JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 12.6
Ce Li,Yichao Yuan,Yaqing Bao,Yeling Ni,Nan Chen,Jigang Piao,Lu Wang,Zhihong Zhu
Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by progressive fibrosis and poor prognosis, with no current therapies capable of reversing the fibrotic changes. The aberrant repair driven by fibroblast activation and an inflammatory microenvironment results in irreversible IPF. In this work, a macrophage-derived apoptotic body delivery system (SA + NAC@AB) co-loaded with sodium arsenite (SA) and N-acetylcysteine (NAC) was developed to exert synergistic antifibrotic activity against IPF via coordinated regulation of TGF-β1 signaling and inflammation. Apoptotic bodies derived from macrophages inherit inflammation-homing capability, enabling targeted delivery to fibrotic lesions. In vivo evaluation in a bleomycin-induced IPF mouse model demonstrated that SA + NAC@AB effectively targeted the lungs, significantly improved body weight and survival, and alleviated pulmonary fibrosis. Immunofluorescence and Western blot analyzes revealed that SA + NAC@AB reduced Smad2/3 phosphorylation and M2 macrophage polarization, indicating regulation of the TGF-β1/Smad2/3 pathway and inflammation as part of its mechanism of action. Furthermore, in vitro studies validated the enhanced efficacy of SA + NAC@AB, which significantly promoted fibroblast uptake, thereby potentiating its inhibitory effects on fibroblast viability, as well as TGF-β1-induced migration and differentiation. In conclusion, our study demonstrates that SA + NAC@AB represents an effective therapeutic strategy for IPF, offering a promising novel approach by modulating both the TGF-β1/Smad2/3 signaling pathway and the inflammatory response.
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Qing Shu,Song Lai,Xiao-Mei Wang,Yun-Long Zhang,Xiao-Lei Yang,Hai-Lian Bi,Hui-Hua Li
Pathological cardiac hypertrophy is the main risk factor for heart diseases. The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation system involved in the development of cardiac hypertrophic remodeling. Ubiquitin-activating enzyme E1, a key component of the UPS, catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation via proteasome . However, the functional role of E1 (UBA1) in regulation of hypertrophic remodeling in angiotensin II (Ang II)-infused mice remains unknown. In this study, male wild-type mice were treated with UBA1 inhibitor PYR-41 at two doses of 5 and 10 mg and infused with Ang II (1000 ng/kg/min) for 14 days. Systolic blood pressure was detected by using tail-cuff system. Cardiac function was assessed by echocardiography. Hypertrophic remodeling was analyzed examined by histological examinations. The expressions of genes and proteins were detected by quantitative real-time PCR and immunoblotting analysis. After 14 days, Ang II infusion significantly increased UBA1 expression at both mRNA and protein levels in the hearts. Furthermore, Ang II-infused mice showed a significant increase in systolic blood pressure compensatory cardiac function, hypertrophy, interstitial fibrosis, inflammation and oxidative stress compared with saline-treated controls, whereas these effects were dose-dependently attenuated in PYR-41-treated mice. These beneficial actions were associated mainly with inhibition of PTEN degradation and multiple downstream mediators (AKT, ERK1/2, STAT3 , TGF-β/Smad2/3 and NF-kB(p65)). In conclusion, these results indicate that inhibition of UBA1 suppresses Ang II-induced hypertrophic remodeling, and suggest that administration of low dose PYR-41 may be a new potential therapeutic approach for treating hypertensive heart diseases.
