BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Zixinying Han,Chenxu Liu,Mingrui Li,Mengyan Deng,Ying Ding,Yunchao Li,Meidan Huo,Haiwei Xu,Hailing Qiao,Na Gao
Considerable evidence indicates that CYP2E1 is associated with a variety of inflammatory diseases. Here we evaluated CYP2E1 as a potential therapeutic target for rheumatoid arthritis (RA) and established the protective effect of a new CYP2E1 inhibitor. Gene-expression datasets were used to analyze the change in expression of CYP2E1 in RA patients; CYP2E1 activity in collagen-induced arthritis (CIA) rats was determined by HPLC. We further evaluated the protective effects of C yp2e1 knockout and a CYP2E1-specific inhibitor, Q11, synthesized by our group, in CIA and adjuvant-induced arthritis (AIA) rats. The expression of CYP2E1 in synovial tissue was elevated in RA patients and in CIA rats and the activity of CYP2E1 in vivo and in vitro in CIA rats was greater than that of controls. C yp2e1 knockout significantly reduced the incidence of CIA and alleviated the severity of symptoms. Treatment with different doses of Q11 decreased paw thickness, volume and arthritis scores and reduced the serum levels of IL‐6, TNF‐α, IL‐1β and MDA, and increased the level of GSH in CIA rats. A similar inhibitory effect was exhibited for Q11 in the AIA rats. Moreover, Q11 significantly impeded proliferation, migration, and invasion of human rheumatoid arthritis synovial fibroblasts cells. Q11 decreased the release of ROS and enhanced Nrf2 nuclear translocation and HO-1 expression in the cell nucleus. Overall, our results indicated that CYP2E1 may be a new target for RA and Q11 has potential protective effects against RA by reducing oxidative stress and opposing the inflammatory response via the ROS/Nrf2/HO-1 signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
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DOI
PubMed
高影响因子
Chinese Herbal Medicines
·
2024
·
IF 4.7
Cuiping Long,Qian Zhou,Min Xu,Xin Ding,Xingxing Zhang,Ya Zhang,Yuping Tang,Guangguo Tan
Objective Myocardial inflammation during myocardial infarction (MI) could be inhibited by regulating arachidonic acid (AA) metabolism. Recent studies demonstrated that Sini Decoction (SND) was identified to be an effective prescription for treating heart failure (HF) caused by MI. But the anti-inflammatory mechanism of SND remained unclear. The work was designed to investigate the anti-inflammatory mechanism of SND through the AA metabolism pathway in vitro and in vivo experiments. Methods An inflammatory injury model of H9c2 cells was established by lipopolysaccharide (LPS)-stimulated macrophage-conditioned media (CM). The animal MI model was built by the ligation of left anterior descending (LAD) branch of coronary artery in rat. Meanwhile, the rats were divided into five groups: sham group, MI group, MI + Celecoxib group, MI + low-dose SND group (SND-L) and MI + high-dose SND group (SND-H). Cardiac function, histopathological changes and serum cytokines were examined four weeks later. Western blot analysis was conducted to verify the key enzymes levels in the AA metabolic pathway, including phospholipase A2 (PLA2), cyclooxygenases (COXs) and lipoxygenases (LOXs). Results These in vivo results demonstrated that SND could improve the cardiac function and pathological changes of rats with MI, and regulate the key inflammatory molecules in the AA metabolism pathway, including sPLA2, COX-1, COX-2, 5-LOX and 15-LOX. In vitro , SND could decrease the release of pro-inflammatory cytokines including TNF-α and IL-6 and inhibit cell apoptosis in CM-induced H9c2 cells. Moreover, SND could protect H9c2 cells from the damage of CM by regulating nuclear factor kappa-B (NF-κB) signal pathway and the expression of COX-2. Conclusion SND may be a drug candidate for anti-inflammatory treatment during MI by regulating the multiple targets in the AA metabolism pathway.
