SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Xiaoxun Lu,Jiabin Hong,Jing Zhang,Qian Liu,Ganzhong Liao,Yanwei Shi,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is an organophosphate flame retardant widely distributed in the environment. The neurodevelopmental toxicity of TPhP has been observed in animals and humans. Previously, we found that prenatal TPhP exposure disturbed placental tryptophan metabolism, impaired neurodevelopment in male offspring, and induced abnormal neurobehavior; however, the underlying mechanisms are unknown. In this study, using the trophoblast cell line JEG-3, we found that TPhP altered gene and protein expression in the tryptophan metabolism pathway, inhibited the tryptophan-serotonin pathway, and activated the tryptophan-kynurenine pathway. Meanwhile, TPhP induced oxidative stress by activating monoamine oxidase A (MAOA), promoting inflammatory factors including nuclear factor kappa-B (NFκB), interleukin-6, and tumor necrosis factor α. The NFκB inhibitor sulfasalazine could alleviate the effects of TPhP on tryptophan metabolism disturbance. The MAOA inhibitor clorgyline or the antioxidant N -acetylcysteine can mitigate oxidative stress and eliminate TPhP-induced inflammatory factors and tryptophan metabolism disturbances. The data above suggest that TPhP disturbed tryptophan metabolism by activating NFκB through MAOA-mediated oxidative stress. Finally, using the mouse intrauterine exposure model, the results confirmed that TPhP induced oxidative stress, activated inflammatory factors, disturbed tryptophan metabolism, and increased the levels of the tryptophan metabolites serotonin, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid in the placenta during the second trimester of pregnancy. Overall, TPhP can disturb placental tryptophan metabolism by activating the inflammatory factor NFkB, which was induced by MAOA-induced oxidative stress. The results of this study confirm that indirect exposure to xenobiotic compounds at an early life stage can impair offspring development and provide a novel perspective on the neurodevelopmental toxicity of TPhP.
研究领域:
毒理学
·
生殖生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Qitao Ye,Bingfeng Lin,Pingcui Xu,Fanxuan Zhang,Nani Wang,Dan Shou
Ethnopharmacological relevance Yunvjian decoction (YNJ) is a traditional Chinese herbal prescription that has been used in the clinical treatment of periodontitis . However, the underlying molecular mechanism of YNJ in the periodontitis treatment is not well understood. Aim of the study The purpose of this study was to evaluate the therapeutic effects of YNJ against periodontitis and its underlying molecular mechanisms. Materials and methods Orthodontic ligation and lipopolysaccharide (LPS)-induced periodontitis rat model was established. YNJ groups were gavaged with YNJ decoction (5 g/kg/d or 10 g/kg/d) for four months. The rats in positive control group were gavaged with metronidazole (MDZ, 100 mg/kg/d) for four months. The maxilla was scanned by micro-computed tomography. The chemical compositions of YNJ were identified using ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry. The molecular mechanism of YNJ were predicted using network pharmacological analysis and validated using immune-staining and Western blot . Results YNJ treatment decreased the distance between cementoenamel junction and alveolar bone crest on the sagittal slide of the periodontitis rats. Western blot showed YNJ downregulated the protein levels of the bone resorption marker (receptor activator of nuclear factor-κB ligand), while upregulated the levels of the bone formation markers (bone morphogenetic protein 2, runt-related transcription factor 2, alkaline phosphatase , and osteoprotegerin) in alveolar bone of the periodontitis rats. Hematoxylin and eosin , immunohistochemical staining, and Western blot analysis indicated that YNJ attenuated the inflammation and decreased the levels of interleukin-6 and tumor necrosis factor-α in the alveolar bone. In addition, a total of 61 compounds were identified from YNJ. Network pharmacology indicated that the nucleotide binding oligomerization domain-like receptor signaling pathway was the main pathway for YNJ in the treatment of periodontitis. The experiments confirmed that YNJ administration inhibited LPS induced-pyroptosis in alveolar bone through suppressing the phosphorylation of nuclear factor κB, reduced expression of NOD-like receptor family pyrin domain containing 3, and Caspase-1, subsequently suppressing the interleukin-1β secretion. Conclusion YNJ is an effective therapeutic strategy for periodontitis and acts by inhibiting pyroptosis and NFκB/NLRP3/IL-1β pathway in alveolar bone.
