LIFE SCIENCES
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2020
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IF 3.647
Li Li,Sufang Zhang,Lei Wei,Zhongfu Wang,Wei Ma,Fangying Liu,Yanhua Shen,Shanfang Zhang,Xiulian Zhang,Yu Hang,Yechang Qian
Aims To investigate the effect and underlying mechanism of melittin and tripartite motif (TRIM) family in human embryonic lung fibroblast (HELF). Materials and methods Lentiviral RNA interference vector and lentiviral overexpression vector were constructed and packaged by transfecting 293T cells; the proliferation of HELF was examined using Cell Counting Kit 8; Western blot and qRT-PCR were performed to examine protein and mRNA expression; the interaction with protein phosphatase magnesium-dependent 1A (PPM1A) was examined by Co-immunoprecipitation. Key findings Compared with the control group, the mRNA expression of the TRIM6, TRIM8 and TRIM47 in the IPF group significantly increased. Melittin inhibited the mRNA expression and protein expression levels of TRIM47, the HELF proliferation, the hydroxyproline levels, and the phosphorylation of Smad2/3; the interference of TRIM47 inhibited the protein expression of Vimentin, α-SMA, CTGF, the phosphorylation of Smad2/3 and the synthesis of hydroxyproline; TRIM47 overexpression elevated the phosphorylation of Smad2/3, induced ubiquitination of PPM1A and decreased the expression level of PPM1A, while TRIM47 RNA interference reversed this result. Significance Melittin has anti-fibrotic effect in HELF by directly reducing the phosphorylation of Smad2/3 or indirectly reducing the phosphorylation of Smad2/3 by decreasing the expression levels of TRIM47 whose overexpression induces ubiquitination of PPM1A.
研究领域:
药理学
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分子生物学
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细胞生物学
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肺纤维化
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DOI
PubMed
高影响因子
Interdisciplinary Medicine
·
2025
·Vol. 3
·期 5
·e70055
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IF 13.6
Zheting Liao,Ru Lian,Shiqi Zhao,Jie Yang,Zhonghao Deng,Desheng Wu,Zhongmin Zhang,Liang Zhao
The management of osteoarthritis (OA) and osteochondral defects faces challenges due to heightened catabolic activity from pro-inflammatory mediators and a lack of reparative cells. Transforming growth factor β1 (TGFβ1) plays a crucial role in cartilage maintenance and cellular recruitment, making it a promising therapeutic target. However, the high cost and unpredictable effects of exogenous TGFβ1 limit its clinical application. Notably, TGFβ1 is primarily found in a latent form within joint tissues, especially during early injury stages. This study proposes that activating endogenous TGFβ1 may serve as an effective treatment strategy. We demonstrate that an ascorbic acid (AA) and ferric chloride (AA/Fe) Fenton reaction system can activate latent TGFβ1 in knee joint tissues. Treatment with AA/Fe-activated synovial fluid protects chondrocytes from interleukin1β-induced damage and enhances chemotactic responses in joint tissues. Intra-articular AA/Fe injections in rats significantly phosphorylated SMAD2/3 and reduced cartilage degradation. Additionally, we developed poly(lactic-co-glycolic acid) microspheres for sustained AA/Fe release within a thermosensitive or photocrosslinkable hydrogel, showing high biocompatibility. These formulations effectively prevented cartilage degeneration and promoted osteochondral repair. Our findings confirm that AA/Fe reliably activates endogenous TGFβ1, providing a novel cell-free and cost-efficient treatment approach for OA and osteochondral defects.
研究领域:
骨科学
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再生医学
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分子生物学
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药剂学
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转化医学
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炎症学
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组织工程
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DOI
高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2022
·Vol. 36
·期 8
·e23084
·
IF 3.568
Qian Shang,Li Zhu,Weina Shang,Jia Zeng,Yong Qi
Dioscin is a natural product that possesses protective effects on multiple chronic injuries, but its effects on asthma are not fully understood. Herein, we evaluated its effects on asthmatic mice established by ovalbumin (OVA) sensitization and challenges and further explored the mechanism. Inflammatory cells in bronchoalveolar lavage fluids (BALFs) were analyzed using Diff-Quik staining. OVA-specific immunoglobulin E (IgE)/IgG1 in serum and inflammatory cytokines (interleukin 4[IL-4], IL-5, IL-13, and tumor necrosis factor-α) in BALFs and lung tissues were measured using Enzyme-Linked Immunosorbent Assay Kits. Hematoxylin and eosin, periodic acid–Schiff, and immunohistochemistry staining showed histopathological changes in lung tissues. Epithelial–mesenchymal transition (EMT) in human bronchial epithelial (16HBE) cells was assessed by immunofluorescence staining. Hydroxyproline content was used to evaluate collagen deposition. Polymerase chain reaction and Western blot were performed to measure messenger RNA and protein expression. We found that dioscin treatment (particularly at the dose of 80 mg/kg) significantly inhibited pulmonary inflammation in asthmatic mice, as evidenced by the decreased serum OVA-specific IgE/IgG1 and the reduced inflammatory cells and cytokines in BALFs and lung tissues. Moreover, dioscin effectively ameliorated the goblet cell hyperplasia, mucus hypersecretion, collagen deposition, and smooth muscle hyperplasia in the airways of asthmatic mice. Mechanistically, dioscin restrained the activated TGF-β1/Smad2/3 and protein kinase B (AKT) signal pathways in lung tissues and potently reversed the TGF-β1-induced EMT and phosphorylation of Smad2/3 and AKT in 16HBE cells. Collectively, dioscin displayed protective effects on OVA-induced asthmatic mice via adjusting TGF-β1/Smad2/3 and AKT signal pathways, supporting the fact that dioscin could be a candidate for chronic asthma prevention in the future.