研究领域:
药理学
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心脏病学
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分子生物学
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炎症研究
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Xianquan Feng,Lingjun Zeng,Lina Wu,Zhenzhen Chen,Wanjing Lin,Hongtao Song,Fenghua Lan
Immunotherapy has captured attention for its high clinical efficacy. However, its efficacy is limited by inadequate immune activation. Therefore, a platform to activate the immune system and amplify the host's immune response against tumors is urgently needed. Herein, a self-delivery photodynamic nanodrug (VAC@HSA) is reported as inducing immunogenic cell death (ICD), promoting the recruitment of dendritic cells (DCs), and normalizing tumor blood vessels. Firstly, verteporfin with laser assistance releases tumor-associated antigen to induce ICD, while celecoxib downregulates prostaglandin E2 and releases CCL5 to activate DC recruitment. Moreover, vasculature is normalized through axitinib, which contributes to reducing tumor hypoxia and reversing the immunosuppressive effects of vascular endothelial growth factor. This joint action promotes the infiltration of immune effector cells into the tumor. Therefore, the amplified photodynamic nanodrug with excellent biocompatibility effectively inhibits tumor growth and lung metastasis and produces a cascade of immune responses. Our study demonstrates a practically innovative strategy for activating cancer immunotherapy, which can alter the "cold" properties of tumors.
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高影响因子
TOXICOLOGY MECHANISMS AND METHODS
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2024
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IF 2.8
Wenqing Sun,Yufeng Xu,Zhiqin Liu,Wei Liu,Hongting Wang,Guanyu Chang,Zihui Yang,Zhen Dong,Jianguo Zeng
Sanguinarine (SAN) is an alkaloid with multiple biological activities, mainly extracted from Sanguinaria canadensis or Macleaya cordata. The low bioavailability of SAN limits its utilization. At present, the nature and mechanism of SAN intestinal absorption are still unclear. The pharmacokinetics, single-pass intestinal perfusion test (SPIP), and equilibrium solubility test of SAN in rats were studied. The absorption of SAN at 20, 40, and 80 mg/L in different intestinal segments was investigated, and verapamil hydrochloride (P-gp inhibitor), celecoxib (MPR2 inhibitor), and ko143 (BCRP inhibitor) were further used to determine the effect of efflux transporter proteins on SAN absorption. The equilibrium solubility of SAN in three buffer solutions (pH 1.2, 4.5 and 6.8) was investigated. The oral pharmacokinetic results in rats showed that SAN was rapidly absorbed (Tmax=0.5 h), widely distributed (Vz/F = 134 L/kg), rapidly metabolized (CL = 30 L/h/kg), and had bimodal phenomena. SPIP experiments showed that P-gp protein could significantly affect the effective permeability coefficient (Peff) and apparent absorption rate constant (Ka) of SAN. Equilibrium solubility test results show that SAN has the best solubility at pH 4.5. In conclusion, SAN is a substrate of P-gp, and its transport modes include efflux protein transport, passive transport and active transport.
研究领域:
药理学
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药剂学
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药物递送
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DOI
PubMed
高影响因子
ULTRASONICS SONOCHEMISTRY
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2025
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IF 9.7
Hong-Fu Zhao,Si-Yi Han,Lu Xiao,Bo-Kang Yu,Ning Xia,Ying-Hua Zhang
Corn silk ( Zea mays L. ), an accessory product of maize, is an unconventional component with potential bioactive compounds. In this study, isoorientin was extracted from maize whiskers by ultrasound-assisted extraction, and the response surface optimization resulted in an extraction amount of 1.26 mg/g. A quantitative structure-effect relationship (QSAR) prediction model was developed, and the R 2 and RMSE of the XGBoost regression algorithm were 0.9582 and 0.01823, respectively. Interpretative analyses of the prediction model were carried out by using the SHAP visualization, which showed that the charge, structure, and lipid solubility of the molecules play a key role. Several anti-inflammatory compounds were screened by combining molecular docking and molecular dynamics. After oral toxicity testing, it was determined that isoorientin performed the best and had a semi-inhibitory concentration of 18.38 μg/mL. This study improves the high-value utilization of maize whiskers and provides a theoretical basis for the rapid screening of food-borne anti-inflammatory compounds.
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高影响因子
Science China-Materials
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2025
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IF 7.4
Huang Lin,Wang Wantao,Liu Lei,Ma Wenzheng,Fan Jinghao,Zhou Dan,Zhao Lei,Zheng Zhaomin,Liu Hongmei,Wu Decheng
The treatment of intervertebral disc (IVD) degeneration remains a significant challenge due to the unique ischemic structure of the IVD, which comprises the scavenging of inflammatory cytokines, alleviation of cellular oxidative stress responses, restoration of nuclei pulposus (NP) cell viability, and recovery of IVD biomechanical function. Herein, we developed an injectable microsphere (CS-MnO 2 @PC) by incorporating chitosan microspheres (CS) with manganese dioxide (MnO 2 ) nanozymes and celecoxib encapsulated in Pluronic F-127 (PC) nanosized micelles, via in situ redox or Schiff base reaction. The hybrid carrier demonstrates robust capabilities in scavenging free radicals, alleviating extracellular oxidative stress, and reducing inflammatory cytokines in NP cells, as evidenced by RT-qPCR and immuno-fluorescence staining assays. In vivo evaluations further indicate that this hybrid carrier helps preserve NP hydration and the lamellar structure of the annulus fibrosus (AF), as confirmed by radiological analysis and histological staining evaluations. These injectable chitosan microspheres, combining nanozymes and nanosized drug micelles, represent a promising therapeutic strategy for degenerative IVD.
