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
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2015
·Vol. 12
·期 1
·192-198
·
IF 1.554
Jinpeng Li,Hao Liu,Jieping Yu,Honggang Yu
Doxorubicin (Dox) is a commonly used chemotherapeutic drug in human colon cancer. However, it becomes increasingly ineffective with tumor progression, the underlying mechanism of which remains to be elucidated. Emerging evidence has led to the identification of an association between chemoresistance and the acquisition of epithelial‑mesenchymal transition (EMT) in cancer. However, it remains to be elucidated whether this process is involved in the development of resistance to Dox in colon cancer. In HCT116 human colon cancer cells treated with Dox (50 nmol/l), EMT was induced, and transforming growth factor (TGF)β signaling and multi‑drug resistant plasma membrane glycoprotein levels were significantly increased. By contrast, silencing of Smad4, using stable RNA interference, inhibited TGFβ signaling, reversed the process of EMT and markedly increased the sensitivity of HCT116 cells to Dox. The results of the present study suggested that the combination of Dox with the downregulation of TGFβ signaling may be a potential novel therapeutic strategy with which to overcome chemoresistance during colon cancer chemotherapy.
研究领域:
肿瘤学
·
分子生物学
·
癌症治疗
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DOI
PubMed
高影响因子
Biomedicines
·
2026
·Vol. 14
·期 7
·1586
·
IF 4.5
Xiaofei Tong,Meina Sun,Xin Gan,Xin Chen,Shiyang Liu,Ieong Sun,Lin Zhang,Weihong Zheng
Background: Capsular contracture is driven by self-amplifying foreign body response (FBR) where inflammatory and fibrotic signals from fibroblasts and macrophages reinforce each other. We hypothesized that cogradient simultaneous blockade of NF-κB as an inflammatory node and TGF-β/Smad as fibrotic node could attenuate the FBR. Emodin has dual inhibitory activity but suffers from poor delivery.Methods: Emodin liposomes (Emo-Lip) were characterized and tested on TGF-β1-stimulated NIH/3T3 fibroblasts and LPS-stimulated RAW264.7 macrophages. In a rat silicone implant model, periprosthetic injections were given for four weeks. Fibrous capsule formation was evaluated by histology, immunofluorescence, and FAPI-PET/CT. Transcriptomic analyses were performed to verify and predict relevant pathways.Results: Emo-Lip had uniform size and high encapsulation efficiency. In vitro, Emo-Lip inhibited fibroblast migration, ROS production, myofibroblast differentiation (α-SMA+) as well asCtgfexpression, while suppressing M1 polarization and reduced IL-12/IL-6 secretion in macrophages. In vivo, Emo-Lip reduced capsule thickness, collagen area, and α-SMA/Col I expression, comparable to dexamethasone. Transcriptomics showed coordinated downregulation of inflammatory/fibrotic genes, and Western blot confirmed suppressed phosphorylation of Smad3.Conclusions: Coordinated two-node blockade of NF-κB and TGF-β/Smad by liposomal emodin reprograms the FBR and effectively prevents capsular contracture in rats, offering a translational strategy for implant-associated fibrosis.
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PubMed
高影响因子
Advanced Science
·
2022
·Vol. 9
·期 10
·2105240
·
IF 17.521
Huiming Peng,Jian Shen,Xin Long,Xiaoqi Zhou,Jiaqi Zhang,Xina Xu,Teng Huang,Hui Xu,Shuguo Sun,Chun Li,Ping Lei,Heshui Wu,Jun Zhao
Pancreatic cancer is a deadly disease with little response to standard therapies. Irreversible electroporation (IRE) has emerged as a novel ablative technique for the clinical treatment of pancreatic cancer. Combinations of IRE and immunotherapies, including anti-programmed death 1 ( α PD1) immune checkpoint blockade, have shown promising efficacy in both preclinical and clinical studies. However, tumor recurrence remains an obstacle that needs to be overcome. It herein is shown that IRE induces a substantial infiltration of neutrophils into pancreatic tumors. These neutrophils are then polarized into a protumor phenotype by immunosuppressive cues, in particular transforming growth factor β (TGF- β ). Using glutathione-responsive degradable mesoporous silica nanoparticles loaded with SB525334, an inhibitor of TGF- β 1 receptor, it is demonstrated that local inhibition of TGF- β within the tumor microenvironment promotes neutrophil polarization into an antitumor phenotype, enhances pancreatic cancer response to combined IRE and α PD1 therapy, and induces long-term antitumor memory. The therapeutic efficacy is also attributed to tumor infiltration by CD8 + cytotoxic T cells, depletion of regulatory T cells, and maturation of antigen-presenting dendritic cells. Thus, modulating neutrophil polarization with nanomedicine is a promising strategy for treating pancreatic cancer.
