Biomaterials Research
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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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DOI
PubMed
高影响因子
Journal of Translational Medicine
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2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Liu Nannan,Fan Xuefei,Shao Yubao,Chen Suhuan,Wang Taorong,Yao Tao,Chen Xiaoyu
Background and purposeInterstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway.Methods We established an arthritis model by combining chicken type II collagen and complete Freund’s adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD.Results Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD.Conclusion In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.Graphical Abstract
研究领域:
药理学
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免疫学
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肺科学
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风湿病学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
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2021
·Vol. 45
·期 5
·e13723
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IF 2.72
Yanyuan Zhou,Huan Lan,Zhewen Dong,Wenjing Cao,Zhen Zeng,Jia-Le Song
This study investigated the effects of proanthocyanidins (PCs) on ovarian fibrosis in letrozole-induced polycystic ovary syndrome (PCOS) in rats. The administration of PCs effectively reduced the body weight (BW) and relative ovarian weight in PCOS rats. ELISA results revealed that PCs significantly reduced the level of serum T, LH, LH/FSH in the PCOS group. In addition, qRT-PCR results revealed that treatment with PCs significantly increased the main antioxidant enzymes (Cat, Sod2, Gpx3, Mgst1, Gsta4, Sod1 and Prdx3) in PCOS rats. Also, the expression analysis of proteins by Western blotting revealed that PCs significantly decreased the level of TGF-βR1, p-Smad3, p-Smad2 and Smad4 and reversed the downregulation of Smad7 in PCOS rats. The study suggested that PCs improved ovarian fibrosis in PCOS rats by regulating the serum hormone level, inhibiting oxidative stress and suppressing the activation of the TGF-β1/Smads signaling pathway. Practical applications Currently, plant extracts are being widely used to treat female reproductive and metabolic disorders. Particularly, proanthocyanidins (PCs), the well-known natural polyphenolic compounds, which are a significant source of antioxidants present in many colored fruits, are consumed as fruits as well as a dietary supplement to prevent many disorders. Recent pharmacological studies have reported that PCs have many health beneficial properties, such as antioxidant activity, improving cholesterol homeostasis, blood lipid regulatory properties, microcirculation improvement effect, antitumor activity and anti-aging activity. Despite these properties of PCs, the antifibrosis effect of PCs has not been studied to date. The main purpose of this study was to research the role and the mechanisms of PCs in ovarian fibrosis in PCOS rats.
研究领域:
药理学
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生殖生物学
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内分泌学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
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IF 3.8
Hancheng Huang,Shuchun Wei,Xiaohan Wu,Mengke Zhang,Benhong Zhou,Debin Huang,Weiguo Dong
The pathophysiological mechanism of hepatic fibrosis (HF) is related to the excessive activation of the DNA repair enzyme poly ADP-ribose polymerase-1 (PARP-1). The drugs, targeting PARP-1, are scarce. Therefore, the lead compound, moderately inhibiting PARP-1, with anti-HF properties should be identified. This study screened dihydrokaempferol (DHK) from herbs based on preliminary studies to intervene in a CCl 4 -induced liver injury and HF model in mice. In vitro , the expression levels of PARP-1-regulated related proteins and phosphorylation were examined. The binding pattern of DHK and PARP-1 was analyzed using molecular docking and molecular dynamics platforms. The results showed that DHK could significantly attenuate CCl 4 -induced liver injury and HF in mice. Moreover, it could also attenuate the toxic effects of CCl 4 on HepG2 and inhibit α-SMA and Collagen 1/3 synthesis of LX-2 cells in-vitro . Molecular docking revealed that DHK could competitively bind to the Glu-988 and His-862 residues of the upstream DNA repair enzyme PARP-1, moderately inhibiting its overactivation. This led to maintaining NAD + levels and energy metabolism in hepatocytes and inhibiting the activation of PARP-1-regulated downstream signaling pathways (TGF-β1, etc. ), related proteins (p-Smd2/3, etc. ), and inflammatory mediators while acting indirectly. Thus, DHK could attenuate CCl 4 -induced liver injury and HF in mice in a different mechanism from those of the existing reported flavonoids. It was associated with inhibiting the expression of downstream pathways and related cytokines by competitively binding to PARP-1. This study might provide a basis and direction for the design and exploration of anti-HF lead compounds.
