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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PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
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IF 5.1
Qihui Wang,Xinlu Huangfu,Huan Ouyang,Jian Liang,Shengyuan Zhang,Hua Nie,Huang Zeng,Li Yang,Hao Fan,Junwei He
Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Toll-like receptor 4 (TLR4) and cyclooxygenase-2 (COX-2) are key mediators in its pathogenesis. Despite their crucial role, few studies have examined inhibitors targeting the TLR4–COX-2 axis. In this study, a combination of affinity ultrafiltration (AUF), surface plasmon resonance (SPR), serum pharmacochemistry, UHPLC-MS/MS, network pharmacology, cellular thermal shift assay (CETSA), isothermal dose–response (ITDR), and drug affinity–responsive target stability (DARTS) techniques were employed to explore TLR4–COX-2 inhibitors from Dendropanax proteus root extract (DPR). As a result, 10 phenylpropanoids were successfully identified from DPR. These constituents exhibited COX-2 inhibitory activity, with IC₅₀ values ranging from 5.2 to 36.2 μM. Molecular docking and molecular dynamics simulations confirmed their strong binding affinity to COX-2. In TNF-α–stimulated MH7A cells, these constituents significantly decreased COX-2 and PGE2 protein expression at concentrations of 2.5 and 5 μM. DPR modulates TLR4-mediated inflammatory signaling pathway against RA through network pharmacology, which was confirmed by CETSA, ITDR, and DARTS experiments. These phenylpropanoids significantly reduced TLR4 protein expression in TNF-α–stimulated MH7A cells at concentrations of 2.5 and 5 μM. Collectively, phenylpropanoids are the major anti-RA constituents of DPR, exerting their effects by inhibition of the TLR4-COX-2 signaling axis. While these findings are limited to in vitro and in silico models, they provide a strong scientific foundation for future in vivo efficacy studies and structural optimization of these phenylpropanoid leads.
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Frontiers in Pharmacology
·
2026
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IF 5.4
Qing-Qing Liao,Li-Ping Chen,Jia-Qi Zheng,Yu-Jie Yang,Jing-Dan Weng,Teng Xie,Xiao-Dong Sun,Yuan-Yuan Zhang
Introduction The pathology of diabetic foot ulcer (DFU) is characterized by keratinocyte dysfunction, non-resolving inflammation, and oxidative stress. We aim to investigate the effects and mechanisms of piroxicam on DFU healing through regulating mitochondrial function and suppressing inflammation. Methods DFU was established in male C57BL/6 J mice and ovariectomized female mice. Piroxicam (1% or 0.33%) solution or saline was then applied for 9 days. HaCaT cells were induced with high glucose (HG) and subsequently incubated with piroxicam (0, 1.2, 3.7, 11, 33, 100 nM). Results and Discussion Piroxicam significantly promoted DFU healing and inhibited the fibrosis in male diabetic mice at a low dose. Consistently, piroxicam enhanced proliferation and migration, and inhibited inflammation, fibrosis, and cellular senescence in HG-induced HaCaT cells. Mechanistically, piroxicam alleviated HG-induced mitochondrial dysfunction by stabilizing the mitochondrial respiratory chain, increasing biogenesis, and enhancing mitophagy. These effects further attenuated oxidative stress and inhibited the cGAS-STING-NF-κB inflammatory pathway, thereby reducing the release of pro-inflammatory factors. Furthermore, molecular docking revealed that piroxicam bound to ERα, a finding further confirmed by a cellular thermal shift assay. HG induced a significant decrease in nuclear ERα protein levels, which was reversed by piroxicam, especially at 11 and 33 nM. Additionally, piroxicam’s pro-healing and anti-inflammation effects were attenuated in ovariectomized female DFU mice. Piroxicam’s protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen. In conclusion, piroxicam alleviates mitochondrial dysfunction and suppresses inflammatory responses by binding to ERα, which ultimately promotes DFU healing at low doses.
