INFLAMMATION
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2023
·
IF 5.1
Feng Yong,Hu Jiapeng,Liu Fen,Shang Yunxiao
Asthma is a chronic inflammatory disease characterized by airway remodeling and lung inflammation. Collagen triple helix repeat containing 1 (CTHRC1), a glycoprotein, is involved in multiple pathological processes, including inflammation and fibrosis. However, the function of CTHRC1 in asthma remains unclear. In the present study, the mouse asthma model was successfully generated by sensitizing and challenging mice with ovalbumin (OVA). CTHRC1 expression at both RNA and protein levels was significantly upregulated in lung tissues of asthmatic mice. Asthmatic mice exhibited significant airway remodeling as evidenced by increased bronchial wall and smooth muscle cell layer thickness, goblet cell hyperplasia and collagen deposition, and epithelial-mesenchymal transition (EMT), but those characteristics were reversed by CTHRC1 silencing. The cell model with transforming growth factor-β1 (TGF-β1) induction in bronchial epithelial cells (BEAS-2B) was conducted to verify the effects of CTHRC1 on EMT, a classic mechanism that mediates airway remodeling. The results showed that TGF-β1 stimulation increased CTHRC1 expression, and CTHRC1 knockdown inhibited TGF-β1-induced EMT. OVA-treated mice also showed increased inflammatory cell infiltration and the production of OVA-specific immunoglobulin E (IgE), interleukin (IL)-4, IL-5, and IL-13, which were decreased by CTHRC1 downregulation. The effects of CTHRC1 on OVA-induced airway inflammation were further determined by treating BEAS-2B cells with IL-13, in which CTHRC1 knockdown reduced the IL-13-induced secretion of pro-inflammatory factors, including IL-4 and IL-5. In conclusion, these results indicate that CTHRC1 silencing attenuates asthmatic airway remodeling and inflammation in vivo and in vitro, suggesting that CTHRC1 may be a potential target for asthma treatment. Graphical Abstract
研究领域:
免疫学
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呼吸医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhu Liang,Keyan Zhang,Hongli Guo,Xujiao Tang,Mingzhu Chen,Jinsong Shi,Jing Yang
Cordycepin (CRD) is an active component derived from Cordyceps militaris , which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro , CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-β1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescence marker p21, and provoked S phase arrest of activated HSC. Remarkably, CRD treatment abolished TGF-β‐induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
LIVER INTERNATIONAL
·
2022
·Vol. 43
·期 2
·500-512
·
IF 8.754
Mengli Yu,Xinjue He,Xin Song,Jianguo Gao,Jiaqi Pan,Tianyu Zhou,Qinqiu Wang,Wei Zhu,Huijian Ma,Hang Zeng,Chengfu Xu,Chaohui Yu
Background Biglycan (BGN) is a small leucine-rich proteoglycan that participates in the production of excess extracellular matrix (ECM) and is related to fibrosis in many organs. However, the role of BGN in liver fibrosis remains poorly understood. This study aimed to investigate the role and mechanism of BGN in liver fibrosis. Methods Human liver samples, Bgn −/0 (BGN KO) mice and a human LX-2 hepatic stellate cells (HSCs) model were applied for the study of experimental fibrosis. GEO data and single-cell RNA-seq data of human liver tissue were analysed as a bioinformatic approach. Coimmunoprecipitation, immunofluorescence staining, western blotting and qRT–PCR were conducted to identify the regulatory effects of BGN on heat shock protein 47 (HSP47) expression and liver fibrosis. Results We observed that hepatic BGN expression was significantly increased in patients with fibrosis and in a mouse model of liver fibrosis. Genetic deletion of BGN disrupted TGF-β1 pathway signalling and alleviated liver fibrosis in mice administered carbon tetrachloride (CCl 4 ). siRNA-mediated knockdown of BGN significantly reduced TGF-β1-induced ECM deposition and fibroblastic activation in LX-2 cells. Mechanistically, BGN directly interacted with and positively regulated the collagen synthesis chaperon protein HSP47. Rescue experiments showed that BGN promoted hepatic fibrosis by regulating ECM deposition and HSC activation by positively regulating HSP47. Conclusion Our data indicate that BGN promotes hepatic fibrosis by regulating ECM deposition and HSC activation through an HSP47-dependent mechanism. BGN may be a new biomarker of hepatic fibrosis and a novel target for disease prevention and treatment.
