CHEMOSPHERE
·
2023
·
IF 8.8
Zhen-Ning Zhang,Dan-Lei Yang,Hai Liu,Jue Bi,Ya-Bo Bao,Jiao-Yang Ma,Qin-Xiang Zheng,Dao-Lei Cui,Wei Chen,Ping Xiang
Tris(2-chloroisopropyl) phosphate (TCPP) and Tris(2-chloroethyl) phosphate (TCEP) are the widely used organophosphorus flame retardants indoors and easily accessible to the eyes as the common adhesive components of dust and particle matter, however, hardly any evidence has demonstrated their corneal toxicity. In this study, the adverse effects of TCPP, TCEP, and TCPP + TCEP exposure on human corneal epithelial cells (HCECs) were investigated. The cell viability and morphology, intracellular reactive oxygen species (ROS), cell cycle, and the expressions of cell cycle and pyroptosis-related genes were assessed to explain the underlying mechanisms. Compared to individual exposure, co-exposure to TCPP 20 +TCEP 20 showed higher cytotoxicity with a sharp decrease of >30% in viability and more serious oxidative damage by increasing ROS production to 110.92% compared to the control group. Furthermore, the cell cycle arrested at the S phase (36.20%) was observed after combined treatment, evidenced by the upregulation of cyclin D1 , CDK2 , CDK4 , CDK6 , p21, and p27 . Interestingly, pyroptosis-related genes GSDMD , Caspase-1 , NLRP3 , IL-1β , IL-18 , NLRP1, and NLRC4 expressions were promoted with cell swelling and glowing morphology. Oxidative stress and cell cycle arrest probably acted as a key role in TCPP 20 +TCEP 20 -induced cytotoxicity and pyroptosis in HCECs. Our results suggested that TCPP 20 +TCEP 20 co-exposure induced severer corneal damage, further illustrating its significance in estimating indoor health hazards to humans.
研究领域:
毒理学
·
细胞生物学
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眼科学
·
环境健康
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Wenyi Xia,Tao Yan,Lianlei Wen,Shijie Zhu,Wang Yin,Miao Zhu,Meidong Lang,Chunsheng Wang,Changfa Guo
Despite the fact that heart transplantation (HTx) is a relatively mature procedure, heart ischemic and reperfusion (I/R) injury during HTx remains a challenge. Even after a successful operation, the heart will be at risk of primary graft failure and mortality during the first year. In this study, temperature-sensitive polymer poly(N-n-propylacrylamide-co-N-tert-butyl acrylamide) (PNNTBA) was coated on diallyl trisulfide (DATS)-loaded mesoporous silica nanoparticles (DATS-MSN) to synthesize hypothermia-triggered hydrogen sulfide (H2S) releasing particles (HT-MSN). Because the PNNTBA shell dissolves in phosphate-buffered saline at 4 °C, the loaded DATS could continuously release H2S within 6 h when activated by glutathione (GSH). Furthermore, after co-culturing biocompatible HT-MSN with cardiomyocytes, H2S released from HT-MSN at 4 °C was found to protect cardiomyocytes from ischemic and reperfusion (I/R) injury. In detail, the rate of cell apoptosis and lactate dehydrogenase activity was decreased, as manifested by increased BCL-2 expression and decreased BAX expression. More importantly, in an isolated heart preservation experiment, HT-MSN demonstrated potent protection against cardiac I/R injury and reduced expression of inflammatory factors TNF-α and IL-1β. This study provided a new method for the controlled release of H2S by the donor and myocardial protection from I/R injury.
研究领域:
药理学
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纳米技术
·
心脏病学
·
生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Jiahui Wang,Wei Liu,Jia Lu,Mengyue Zhu,Yanni Wu,Wenhui Pan,Boyi Fan,Yan Song,Wenli Wang,Guangtong Chen
The prevalence of neurodegenerative diseases has increased in recent decades. Its exact pathogenesis is not yet fully understood, and only a few drugs can be used clinically to alleviate disease symptoms. Increasing evidence highlights plant-derived compounds are becoming a promising resource for mitigating the onset and progression of neurodegenerative diseases. Uvaol (1) is an ursane-type triterpenoid commonly found in olive leaves, fruits, and virgin olive oil. It is one of the rare compounds in olive oil that can penetrate the blood–brain barrier. Despite its potential neuroprotective activity, research on its structural variations and antineuroinflammatory properties remains sparse. This study explored the biotransformation of uvaol using three fungal species: Actinomucor elegans, Aspergillus flavus, and Circinella muscae. This process yielded 15 new compounds along with seven known ones. Their structures were determined through comprehensive spectroscopic analysis. Furthermore, the antineuroinflammatory activities of compounds were evaluated by using MTT and Griess assays. Notably, compound 9 was found to markedly suppress the transcriptional levels of inflammation-associated elements such as TNF-α, IL-1β, IL-6, iNOS, and COX-2 in BV-2 cells stimulated by lipopolysaccharides (LPS). Moreover, compound 9 also facilitated autophagy by upregulating ULK1 mRNA expression and downregulating the p62 protein. These results suggested that biotransformation was an effective approach for rapidly diversifying uvaol and providing a basal material for the discovery of candidates in treating neurodegenerative diseases.