研究领域:
生物医学工程
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骨科
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材料科学
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药剂学
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高影响因子
AICHE JOURNAL
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2021
·Vol. 68
·期 2
·e17526
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IF 3.993
Changyou Yu,Menghui Yao,Yiming Ma,Yanbo Liu,Shilin Guo,Shijie Xu,Sohrab Rohani,Mingyang Chen,Junbo Gong
Spherical agglomeration technology can produce high-performance spherical particles in a single crystallization unit, although it is still challenging to control the particle size and shape. To solve this issue, a two-step bridging (TSB) mechanism containing a preconditioning period, size period, and shape period is proposed. The dynamic balance among the forces of adhesion, dispersion, and capillary action in the multi-liquid phases plays a key role. This is fully considered to establish the TSB-based thermodynamic size model and particle design framework by weighting the force action regions in multi-liquid phases with dynamic composition. The spherical agglomerates of benzoic acid, celecoxib, and salicylic acid with narrow particle size distributions and tunable particle size ranges of 2000–5000, 800–3500, and 1500–4500 μm, respectively, were designed and prepared successfully, showing good correlation with the calculation, which is superior to the reported methods and indicates that the mechanism has certain universality and guiding significance.
研究领域:
化学工程
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制药工程
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DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Xin Zhao,Lingyu Li,Shuang Li,Jinyu Liu,Hongya Wang,Yulin Lin,Dayong Cai
Portal hypertension (PHT) is a complication of liver diseases. Increased intrahepatic vascular resistance is attributed to reduced bioavailability of vasodilator substances . The macrophage activation and superoxide dismutase 3 (SOD3) involve in the pathogenesis of PHT. Diammonium glycyrrhizinate (DG) is the salt form of glycyrrhizin derived from Radix glycyrrhizae , exerting anti-oxidant activities and be beneficial for liver injury. Here, we aimed to investigate effects of DG on PHT and explore its underlying mechanisms on regulation of macrophages and SOD3. The carbon tetrachloride induced PHT rats received administration of liposome-encapsulated clodronate for hepatic macrophage depletion, or PBS liposomes for matched control. DG (25 mg/kg) or vehicle was gavaged. Portal pressure in vivo, and serum biomarkers of macrophage activation were measured. The nitric oxide (NO) and prostacyclin (PGI 2 ) bioavailability was evaluated in the isolated portal perfused rat livers. Liver tissues were collected to evaluate cirrhosis , macrophage oxidation, and SOD3 activity. Depletion of hepatic macrophages decreased portal pressure, increased bioavailability of NO and PGI 2 , and restored SOD3 activity. DG effectively decreased portal pressure, relieved cirrhosis, inhibited macrophage activation. DG increased bioavailability of NO and PGI 2 to relax portal veins. DG relieved portal macrophage oxidation through decreasing nicotinamide adenine dinucleotide phosphate oxidase 2 and inducible NO synthase expressions, elevated SOD3 activities and increased SOD3 expressions at portal triads. These findings indicated that DG restored SOD3 activity, against portal macrophage oxidation, protected bioavailability of NO and PGI 2 , thereby reduced portal pressure. It suggested a potential use of DG for PHT treatment.