研究领域:
心脏病学
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药理学
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分子生物学
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PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2024
·
IF 4.8
Xiaowei Zhang,Jiajun Wang,Shixie Xiang,Liang Zhao,Mingzhen Lv,Yafei Duan,Gai Gao,Pan Wang,Jenny Jie Chen,Jiangyan Xu,Zhishen Xie,Zhenqiang Zhang
Diabetic kidney disease (DKD) has become the primary cause of end-stage renal disease (ESRD), causing an urgent need for preventive strategies for DKD. Astragaloside I (ASI), a bioactive saponin extracted from Astragalus membranaceus (Fisch.) Bunge has been demonstrated to possess a variety of biological activities. This study investigates the therapeutic potential of ASI in DKD and the underlying molecular mechanism using db/db mice in vivo and high glucose (HG)-induced SV40-MES-13 cells in vitro . The results indicated that ASI significantly ameliorated renal dysfunction and mitigated the pathological alterations in the renal tissues of db/db mice. Moreover, ASI was found to reduce the levels of renal fibrosis makers and suppress the activation of TGF- β 1/Smad2/3 pathway in both db/db mice and HG-induced SV40-MES-13 cells. Furthermore, ASI downregulated HDAC3 expression, upregulated Klotho expression, and enhanced Klotho release. ASI is directly bound to HDAC3, and the beneficial effects of ASI on Klotho/TGF- β 1/Smad2/3-mediciated renal fibrosis in DKD were reversed by the HDAC3 agonist ITSA-1. In conclusion, ASI attenuates renal fibrosis in DKD, and may act through concurrently inhibiting HDAC3 and TGF- β 1, thereby regulating HDAC3-mediciated Klotho/TGF- β 1/Smad2/3 pathway.
研究领域:
药理学
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肾病学
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分子生物学
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糖尿病
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DOI
PubMed
高影响因子
Journal of Biomaterials and Tissue Engineering
·
2020
·Vol. 10
·期 6
·812-822
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IF 0.511
Bai Yi-Hua,Yang Min,Wang Jia-Ping,Jiang Hong-Ying,Li Luo-Hua,Zhang Xin-Xin,Ma Li
The present study aims to probe the impact of mesenchymal stem cells (MSCs) on the HMGA2 gene and renal tubular epithelial cell EMT in diabetic nephropathy (DN). The advanced glycation end product (AGE) in the later period was used to interfere with the HK-2 cell modeling of humans
in vitro, while STZ was used for the modeling of mice DN in vivo. Allogeneic MSCs were used to interfere with the model to detect the concentration of the correlation factor in cells and mice kidney tissues and HMGA2 expression level. The following aspects were prompted after
treatment with MSCs in vitro and in vivo: (1) TGF-β1 concentration, Smad2, HMGA2, vimentin and α-SMA expression levels were significantly reduced, when compared to the model group (P <0.05), while Smad7 and E-cadherin expression levels significantly
increased, when compared to the model group (P <0.05); (2) The proteinuria and serum creatinine level of mice were alleviated, and the ultrastructure damage condition of kidneys also improved, when compared to the model group. MSCs can restrain the high expression of HMGA2 in DN,
EMT and kidney fibrosis, and postpone renal function progression.
研究领域:
分子生物学
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干细胞研究
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肾病学
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糖尿病学
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高影响因子
Journal of Cachexia Sarcopenia and Muscle
·
2022
·Vol. 13
·期 6
·2740-2751
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IF 12.063
Fengju Li,Ting Luo,Honghui Rong,Lu Lu,Ling Zhang,Chuanfeng Zheng,Dali Yi,Yi Peng,Enyu Lei,Xiaotao Xiong,Fengchao Wang,Jose M. Garcia,Ji-an Chen