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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毒理学
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PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
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2020
·Vol. 72
·期 7
·956-968
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IF 2.571
Wang Youpeng,Jing Weichao,Qu Wanying,Liu Zhiwei,Zhang Di,Qi Xiaoyu,Liu Lujia
ObjectivesThe aim of this study was to evaluate the effect of tectorigenin on treating allergic asthma model of guinea pigs and investigate the underlying mechanisms.MethodsAllergic asthma model of guinea pigs was established by sensitizing with ovalbumin (OVA). Then OVA-sensitized guinea pigs were injected with 10 mg/kg tectorigenin, 25 mg/kg tectorigenin or dexamethasone to investigate the effect of tectorigenin.Key findingsHigh dose of tectorigenin effectively decreased the number of coughs, the number of inflammatory cells and the levels of pro-inflammatory factors. Moreover, tectorigenin could inhibit pulmonary fibrosis in guinea pigs sensitized with OVA. In addition, the functions of tectorigenin were realized through downregulating profibrotic factors of transforming growth factor (TGF)-β1, phosphorylated (p)-Smad2/3 and Smad4, upregulating fibrosis-inhibitor of Smad7 and decreasing pro-inflammatory factors of vascular endothelial growth factor A (VEGFA), tumour necrosis factor-α (TNF-α), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), p-inhibitor of nuclear factor-kappa B (NF-κB) kinase β (p-IKKβ) and NF-κB.ConclusionsTectorigenin could inhibit pulmonary fibrosis and airway inflammation through TGF-β1/Smad signalling pathway and TLR4/NF-κB signalling pathway. Therefore, tectorigenin might be a promising medicine to treat allergic asthma.
研究领域:
药理学
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免疫学
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呼吸医学
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DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 5
·4582-4590
·
IF 4.171
Xiaohua Lei,Qiang Liu,Qiang Liu,Zhenyu Cao,Ju Zhang,Tao Kuang,Yu Fang,Guoxing Liu,Ke Qian,Jie Fu,Huihui Du,Zhiqiang Liu,Zhihong Xiao,Changzhu Li,Xundi Xu
Liver fibrosis is a common part of the pathological development of many chronic liver diseases. As liver fibrosis progresses, it may lead to cirrhosis, portal hypertension, liver decompensation, liver tumours, and death. Camellia oil (Camellia oleifera Abel.) is widely used as an edible oil in China. It has a wide range of biological activities and is used as a traditional medicine to treat conditions such as burns and stomach pains. However, whether camellia oil can ameliorate liver fibrosis remains unclear. We constructed a liver fibrosis model induced by carbon tetrachloride (CCl4) and then confirmed the role of camellia oil in liver fibrosis by biochemical examination, histopathological morphology, immunohistochemistry, and western blot analysis. We found that camellia oil ameliorated histopathological lesions, improved liver function and antioxidant capacity, decreased the expression of TGF-β1 and α-SMA proteins, and downregulated the expression of the pro-apoptotic proteins in CCl4-induced liver fibrosis. Therefore, these results suggest that camellia oil attenuates CCl4-induced liver fibrosis in mice, and its mechanism may function via reduction of hepatocyte apoptosis to inhibit hepatic stellate cell (HSC) activation. Camellia oil may provide a potential new treatment for liver fibrosis as an auxiliary treatment by addition of the edible oil to the daily diet.