研究领域:
肿瘤学
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纳米医学
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免疫学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Hui Li,Junyi Zeng,Qing You,Miaomiao Zhang,Yuanchao Shi,Xiaodong Yang,Wenxing Gu,Yajie Liu,Ning Hu,Yu Wang,Xiaoyuan Chen,Jing Mu
Radiotherapy, employing high-energy rays to precisely target and eradicate tumor cells, plays a pivotal role in the treatment of various malignancies. Despite its therapeutic potential, the effectiveness of radiotherapy is hindered by the tumor's inherent low radiosensitivity and the immunosuppressive microenvironment. Here we present an innovative approach that integrates peroxynitrite (ONOO − )-mediated radiosensitization with the tumor-associated neutrophils (TANs) polarization for the reversal of immunosuppressive tumor microenvironment (TME), greatly amplifying the potency of radiotherapy. Our design employs X-ray-activated lanthanide-doped scintillators (LNS) in tandem with photosensitive NO precursor to achieve in-situ ONOO − generation. Concurrently, the co-loaded TGF-β inhibitor SB525334, released from the LNS-RS nanoplatform in response to the overexpressed GSH in tumor site, promotes the reprogramming of TANs from N2 phenotype toward N1 phenotype, effectively transforming the tumor-promoting microenvironment into a tumor-inhibiting state. This ‘one-two punch’ therapy efficiently trigger a robust anti-tumor immune response and exert potent therapeutic effects in orthotopic colorectal cancer and melanoma mouse model. Meanwhile, it also significantly prevents liver metastasis and recurrence in metastatic colorectal cancer. The development of X-ray-controlled platforms capable of activating multiple therapeutic modalities may accelerate the clinical application of radiotherapy-based collaborative therapy.
研究领域:
肿瘤学
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放射生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
BMC MUSCULOSKELETAL DISORDERS
·
2024
·Vol. 25
·期 1
·1-11
·
IF 2.2
Du Xiao,Zang Chuanyi,Wang Qinglei
Background Osteoporosis is a genetic disease caused by the imbalance between osteoblast-led bone formation and osteoclast-induced bone resorption. However, further gene-related pathogenesis remains to be elucidated.Methods The aberrant expressed genes in osteoporosis was identified by analyzing the microarray profile GSE100609. Serum samples of patients with osteoporosis and normal group were collected, and the mRNA expression of candidate genes was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mouse cranial osteoblast MC3T3-E1 cells were treated with dexamethasone (DEX) to mimic osteoporosis in vitro. Alizarin Red staining and alkaline phosphatase (ALP) staining methods were combined to measure matrix mineralization deposition of MC3T3-E1 cells. Meanwhile, the expression of osteogenesis related genes including alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), Osterix, and bone morphogenetic protein 2 (BMP2) were evaluated by qRT-PCR and western blotting methods. Then the effects of candidate genes on regulating impede bone loss caused by ovariectomy (OVX) in mice were studied.Results Cyclin A1 (CCNA1) was found to be significantly upregulated in serum of osteoporosis patients and the osteoporosis model cells, which was in line with the bioinformatic analysis. The osteogenic differentiation ability of MC3T3-E1 cells was inhibited by DEX treatment, which was manifested by decreased Alizarin Red staining intensity, ALP staining intensity, and expression levels of ALP, OCN, OPN, Osterix, and BMP2. The effects of CCNA1 inhibition on regulating osteogenesis were opposite to that of DEX. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that genes negatively associated with CCNA1 were enriched in the TGF-beta signaling pathway. Inhibitor of TGF-beta signaling pathway partly reversed osteogenesis induced by suppressed CCNA1. Furthermore, suppressed CCNA1 relieved bone mass of OVX mice in vivo.Conclusion Downregulation of CCNA1 could activate TGF-beta signaling pathway and promote bone formation, thus playing a role in treatment of osteoporosis.