研究领域:
分子生物学
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肝病学
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细胞生物学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
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2011
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IF 3.463
Jiliang Wu,Chunyan Liao,Jun Zhang,Wenze Cheng,Nuo Zhou,Sheng Wang,Ying Wan
Chitosan microspheres loaded with transforming growth factor-β1 (TGF-β1) were first prepared with an emulsification method using genipin as crosslinker, and the selected microspheres were then embedded into porous scaffolds built by chitosan-polycaprolactone with polycaprolactone content of around 42 wt.%. Some optimized chitosan-polycaprolactone scaffolds with porosity higher than 80% and having an initial TGF-β1 load of around 3 ng(TGF-β1)/mg(dry scaffold) were capable of maintaining sustained release of TGF-β1 in a simulant in vivo environment at controlled rates over a period of time longer than four weeks without severely initial burst. The chitosan-polycaprolactone scaffolds also showed well-defined compressive properties in wet state with compressive stress at 10% strain and modulus higher than 100 kPa and 1000 kPa, respectively, which are almost ten-fold higher than that of corresponding microsphere-embedded chitosan scaffolds. The obtained results suggest that potential applications of the scaffolds in articular cartilage repair.
研究领域:
生物材料
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组织工程
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生物医学工程
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产品关联
DOI
高影响因子
Nano Research
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2022
·Vol. 15
·期 9
·8214-8227
·
IF 10.269
Ding Yifan,Wang Huan,Wang Yunyun,Li Long,Ding Jiahui,Yuan Caiyan,Xu Tao,Xu Haoran,Xie Hui,Zhu Ning,Hu Xin,Fang Huang,Tan Songwei
Intervertebral disc degeneration (IDD) is closely related to inflammation and imbalance of synthesis/catabolism of extracellular matrix (ECM) in intervertebral disc (IVD). Considering this, luteolin (LUT), a kind of natural flavonoid with good anti-inflammatory effect and TGF-β1 (a gene that promotes the regeneration of ECM) plasmid was co-loaded and co-delivered to nucleus pulposus cells (NPCs). Reactive oxygen species (ROS) responsive cationic copolymer, poly(β-amino ester)-poly(ε-caprolactone) (PBC), with high plasmid DNA (pDNA) compression affinity was synthesized. It can self-assemble into nano-sized polyplexes (pDNA@PBC) with virus-inspired structure and function through which it can transfect pDNA into NPCs with very high efficiency and negligible cytotoxicity. LUT was encapsulated in the hydrophobic core of pDNA@PBC. The co-delivery system, LUT-pTGF-β1@PBC, could enhance the cellular uptake of NPCs and manifest excellent sustained drug release in IVD. Real time quantitative polymerase chain reaction (RT-qPCR) and Western blot experiments reveal that the co-delivery system could inhibit inflammation in NPCs and restore the balance of anabolism and catabolism in vitro by activating TGF/SMAD3 and inhibiting NF- k B/p65. Moreover, LUT-pTGF-β1@PBC retards IDD in vivo as detected by radiological and histological methods with good biosafety in rats. LUT-pTGF-β1@PBC may be a promising option for the treatment of IDD.
研究领域:
生物医学工程
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药学
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骨科
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纳米技术
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DOI
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 22
·7669
·
IF 4.6
Hongxing Zheng,Yingjun Hu,Mengli Shao,Simin Chen,Shanshan Qi
Chromium picolinate (CP) is an organic compound that has long been used to treat diabetes. Our previous studies found CP could relieve diabetic nephropathy. Thus, we speculate that it might have a positive effect on diabetic testicular injury. In this study, a diabetic rat model was established, and then the rats were treated with CP for 8 weeks. We found that the levels of blood glucose, food, and water intake were reduced, and body weight was enhanced in diabetic rats after CP supplementation. Meanwhile, in CP treatment groups, the levels of male hormone and sperm parameters were improved, the pathological structure of the testicular tissue was repaired, and testicular fibrosis was inhibited. In addition, CP reduced the levels of serum inflammatory cytokines, and decreased oxidative stress and apoptosis in the testicular tissue. In conclusion, CP could ameliorate testicular damage in diabetic rats, as well as being a potential testicle-protective nutrient in the future to prevent the testicular damage caused by diabetes.
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2024
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IF 8.7
Yun Zhou,Xu He,Wen Zhang,Weiguo Zhang,Huan Zhao,Xichao Zhou,Qiaoli Gu,Hao Shen,Huilin Yang,Xingzhi Liu,Lixin Huang,Qin Shi
Osteoarthritis (OA) is a degenerative disease potentially exacerbated due to inflammation, cartilage degeneration, and increased friction. Both mesenchymal stem cells (MSCs) and pro-inflammatory macrophages play important roles in OA. A promising approach to treating OA is to modify multi-functional hydrogel microspheres to target the OA microenvironment and structure. Arginyl-glycyl-aspartic acid (RGD) is a peptide widely used in bioengineering owing to its cell adhesion properties, which can recruit BMSCs and macrophages. We developed TLC-R, a microsphere loaded with TGF-β1-containing liposomes. The recruitment effect of TLC-R on macrophages and BMSCs was verified by in vitro experiments, along with its function of promoting chondrogenic differentiation of BMSCs. And we evaluated the effect of TLC-R in balancing OA metabolism in vitro and in vivo . When TLC-R was co-cultured with BMSCs and lipopolysaccharide (LPS)-treated macrophages, it showed the ability to recruit both cells in substantial numbers. As the microspheres degraded, TGF-β1 and chondroitin sulfate (ChS) were released to promote chondrogenic differentiation of the recruited BMSCs, modulate chondrocyte metabolism and inhibit inflammation induced by the macrophages. Furthermore, in vivo analysis showed that TLC-R restored the narrowed space, reduced osteophyte volume, and improved cartilage metabolic homeostasis in OA rats. Altogether, TLC-R provides a comprehensive and novel solution for OA treatment by dual-modulating inflammatory and chondrocyte metabolism.