研究领域:
药理学
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肝病学
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病理学
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PubMed
高影响因子
DRUG DELIVERY
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2021
·
IF 6.419
Ya-Wen Zhang,Ling-Lan Tu,Yi Zhang,Jie-Chao Pan,Gao-Li Zheng,Li-Na Yin
Liver fibrosis is a major global health concern. Management of chronic liver disease is severely restricted in clinics due to ineffective treatment approaches. However, a lack of targeted therapy may aggravate this condition. Asiatic acid (AA), a pentacyclic triterpenoid acid, can effectively protect the liver from hepatic disorders. However, the pharmaceutical application of AA is limited by low oral bioavailability and poor targeting efficiency. This study synthesized a novel liver-targeting material from PEG-SA, chemically linked to ursodeoxycholic acid (UA), and utilized it to modify AA nanostructured lipid carriers (UP-AA-NLC) with enhanced targeting and improved efficacy. The formulation of UP-AA-NLC was optimized via the Box–Behnken Experimental Design (BBD) and characterized by size, zeta potential, TEM, DSC, and XRD. Furthermore, in vitro antifibrotic activity and proliferation of AA and NLCs were assessed in LX-2 cells. The addition of UP-AA-NLC significantly stimulated the TGF-beta1-induced expression of α-SMA, FN1, and Col I α1. In vivo near-infrared fluorescence imaging and distribution trials in rats demonstrated that UP-AA-NLC could significantly improve oral absorption and liver-targeting efficiency. Oral UP-AA-NLC greatly alleviated carbon tetrachloride-induced liver injury and fibrosis in rats in a dosage-dependent manner, as reflected by serum biochemical parameters (AST, ALT, and ALB), histopathological features (H&E and Masson staining), and antioxidant activity parameters (SOD and MDA). Also, treatment with UP-AA-NLC lowered liver hydroxyproline levels, demonstrating a reduction of collagen accumulation in the fibrotic liver. Collectively, optimized UP-AA-NLC has potential application prospects in liver-targeted therapy and holds great promise as a drug delivery system for treating liver diseases.
研究领域:
药理学
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肝病学
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药物递送系统
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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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PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
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2021
·Vol. 297
·期 4
·
IF 5.157
Ge Liu,Rui Liu,Yeqi Shan,Chaomin Sun
Many natural polysaccharides have significant anticancer activity with low toxicity, but the complex chemical structures make in-depth studies of the involved mechanisms extremely difficult. The purpose of this study was to investigate the effect of the marine bacterial exopolysaccharide (exopolysaccharide 11 [EPS11]) on liver cancer metastasis to explore the underlying target protein and molecular mechanism. We found that EPS11 significantly suppressed cell adhesion, migration, and invasion in liver cancer cells. Proteomic analysis showed that EPS11 induced downregulation of proteins related to the extracellular matrix–receptor interaction signaling pathway. In addition, the direct pharmacological target of EPS11 was identified as collagen I using cellular thermal shift assays. Surface plasmon resonance and pull-down assays further confirmed the specific binding of EPS11 to collagen I. Moreover, EPS11 was shown to inhibit tumor metastasis by directly modulating collagen I activity via the β1-integrin–mediated signaling pathway. Collectively, our study demonstrated for the first time that collagen I could be a direct pharmacological target of polysaccharide drugs. Moreover, directly targeting collagen I may be a promising strategy for finding novel carbohydrate-based drugs.