Background Di-(2-ethylhexyl) phthalate (DEHP) and its metabolites can cross the placenta and may cause birth defects and developmental disorders. However, whether maternal DEHP exposure affects skeletal muscle development in the offspring and the pathways involved are unknown. This study investigated the effects of maternal DEHP exposure and the contribution of myostatin (MSTN) to skeletal muscle development in the offspring. Methods Pregnant wild-type and muscle-specific myostatin knockout (MSTN KO) C57BL/6 mice were randomized to receive vehicle (corn oil) or 250 mg/kg DEHP by gavage every other day until their pups were weaned (postnatal day 21 [PND21]). Body weights of the offspring mice were measured longitudinally, and their hindleg muscles were harvested at PD21. Also, C2C12 cells were treated with mono-2-ethylhexyl phthalate (MEHP), the primary metabolite of DEHP, and proteolysis, protein synthesis, and myogenesis markers were measured. The contribution of myostatin to maternal DEHP exposure-induced muscle wasting in the offspring was determined. Results Maternal DEHP exposure reduced body weight growth, myofibre size, and muscle mass in the offspring compared to controls (Quad: 2.70 ± 0.1 vs. 3.38 ± 0.23, Gastroc: 2.29 ± 0.09 vs. 2.81 ± 0.14, Tibialis: 1.01 ± 0.07 vs. 1.25 ± 0.11, mg/tibial length in mm, all P < 0.01, n = 35). Maternal DEHP exposure significantly increased Myostatin expression (2.45 ± 0.41 vs. 0.03 ± 0.00 DEHP vs. controls, P < 0.01, n = 5), Atrogin-1(2.68 ± 0.65 vs. 0.63 ± 0.01, P < 0.05, n = 5), MuRF1 (1.56 ± 0.51 vs. 0.31 ± 0.01, P < 0.05, n = 5), and Smad2/3 phosphorylation (4.12 ± 0.35 vs. 0.49 ± 0.18, P < 0.05), and decreased MyoD (0.27 ± 0.01 vs. 1.52 ± 0.01, P < 0.05, n = 5), Myogenin (0.25 ± 0.03 vs. 1.95 ± 0.56, P < 0.05, n = 5), and AKT phosphorylation (4.12 ± 0.35 vs. 1.00 ± 0.06, P < 0.05, n = 5), in skeletal muscle of the offspring in MSTN flox/flox , but not in MSTN KO mice. Maternal DEHP exposure resulted in up-regulation of CCAAT/enhancer-binding protein δ (C/EBPδ, 4.12 ± 0.35 vs. 1.00 ± 0.19, P < 0.05, n = 5) in skeletal muscle of the offspring in MSTN flox/flox and MSTN KO mice (4.12 ± 0.35 vs. 4.35 ± 0.28, P > 0.05, n = 5). In vitro, C/EBPδ silencing abrogated the MEHP-induced increases in Myostatin, MuRF-1, and Atrogin-1 and decreases in MyoD and Myogenin expression. Conclusions Maternal DEHP exposure impairs skeletal muscle development in the offspring by enhancing the C/EBPδ-myostatin pathway in mice.
研究领域:
发育生物学
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毒理学
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肌肉生理学
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分子生物学
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PubMed
高影响因子
Cancer Immunology Research
·
2024
·
IF 8.1
Shi Yongjing,Zheng Xiaodong,Peng Hui,Xu Chenqi,Sun Rui,Tian Zhigang,Sun Haoyu,Wang Xianwei
Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-β signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL-15Rβ and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity, and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell–based cancer immunotherapy.
研究领域:
癌症生物学
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免疫学
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分子生物学
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高影响因子
PULMONARY PHARMACOLOGY & THERAPEUTICS
·
2024
·
IF 3.3
Huijuan Zhang,Jianli Qiu,Qianyi Zhao,Yong Zhang,Haitao Zheng,Ziying Dou,Yongbin Yan
Pulmonary fibrosis is a complex disease that can occur in a variety of clinical settings. The Zinc Finger and BTB Domain Containing 16 (Zbtb16) is a transcription factor and has not been studied in pulmonary fibrosis. Lung tissues from rats which were treated with bleomycin and Tanshinone IIA (Tan IIA) were collected for mRNA sequencing. Zbtb16, a differentially expressed gene, was screened. Using adeno-associated virus to knock down Zbtb16 in rats, it was found that the lung index and the content of hydroxyproline in lung tissue were decreased. HE and Masson staining revealed that pathological symptoms of lung histopathology were relieved after Zbtb16 knockdown. Protein expressions of α-SMA, Collagen I and Fibronectin were significantly decreased after Zbtb16 knockdown in vivo and in vitro . Meanwhile, the protein content of TGF-β1 and the phosphorylation of Smad2/3 were inhibited by Zbtb16 knockdown. Conversely, under the treatment of Tan IIA and TGF-β1, overexpression of Zbtb16 improved cell viability, increased the expression of fibrosis-related proteins, and promoted the phosphorylation of Smad 2/3. All above demonstrates that Zbtb16 inhibition ameliorates pulmonary fibrosis and suppresses the TGF-β/Smad pathway. Furthermore, Zbtb16 mediates the inhibitory process of Tan IIA on pulmonary fibrosis. This study provides a novel candidate therapeutic target for pulmonary fibrosis.
