Chinese Medicine
·
2024
·
IF 5.3
MingShan Zhang,YuFei Zhang,JingGang He,XinRui Wang,YinYin Wang,LinYan Li,Ling Tao,Min Zhang,Xiangchun Shen
Background Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated. Methods In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS. Results GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling. Conclusion GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13020-024-01035-4.
研究领域:
医学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Marine Science
·
2025
·
IF 3
Fengxia Xu,Limin Dong,Chengxue Qin,Yanru Ren,Liang Kong,Mengru Zhang,Haitao Du,Qing Xia,Cheng Wang,Ping Wang
Introduction: Bone, as both a crucial organ with mechanical support and immune regulatory functions, profoundly influencing the growth and development of fish in aquaculture systems. Deer antler and its aqueous extract Cervi Cornus Colla (CCC), are natural medicinal substances known for their bone-protective properties.Methods: This study investigated the osteoprotective effects of CCC against lipopolysaccharide (LPS)-induced injury to fish bones. An LPS-mediated zebrafish skeletal injury model was established and evaluated using Alcian Blue/Alizarin Red staining, fluorescence tracing, ELISA, and qPCR.Results: The median lethal concentration (LC50) of CCC in zebrafish was 206.3 mg/mL, and staining revealed that CCC reversed LPS-induced reduction in cartilage and bone formation in a dose-dependent manner. In Tg (mpeg1: EGFP) zebrafish, CCC treatment significantly decreased macrophages-associated green fluorescence, suggesting that the extract suppressed the activation of macrophages caused by LPS. CCC also reduced the production of several inflammatory factors (IL-6, IL- 1β, and NO). Furthermore, qRT-PCR confirmed CCC restored COL2α1 and Sox9a mRNA levels. Additional studies revealed CCC inhibits LPS-induced activation of the TGF-β/Smad3 signaling pathway.Discussion: This study demonstrates that CCC can alleviate zebrafish bone injury, thereby providing an experimental basis for its application in the prevention and treatment of bone diseases in farmed fish.
研究领域:
水产养殖
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药理学
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免疫学
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分子生物学
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兽医学
✓ 已验证
产品关联
DOI
高影响因子
Emergent Materials
·
2023
·
IF 3.8
Shen Yuxin,Zhang Yao,Gao Xiyue,Shang Mengdi,Cai Yanfei,Yang Zhaoqi
The most prevalent malignant neoplasm identified in females is breast cancer. Multidrug resistance is a significant obstacle for breast cancer chemotherapy, despite the availability of several therapies. This article describes the development of a nanocomposite based on ZIF-90 to reduce multidrug resistance in breast cancer cells. Synthesized ZIF-90 is utilized to transport MiR-489 and Adriamycin into drug-resistant cancer cells. The epithelial-mesenchymal transition that is initiated by TGF-β is dependent on Smad3, and MiR-489 may target Smad3. MiR-489 ultimately suppresses the epithelial-mesenchymal transition pathway, hence increasing the efficacy of Adriamycin therapy. The results of Western blot analysis indicated that the Smad3 is effectively reduced by MiR-489. The cell viability assay showed that the IC 50 of nanocomposite to the drug-resistant breast cancer cells (1.032 μg/mL) was nearly 40 times lower than the IC 50 of ADM to the same cells (39.87 μg/mL), and was closer to the IC 50 of nanocomposite to the non-drug-resistant cells (0.49 μg/mL). These findings conclusively shown that our developed nanocomposite has ameliorated the multidrug resistance issue.