研究领域:
生物医学工程
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骨科
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再生医学
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炎症生物学
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产品关联
DOI
PubMed
高影响因子
Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-21
·
IF 8.2
Wu Chengyan,Hu Li,Liu Bing,Zeng Xingyue,Ma Haixiang,Cao Yongkai,Li Huijun,Zhang Xiaohan
Background Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D 2 -like receptors (D 2 R, D 3 R, D 4 R), have suggested the existence of other desensitization mechanisms. The present study employed D 2 R/D 3 R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. Results AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D 3 R, ubiquitination of AKT is also involved in the desensitization of β 2 adrenoceptors. Conclusion Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
研究领域:
细胞生物学
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分子生物学
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药理学
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信号转导
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Ma Yucong,Ye Suping,Sun Kunpeng,Gu Yue
Curcumin (CUR) possesses the capability to inhibit various inflammatory factors, exert anti-inflammatory effects, and alleviate asthma attacks; however, its hydrophobicity and instability significantly impede its clinical application. In this study, we synthesized CUR-loaded nanoparticles (CUR-NPs) and evaluated their impact on the proliferation, migration, and inflammatory infiltration of mouse airway smooth muscle cells (ASMCs), while investigating their underlying mechanisms. To achieve this objective, ASMCs were isolated from BALB/c mice and subjected to TGF-β1-induced cell proliferation and migration. Our findings demonstrate that CUR-NPs effectively regulate the release of CUR within cells with superior intracellular uptake compared to free CUR. The CCK-8 assay results indicate that the blank carrier does not exhibit any cytotoxic effects on cells, thus rendering the impact of the carrier itself negligible. The TGF-β1 group exhibited a significant increase in cell proliferation, whereas treatment with CUR-NPs significantly suppressed TGF-β1-induced cell proliferation. The findings from both the cell scratch assay and transwell assay demonstrated that TGF-β1 substantially enhanced cell migration, while CUR-NPs treatment effectively attenuated TGF-β1-induced cell migration. The Western blot analysis demonstrated a substantial increase in the expression levels of TGF-β1, p-STAT3, and CTGF in ASMCs following treatment with TGF-β1 when compared to the control group. Nevertheless, this effect was effectively counteracted upon administration of CUR-NPs. Furthermore, an asthma mouse model was successfully established and CUR-NPs were administered through tail vein injection. The serum levels of TGF-β1 and the expression levels of TGF-β1, p-STAT3, and CTGF proteins in the lung tissue of mice in the model group exhibited significant increases compared to those in the control group. However, CUR-NPs treatment effectively attenuated this change. Our research findings suggest that CUR-NPs possess inhibitory effects on ASMC proliferation, migration, and inflammatory infiltration by suppressing activation of the TGF-β1/p-STAT3/CTGF signaling pathway, thereby facilitating inhibition of airway remodeling.
研究领域:
药理学
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呼吸病学
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纳米技术
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免疫学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Regenerative Biomaterials
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2025
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IF 8.1
Wen Zhuohao,Li Shuyi,Qiu Huiguo,Liu Xueyan,You Zhiying,Yan Yuhan,Che Yuejuan,Zhou Miao
Periosteum plays an indispensable role in bone regeneration by providing osteogenic and angiogenic cues essential for tissue repair. In cases of severe bone defects or nonunion, autologous vascularized periosteum transplantation remains a highly effective clinical solution. However, its application is restricted by donor site morbidity and limited tissue availability, thereby underscoring the urgent need for artificial periosteum that mimics both the composition and structure of the native counterpart. Among these properties, the topological morphology of the periosteum is believed to be critical, yet its influence on bone regeneration remains insufficiently understood. In this study, biomimetic periosteum membranes composed of coaxially electrospun poly(ε-caprolactone) (PCL) and periosteal extracellular matrix (pECM) were fabricated with either random or aligned nanofiber architectures. Their osteogenic potential was systematically evaluated in vitro and in vivo. Compared to the randomly arranged structure, aligned pECM (aPEC) significantly enhanced the adhesion, alignment, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by activating the ITGB1/PI3K/AKT signaling pathway, whereas these effects were not observed in pure PCL membranes. These findings demonstrate that aligned topological morphology in biomimetic periosteum plays a pivotal role in directing stem cell behavior and promoting bone regeneration. This work provides mechanistic insight and technical guidance for the future design of functionally enhanced artificial periosteum for bone tissue engineering applications.
