JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
·
2024
·
IF 3.6
Shanjiang Chen,Jianjian Yang,Fuli Liu
Celastrol (CEL) belongs to the group of non-steroidal immunosuppressants with the potential to improve cardiac hypertrophy (CH). However, the poor biocompatibility and low bioavailability of CEL limit its in vivo application. This study was aimed to develop a targeted drug delivery system that can efficiently and safely deliver CEL to target tissues, providing a research basis for the application of CEL in CH therapy. A novel ROS-sensitive drug-loaded nanomicelle, dodecanoic acid (DA)-phenylboronic acid pinacol ester-dextran polymer encapsulating CEL (DBD@CEL), was synthesized using chemical synthesis. Then, the morphology, particle size, drug-loaded content, and ROS-responsive release behavior of DBD@CEL were studied. Pharmacokinetics and biocompatibility were evaluated using healthy mice. Finally, the ability and mechanism of DBD@CEL in improving CH in vivo were investigated using a mouse CH model. DBD@CEL was successfully prepared with a drug loading of 18.9%. It exhibited excellent stability with an average particle size of 110.0 ± 1.7 nm. Within 48 h, DBD@CEL released only 19.4% in the absence of H2O2, while in the presence of 1 mM H2O2, the release rate increased to 71.5%. Biocompatibility studies indicated that DBD@CEL did not cause blood cell hemolysis, had no impact on normal organs, and did not result in abnormal blood biochemical indicators, demonstrating excellent biocompatibility. In vivo studies revealed that DBD@CEL regulated the activation of NF-κB signaling, inhibits pyroptosis and oxidative stress, and thereby ameliorates CH. The ROS-responsive DBD@CEL nanodrug delivery system enhances the therapeutic activity of CEL for CH, providing a promising drug delivery system for the clinical treatment of CH.
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Biomed Research International
·
2022
·
IF 3.246
Cheng Shi,Fei Yuan,Zhilong Li,Zhenhua Zheng,Changliang Yuan,Ziyang Huang,Jianping Liu,Xuping Lin,Taoyi Cai,Guofeng Huang,Zhenqi Ding
Background. The microenvironment of bone defects displayed that M2 polarization of macrophagocyte could promote the osteoblast growth and benefit the wound healing. Bone scaffold transplantation is considered to be one of the most promising methods for repairing bone defects. The present research was aimed at constructing a kind of novel bone scaffold nanomaterial of [email protected] for treating bone defects responding to the wound microenvironment of bone defects and elucidating the mechanics of [email protected] treating bone defect via controlling release of IL-4, inducing M2 polarization and active factor release of macrophagocyte, and eventually relieving osteoblast injury. Methods. [email protected] was firstly fabricated and its release of IL-4 was assessed in vitro. Following, the effects of [email protected] nanocomplex on the release of active factors of macrophage were examined using Elisa assay and promoting M2 polarization of the macrophage by immunofluorescence staining. And then, the effects of active factors from macrophage supernatant induced by [email protected] on osteoblast growth were examined by CCK-8, flow cytometry, and western blot assay. Results. The release curve of IL-4 in vitro displayed that there was more than 80% release ratio for 30th day with a sustained manner in pH 5.5. Elisa assay data showed that [email protected] nanocomplex could constantly promote the release of proproliferative cytokine IL-10, SDF-1α, and BMP-2 in macrophagocyte compared to only IL-4 treatment, and immunofluorescent image showed that [email protected] could promote M2 polarization of macrophagocytes via inducing CD206 expression and suppressing CD86 expression. Osteoblast injury data showed that the supernatant from macrophagocyte treated by [email protected] could promote the osteoblast proliferation by MTT assay. Flow cytometry data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the osteoblast apoptosis from 22.1% to 14.6%, and apoptosis-related protein expression data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the expression of Bax, cleaved caspase 3, and cleaved caspase 8. Furthermore, the immunofluorescent image showed that the supernatant from macrophagocyte treated by [email protected] could inhibit nucleus location of p65, and western blot data showed that the supernatant from macrophagocyte treated by [email protected] could suppress the phosphorylation of IKK and induce the expression of IκB. Conclusion. [email protected] could control the sustaining release of IL-4, and it exerts the protective effect on osteoblast injury via inducing M2 polarization and proproliferative cytokine of macrophagocyte and following inhibiting the apoptosis and NF-κB pathway-associated inflammation of osteoblast.