研究领域:
肿瘤学
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Research
·
2025
·
IF 9.6
Peng Lu,Tun Wang,Sheng Liao,Zhenyu He,Siyuan Cheng,Tianjian Wang,Zibo Cheng,Yangyang An,Sirui Zhou,Mo Wang,Qian Zhang,Chang Shu
Traditional polymer-based arteriovenous grafts (AVGs) for hemodialysis access suffer from poor long-term patency, high reintervention rates, and susceptibility to infection. In contrast, decellularized tissue-engineered vascular grafts (dTEVGs) demonstrate improved patency, long-term durability, and resistance to infection. However, vascular stenosis and occlusion caused by anastomotic intimal hyperplasia (AIH), as well as vascular stiffening and calcification from excessive perigraft fibrosis (PGF), remain major challenges in the clinical use of dTEVGs for AVGs. M2 macrophage infiltration plays a key role in the biological processes of pro-regeneration and the clinical application of dTEVGs. However, in elastin-rich dTEVGs commonly used clinically, the elastic fiber layers form a barrier to cell infiltration, potentially limiting their biological functions. Therefore, the specific impact of M2 macrophage infiltration on dTEVGs in AVGs remains unclear. Through parallel analysis of human explants and a rat dTEVG-AVG model, we found that M2 macrophage infiltration predominates in dTEVGs, and this infiltration is associated with AIH and PGF. Furthermore, IL-4-loaded poly(lactic- co -glycolic acid)/gelatin methacryloyl delivery systems selectively enhanced M2 macrophage polarization, while sustained M2 macrophage infiltration triggered TGF-β1/Smad3-dependent myofibroblast activation, leading to increased AIH and PGF. Pharmacological inhibition of Smad3 phosphorylation selectively alleviated AIH and PGF without affecting M2 macrophage recruitment or other associated biological functions. These findings reveal the dual role of M2 macrophages in dTEVGs for AVGs, which, while promoting pro-regeneration, unexpectedly accelerate AIH and PGF. A targeted Smad3 inhibition strategy selectively alleviates AIH and PGF caused by M2 macrophage infiltration, without compromising M2 macrophage-associated functions.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Tingjuan Huang,Ziyi Shang,Lina Nie,Haichao Diao,Qizhi Shuai,Junjie Ren,Jun Xu,Jun Xie
Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
研究领域:
分子生物学
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遗传学
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肝病学
✓ 已验证
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2024
·Vol. 38
·期 15
·e23495
·
IF 4.4
Yuwei Liu,Xiaomei Wang,Zhongfeng Wang,Xiuzhu Gao,Hongqin Xu,Yanhang Gao,Junqi Niu
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl 4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
研究领域:
分子生物学
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细胞生物学
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肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2026
·
IF 13.2
Kai Chen,Jiawei Wang,Qian Liu,Huiru Wang,Xueqing Ning,Jingxin Wang,Xiaojia Hu,Lu Zong,Limin Wu,Tianzhi Luo,Jialyu Huang,Shengxia Zheng
Intrauterine adhesion (IUA) plays a significant role in female infertility, primarily due to endometrial fibrosis resulting from abnormal activation of the endometrial TGF-β/SMAD3 signaling pathway. However, effectively preventing the high recurrence rate after IUA surgery remains a major challenge that needs to be addressed. To address this challenge, Herein, a novel in situ injectable QOHP@siRNA hydrogel is introduced for the prevention of IUA by silencing SMAD3 . This hydrogel addresses the challenges of poor uptake, short half-life, and rapid degradation of siRNA in the treatment of IUA. Additionally, it has demonstrated strong antibacterial activity against gram-negative bacilli and gram-positive cocci, as well as favorable endometrial adhesion and Internal hemostatic properties. The in vitro and in vivo experimental results demonstrate that QOHP@siRNA sustained SMAD3 silencing, anti-fibrotic effects, and microenvironment protection properties. Furthermore, it promotes endometrial angiogenesis and cellular proliferation, and ultimately restores fertility. This therapeutic strategy demonstrates significant potential for the treatment of IUA, while also providing novel insights into gene delivery vector-based therapies for other diseases.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Xinqi Zeng,Yanhao Li,Gang Zhao,Xiaoer Wei,Rongpu Wu,Sa Pang,Yuange Li,Zaijing Tao,Shuo Wang,Jixian Yue,Xu Chen,Yajun Xu,Yongjun Rui,Jingyi Mi,Yang Liu,Jinglei Wu,Jian Tian