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高影响因子
Crystals
·
2025
·Vol. 15
·期 4
·323
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IF 2.4
Wenling Zheng,Junni Ke,Kaerdun Liu,Rongrong Xue,Fenghua Chen
Spray drying of poorly water-soluble drugs in organic solvents is a mature process in the preparation of drugs amorphous solids dispersions (ASDs). The use of organic solvents is under increasing environmental protection and safety pressure and restricts the application of advanced polymers as proteins which are usually insoluble and unstable in organic solvents. Aqueous solution spray drying technology is a candidate method for preparing ASDs without the use of organic solvents. Increasing temperature and adding volatile additives can improve the solubility of poorly water-soluble drugs in water without introducing additional components and energy needed. In this work, ammonia assisted aqueous solution spray drying method was successfully used to prepare various ASDs of indomethacin (25%) with synthetic polymers as polyvinylpyrrolidone and proteins as β-lactoglobulin, lactalbumin hydrolysate, bovine serum albumin, with high yields, special micro golfs morphology, precise compositions and longtime stabilities, compared to high-temperature aqueous solution spray drying method. ASDs with lactalbumin hydrolysate and bovine serum albumin show better dissolution profiles than other ASDs. Aqueous solution spray drying is easily extended to prepare the ASDs of sulfamerazine and celecoxib, providing a possibility to avoid the use of organic solvents in advanced ASDs preparations via spray drying.
研究领域:
药剂学
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生物技术
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Xianbang Hou,Ran Chen,Juan Wu,Yujie Huang,Xueyuan Zhang,Shaobao Xu,Liwei He
Ethnopharmacological relevance Isatis tinctoria L. (Isatidis Radix) is a type of Chinese medicine used to treat various inflammations. Lignans are the main active ingredients of Isatidis Radix, which exhibit potent anti-inflammatory properties. However, the targets underlying the anti-inflammatory effects of Isatidis Radix remain unclear. Aim of the study The objective of this research was to investigate the active constituents of Isatidis Radix and the molecular mechanisms behind its anti-inflammatory properties. Materials and methods Firstly, Liquid Chromatography-Mass Spectrometry (LC-MS), network pharmacology, and molecular docking were employed to identify the active ingredients and key targets of Isatidis Radix lignans and predict their underlying anti-inflammatory mechanisms. Secondly, the enzyme-linked immunosorbent assay (ELISA) and the LPS-induced cell model were employed to verify the selective inhibitory effect of the active ingredients on the key target COX-2. Finally, the analgesic and anti-inflammatory effects were evaluated using the hot-plate test, acetic acid-induced writhing, complete Freund’s adjuvant-induced paw edema, and xylene-induced ear edema assays. Results A total of 24 compounds were found to be absorbed into the bloodstream, including 15 prototype components and 9 metabolites, as determined by LC-MS analysis. Furthermore, Network pharmacology analysis revealed that COX-2 served as the central target in the anti-inflammatory mechanism of Isatidis Radix lignans. Lariciresinol, a class of lignans derived from Isatidis Radix, selectively inhibited COX-2 and reduced inflammatory marker production in vitro and in vivo . It significantly increased the incubation period of heat pain, reduced writhing frequency, and decreased the severity of ear and foot swelling. Moreover, lariciresinol had no obvious gastrointestinal side effects and was not toxic to cardiomyocytes. Conclusion Our study indicates that Isatidis Radix lignans exert their anti-inflammatory effect by selectively inhibiting the COX-2 enzyme and confirms lariciresinol as a natural selective COX-2 inhibitor.
研究领域:
中药学
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分子生物学
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药理学
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PubMed
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Dong-Wei Shao,Tong Xie,Ya-Tao Wang
Osteoarthritis (OA) is a widespread chronic degenerative joint disease, for which new treatment strategies are urgently needed. In this study, we developed an injectable, pH-responsive hydrogel (HA-TA-CS) aimed at improving joint drug delivery by enhancing retention within the joint cavity, while exhibiting excellent biocompatibility. The hydrogel was loaded with celecoxib for localized, in situ release (HA-TA-CS@Cel). OA is characterized by elevated levels of reactive oxygen species (ROS), which promote oxidative stress, inflammatory cytokine production, and further exacerbate the inflammatory response. HA-TA-CS@Cel effectively mitigates inflammation by scavenging excess ROS through the sustained release of TA and celecoxib. Our results demonstrate that HA-TA-CS@Cel significantly alleviates OA progression. In a mouse OA model, the system reduced pro-inflammatory factors and alleviated disease severity. Furthermore, HA-TA-CS@Cel promoted the polarization of macrophages from the M1 to the M2 phenotype, suggesting its ability to modulate the immune microenvironment and thereby attenuate joint inflammation and slow OA progression. These findings indicate that the injectable HA-TA-CS@Cel hydrogel system holds great promise for treating OA through enhanced cartilage protection and macrophage polarization, with potential applications in other inflammatory diseases.