研究领域:
生物医学工程
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组织工程
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细胞生物学
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材料科学
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Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Haiwen Zhang,Youming Liu,Xin Fang,Lihong Gu,Caiwei Luo,Lu Chen,Qian Wang
Vitamin D 3 , as an indispensable and fat-soluble micronutrient, plays an important role in the health of humans and animals. At present, studies are focusing on the calcium absorption and immunoregulation function of vitamin D 3 ; this study was aimed at exploring the antioxidative stress ability of vitamin D 3 on diquat-induced intestinal dysfunction of ICR mice and the underlying mechanism. The results showed that oral gavage of vitamin D 3 daily significantly improved the body weight gain and immune organ index and significantly reverted the abnormal changes of ALT, AST, SOD, GSH-Px, T-AOC, and MDA in the serum and jejunum induced by diquat. The addition of vitamin D 3 also significantly reduced the concentration of DAO, D-LA, and certain proinflammatory cytokines in serum. Moreover, vitamin D 3 improved the pathological morphology of the duodenum, jejunum, colon, liver, and kidney tissues, and it also largely attenuated the degree of inflammatory infiltration of macrophages and cell apoptotic index of jejunal epithelial tissue induced by diquat. The results demonstrated that vitamin D 3 significantly recovered the intestinal barrier injury by enhancing the expression of mucins and tight junction proteins in the jejunum. In addition, the results indicated that vitamin D 3 could significantly reduce the phosphorylation level of NF- κ B (p65) and enhance the expression of Nrf2 and HO-1 in the jejunum compared with the diquat-induced group. This study suggested that oral administration of vitamin D 3 can protect mice against oxidative damage by inhibiting the phosphorylation level of NF- κ B (p65) and activating Nrf2-related signaling pathways.
研究领域:
药理学
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免疫学
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分子生物学
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毒理学
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TISSUE & CELL
·
2022
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IF 2.586
Taiding Wu,Xin Li,Shiwei Tu,Wenbo Tan,Longju Chen
Demyelination disease as diabetes mellitus (DM) complication is characterized by apoptosis of Schwann cells (SCs) and several reports have demonstrated that high glucose content can induce an inflammation response and lead to the apoptosis of SCs. For NF-κB plays a pivotal role in the inflammatory response, hence we hypothesized that high glucose content can induce inflammation though the NF-κB pathway. First we verified that 150 mM high glucose can increase the expression of cleaved caspase 3 , interleukin (IL)− 1β, Cyto-C and NF-κB with time through Western blot and increase the apoptosis of RSC96s through Flow Cytometry. Then we found that high glucose can increase the nuclear translocation NF-κB through confocal system which can promote the expression of inflammation genes such as IL-1β. Curcumin has been reported to possess anti-inflammation activities to protect cells. In this study, we found that application with 25 μM curcumin could alleviate the inflammation response and protect the cells from apoptosis. We revealed that the expression of NF-κB and p-NF-κB was decreased and the translocation was also inhibited after curcumin application. Accordingly, the secretion of IL-1β and the apoptosis of RSC96s induce by high glucose was suppressed. Our cumulative findings suggest that curcumin can protect SCs from apoptosis through the inhibition of the inflammatory response though the NF-κB pathway.
