stimulation in renal tubular epithelial cells.Results:IL-7 was significantly decreased in patients with IgAN compared to healthy subjects(2.3077 vs.8.6294 pg/mL,P<0.0001).There was a significant difference in the plasma IL-7 level between tubular atrophy/interstitial fibrosis TO and T2 classes(P=0.0064).A lower plasma IL-7 value in patients at the time of biopsy indicated a poor renal outcome.In addition,IL-7 was over-expressed in renal tubular epithelial cells and significantly attenuated transforming growth factor β1-induced extracellular matrix production by suppression of cellular autophagy via activation of mTOR1 signaling.Conclusion:These results suggested that IL-7 might be a noninvasive biomarker for predicating IgAN.It protected renal proximal tubular epithelial cells from cellular fibrosis by inhibiting autophagy via mTORl signaling.展开更多
The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multi...The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.展开更多
OBJECTIVE:To investigate the pharmacological effects and underlying mechanisms of Pinggan Yuyin Qingre formula(平肝育阴清热方,PGYYQR)in the treatment of meibomian gland dysfunction(MGD)through network pharmacology and...OBJECTIVE:To investigate the pharmacological effects and underlying mechanisms of Pinggan Yuyin Qingre formula(平肝育阴清热方,PGYYQR)in the treatment of meibomian gland dysfunction(MGD)through network pharmacology and in vivo validation.METHODS:A mouse model of MGD was induced using the stearoyl-coenzyme a desaturase 1 inhibitor,followed by PGYYQR treatment for 2 weeks.MGD sign scoring,hematoxylin and eosin(HE)staining,oil red o(ORO)staining,and serum inflammatory cytokine analysis were conducted to assess the effects of PGYYQR on meibomian gland(MG)function,histopathology,and associated inflammation.Network pharmacology was employed to identify the active compounds and potential targets of PGYYQR.Molecular mechanisms were further investigated using Western blotting,reverse transcription quantitative real-time polymerase chain reaction,and reactive oxygen species(ROS)assays.RESULTS:PGYYQR treatment significantly reduced the scores of MG orifice obstruction and meibum quality in MGD mice.HE and ORO staining further demonstrated that PGYYQR ameliorated glandular damage and lipid dysfunction.Enzyme-linked immunosorbent assay results revealed that PGYYQR markedly decreased the serum levels of key inflammatory cytokines,including interleukin(IL)-1β,IL-6,and tumor necrosis factor-α.Network pharmacology identified 162 active compounds and 598 target genes in PGYYQR.Among these,IL-6,IL-1β,matrix metalloproteinase-9,and C-X-C motif chemokine ligand 8 were recognized as core targets related to MGD and were mainly enriched in the IL-17/nuclear factor kappa B(NF-κB)signaling pathway.Further molecular analyses confirmed that PGYYQR significantly inhibited the IL-17/NF-κB axis by downregulating IL-17 expression and reducing phosphorylated NF-κB p65 levels at both the protein and m RNA levels in MG tissues.PGYYQR also effectively reduced ROS levels in the conjunctival tissues of MGD mice.CONCLUSION:PGYYQR effectively improves MG function and preserves local tissue morphology in MGD model mice,primarily by suppressing the inflammatory response through coordinated modulation of the IL-17/NF-κB signaling pathway and oxidative stress.展开更多
基金supported by grants from Huazhong University of Science and Technology Research Funds for Self-dependent Innovation(No.2017KFYXJJ101)the National Natural Science Foundation of China(No.81703058,No.81970591,and No.82000656).
文摘Objective:Diagnosis of immunoglobulin A nephropathy(IgAN)requires the evaluation of renal biopsy specimens.However,renal biopsy is an invasive procedure and is not frequently performed for various reasons.Thus,recognized noninvasive biomarkers for predicting IgAN progression are urgently needed.Methods:In the present study,we included 86 IgAN patients with renal biopsy from June 2015 to May 2016 and had their plasma interleukin-7(IL-7)level measured with ELISA.The association between the plasma IL-7 level and clinico-pathological characteristics was analyzed.Immunohistochemical staining was used to assay the in situ expression of IL-7 in vivo.Western blotting was perfonned to examine the production of extracellular matrix,p-mTOR and the markers of autophagy under the treatment of IL-7 after TGF-β1 stimulation in renal tubular epithelial cells.Results:IL-7 was significantly decreased in patients with IgAN compared to healthy subjects(2.3077 vs.8.6294 pg/mL,P<0.0001).There was a significant difference in the plasma IL-7 level between tubular atrophy/interstitial fibrosis TO and T2 classes(P=0.0064).A lower plasma IL-7 value in patients at the time of biopsy indicated a poor renal outcome.In addition,IL-7 was over-expressed in renal tubular epithelial cells and significantly attenuated transforming growth factor β1-induced extracellular matrix production by suppression of cellular autophagy via activation of mTOR1 signaling.Conclusion:These results suggested that IL-7 might be a noninvasive biomarker for predicating IgAN.It protected renal proximal tubular epithelial cells from cellular fibrosis by inhibiting autophagy via mTORl signaling.