研究领域:
药理学
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免疫学
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分子生物学
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呼吸医学
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DOI
PubMed
高影响因子
Redox Biology
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2022
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IF 10.787
Chenxu Ge,Jun Tan,Deshuai Lou,Liancai Zhu,Zixuan Zhong,Xianling Dai,Yan Sun,Qin Kuang,Junjie Zhao,Longyan Wang,Jin Liu,Bochu Wang,Minxuan Xu
Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl 4 )-induced liver injury and dysfunction in mice. Furthermore, CCl 4 -triggerd collagen deposition and liver fibrosis were remarkably attenuated in mice with Mul supplementation through suppressing transforming growth factor β1 (TGF-β1)/SMAD2/3 signaling pathway. Additionally, Mul treatments strongly restrained the hepatic inflammation in CCl 4 -challenged mice via blocking nuclear factor-κB (NF-κB) signaling. Importantly, we found that Mul markedly increased liver TRIM31 expression in CCl 4 -treated mice, accompanied with the inactivation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCl 4 -triggered hepatic oxidative stress was also efficiently mitigated by Mul consumption via improving nuclear factor E2-related factor 2 (Nrf2) activation. Our in vitro studies confirmed that Mul reduced the activation of human and mouse primary hepatic stellate cells (HSCs) stimulated by TGF-β1. Consistently, Mul remarkably retarded the inflammatory response and reactive oxygen species (ROS) accumulation both in human and murine hepatocytes. More importantly, by using hepatocyte-specific TRIM31 knockout mice (TRIM31 Hep-cKO ) and mouse primary hepatocytes with Nrf2-knockout (Nrf2 KO ), we identified that the anti-fibrotic and hepatic protective effects of Mul were TRIM31/Nrf2 signaling-dependent, relieving HSCs activation and liver fibrosis. Therefore, Mul-ameliorated hepatocyte injury contributed to the suppression of HSCs activation by improving TRIM31/Nrf2 axis, thus providing a novel therapeutic strategy for hepatic fibrosis treatment.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cardiovascular Medicine
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2022
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IF 5.846
Kai-Wen Ren,Xiao-Hong Yu,Yu-Hui Gu,Xin Xie,Yu Wang,Shi-hao Wang,Hui-Hua Li,Hai-Lian Bi
Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.
研究领域:
心脏病学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
ORAL DISEASES
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2026
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IF 3.1
Jiaying Shi,Shuxian Lin,Jiayu Yan,Wanyi Tang,Xiaohua Wu,Shuwen Ding,Siyi Chen,Ruowen Zhao,Junhua Wu
Background Osteoradionecrosis of the jaw (ORNJ) is a severe radiotherapy complication with unclear molecular drivers. CDKN1A/p21 is upregulated by radiation-induced DNA damage, but its role in ORNJ remains unknown. Methods An ORNJ mouse model was established. Single-cell RNA-sequencing of irradiated mandibles was analyzed and validated in vivo. Irradiated jaw bone marrow mesenchymal stem cells (JBMMSCs) were characterized. p21 was inhibited using UC2288 and siRNA. A UC2288-loaded AlgMA hydrogel was developed for local delivery. Results Bone healing was compromised in ORNJ. Radiation induced p21 upregulation in osteogenic lineage cells, which promoted Rb dephosphorylation and aberrant Smad2/3 phosphorylation, thereby suppressing Runx2-mediated osteogenesis. p21 inhibition reversed this cascade and restored osteogenic differentiation. Local delivery of UC2288@AlgMA significantly enhanced bone regeneration. Conclusion p21-related signaling impairs bone healing after irradiation, and local UC2288 delivery via AlgMA hydrogels represents a viable strategy to enhance ORNJ regeneration.