研究领域:
神经科学
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药理学
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糖尿病研究
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细胞生物学
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Jing-Mei Lu,Guang-Nan Jin,Yu-Nan Lu,Xu-Dong Zhao,Hui-Wen Lan,Shuai-Ru Mu,Xin-Yu Shen,Guang-Hua Xu,Cheng-Hua Jin,Juan Ma,Xuejun Jin,Xiang Xu,Lian-Xun Piao
Toxoplasma gondii ( T. gondii ) is an obligate intracellular parasite that can cause liver diseases in the host, including hepatitis and hepatomegaly . High mobility group box 1 (HMGB1) is the main inflammatory mediator causing cell injury or necrosis. HMGB1 binds to toll like receptor 4 (TLR4), then activates the nuclear factor-κB (NF-κB) signaling pathway, which promotes the release of inflammatory factors. Our previous studies showed that HMGB1 mediated TLR4/NF-κB signaling pathway plays an important role in liver injury induced by T. gondii infection. Resveratrol (RSV) is a small polyphenol, which has anti-inflammatory, anti-cancer, anti- T. gondii effect. However, the effect of RSV on liver injury caused by T. gondii infection is unclear. This study used the RH strain tachyzoites of T. gondii to infect murine liver line, NCTC-1469 cells to establish an in vitro model and acute infection of mice for the in vivo model to explore the protective effect of RSV on liver injury induced by T. gondii infection. The results showed that RSV inhibited the proliferation of T. gondii in the liver, reduced the alanine aminotransferase/aspartate aminotransferase levels and pathological liver damage. Additionally, RSV inhibited the production of tumor necrosis factor-α, inducible nitric oxide synthase and HMGB1 by interfering with the TLR4/NF-κB signaling pathway. These results indicate that RSV can protect liver injury caused by T. gondii infection by intervening in the HMGB1/TLR4/NF-κB signaling pathway. This study will provide a theoretical basis for RSV treatment of T. gondii infection induced liver injury.
研究领域:
免疫学
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药理学
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寄生虫学
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分子生物学
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病理学
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PubMed
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Frontiers in Pharmacology
·
2022
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IF 5.988
Chenxi Wu,Fenfen Li,Xiaoxi Zhang,Wenjing Xu,Yan Wang,Yanjing Yao,Ziwei Han,Daozong Xia
Background: Gouty arthritis is a common and complex inflammatory disease that will reduce the life quality of human beings (−)-Epicatechin (EC) is famous for antioxidant and anti-inflammatory activities. Thus, the aim of this study was to investigate the therapeutic effect of EC on gouty arthritis and its mechanisms. Methods and results: EC was added into a monosodium urate (MSU)-stimulated THP-1 cell that was induced by phorbol 12-myristate 13-acetate and lipopolysaccharide (LPS) in advance to establish a gout model in vitro . The efficiency of EC on acute gouty arthritis mice induced by MSU was further investigated. The results showed that EC concentration-dependently improved the cell viability of LPS and MSU stimulated THP-1 cells, and significantly alleviated MSU-induced ankle edema in mice in a dose-dependent manner. In addition, EC inhibited the infiltration of inflammatory cells and local cascular congestion in ankle joint tissue. Furthermore, the secretion of inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α) activation of NLRP3 inflammasome and NF-κB signaling pathway were markedly suppressed by EC in vitro and in vivo . Conclusion: These results indicated that EC could effectively improve MSU-induced acute gouty arthritis via inhibiting NLRP3 inflammasome and the NF-κB signaling pathway in vitro and in vivo , which suggested that EC might be a promising active ingredient for the prevention and treatment of gouty arthritis.
研究领域:
药理学
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免疫学
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炎症性疾病
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细胞生物学
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Journal of Translational Medicine
·
2026
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IF 9.7
Gao Hengyuan,Lin Junqing,Chen Xiaobing,Su Yingshi,Huang Yibin,Zhang Yubo,Zhang Junchang,Xu Nan,Dai Xiaoyong
Background Inter-tumor heterogeneity poses significant challenges for precision therapy in thyroid cancer (TC). The conventional organoid models are limited by inefficiency and poor physiological relevance. Methods We developed droplet-engineered organoids (DEOs) using microfluidic 3D bioprinting to rapidly generate patient-derived TC models. These DEOs were characterized via histology, whole-exome and RNA sequencing, and utilized for drug sensitivity testing and metastasis modeling. Results DEOs were generated within 10 days, exhibiting superior uniformity (CV: 2.54%) and a high success rate (76%). They faithfully recapitulated the histopathological architecture, genomic landscape (92% driver gene concordance), and native immune microenvironment (CD3+/CD56+/CD68+/α-SMA+) of parental tumors. Drug screening revealed patient-specific heterogeneity, accurately mirroring clinical responses, including cisplatin sensitivity and anti-PD-1 resistance. We established a novel TC and lung organoids co-culture model, which could be used to study the TC lung metastasis. Crucially, transcriptomics identified stage-specific maturation driven by NF-κB signaling. Pharmacological inhibition of NF-κB synergistically enhanced the efficacy of dasatinib, anti-PD-1, and paclitaxel, with combination index (CI) values of 0.58, 0.45, and 0.80, respectively. Conclusions Our microfluidic platform enables rapid, high-fidelity modeling of TC, offering a scalable and physiologically relevant tool for mechanistic studies, drug screening, and personalized therapy prediction, with highly promising translational potential.