基金supported by the National Natural Science Foundational of China(Key Program),No.U24A20692(to CJZ)the National Natural Science Foundational of China,Nos.82101414(to MLJ),82371355(to CJZ)+4 种基金the National Natural Science Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovation and Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’s Hospital,No.30420230005(to CJZ)Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(to CJZ)。
文摘The interleukin-17 family is the key group of cytokines and displays a broad spectrum of biological functions,including regulating the inflammatory cascade in various autoimmune and inflammatory diseases,such as multiple sclerosis,neuromyelitis optica spectrum disorder,myasthenia gravis,Guillain–Barre syndrome,acute disseminated encephalomyelitis,diabetes,inflammatory skin diseases,joint inflammation,and cancer.Although the function of the interleukin-17 family has attracted increasing research attention over many years,the expression,function,and regulation mechanisms of different interleukin-17 members are complicated and still only partially understood.Currently,the interleukin-17A pathway is considered a critical therapeutic target for numerous immune and chronic inflammatory diseases,with several monoclonal antibodies against interleukin-17A having been successfully used in clinical practice.Whether other interleukin-17 members have the potential to be targeted in other diseases is still debated.This review first summarizes the recent advancements in understanding the physicochemical properties,physiological functions,cellular origins,and downstream signaling pathways of different members and corresponding receptors of the interleukin-17 family.Subsequently,the function of interleukin-17 in various immune diseases is discussed,and the important role of interleukin-17 in the pathological process of immune diseases is demonstrated from multiple perspectives.Then,the current status of targeted interleukin-17 therapy is summarized,and the effectiveness and safety of targeted interleukin-17 therapy are analyzed.Finally,the clinical application prospects of targeting the interleukin-17 pathway are discussed.
基金Supported by National Famous and Senior Chinese Medicine Expert Heritage Studio Construction Project:Zhi Nan Heritage Studio(No.75[2022])Beijing Municipal Key Traditional Chinese Medicine Specialty Development Project during the 14th Five-Year Plan Period(No.BJZKBC0029)。
文摘OBJECTIVE:To investigate the pharmacological effects and underlying mechanisms of Pinggan Yuyin Qingre formula(平肝育阴清热方,PGYYQR)in the treatment of meibomian gland dysfunction(MGD)through network pharmacology and in vivo validation.METHODS:A mouse model of MGD was induced using the stearoyl-coenzyme a desaturase 1 inhibitor,followed by PGYYQR treatment for 2 weeks.MGD sign scoring,hematoxylin and eosin(HE)staining,oil red o(ORO)staining,and serum inflammatory cytokine analysis were conducted to assess the effects of PGYYQR on meibomian gland(MG)function,histopathology,and associated inflammation.Network pharmacology was employed to identify the active compounds and potential targets of PGYYQR.Molecular mechanisms were further investigated using Western blotting,reverse transcription quantitative real-time polymerase chain reaction,and reactive oxygen species(ROS)assays.RESULTS:PGYYQR treatment significantly reduced the scores of MG orifice obstruction and meibum quality in MGD mice.HE and ORO staining further demonstrated that PGYYQR ameliorated glandular damage and lipid dysfunction.Enzyme-linked immunosorbent assay results revealed that PGYYQR markedly decreased the serum levels of key inflammatory cytokines,including interleukin(IL)-1β,IL-6,and tumor necrosis factor-α.Network pharmacology identified 162 active compounds and 598 target genes in PGYYQR.Among these,IL-6,IL-1β,matrix metalloproteinase-9,and C-X-C motif chemokine ligand 8 were recognized as core targets related to MGD and were mainly enriched in the IL-17/nuclear factor kappa B(NF-κB)signaling pathway.Further molecular analyses confirmed that PGYYQR significantly inhibited the IL-17/NF-κB axis by downregulating IL-17 expression and reducing phosphorylated NF-κB p65 levels at both the protein and m RNA levels in MG tissues.PGYYQR also effectively reduced ROS levels in the conjunctival tissues of MGD mice.CONCLUSION:PGYYQR effectively improves MG function and preserves local tissue morphology in MGD model mice,primarily by suppressing the inflammatory response through coordinated modulation of the IL-17/NF-κB signaling pathway and oxidative stress.