研究领域:
药理学
·
牙科学
·
免疫学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Xin Yan,Jun Huang,Youjie Zeng,Xuefeng Zhong,Yangxia Fu,Haiyan Xiao,Xia Wang,Huilin Lian,Hui Luo,Dai Li,Ren Guo
Background Hyperproliferation, inflammation, and mitochondrial abnormalities in pulmonary artery smooth muscle cells (PASMCs) underlie the pathological mechanisms of vascular remodeling in pulmonary arterial hypertension (PAH). Cytoplasmic mtDNA activates the cGAS-STING-NFκB pathway and secretes pro-inflammatory cytokines that may be involved in the pathogenesis of PAH. Calcitonin gene-related peptide (CGRP) acts as a vasodilator to regulate patterns of cellular energy metabolism and has vasodilatory and anti-inflammatory effects. Methods The role of the cGAS-STING-NFκB signaling pathway in PAH vascular remodeling and the regulation of CGRP in the cGAS-STING-NFκB signaling pathway were investigated by echocardiography, morphology, histology, enzyme immunoassay, and fluorometry. Results Monocrotaline (MCT) could promote right heart hypertrophy, pulmonary artery intima thickening, and inflammatory cell infiltration in rats. Cinnamaldehyde (CA)-induced CGRP release alleviates MCT-induced vascular remodeling in PAH. CGRP reduces PDGF-BB-induced proliferation, and migration, and downregulates smooth muscle cell phenotypic proteins. In vivo and in vitro experiments confirm that the mitochondria of PASMCs were damaged during PAH, and the superoxide and mtDNA produced by injured mitochondria activate the cGAS-STING-NFκB pathway to promote PAH process, while CGRP could play an anti-PAH role by protecting the mitochondria and inhibiting the cGAS-STING-NFκB pathway through PKA. Conclusion This study identifies that CGRP attenuates cGAS-STING-NFκB axis-mediated vascular remodeling in PAH through PKA.
研究领域:
心脏病学
·
肺医学
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-16
·
IF 3.8
Wei Wei,Heng Yan-Yan,Wu Fei-Fei,Dong Hao-Yu,Zhang Peng-Fei,Li Jing-Xia,Liu Chun-Yan,Yang Bing-Jie,Fu Jia-Ning,Liang Xin-Yue
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence β-Galactosidase Staining (SA-β-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-β-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.
研究领域:
药理学
·
心血管疾病
·
分子生物学
·
糖尿病
·
炎症
·
氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Neuroscience
·
2024
·
IF 3.2
Shuo Li,Alhamdu Adamu,Yucai Ye,Fankai Gao,Rulin Mi,Guofang Xue,Zhaojun Wang
Objective: To investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.Methods: Based on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia in vitro, we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia’s M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.Results: (+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.Conclusion: (+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.
研究领域:
神经科学
·
药理学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Minghui Wang,Xiaoxuan Xu,Mingxuan Sheng,Ming Zhang,Fang Wu,Zhi Zhao,Meng Guo,Bing Fang,Jianmin Wu
Tannic acid, a bioactive polyphenol found in various phytogenic foods and medicinal plants, has potential prevention effects on colitis, though more evidence and mechanistic studies are required to substantiate this. In this study, we investigated the effects of different doses from 0 to 3 mg/mL of tannic acid on mice, ultimately selecting a dose of 3 mg/mL for the anti-colitis trial based on growth and intestinal morphology assessments. Using the DSS-induced colitis model, we found that tannic acid may alleviate colitis by inhibiting the IL-17 - NF-κB p65 signaling pathway and modulating epigenetic pathways, particularly methylation modifications. Additionally, tannic acid altered the gut microbiota, increasing the abundances of Prevotella , Eubacterium_siraeum_group , and Enterorhabdus in the colon. Supplementation with Eubacterium siraeum via gavage also inhibited colitis, accompanied by increased folate and methylation regulators in the colon. These findings suggest that tannic acid may inhibit colitis through the suppression of the IL-17 - NF-κB pathway and the enhancement of microbiota-mediated methylation pathways.
研究领域:
免疫学
·
胃肠病学
·
微生物学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2026
·
IF 10.9
Tianwei Lan,Xiaoping Guo,Chang Liu,Pai Wang,Shichen Zhang,Lei Guo,Siyuan Wang,Lu Wang,Rui Zhou,Xinran Yan,Baiqiao Chen,Mujie Kan,Fang Wang,Caina Xu
Allergic asthma (AAS) is a chronic inflammatory airway disease. While zileuton (ZIL) has the efficient ability to relieve AAS symptoms, its systemic, untargeted administration could lead to adverse neurological effects. Thus, we constructed a drug combination nanomicelle (NMs) platform, H(BZP)-NMs, to reach synergistic effect therapy. It was comprised of a hydrophilic end formed from methoxy poly(ethylene glycol) (mPEG) and poly( L -glutamic acid) (PGlu), and a ROS/pH dual-sensitive hydrophobic core. The core was created by coupling 4-(hydroxymethyl)phenylboronic acid (HPBA) to betamethasone (BMZ). Zileuton (ZIL) was strategically loaded in the core. Hyaluronic acid (HA) functionalization further enabled CD44-targeting ability. In pathological microenvironments, the boronate ester bonds undergo responsive cleavage, causing the parallel delivery of the drugs. The slow-release profile addressed the need for rapid early-stage control and prolonged late-stage relief. In vivo, H(BZP)-NMs significantly decreased Penh values, lowered the IL-4, IL-5, IL-13, and LTB4 levels, and ameliorated airway pathological injuries. Given the molecular docking and verification of network pharmacology, these effects were associated with the dual-drug synergistic inhibition of the TLR4-MyD88-NF-κB p65 signals. Collectively, this study shows that H(BZP)-NMs are an inventive nanomedicine approach that unifies targeted delivery and extended co-release, offering promise for accurate and synergistic treatment of AAS.