研究领域:
骨生物学
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分子生物学
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遗传学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Natural Products and Bioprospecting
·
2026
·Vol. 16
·期 1
·13
·
IF 4.9
Mei Mei,Sun Huawei,Zhang Kai,Zhang Feng,Sun Shiqing,Zhang Yu
In this study, a diabetic nephropathy (DN) rat model was established using 2% Streptozocin (STZ) solution, and an in vitro DN model was constructed by stimulating HK-2 cells with 30 mM glucose to investigate the mechanism of Phellodendron amurense Rupr. Polysaccharides (PAP) in ameliorating DN. Results demonstrated that PAP, a neutral homogeneous polysaccharide with molecular weight of 1.98 × 105 Da composed of Rha, GalA, Gal, and D-Xyl, exerted renal protective effects through multiple pathways. It enhanced renal antioxidant capacity and alleviated oxidative damage in DN by upregulating PI3K/AKT pathway-related protein expression. Simultaneously, PAP activated the TGF-β/Smad pathway via Nrf2 to mitigate renal fibrosis symptoms in DN, while inhibiting cellular apoptosis. Furthermore, PAP suppressed renal inflammation through gut microbiota reduction, thereby protecting against renal injury in DN rats. This study reveals that PAP alleviates DN symptoms by modulating gut microbiota, enhancing antioxidant and anti-fibrotic capacities, and inhibiting apoptotic pathways, comprehensively elucidating its multifaceted therapeutic mechanisms against DN. Graphical
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PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2026
·
IF 13.2
Hao Yuan,Xin Xu,Jie Gao,Yu Cao,Can Jin,Kan Ding,Wenfeng Liao
Macrophages can secrete various cytokines associated with liver fibrosis. Galactomannoglucan may activate macrophages. We further hypothesize that galactomanoglucan might impact liver fibrosis. Here we report a novel homogeneous branched galactomannoglucan, AW1, from Acorus tatarinowii , composed of Man, Rha, Glc, Gal, Xyl, and Ara with a molar ratio of 10.8: 0.9: 23.1: 9.2: 6.8: 7.3. AW1 has a backbone composed of alternating 1, 4-linked Glc p and 1, 4-linked Man p residues with branches at the C-6 position of 1,4, 6-linked Glc p, and terminal Xyl p , and an arabinogalactan composed of Gal p , Ara f , and terminal T-Glc p . Interestingly, AW1 markedly inhibits transforming growth factor-β (TGF-β)-induced activation of human hepatic stellate cell (LX-2) in vitro and alleviates carbon tetrachloride (CCl₄)-induced liver fibrosis in mice upon oral administration . Mechanism studies reveal that AW1 suppresses the expression of the Trk-fused gene protein (TFG) and the secretion-defective gene (SEC), thereby attenuating the TFG/SEC trafficking pathway and ultimately blocking the transport of collagen from the endoplasmic reticulum (ER) into the Golgi apparatus (Golgi). Simultaneously, AW1 may dramatically impede the TGF-β/Smad signaling pathway. Accordingly, AW1 shows dual regulatory actions on mitigating hepatic fibrogenesis. The above evidence suggests that AW1 may be a promising lead compound for the development of new anti-liver fibrosis drugs.