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TOXICOLOGY
·
2026
·
IF 5.2
Yu Zhang,Yu-Qi Hong,Yi Liu,Ye Yuan,Zi-Xuan Lu,Xiang Zhang,Ting-Ting Zhu
Indium tin oxide nanoparticles (ITO NPs) are widely used in optoelectronic industries, and increasing occupational exposure has raised concern about their pulmonary toxicity. Although ITO exposure has been associated with severe lung diseases, the mechanisms underlying epithelial injury remain unclear. Here, a simplified macrophage–epithelial cell model using RAW264.7 macrophages and BEAS-2B epithelial cells was established to investigate how macrophages modulate ITO NP-induced epithelial toxicity. Direct exposure to ITO NPs caused limited toxicity in BEAS-2B cells, whereas conditioned medium from ITO NP-exposed RAW264.7 cells was associated with reduced epithelial viability, increased LDH release, and EMT-like changes. Dissolved indium species alone did not fully account for the observed effects, whereas macrophage-derived oxidative stress and associated inflammatory responses appeared to contribute more substantially to the epithelial responses. Transcriptomic and biochemical analyses showed that ITO NPs induced oxidative stress and activated NF-κB signaling in macrophages. Inhibition of ROS or NF-κB attenuated macrophage-derived cytotoxicity and reduced EMT-like changes in epithelial cells. These findings support a role for macrophages as important regulators of ITO NP-induced epithelial injury and provide additional mechanistic insight into ITO-related pulmonary toxicity.
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RESEARCH IN VETERINARY SCIENCE
·
2023
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IF 2.4
Jirao Shen,Feng Yang,Guibo Wang,Xiaoqing Mou,Jinyu Li,Xuezhi Ding,Xurong Wang,Hongsheng Li
Staphylococcus haemolyticus ( S. haemolyticus ) is one of the most common coagulase-negative staphylococci (CoNS) isolates from bovine mastitis . Paeoniflorin (PF) shows anti-inflammatory effects on different inflammatory diseases in vitro studies and in vivo animal experiments. In this study, the viability of bovine mammary epithelial cells (bMECs) was detected by the cell counting kit-8 experiment. Subsequently, bMECs were induced with S. haemolyticus , and the induction dosage was determined. The expression of pro-inflammatory cytokines and toll-like receptor (TLR2) and nuclear factor kappa-B (NF-κB) signaling pathway-related genes were investigated by quantitative real-time PCR. The critical pathway proteins were detected by western blot . The results showed that the multiplicity of infection (MOI; the ratio of bacteria to bMECs) 5:1 of S. haemolyticus for 12 h could cause cellular inflammation, which was selected to establish the inflammatory model. Incubation with 50 μg/ml PF for 12 h was the best intervention condition for cells stimulated by S. hemolyticus . Quantitative real-time PCR and western blot analysis showed that PF inhibited the activation of TLR2 and NF-κB pathway-related genes and the expression of related proteins. Western blot results showed that PF suppressed the expression of NF-κB unit p65, NF-κB unit p50, and MyD88 in bMECs stimulated by S. haemolyticus . The inflammatory response pathway and molecular mechanism caused by S. haemolyticus on bMECs are related to TLR2-mediated NF-κB signaling pathways. The anti-inflammatory mechanism of PF may also be through this pathway. Therefore, PF is expected to develop potential drugs against CoNS-induced bovine mastitis.