Post-traumatic tendon adhesions significantly affect patient prognosis and quality of life, primarily stemming from the absence of effective preventive and curative measures in clinical practice. Current treatment modalities, including surgical excision and non-steroidal anti-inflammatory drugs, frequently exhibit limited efficacy or result in severe side effects. Consequently, the use of anti-adhesive barriers for drug delivery and implantation at the injury site to address peritendinous adhesion (PA) has attracted considerable attention. Electrospun nanofiber membranes (ENMs) have been extensively employed as drug-delivery platforms. In this study, we fabricated a polylactic acid (PLA)–dipyridamole (DP)-graft copolymer ENM called PLC-DP. This membrane exhibits enzyme-sensitive features, allowing more controlled and sustained drug release compared with conventional drug-loaded ENMs. In experiments, PLC-DP implantation reduced tissue adhesion by 47 % relative to the control group while not adversely affecting tendon healing. Mechanistically, PLC-DP effectively activates the FXYD domain containing ion-transport regulator 2 (FXYD2) protein, thereby downregulating the fibroblast-transforming growth factor beta (TGF-β)/Smad3 signaling pathway. PLC-DP leverages the anti-adhesive properties of DP and the enzyme-sensitive characteristics of graft copolymers, providing a promising approach for the future clinical treatment and prevention of PA. Statement of significance Peritendinous adhesions (PA) are a common and disabling condition that seriously affects the prognosis and quality of life of post-trauma patients. Current treatments often have limited efficacy or severe side effects, leaving a serious gap in clinical practice. We developed a significant biomaterial, poly(lactic acid)-dipyridamole graft copolymer electrospun nanofibrous membrane (PLC-DP), specifically for PA inhibition. In addition, this study uniquely combines dipyridamole, an anti-adhesive agent, and enzyme-sensitive copolymers in electrospun nanofibrous membrane. Unlike conventional drug-loaded electrospun nanofibrous membranes, PLC-DPs have enzyme-sensitive drug properties that allow for sustained drug release on demand. Our experiments showed that implantation of PLC-DP was effective in reducing tissue adhesions by 47 % without affecting tendon healing. We elucidated the mechanism behind this phenomenon, suggesting that PCD activates FXYD2 to inhibit TGF-β-induced expression of Col III, which is a key factor in PA development.
研究领域:
生物材料学
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医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Zhao Tong,Zhou Zhi-ruo,Wan Hui-qi,Feng Tian,Hu Xu-hui,Li Xiao-qian,Zhao Shi-mei,Li Hong-lin,Hou Ji-wei,Li Wei,Lu Da-yun,Qian Min-yi,Shen Xu
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC 50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg −1 ·d −1 , i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
研究领域:
药理学
·
肺病学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2024
·
IF 4.2
Lin Lv,Keying Yuan,Jiahao Li,Jing Lu,Qi Zhao,Hongyan Wang,Qiuyu Chen,Xinyu Dong,Siqi Sheng,Mingyu Liu,Yuanqi Shi,Hongquan Jiang,Zengxiang Dong
Myocardial fibroblasts transform into myofibroblasts during the progression of cardiac fibrosis, together with excessive cardiac fibroblast proliferation. Hence, the prevention and treatment of cardiac fibrosis are significant factors for inhibiting the development of heart failure. P-element Induced WImpy testis-interacting RNAs (PiRNA) are widely expressed in the heart, but their involvement in cardiac fibrosis has not yet been confirmed. We identified differentially expressed PiRNAs using Arraystar PiRNA expression profiling in Angiotensin II models of cardiac fibrosis in vivo and in vitro. We then explored cardiac-fibrosis-associated PiRNA-related proteins, RNA-protein interactomes, immunoprecipitation, and pulldown. We detected fibrosis markers and pathway-related proteins using immunofluorescence, qRT-PCR, and Western blot. We uncovered cardiac fibrosis associated PiRNA (CFAPIR) that was obviously dysregulated during cardiac fibrosis, whereas its overexpression reversed fibrosis in vivo and in vitro. Mechanistically, CFAPIR competitively bound muscleblind like protein 2 (MBNL2) and the cyclin-dependent kinase inhibitor P21 to regulate the TGF-β1/SMAD3 signaling pathway.