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DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2021
·
IF 2.63
Wen-Jie Wu,Yu-Fang Tang,Shuang Dong,Jie Zhang
Objective. The research aimed to confirm the role of the transforming growth factor-β (TGF-β) in cisplatin- (CPT-) evoked kidney toxicity and elucidate the mechanism that ginsenoside Rb3 (Rb3) could alleviate the kidney toxicity by CPT during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis. Methods. The model of xenograft nude mice bearing oral carcinoma cells ACC83 was established and treated with CPT and/or Rb3, respectively. Bodyweights of the treated mice were weighed, and the kidney tissues were collected; following, the histopathology and the expression of TGF-β were examined using H&E staining and immunohistochemistry. Afterward, the renal cells GP-293 were treated with CPT and/or Rb3. The expression and phosphoration of TGF-β, Smad2, Smad3, Bcl-2, and Bax in GP-293 cells were detected by Western blotting. The cellular apoptosis and mitochondrial membrane potential were analyzed using flow cytometry. Results. The xenograft nude mice exposure to CPT presented the bodyweight loss, necrotic areas, and the increased expression of TGF in kidney tissue, and Rb3 pretreatment relieved these changes evoked by CPT. In GP-293 cells, CPT administration induced the phosphorylation of Smad2 and Smad3, and Rb3 pretreatment suppressed the induced phosphorylation by CPT. Besides, flow cytometry analysis showed that Rb3 inhibited the CPT-evoked cellular apoptosis ratio and mitochondrial membrane depolarization. The Western blotting test indicated that Rb3 alleviated the cleavage of PARP, caspase 3, caspase 8, and caspase 9, the induction of Bax expression, and inhibition of Bcl-2 expression. Additionally, after treating with the TGF inhibitor of disitertide, Rb3 exhibited no alleviation effects on CPT-evoked cellular apoptosis ratio, inhibition of Bax expression, and induction of Bcl-2 expression in GP-293 cells. Conclusion. Rb3 could alleviate CPT-evoked toxic effects on kidney cells during its treatment to oral cancer via TGF-β-mediated mitochondrial apoptosis.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND FUNCTION
·
2023
·Vol. 42
·期 1
·e3899
·
IF 3.6
Tingting Wang,Guihua Song,Mengmeng Sun,Yan Zhang,Bingxue Zhang,Minghao Peng,Mengyin Li
Asthma is a common respiratory disease associated with airway inflammation. Nerolidol is an acyclic sesquiterpenoid with anti-inflammatory properties. BALB/C mice were sensitized with ovalbumin (OVA) to induce asthma symptoms and given different doses of Nerolidol. We found that Nerolidol reduced OVA-induced inflammatory cell infiltration, the number of goblet cells and collagen deposition in lung tissue. Nerolidol reduced the OVA-specific IgE levels in serum and alveolar lavage fluid in an asthma model. Immunohistochemical staining of α-SMA (the marker of airway smooth muscle) showed that Nerolidol caused bronchial basement membrane thinning in asthmatic mice. The hyperplasia of airway smooth muscle cells (ASMCs) is an important feature of airway remodeling in asthma. ASMCs were treated with 10 ng/mL TGF-β to simulate the pathological environment of asthma in vitro and then treated with different doses of Nerolidol. Nerolidol inhibited the activity of TGF-β/Smad signaling pathway both in the lung tissue of OVA-induced mouse and TGF-β-stimulated ASMCs. 16s rRNA sequencing was performed on feces of normal mice, the changes of intestinal flora in OVA-induced asthmatic mice and Nerolidol-treated asthmatic mice were studied. The results showed that Nerolidol reversed the reduced gut microbial alpha diversity in asthmatic mice. Nerolidol changed the relative abundance of gut bacteria at different taxonomic levels. At the phylum level, the dominant bacteria were Bacteroidota, Firmicutes, and Proteobacteria. At the genus level, the dominant bacteria were Lactobacillus, Muribaculaceae, Bacteroides , and Lachnospiraceae . We conclude that Nerolidol attenuates OVA-induced airway inflammation and alters gut microbes in mice with asthma via TGF-β/Smad signaling. Significance statement This research has demonstrated a mitigating effect of Nerolidol on the progress of asthma. TGF-β/Smad signaling pathway is the critical target of Nerolidol. Intestinal flora disorders induced by asthma are also regulated by Nerolidol.