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高影响因子
Biomaterials Research
·
2024
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IF 8.1
Chenyang Li,Shuai Wang,Chenghui Liao,Ying Li,Yunfeng Zhou,Haiqiang Wu,Wei Xiong
Klotho (KLO) is an anti-fibrotic protein expressed in the kidneys and has been decreasing in the development of renal fibrosis (RF). However, restoring the decline in KLO levels remains a great challenge during RF treatment. Herein, an injectable KLO-loaded chitosan (CS) hydrogel (KLO-Gel) is designed to achieve localized and prolonged release of KLO in the RF treatment. KLO-Gel was prepared by cross-linking CS with β-glycerophosphate (β-GP), followed by rapid (within 3 min) thermosensitive gelation at 37 °C. Furthermore, KLO-Gel exhibited a slow and sustained release (over 14 d) of KLO both in PBS and in the kidneys of mice with unilateral ureter obstruction (UUO). A single local injection of KLO-Gel into the renal capsule of UUO mice was more effective at reducing RF (i.e., maintaining renal function and tissue structure, alleviating extracellular matrix accumulation, and inhibiting the TGF-β1/Smad2/3 signaling pathway) over a 14-d period than daily intraperitoneal injections of free KLO or captopril. Crucially, CS was found to induce endogenous KLO secretion, highlighting the added value of using CS in RF treatment. Overall, this study demonstrated that KLO-Gel enhanced the anti-fibrotic efficacy of KLO while minimizing its off-target toxicity, and its clinical potential awaits further validation.
研究领域:
药理学
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生物医学工程
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
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2022
·
IF 1.798
Kai KANG,Lukuan CUI,Qian ZHANG,Shijun GAO
Although many surgical or non-operative therapies have been developed to treat Achilles tendon injuries, the prognosis of which is often unsatisfactory. Recently, biologic approaches using multipotent stem cells like tendon-derived stem cells (TDSCs) pose a possible treatment option. To evaluate whether the Leucine rich repeat containing 32 (Lrrc32) affects the tenogenic differentiation of TDSCs and thus promotes Achilles tendon healing. TDSCs were infected with the recombinant Lrrc32-overexpressing lentivirus (LV-Lrrc32) and then locally injected into the injured site of rat. Four weeks after surgery, the Achilles tendon tissue (~0.5 cm) around the injured area was harvested for analysis. Pathological results showed that Lrrc32-overexpressing TDSCs significantly improved the morphological changes of the injured tendons. Specifically, the increased collagen-I expression and hydroxyproline content in extracellular matrix, and more orderly arrangement of the regenerated collagen fibers were observed in the Lrrc32 overexpression group. Moreover, 4 weeks after injection of Lrrc32-overexpressing TDSCs, the expression of tenocyte-related genes such as tenomodulin (Tnmd), scleraxis (Scx) and decorin (Dcn) were upregulated in the area of the healing tendon. These findings indicated that Lrrc32 promoted the tenogenic differentiation of TDSCs in vivo. Additionally, Lrrc32 overexpression also increased the expression of TGF-β1 and p-SMAD2/3, suggesting that the beneficial effects of Lrrc32 on tendon repair might be associated with the expression of TGF-β1 and p-SMAD2/3. Our findings collectively revealed that Lrrc32-overexpressed TDSCs promoted tendon healing more effectively than TDSCs alone.
研究领域:
干细胞生物学
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组织工程
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再生医学
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骨科
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
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IF 8.2
Wang Jie,Bai Mei,Zhang Cui,An Ning,Wan Li,Wang Xiao-ning,Du Rong-hui,Shen Yan,Yuan Zhi-yao,Wu Xu-dong,Wu Xue-feng,Xu Qiang
Intestinal fibrosis is a common complication of inflammatory bowel disease. There is still a lack of effective drugs for the prevention or treatment of intestinal fibrosis. Heat shock protein 47 (HSP47) plays a key role in the development of intestinal fibrosis. In this study we investigated the therapeutic potential and underlying mechanisms of fraxinellone, a degraded limonoid isolated from the root bark of Dictamnus dasycarpus , in the treatment of intestinal fibrosis. Intestinal fibrosis was induced in mice by dextran sodium sulfate (DSS) treatment. DDS-treated mice were administered fraxinellone (7.5, 15, 30 mg·kg −1 ·d −1 , i.g .) for 45 days. We showed that fraxinellone administration dose-dependently alleviated DSS-induced intestinal impairments, and reduced the production of intestinal fibrosis biomarkers such as α-smooth muscle actin (SMA), collagen I, hydroxyproline, fibronectin and laminin, and cytokines such as TGF-β, TNF-α and IL-β. We then established in vitro intestinal fibrosis cell models in SW480 and HT-29 cells, and demonstrated that treatment with fraxinellone (3, 10, 30 μM) significantly relieved TGF-β-induced fibrosis responses by inhibiting the TGF-β/Smad2/3 signaling pathway. Molecular docking suggested that the fraxinellone might disrupt the interaction between HSP47 and collagen, which was confirmed by coimmunoprecipitation experiments. SPR analysis showed that fraxinellone had a high affinity for HSP47 with a K d value of 3.542 × 10 −5 M. This study provides a new example of HSP47-collagen intervention by a natural compound and has important implications for the clinical treatment of inflammation-induced issue fibrosis.