研究领域:
药理学
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肺病学
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分子生物学
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病理学
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PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 3
·95-101
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IF 1.5
Shanfu Wang,Bing Xu,Heng Yin,Zhen Hua,Yang Shao,Jianwei Wang
Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. μ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-β/Smad pathway by increasing TGF-β as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-β/Smad pathway.
研究领域:
药理学
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骨科
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内分泌学
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分子生物学
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高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Wenjuan Ning,Xiaoxiao Xu,Shican Zhou,Xiao Wu,Hang Wu,Yijie Zhang,Jichang Han,Junpeng Wang
This study explored the profibrotic impact of high glucose in the lung and potential mechanisms using latent TGF-β1-induced human epithelial cell pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrosis models. Results demonstrated that high glucose administration induced epithelial-mesenchymal transition (EMT) in human epithelial cells in a dose-dependent manner via activating latent TGF-β1, followed by increased expression of mesenchymal-related proteins and decreased expression of epithelial marker protein E-cadherin. Further mechanism analysis showed that administration of high glucose dose-dependently promoted total and mitochondrial reactive oxygen species (ROS) accumulation in human epithelial cells, which promoted latent TGF-β1 activation. However, N -acetyl-L-cysteine, a ROS eliminator, inhibited such effects. An in vivo feed study found that mice given a high-glucose diet had more seriously pathological characteristics of pulmonary fibrosis in BLM-treated mice, including increasing infiltrated inflammatory cells, collagen I deposition, and the expression of mesenchymal-related proteins while decreasing the expression of the epithelial marker E-cadherin. In addition, high glucose intake further increased TGF-β1 concentration and upregulated p-Smad2/3 and snail in lung tissues from BLM-treated mice when compared to BLM-treated mice. Finally, supplementation with high glucose further increased the production of lipid peroxidation metabolite malondialdehyde and decreased superoxide dismutase activity in BLM-treated mice. Collectively, these findings illustrate that high glucose supplementation activates a form of latent TGF-β1 by promoting ROS accumulation and ultimately exacerbates the development of pulmonary fibrosis.
研究领域:
肺科学
·
细胞生物学
·
药理学
·
病理学
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PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8587
·
IF 13.3
Wei-Jia Yu,Wen-Xi Jiang,Shu-Jing Liu,Hui-Hua Li,Qiu-Yue Lin
Rationale: Infiltration of immune cells into the heart plays a crucial role in the transition from adaptive hypertrophy to heart failure (HF) following chronic pressure overload. However, the key factors in myeloid cells that regulate this process are still not well defined. Here, we studied the functional role of S100A8/A9 in myeloid cells during this transition. Methods: Cardiac hypertrophy and HF models were induced by transverse aortic constriction (TAC) for 1 to 4 weeks. The heterogeneity of CD45 + immune cells and the cellular sources of S100A8/A9 were analyzed using published single-cell RNA sequencing datasets. The effects of S100A8/A9 on TAC-induced hypertrophy and HF were verified in S100A9 knockout (KO) and bone marrow (BM)-chimeric mice and in an in vitro coculture system. Results: S100A8/A9 levels were significantly increased in HF patients and in TAC-induced HF model mice. Moreover, the TAC-induced transition from adaptive hypertrophy to HF was significantly attenuated in S100A9-KO mice and WT mice transplanted with S100A9-KO BM cells. Mechanistically, TAC-stimulated upregulation of S100A8/A9 in neutrophils induced an early inflammatory response and adaptive hypertrophy through activation of the p38 MAPK/JNK/AP-1 pathway, leading to increased production of IL-1β and chemokines (CCL2 and CCL6). These chemokines promoted the infiltration of CCR2 + macrophages to the damaged heart. Therefore, they exhibited upregulation of S100A8/A9, which led to exacerbation of inflammation, cardiac hypertrophy and fibrosis via activation of the NF-κB/NLRP3, AKT/Calcineurin A and TGF-β/Smad2 signaling pathways. Additionally, treating WT mice with the S100A9 inhibitor ABR-238901 prevented TAC-induced cardiac hypertrophy-related dysfunction. Conclusion: The present findings establish an S100A8/A9-related axis between myeloid cells and cardiac cells that drives the pressure overload-induced transition from hypertrophy to HF, suggesting that S100A8/A9 is a promising therapeutic target for this disease.