研究领域:
心脏病学
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分子生物学
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基因组学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Zhenghao Wu,Guqing Luo,Hongjie Li,Min Chen,Guangbo Wu,Qiang Fan,Chihao Zhang,Jiwei Yu,Jiayun Lin,Jinbo Zhao,Xiaoliang Qi,Haizhong Huo,Meng Luo,Lei Zheng
Introduction: Formononetin regulates intrahepatic fibrogenesis and macrophage polarization to improve portal pressure and liver function in rats with cirrhotic PHT through SMAD3, STAT1, STAT3 and GSK-3β signaling pathways, and modulates lymphangiogenesis through direct action and macrophage polarization-mediated indirect effects. Formononetin has the potential function of treating cirrhotic PHT.Background and aims: Formononetin (FN) has been reported to have anti-fibrotic effects in the kidneys and anti-M1 polarization effects on macrophages. Lymphangiogenesis is closely associated with macrophages, but its role in cirrhosis and portal hypertension (PHT) remains unclear. This study aims to explore the effects of FN on cirrhotic PHT and the disease-related intrahepatic lymphangiogenesis.Methods: In vivo experiments, bile duct ligation (BDL) induced PHT models were conducted in rats, followed by a 4-week FN treatment (50 mg/kg/day) administered via gavage. Hemodynamics, liver fibrosis, infiltration and polarization of intrahepatic macrophages, as well as intrahepatic lymphangiogenesis, were observed. For in vitro experiments, hepatic stellate cells, macrophages and lymphatic endothelial cells were used to observe the multiple effects of FN.Results: FN significantly ameliorated portal pressure in cirrhosis-induced PHT, improved liver function, and reduced liver fibrosis and hepatic stellate cell activation with decreased SMAD3 protein expression. The intrahepatic macrophage infiltration were markedly decreased, and M1-type macrophage polarization was suppressed by FN, accompanied by inhibition of STAT1, STAT3 and GSK-3β signaling pathways. In PHT models, FN reduced VEGF-C and VEGF-D levels in both the liver and blood, inhibiting intrahepatic lymphangiogenesis in portal area. In vitro, high-dose FN significantly inhibited lymphatic endothelial cell proliferation, while the pro-lymphangiogenic effect of conditioned medium from FN-treated M1 macrophages was diminished.Conclusions: FN significantly ameliorates cirrhotic PHT while reducing fibrosis, suppressing macrophage M1 polarization and inhibiting lymphangiogenesis. This may result from its modulation of multiple signaling pathways (SMAD3, STAT1, STAT3 and GSK-3β).
研究领域:
肝病学
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药理学
·
细胞生物学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
·
IF 5.195
Xiao-guo Suo,Fang Wang,Chuan-hui Xu,Xiao-yan He,Jia-nan Wang,Yao Zhang,Wei-jian Ni,Hao Lu,Ming-lu Ji,Yuan He,Shuai-shuai Xie,Ya-ru Yang,Jia-gen Wen,Juan Jin,Qian Gong,Jun Li,Ming-ming Liu,Xiao-ming Meng
Renal fibrosis , a common feature of chronic kidney disease , causes the progressive loss of renal function, in which TGF-β 1 plays a critical role. In this study, we found that expression levels of TGF-β 1 and its receptor 1 (TGF-βR1) were both significantly increased in obstructive fibrosis kidneys. AZ12601011 is a small molecular inhibitor of TGF-βR1; however, its therapeutic potential for renal fibrosis remains unclear. During the experiments, AZ12601011 was applied to various models of renal fibrosis followed by unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) in vivo , in addition to renal tubular epithelial cells (TECs) challenged by hypoxia/reoxygenation (H/R) and TGF-β 1 in vitro. Our results revealed that AZ12601011 ameliorated renal injuries and fibrosis shown by PAS, HE , and Masson staining , which was consistent with the decrease in Col-1 and α-SMA expression in the kidneys from UUO and I/R mice. Similarly, in vitro data showed that AZ12601011 inhibited the induction of Col-1 and α-SMA in both TECs treated with TGF-β 1 and H/R. In addition, the results of cellular thermal shift assay (CETSA), molecular docking , and western bolt indicated that AZ12601011 could directly bind to TGF-βR1 and block activation of the downstream Smad3. Taken together, our findings suggest that AZ12601011 can attenuate renal fibrosis by blocking the TGF-β/Smad3 signaling pathway and it might serve as a promising clinical candidate in the fight against fibrotic kidney diseases.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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