研究领域:
组织工程
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生物材料学
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分子生物学
·
再生医学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2023
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IF 5.8
Jialin Chen,Qingyun Mo,Qiuzi Long,Renwang Sheng,Zhixuan Chen,Yifan Luo,Chuanquan Liu,Ludvig J. Backman,Yanan Zhang,Wei Zhang
Corneal fibrosis is a common outcome of inappropriate repair associated with trauma or ocular infection. Altered biomechanical properties with increased corneal stiffness is a feature of fibrosis that cause corneal opacities, resulting in severe visual impairment and even blindness. The present study aims to determine the effect of hydroxycamptothecin (HCPT) and matrix stiffness on transforming growth factor-β1 (TGF-β1)-induced fibrotic processes in human corneal fibroblasts (HTK cells). HTK cells were cultured on substrates with different stiffnesses (“soft”, ∼261 kPa; “stiff”, ∼2.5 × 103 kPa) and on tissue culture plastic (TCP, ∼106 kPa) and simultaneously treated with or without 1 μg/mL HCPT and 10 ng/mL TGF-β1. We found that HCPT induced decreased cell viability and antiproliferative effects on HTK cells. TGF-β1-induced expression of fibrosis-related genes (FN1, ACTA2) was reduced if the cells were simultaneously treated with HCPT. Substrate stiffness did not affect the expression of fibrosis-related genes. The TGF-β1 induced expression of FN1 on both soft and stiff substrates was reduced if cells were simultaneously treated with HCPT. However, this trend was not seen for ACTA2, i.e., the TGF-β1 induced expression of ACTA2 was not reduced by simultaneous treatment of HCPT in either soft or stiff substrate. Instead, HCPT treatment in the presence of TGF-β1 resulted in increased gene expression of keratocyte phenotype makers (LUM, KERA, AQP1, CHTS6) on both substrate stiffnesses. In addition, the protein expression of keratocyte phenotype makers LUM and ALDH3 was increased in HTK cells simultaneously treated with TGF-β1 and HCPT on stiff substrate as compared to control, i.e., without HCPT. In conclusion, we found that HCPT can reduce TGF-β1-induced fibrosis and promote the keratocyte phenotype in a substrate stiffness dependent manner. Thus, HCPT stimulation might be an approach to stimulate keratocytes in the appropriate healing stage to avoid or reverse fibrosis and achieve more optimal corneal wound healing.
研究领域:
眼科学
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细胞生物学
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生物力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Zhi Zheng,Jian Sun,Jun Wang,Suisui He,Yun Huang,Xu Yang,Yuqi Zhao,Cui-Yun Yu,Hua Wei
The compromised microenvironment after cartilage injury generally leads to low survival or abnormal differentiation of implanted stem cells for fibrocartilage formation with weak mechanical properties. Suitable and safe bionic materials can provide mechanical properties for cartilage repair while promoting cartilage regeneration effects. However, to our knowledge, mechanical strength modulation of therapeutic peptide-based bionic hydrogels remains relatively unexplored, and further application of peptide-based bionic hydrogels in a negative feedback manner for defective cartilage repair has been seldom reported so far. In this study, we reported the first sophisticated design and fabrication of a dual cross-linked peptide-based hydrogel for promoted cartilage regeneration in a feedback-regulated manner. The integration of multiple supramolecular forces including host–guest interactions and extensive hydrogen bonding endow the resulting hydrogels with excellent self-healing and mechanical strength for highly synergistic lubrication properties and compressive performance. More importantly, the unique integrative peptide VPM-pmTGF-β1 can realize on-demand pmTGF-β1 release that is triggered by the MMP-3-responsive cleavage of a VPM sequence. When the VPM-pmTGF-β1-modified hydrogel system is implanted into the cartilage defect sites in a model of SD rats, MMP-3-triggered on-demand pmTGF-β1 release suppresses IκBα/NF-κB signaling pathway-induced cartilage inflammation in a negative feedback manner while promoting the targeted cartilage differentiation of BMSCs for efficient cartilage regeneration. The novel strategy developed herein contributes to a more comprehensive and in-depth understanding of the biological properties of peptide-based hydrogels for cartilage defect repair and provides a simple yet powerful means for clinical translations.
研究领域:
生物材料
·
组织工程
·
再生医学
·
生物力学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
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