研究领域:
肝病学
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药理学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 3
·2126
·
IF 5.6
Shouchao Xu,Jiehong Yang,Haitong Wan,Li Yu,Yu He
Promotion of angiogenesis and restoration of the blood flow in the ischemic penumbra is an effective treatment for patients with ischemic stroke (IS). Radix astragali-safflower (AS), a classic herbal pair for accelerating blood circulation and dispersing blood stasis, has been used for thousands of years to treat patients with IS in China. Even so, the mechanism of the treatment of IS by AS is still undecipherable. In the current study, network pharmacology was firstly employed to unveil the mechanism of AS in treating IS, which showed that AS might promote angiogenesis associated with PTGS2 silence. Middle cerebral artery occlusion/reperfusion (MCAO/R) model rats were then used as the experimental animals to verify the prediction result. The experimental results revealed that treatment with AS improved the cerebral infarct volume, neurological damage, and cerebral histopathological damage; inhibited cell apoptosis; increased the contents of PDGF-BB, EPO, and TGF-β1; and reduced the levels of PF4, Ang-2, and TIMP-1 in serum. Immunohistochemical staining demonstrated that the expression of PTGS2 was dramatically increased in the hippocampus and cerebral cortex of rats with MCAO/R, and this trend was reversed by the treatment of AS. Immunofluorescent staining expressed that AS reversed the down-regulation of VEGF and further promoted the expression of CD31, which indicated that AS promoted angiogenesis in MCAO/R rats. The abnormal protein or mRNA expression of PTGS2, PGI2, bFGF, TSP-1, and VEGF in the penumbra were transposed by AS or Celecoxib (an inhibitor of PTGS2). In conclusion, the protective mechanism of AS for IS promoted angiogenesis and was involved with PTGS2 silence.Keywords:Radix astragali and safflower;angiogenesis;ischemic stroke;ischemic penumbra;PTGS2
研究领域:
药理学
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神经科学
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中医药学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
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IF 9.5
Yongjing Cao,Juan Li,Qiangwei Liang,Jiayu Yang,Xiaojie Zhang,Juntao Zhang,Min An,Jiawei Bi,Yanhua Liu
The antitumor immune response of cancer immunotherapy is a cascade of cancer–immunity cycles (CIC). The immunosuppression of the tumor microenvironment and low immunogenicity of tumor cells, insufficient T lymphocyte activation, trafficking, and infiltration caused the failure to initiate and run the continuous multistage CIC, leading to unsatisfactory cancer immunotherapy outcomes. A doxorubicin/interleukin-12 plasmid DNA/celecoxib (DOX/pIL-12/CXB) combination strategy was designed by targeting the cascade CIC. Then, an intratumoral CXB-detachable nanosystem, or DOX/PAC/pIL-12 micelleplexes, was developed for sequential drug/gene delivery to facilitate the multistage boosting of CIC on synergistic cancer immunotherapy. The DOX/PAC/pIL-12 micelleplexes could program intratumorally sequential release of CXB to remodulate the tumor microenvironment immunosuppression by suppressing the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway. The smaller sizes and surface charge-switched micelleplexes facilitated the codelivery and corelease of DOX and pIL-12 inside 4T1 tumor cells. These micelleplexes exerted a synergistic antitumor immune response using CIC cascade activation and amplification, providing therapeutic antitumor and antimetastasis efficacy. The drug/gene sequential delivery nanosystem provides a complete CIC-boosted combinatory strategy for developing immunotherapy against cancer.
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高影响因子
ADVANCED MATERIALS
·
2023
·
IF 29.4
Xiaoyu Han,Fan Wang,Jieliang Shen,Shuyu Chen,Pengcheng Xiao,Ying Zhu,Weiwei Yi,Zhengyu Zhao,Zhengwei Cai,Wenguo Cui,Dingqun Bai
Conventional coupling agents (such as polyvinylpyrrolidone, methylcellulose, and polyurethane) are unable to efficiently transport drugs through the skin's dual barriers (the epidermal cuticle barrier and the basement membrane barrier between the epidermis and dermis) when exposed to ultrasound, hindering deep and noninvasive transdermal drug delivery. In this study, nanobubbles prepared by the double emulsification method and aminated hyaluronic acid are crosslinked with aldehyde-based hyaluronic acid by dynamic covalent bonding through the Schiff base reaction to produce an innovative ultrasound-nanobubble coupling agent. By amplifying the cavitation effect of ultrasound, drugs can be efficiently transferred through the double barrier of the skin and delivered to deep layers. In an in vitro model of isolated porcine skin, this agent achieves an effective penetration depth of 728 µm with the parameters of ultrasound set at 2 W, 650 kHz, and 50% duty cycle for 20 min. Consequently, drugs can be efficiently delivered to deeper layers noninvasively. In summary, this ultrasound nanobubble coupling agent efficiently achieves deep-layer drug delivery by amplifying the ultrasonic cavitation effect and penetrating the double barriers, heralding a new era for noninvasive drug delivery platforms and disease treatment.
研究领域:
药学
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生物医学工程
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药物递送系统
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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）