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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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Materials Today Bio
·
2025
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IF 10.2
Yue Wang,Chen Wei,Xiaoyu Zhao,Fantao Lin,Shijie Liu,Jingkun Bai
Chemotherapy is crucial for treating intermediate and advanced hepatocellular carcinoma (HCC). However, anthracycline agents such as doxorubicin (DOX) are often expelled from tumor cells by P-glycoprotein (P-gp), which decreases the intracellular drug levels and leads to treatment failure. Activated hepatic stellate cells (aHSCs) are critical in liver fibrosis and HCC progression and facilitate liver cancer development. Importantly, liver fibrosis progression is closely linked to the expression of cyclooxygenase-2 (COX-2). Here, we developed a pH-responsive peptide drug delivery system, Pep loaded with DOX and CXB (DC/Pep), which targets HCC by transporting the COX-2 inhibitor celecoxib (CXB) alongside the conventional chemotherapeutic drug DOX. DC/Pep targeted HCC cells and transitioned from spherical particles to high aspect ratio aggregates in a mildly acidic environment, effectively delaying chemotherapeutic agent efflux from the tumor. DC/Pep effectively inhibited hepatic stellate cell activation and reduced collagen fiber synthesis, thereby preventing the development of liver fibrosis. Consequently, the proliferation of ectopic and orthotopic HCC tumors was effectively inhibited, leading to an enhanced antitumor effect. This study is important for designing novel drug delivery systems using peptide amphiphiles for the treatment of intermediate and advanced HCC.
研究领域:
肿瘤学
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药剂学
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分子生物学
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International Journal of Pharmaceutics-X
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2025
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IF 6.4
Shiying Xu,Lina Wu,Boxin Chen,Xiaoliang Deng,Zhihui Zheng,Fei Wu,Lingjun Zeng,Changqing Zheng,Xiaomu Hu,Aiwen Huang,Xin Zhou,Xianquan Feng,Zhihong Liu
Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment due to its selective tumor ablation and excellent safety characteristics. However, its efficacy is limited by tumor hypoxia and excessive inflammation. In this study, we fabricated human serum albumin-based nanoparticles (CAI NPs) encapsulating celecoxib (CXB), atovaquone (ATO), and IR820 via sonication. The CAI NPs exhibited favorable physicochemical properties, including a uniform size distribution (<200 nm), high encapsulation efficiency and excellent colloidal stability. Initially, ATO acts as a mitochondrial complex III inhibitor, suppressing oxidative phosphorylation to ameliorate tumor hypoxia. This hypoxia alleviation potentiates PDT efficacy by enhancing tumor cell ROS generation. Furthermore, concomitant COX-2/PGE2 inhibition by CXB attenuates the excessive inflammatory cascade triggered during PDT, resulting in enhanced therapeutic outcomes through microenvironment modulation. Eventually, the dual-enhanced CAI NPs demonstrate potent antitumor activity in both in vivo and ex vivo models, while maintaining excellent biocompatibility under physiological conditions. In summary, the integrated three-drug regimen conclusively enhances photodynamic therapeutic outcomes through multimodal mechanisms, establishing a viable treatment approach for esophageal cancer.
研究领域:
肿瘤学
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纳米医学
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光动力治疗
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分子药理学
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肿瘤微环境
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转化医学
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药物递送系统
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Xiaoliang Deng,Xianquan Feng,Xiaohui Tang,Zhihui Zheng,Da Zheng,Enqin Zheng,Lingjun Zeng,Shiying Xu,Boxin Chen,Qian Zhang,Zhihong Liu,Hongtao Song
The clinical efficacy of immunotherapy in triple-negative breast cancer (TNBC) faces dual barriers: poor immunogenicity and a suppressive tumor microenvironment. While low-temperature photothermal therapy (LTPTT) has emerged as a potential immunostimulatory strategy, its efficacy is counteracted by heat shock protein (HSP) induction and COX-2/PGE2-mediated immunosuppression. To address these challenges, we developed a multifunctional immunophotothermal nanoplatform (IAC NPs) through rational engineering of human serum albumin for combinatorial delivery of indocyanine green as a photothermal converter, atovaquone for HSP70-mediated thermoresistance blockade, and celecoxib for COX-2/PGE2 pathway inhibition. The IAC NPs achieved tumor-targeted delivery and NIR-activated immunogenic phototherapy while coinhibiting HSP70 (via atovaquone’s mitochondrial complex III blockade) and the COX-2/PGE2 immunosuppressive axis (via celecoxib). The triple medications’ synergistic action improved the expression of effector memory T cells, boosted the maturation of dendritic cells, encouraged the infiltration of CD4+ and CD8+ T cells, and reduced regulatory T cells. In vivo, the IAC NPs mediated profound suppression of both primary tumors and metastatic dissemination while exhibiting optimal biocompatibility for clinical translation. Our work validates a nanoenabled self-delivery system that augments the efficacy of LTPTT immunotherapy against TNBC by orchestrating coordinated inhibition of HSPs and inflammatory responses.