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY LETTERS
·
2025
·
IF 2.9
Leina Jia,Xiaoning Meng,Yu Ma,Jinyu Luo,Xiaoqi Luo,Huifang Yang,Jian Zhou
Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765+CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.
研究领域:
毒理学
·
内分泌学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2022
·Vol. 68
·期 3
·778-790
·
IF 3.487
Gu Dan,Cao Ting,Yi Shijie,Liu Ya,Fan Chao
Background Ulcerative colitis (UC) features chronic, non-infectious inflammation of the colon. Insulin-like growth factor binding protein 5 (IGFBP5) has been indicated to be related to various inflammation-related diseases. However, its association with UC remains largely unclear. Aims Here, we investigate the role of IGFBP5 in colonic mucosal epithelial cell injury in UC. Methods Differentially expressed genes in the colonic tissues of UC mice were screened using the Gene Expression Omnibus database, and IGFBP5 was identified. UC mice were developed using dextran sulfate sodium, and IGFBP5 expression in the colonic tissues of UC mice was confirmed by immunohistochemistry and RT-qPCR. The effects of IGFBP 5 in vivo and in vitro were investigated by intraperitoneal injection of adeno-associated virus into UC mice or by transfection with an IGFBP5 overexpression plasmid into lipopolysaccharide-treated colonic mucosal epithelial cells. The mechanisms causing IGFBP5 deletion in UC were predicted by bioinformatics analysis and ChIP-qPCR and verified by rescue experiments. Results IGFBP5 was reduced in UC. IGFBP5 impaired the NFκB pathway in the colonic tissue of UC mice and ameliorated inflammatory infiltration and colonic mucosal cell injury. IGFBP5 depletion was associated with H3K27me3 modification, which was induced by EZH2. CTCF was responsible for recruiting EZH2 to the promoter region of IGFBP5. CTCF inhibition repressed UC progression by reducing H3K27me3 modification via the discouragement of the enrichment of EZH2 in the IGFBP5 promoter. Conclusions CTCF modulates H3K27me3 modification of the IGFBP5 promoter by recruiting EZH2, thereby downregulating IGFBP5 to accentuate colonic mucosal epithelial cell injury in UC mice.
研究领域:
免疫学
·
分子生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2023
·
IF 4.5
Linlin Zhang,Lei Cheng,Zhemeng Chen,Yi Fang,Changjiang Li,Min Chen,Peijie He,Haitao Wu,Jianzhang Wu,Jian Chen
Hypopharyngeal carcinoma is notorious for its poor prognosis among all head and neck cancers, posing a persistent challenge in clinical settings. The continuous hyperactivation of the NFκB signalling pathway has been noted in various cancer types, including hypopharyngeal carcinoma. In our quest to develop a novel drug that targets hypopharyngeal cancer via the NFκB pathway, we employed curcumin, a well-known lead compound, and performed chemical modifications to create a mono-carbonyl analogue called L42H17. This compound exhibited exceptional stability and displayed an enhanced binding affinity to myeloid differentiation protein 2 (MD2). Consistent with expectations, L42H17 demonstrated the ability to inhibit TNF-α-induced phosphorylation of inhibitor of κB (IκB) kinase (IKK), prevent IκB degradation, and subsequently impede NFκB-p65 nuclear translocation in hypopharyngeal cancer cells. Additionally, L42H17 exhibited a remarkable capacity to induce cell cycle arrest at the G2-M phase by inactivating the cdc2-cyclin B1 complex. Moreover, it facilitated cell apoptosis by reducing Bcl-2 levels and augmenting the expression of cle-PARP and cle-caspase3. Importantly, we observed a significant enhancement in the anti-cancer efficacy of L42H17 in a patient-derived tumour xenograft (PDTX) model of hypopharyngeal carcinoma. In conclusion, our findings strongly suggest that L42H17 holds promise as a potential candidate drug for the treatment of hypopharyngeal carcinoma in the future.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Hailin Liu,Lian Zhou,Xifeng Wang,Qingcui Zheng,Fenfang Zhan,Lanqian Zhou,Yao Dong,Yanhong Xiong,Pengcheng Yi,Guohai Xu,Fuzhou Hua
The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca 2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca 2+ influx and cytoskeletal remodelling. The increase in intracellular Ca 2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca 2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 5
·5056
·
IF 5.6
Xunshan Ren,Huangming Zhuang,Fuze Jiang,Yuelong Zhang,Panghu Zhou
Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of ROS scavenging. However, the role of CeNP in OA remains unknown. Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O–fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group. Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment.Keywords:osteoarthritis;senescence;synoviocytes;ceria
研究领域:
骨科
·
纳米技术
·
衰老研究
·
风湿病学
✓ 已验证
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）