研究领域:
药理学
·
免疫学
·
微生物学
·
呼吸系统疾病
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DOI
PubMed
高影响因子
MOLECULES
·
2026
·Vol. 31
·期 12
·1990
·
IF 5.1
Jinghan Zhang,Yue Sun,Jinhao Zheng,Can Yang,Mingshuo Yang,Liming Pan
Dendrobium officinalehas attracted increasing attention as a functional food because of its diverse biological activities; however, the photoprotective potential of its protein-derived peptides remains poorly understood. In this study,D. officinaleprotein hydrolysates were fractionated by ultrafiltration according to molecular weight, and their protective effects against ultraviolet B (UVB)-induced photoaging were systematically evaluated in HaCaT keratinocytes. Among the tested fractions, low-molecular-weight peptide fractions exhibited relatively stronger antioxidant activity and effectively reduced intracellular reactive oxygen species (ROS) accumulation in UVB-irradiated cells. In addition, the peptide fractions alleviated UVB-induced inflammatory responses and decreased matrix metalloproteinase (MMP) expression, which was associated with modulation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways. Higher-molecular-weight fractions showed relatively stronger effects on maintaining skin barrier-related functions and were associated with regulation of transforming growth factor-β/Smad (TGF-β/Smad) signaling and collagen-related protein expression. Overall, these findings demonstrate functional differences amongDendrobium officinalepeptide fractions and suggest their potential application as natural photoprotective ingredients in functional foods and cosmeceutical products.
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PubMed
高影响因子
AQUACULTURE NUTRITION
·
2020
·Vol. 26
·期 5
·1792-1805
·
IF 2.231
Hua Rong,Fan Lin,Samwel Mchele Limbu,Zhideng Lin,Baoliang Bi,Tengfei Dou,Lei Zhao,Xiaobo Wen
Swim bladder is an ideal source of collagen production in fish for improved human health. Proline (Pro) is the main proteinogenic amino acid needed for collagen production. However, the effects of Pro supplementation on the swim bladder collagen synthesis have rarely been evaluated in fish. We determined the effects of dietary Pro supplementation on swim bladder collagen synthesis and its possible signalling pathway in spotted drum, Nibea diacanthus . A total of 450 N. diacanthus (100 ± 3.05 g) were randomly assigned into six treatments and fed with diets supplemented with different levels of Pro (0, 2.5, 5, 7.5, 10 and 12.5 g/kg of dry diet, hereafter P0, P1, P2, P3, P4 and P5, respectively) for 8 weeks. At the end, we evaluated collagen synthesis in swim bladder and the expression of genes related to TGF-β/Smad pathway in the fish. Dietary Pro levels increased significantly the contents of crude protein, total collagen (TC) and the levels of some amino acids in swim bladder than the control diet ( p < .05). The optimum amount of dietary Pro inclusion in diets for swim bladder collagen synthesis in N. diacanthus was 7.6 and 7.5 g/kg based on crude protein and TC in swim bladder, respectively. Dietary Pro levels increased significantly the proline 4-hydroxylase ( P4H ) content in fish serum, swim bladder, muscle and liver tissues than control ( p < .05). The relative expression of collagen type I alpha 1 ( COL1A1 ), alpha 2 ( COL1A2 ) and mothers against decapentaplegic homolog 2 ( Smad2 ) genes in liver and swim bladder initially increased significantly as the concentration of Pro and later decreased ( p < .05). Similarly, the relative expression of transforming growth factor beta ( TGF-β ), P4Ha2 and P4Ha3 genes in the swim bladder increased significantly as dietary Pro levels increased ( p < .05). Using K -means clustering analysis, dietary proline partly promoted collagen accumulation in swim bladder through upregulation of Smad2 and TGF-βRT genes. Taken together, Pro affected the collagen metabolism in swim bladder, probably by regulating the TGF-β/Smad pathway, most likely via transient overexpression of Smad2 gene.
研究领域:
水产养殖
·
营养学
·
分子生物学
·
鱼类生理学
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DOI
高影响因子
危险品化学品经营许可证（带存储）