研究领域:
癌症免疫治疗
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纳米医学
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光热治疗
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分子靶向治疗
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肿瘤微环境
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药物递送系统
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SEPARATION AND PURIFICATION TECHNOLOGY
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2025
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IF 9
Xiaoxiang Cheng,Zhe Xu,Xinsheng Luo,Yi Chai,Jiajian Xing,Xinyu Zhang,Jingtao Xu
Inorganic membranes are prime candidates for organic solvent recovery in the pharmaceutical industry due to their excellent solvent resistance, mechanical strength and durability. However, constructing high-performance inorganic separation layers is still the most challenging aspect in the fabrication of inorganic membranes for organic solvent nanofiltration (OSN). Prussian blue analogues (PBAs) exhibit high chemical stability for their rigid cubic framework with strong covalent metal-cyanide coordination bonds. Inspired by the interfacial polymerization (IP) strategy, this study proposes a simple synthesis method for prussian blue analog thin films (PBA TFs) on porous ceramic substrates, using coordination reactions between K 3 [Fe(CN) 6 ] and acetylacetonate (e.g. Cu(acac) 2 , Mn(acac) 3 or Co(acac) 2 ). The Mn-Fe PBA membrane exhibits high solvent permeance (e.g., 176.4 L·m −2 ·h −1 ·bar −1 for ethyl acetate) and demonstrates a molecular weight cut-off ranging from 665 to 760 Da across six tested solvents. To evaluate the industrial potential of Mn-Fe PBA membranes, solvent recovery experiments were conducted in a twin-stage OSN system using seven active pharmaceutical ingredient (API)/solvent systems. In the tylosin/dimethyl sulfoxide system, the Mn-Fe PBA membrane achieved over 80 % total API retention, maintaining stable performance across multiple cycles. The formation process of PBA TFs was analyzed by adjusting monomer diffusion conditions. Furthermore, molecular dynamics simulations elucidated the film formation mechanism. The self-limiting nature of the IP strategy not only inhibits the formation of PBA large crystals, but also induces the self-assembly of PBA nanocrystals along the n-hexane/water interface, resulting in a complete PBA TF. This IP strategy blazes a new trail for fabrication of high-performance inorganic OSN membranes.
研究领域:
材料科学
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化学工程
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膜分离技术
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制药工程
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 15
·e70778
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IF 4.2
Hong Tang,Qi Dai,Ziyan Zhao,Weiye Ge,Danlei Li,Zelin Chang,Penglai Pi,Jia Li,Zheng Sun
Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumour, accounting for a significant proportion of adult brain tumours. It is associated with a poor prognosis and high recurrence rates. Although temozolomide (TMZ) remains the standard first-line chemotherapy for GBM, its clinical efficacy is often limited by the development of drug resistance and toxic effects on normal tissues. Melatonin (Mel), a natural indoleamine synthesised by the pineal gland, has demonstrated synergistic anti-tumour effects when combined with various chemotherapy agents in multiple studies. This study investigates the synergistic potential of Mel to enhance TMZ's therapeutic efficacy against GBM. The results demonstrate that the combination of Mel and TMZ significantly inhibits glioblastoma cell proliferation, migration, and invasion. Mechanistically, this synergistic effect is mediated through the NF-κB/COX-2 signalling pathway. Mel enhances TMZ's anti-tumour activity by inhibiting IκBα phosphorylation, suppressing NF-κB activation, and downregulating COX-2 expression. Additionally, the combination treatment induced apoptosis via activation of the Caspase-3 pathway. These results suggest that Mel can potentiate the therapeutic efficacy of TMZ in glioblastoma treatment, offering a promising strategy to overcome TMZ resistance while reducing its associated toxicity.
研究领域:
肿瘤学
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药理学
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神经病学
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分子生物学
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癌症研究
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高影响因子
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