研究领域:
药理学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2024
·
IF 3.2
Mingkang Zhang,Jinru Yang,Yufan Yuan,Yan Zhou,Yazhi Wang,Ruirui Cui,Yimai Maliu,Fen Xu,Xin’an Wu
Liver diseases caused by viral infections, alcoholism, drugs, or chemical poisons are a significant health problem: Liver diseases are a leading contributor to mortality, with approximately 2 million deaths per year worldwide. Liver fibrosis, as a common liver disease characterized by excessive collagen deposition, is associated with high morbidity and mortality, and there is no effective treatment. Numerous studies have shown that the accumulation of mast cells (MCs) in the liver is closely associated with liver injury caused by a variety of factors. This study investigated the relationship between MCs and carbon tetrachloride (CCl4)-induced liver fibrosis in rats and the effects of the MC stabilizers sodium cromoglycate (SGC) and ketotifen (KET) on CCl4-induced liver fibrosis. The results showed that MCs were recruited or activated during CCl4-induced liver fibrosis. Coadministration of SCG or KET alleviated the liver fibrosis by decreasing SCF/c-kit expression, inhibiting the TGF-β1/Smad2/3 pathway, depressing the HIF-1a/VEGF pathway, activating Nrf2/HO-1 pathway, and increasing the hepatic levels of GSH, GSH-Px, and GR, thereby reducing hepatic oxidative stress. Collectively, recruitment or activation of MCs is linked to liver fibrosis and the stabilization of MCs may provide a new approach to the prevention of liver fibrosis.
研究领域:
肝病学
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药理学
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病理学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 10
·期 3
·753-769
·
IF 6.843
Zhiwei Yin,Lu Sun,Liyang Shi,Hemin Nie,Jianwu Dai,Can Zhang
Poor tendon repair remains a clinical problem due to the difficulties in replicating the complex multiscale hierarchical structure of native tendons. In this work, a bioinspired fibrous scaffold with bimodal micro-nanofibers and a teno-inductive aligned topography was developed to replicate microscale collagen fibers and nanoscale collagen fibrils that compose native tendons. The results showed indicated that the combination of micro- and nanofibers enhanced the mechanical properties. Furthermore, their biological performance was assessed using tendon stem/progenitor cells (TSPCs). Micro-nanofibers induced a higher cell aspect ratio and enhanced the tenogenic differentiation of TSPCs compared to micro- and nanocontrols. Interestingly, it was observed that scaffold nanotopography and microstructures promoted tenogenesis via activating the TGF-β/Smad2/3-mediated signaling pathway. The in situ implantation study confirmed that micro-nanofibrous scaffolds promoted the structural and mechanical properties of the regenerated Achilles tendon. Overall, our study shows that the bimodal micro-nanofibrous scaffold developed here presents a promising potential to improve the outcomes of tendon tissue engineering.
研究领域:
组织工程
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生物材料
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再生医学
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细胞生物学
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机械工程
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 7
·6172
·
IF 5.6
Tianxiao Sun,Haihua Li,Yan Zhang,Guixin Xiong,Yuerun Liang,Fang Lu,Rong Zheng,Qi Zou,Jiejie Hao
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by lung inflammation and excessive deposition of extracellular matrix components. Transforming growth factor-β1 (TGF-β1) induced epithelial–mesenchymal transformation of type 2 lung epithelial cells leads to excessive extracellular matrix deposition, which plays an important role in fibrosis. Our objective was to evaluate the effects of 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid (DGM) on pulmonary fibrosis and aimed to determine whether EMT plays a key role in the pathogenesis of pulmonary fibrosis and whether EMT can be used as a therapeutic target for DGM therapy to reduce IPF. Firstly, stimulation of in vitro cultured A549 cells to construct EMTs with TGF-β1. DGM treatment inhibited the expression of proteins such as α-SMA, vimentin, and collagen Ⅰ and increased the expression of E-cadherin. Accordingly, Smad2/3 phosphorylation levels were significantly reduced by DGM treatment. Secondly, models of tracheal instillation of bleomycin and DGM were used to treat rats to demonstrate their therapeutic effects, such as improving lung function, reducing lung inflammation and fibrosis, reducing collagen deposition, and reducing the expression of E-cadherin. In conclusion, DGM attenuates TGF-β1-induced EMT in A549 cells and bleomycin-induced pulmonary fibrosis in rats.Keywords:IPF;A549;EMT;TGF-β1/Smad;ECM
研究领域:
药理学
·
呼吸医学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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