研究领域:
心脏病学
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免疫学
·
分子生物学
·
基因组学
·
生物医学研究
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高影响因子
JOURNAL OF ENDODONTICS
·
2019
·
IF 2.833
Jing Zhang,Cheng Fei Zhang,Quan Li Li,Chun Hung Chu
Introduction Stem cells from the apical papilla (SCAPs) possess strong odonto/osteogenic differentiation potential. This study investigated the effect of cyclic adenosine monophosphate (cAMP) on odonto/osteogenic differentiation of SCAPs and the underlining interplay between cAMP and transforming growth factor beta 1 (TGF-β1). Methods SCAPs were stimulated with an activator of cAMP (forskolin) in the presence of either TGF-β1 or a TGF-β1 inhibitor. The amounts of calcium mineral deposition and alkaline phosphatase activity were determined. Quantitative real-time polymerase chain reaction was performed to elucidate cAMP on the TGF-β1–mediated odonto/osteogenic differentiation of SCAPs. The effect of cAMP on the phosphorylation of Smad2/Smad3 and extracellular-regulated kinase (ERK)/P38 induced by TGF-β1 was analyzed by Western blotting . Results Cotreatment with forskolin and a TGF-β1 inhibitor enhanced alkaline phosphatase activity and deposition of calcium minerals in SCAPs. Moreover, the TGF-β1 inhibitor synergized the effect of forskolin on the expression of type I collagen and runt-related transcription factor 2. The results of Western blotting revealed that forskolin attenuated the unregulated expression of the phosphorylation of Smad3 and ERK induced by TGF-β1, and a cAMP inhibitor (H89) antagonized this effect. Conclusions This study showed that cAMP signaling exerts its up-regulating effects on the odonto/osteogenic differentiation of SCAPs by interfering with TGF-β1 signaling via inhibiting Smad3 and ERK phosphorylation.
研究领域:
口腔科学
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细胞生物学
·
分子生物学
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PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Xionghua Sun,Mei Zhu,Wei Xia,Xihan Xu,Jian Zhang,Xiaogang Jiang
Eupatorium lindleyanum DC . has been used as a functional food in China for a long time. However, the antifibrotic activity of total sesquiterpenoids from Eupatorium lindleyanum DC . (TS-EL) is still unknown. In this study, we discovered that TS-EL reduced the increase in α-smooth muscle actin (α-SMA), type I collagen and fibronectin content, the formation of cell filaments and collagen gel contraction in transforming growth factor-β1-stimulated human lung fibroblasts. Intriguingly, TS-EL did not change the phosphorylation of Smad2/3 and Erk1/2. TS-EL decreased the levels of serum response factor (SRF), a critical transcription factor of α-SMA, and SRF knockdown alleviated the transition of lung myofibroblasts. Furthermore, TS-EL significantly attenuated bleomycin (BLM)-induced lung pathology and collagen deposition and reduced the levels of two profibrotic markers, total lung hydroxyproline and α-SMA. TS-EL also decreased the levels of SRF protein expression in BLM-induced mice. These results suggested that TS-EL attenuates pulmonary fibrosis by inhibiting myofibroblast transition via the downregulation of SRF.
研究领域:
药理学
·
肺科学
·
分子生物学
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PubMed
高影响因子
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