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ACTA BIOCHIMICA POLONICA
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2022
·Vol. 69
·期 2
·363-370
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IF 2.349
Jian-li Qiu,Yu-na Chai,Feng-yang Duan,Hui-juan Zhang,Xiao-yan Han,Ling-yan Chen,Fei Duan
Liver fibrosis is a global health problem caused by a number of diseases related to liver damage. 6-Shogaol is a biologically active substance derived from the rhizome of Zingiber officinale Roscoe with anti-tumor, anti-inflammatory, and antioxidant properties. To explore the effects of 6-Shogaol on liver fibrosis, we used a mouse model of the condition in which mice were injected intraperitoneally with carbon tetrachloride (CCl4) at a dose of 2 mL/kg three times per week for a period of 4 weeks. 6-Shogaol was administered orally at two different doses (5 mg/kg, 20 mg/kg) 30 min before CCl4 injection. CCl4 induced severe liver injury and fibrosis, as indicated by significant inflammatory cell infiltration, disordered liver structure, increased activities of aspartate aminotransferase and alanine aminotransferase (liver damage markers) in serum, elevated collagen deposition, and overexpressed alpha-smooth muscle actin (α-SMA, marker of hepatic stellate cells activation) in liver tissues, whereas 6-Shogaol administration rescued those alterations dose-dependently. We found that 6-Shogaol suppressed CCl4-induced inflammatory response by inhibiting macrophage recruitment, release of pro-inflammatory factors, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in liver tissues. Additionally, we demonstrated that 6-Shogaol blocked CCl4-induced activation of the nuclear factor-kappa B (NF-κB) pathway, which is a vital transcriptional regulator of the inflammatory response. Altogether, this study demonstrates that 6-Shogaol can prevent CCl4-induced liver fibrosis by suppressing inflammatory response through the NF-κB pathway and suggests that 6-Shogaol can be used for liver fibrosis prevention.
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Frontiers in Immunology
·
2022
·
IF 8.786
Huanhuan Xu,Titi Liu,Jin Li,Fei Chen,Jing Xu,Lihong Hu,Li Jiang,Zemin Xiang,Xuanjun Wang,Jun Sheng
Tumor necrosis factor (TNF)-stimulated nuclear factor-kappa B (NF-κB) signaling plays very crucial roles in cancer development and progression, and represents a potential target for drug discovery. Roburic acid is a newly discovered tetracyclic triterpene acid isolated from oak galls and exhibits anti-inflammatory activity. However, whether roburic acid exerts antitumor effects through inhibition of TNF-induced NF-κB signaling remains unknown. Here, we demonstrated that roburic acid bound directly to TNF with high affinity ( K D = 7.066 μM), blocked the interaction between TNF and its receptor (TNF-R1), and significantly inhibited TNF-induced NF-κB activation. Roburic acid exhibited antitumor activity in numerous cancer cells and could effectively induce G0/G1 cell cycle arrest and apoptosis in colorectal cancer cells. Importantly, roburic acid inhibited the TNF-induced phosphorylation of IKKα/β, IκBα, and p65, degradation of IκBα, nuclear translocation of p65, and NF-κB-target gene expression, including that of XIAP, Mcl-1, and Survivin, in colorectal cancer cells. Moreover, roburic acid suppressed tumor growth by blocking NF-κB signaling in a xenograft nude mouse model of colorectal cancer. Taken together, our findings showed that roburic acid directly binds to TNF with high affinity, thereby disrupting its interaction with TNF-R1 and leading to the inhibition of the NF-κB signaling pathway, both in vitro and in vivo . The results indicated that roburic acid is a novel TNF-targeting therapeutics agent in colorectal cancer as well as other cancer types.
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BIOSENSORS & BIOELECTRONICS
·
2022
·
IF 12.545
Feng Qiu,Xiaoyan Gan,Jianglong Yao,Bingying Jiang,Ruo Yuan,Yun Xiang
Transcription factors (TFs) are key substances in regulating the transcription, replication and expression of genes, and the detection of TFs can provide valuable information to diagnose a variety of diseases. By integrating hybridization chain reaction (HCR)-activated Cas12a enzyme with bio-responsive DNA hydrogels, we propose a dual amplification and label-free homogeneous electrochemical detection method to realize sensitive nuclear factor-kappa B p50 (NF-κB p50) detection. The presence of the target molecules protects the DNA duplex probes from digesting by exonuclease III and initiates HCR to generate long double stranded DNAs that can activate the activity of RNA-guided Cas12a enzymes. The single-stranded region of the DNA linkers that crosslink the DNA hydrogels can be cleaved by the activated Cas12a to release a large number of electroactive substances embedded in the gels, which exhibit highly enhanced electrochemical signals for detecting target molecules at the detection limit of 54.1 fM. In addition, the successful interrogation of NF-κB p50 spiked into lysate of HeLa cells by such method is also verified. The established method thus shows new opportunities for sensitive and convenient monitoring of other transcription factors and biomarkers.
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