研究领域:
癌症生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Zhijing Chen,Xiaole Hu,Zhengjie Lin,Haoran Mao,Zhen Qiu,Kerong Xiang,Tiancheng Ke,Lihua Li,Lu Lu,Liling Xiao
Hypertrophic scar (HS) is an unfavorable skin disorder that typically develops after trauma, burn injury, or surgical procedures and causes numerous physical and psychological issues in patients. Currently, intralesional multi-injection of corticosteroid, particularly compound betamethasone (CB), is one of the most prevalent treatments for HS. However, injection administration could result in severe pain and dose-related side effects. Additionally, the vacuum therapeutic efficacy of this treatment relies on the level of expertise of the healthcare professional. To overcome the limitations of conventional injections, a new method that is convenient, painless, and self-administrable is urgently required. In this study, we developed a methacrylate gelatin (GelMA)/polyethylene glycol diacrylate (PEGDA) double-network hydrogel microneedle patch loaded with CB (CB-HMNP) as an intradermal delivery system for HS treatment. The double-network structure conferred the CB-HMNP with sufficient mechanical properties to successfully penetrate scar tissue while also helping to regulate the drug’s sustained release rate. Subsequently, we confirmed that the CB-HMNP had a pronounced inhibitory effect on human HS fibroblasts (hHSFs), whereas drug-free HMNPs had no effect on hHSFs, indicating its high biocompatibility. In order to assess the therapeutic efficacy of CB-HMNPs, HS models of New Zealand rabbit ears were developed. The administration of CB-HMNP three times significantly decreased the scar elevation index (SEI), collagen I/III, and transforming growth factor-β1 (TGF-β1) protein. Therefore, the CB-HMNP may offer an administration pathway for the treatment of HS that is less painful, more convenient, less invasive, and sustain-released.
研究领域:
药学
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材料科学
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生物医学工程
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皮肤科
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2024
·
IF 2.4
Xingbo Wang,Hong Huang,Wenxiu Xu,Yanling Gong,Songbo Shi,Xu Wan,Li Pengbiao
Introduction Triple negative breast cancer (TNBC) is characterized with higher malignancy and mortality and is prone to distant metastasis, among which bone is the most common site. It’s urgent to explore new strategies for treatment of TNBC and its bone metastases.Methods A tumor environment responsive vector, poly-(dimethylaminoethyl methacrylate)-SS-poly(ethylene glycol)-SS-poly-(dimethylaminoethyl methacrylate) (PDMAEMA-SS-PEG-SS-PDMAEMA), was constructed to co-delivery transforming growth factor-β1 (TGF-β1) siRNA and forkhead box M1 (FOXM1) siRNA in MDA-MB-231 cells. The preparation, characterization, in vitro release, stability, and transfection efficiency of nanoparticles were measured. Cell viability, migration and invasion of MDA-MB-231 cells were determined. Cell chemotactic migration and cell heterogeneity adhesion of MDA-MB-231 cells to the human osteoblast-like cell line MG-63 were determined.Results PDMAEMA-SS-PEG-SS-PDMAEMA self assembled with siRNA at N/P of 15:1 into nanoparticles with particle size of 122 nm. In vitro release exhibited redox and pH sensitivity, and the nanoparticles protected siRNA from degradation by RNase and serum protein, remaining stable at 4 °C with similar transfection efficiency with lipo2000. Nanoparticles co-loaded with TGF-β1 siRNA and FOXM1 siRNA inhibited the cell viability, migration and invasion of MDA-MB-231 cells, as well as chemotactic migration and heterogeneous adhesion of MDA-MB-231 cells to MG-63 cells, showing a synergetic effect. After gene silencing on TGF-β1 and FOXM1, the epithelial to mesenchymal transition (EMT) related molecules vimentin mRNA expression decreased while E-cadherin increased.Conclusion PDMAEMA-SS-PEG-SS-PDMAEMA was suitable for TGF-β1 siRNA and FOXM1 siRNA delivery, exhibiting synergetic inhibition effect on TNBC and its bone metastases, which might be related to its synergetic inhibition on EMT.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Dan Wang,Yimeng Zou,Tianqi Zhao,Weiyue Cao,Jiachi Han,Qing Wu,Zhitong Li,Xinyu Li,Peijing Liu,Lin Bai,Guiping Ren
Background The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms. Methods The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21 −/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses. Results The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21 −/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21 −/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK. Conclusions To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.
研究领域:
免疫学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）