研究领域:
药理学
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神经科学
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
IMMUNOBIOLOGY
·
2024
·
IF 2.5
Min Li,Wenjia Tong,Chao Dai,Guoping Lu,Danqun Jin,Fang Deng
Sepsis-associated acute kidney injury (S-AKI) is a prevalent and life-threatening complication in hospitalized and critically ill patients. Recent researches indicates that immunoproteasome, especially proteasome 20S subunit beta 8 (PSMB8), is highly associated with various kidney diseases. This study aims to investigate the potential involvement of PSMB8 in S-AKI and its impact on apoptosis and inflammation. The model of S-AKI induced by LPS (10 mg/kg) was assessed by histological examination. ELISA and Real-time PCR were used to detect the levels of inflammatory cytokines in the renal cortex. The role of shPSMB8 in LPS-induced apoptosis was detected by flow cytometry. Finally, western blot was performed to assess the NF-κB signaling pathway related proteins, and the nuclear translocation of NF-kB P65 was detected by immunofluorescence microscopy. PSMB8 knockdown substantially protected against renal injury by reducing blood urea nitrogen and creatinine levels and ameliorating inflammation. PSMB8 knockdown inhibited renal expression of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and COX-2 to improve inflammatory response. Mechanistic studies demonstrated that downregulation of PSMB8 blocked LPS-induced S-AKI phosphorylation and nuclear translocation of NF-κB P65. Collectively, our results suggest that inhibition of PSMB8 significantly contributes to S-AKI via regulation of NF-κB. These findings reveal the pathogenic role of PSMB8 in AKI and suggest a novel therapeutic target for the condition.
研究领域:
免疫学
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肾病学
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炎症研究
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Xiaoguang Gao,Ting Fu,Changyuan Wang,Chenqing Ning,Yulong Kong,Zhihao Liu,Huijun Sun,Xiaodong Ma,Kexin Liu,Qiang Meng
Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis . Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro . Importantly, AUR was found to significantly decrease the mortality of cholestatic mice. Dynamic change analysis of bile acids and gene analysis revealed that AUR promoted bile acid efflux from liver into intestine via an induction in FXR-target genes Bsep and Mrp2 expression, and reduced hepatic uptake through an inhibition in Ntcp . Furthermore, AUR reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in Sult2a1 . In addition, AUR promoted liver repair through an induction in liver regeneration-related gene, and suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α, IL-1β and IL-6. However, the changes in these genes and protein, as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro . These findings suggest that AUR may be an effective approach for the prevention against cholestatic liver diseases.
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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产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2019
·Vol. 7
·期 3
·949-958
·
IF 1.747
Yaqiong Zhang,Ming Li,Hang Gao,Bo Wang,Xu Tongcheng,Boyan Gao,Liangli (Lucy) Yu
In this study, a new red sorghum variety (Ji Liang No. 1) was investigated for its triacylglycerol (TAG) and fatty acid profiles, carotenoid and tocopherol compositions, total phenolic, total flavonoid and phenolic acid contents, and antioxidant and anti-inflammatory properties. A total of 17 TAGs were identified in the red sorghum oil. Linoleic and oleic acids were the primary fatty acids, contributing more than 80% of the total fatty acids. β-Carotene was the primary carotenoid at a level of 26.14 μg/g. α-, γ-, and δ-tocopherols were at levels of 0.19, 4.08, and 0.10 μg/g, respectively. Moreover, acetone–water (60:40, v/v) extract of the red sorghum exhibited the greatest total phenolic content of 2.77 mg GAE/g and total flavonoid content of 5.44 mg RE/g. The extract had scavenging capacities against DPPH, ABTS + , and peroxyl radicals and suppressed LPS stimulated IL-1β, IL-6, and COX-2 mRNA expressions in a dose-dependent manner. Ferulic, p -coumaric, isoferulic, and p -hydroxybenzoic acids were found in the red sorghum, with ferulic acid as the predominant phenolic acid and mostly in an insoluble bound form. These data indicated a potential utilization of the red sorghum in health-promoting functional food or supplemental products.
研究领域:
农业
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食品科学
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营养学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Wenze Zhang,Zhuoxia Shen,Chaoran Li,Yumeng Yang,Tiange Zhang,Bo-Yang Yu,Xianchuang Zheng,Jiangwei Tian
Hepatic ischemia reperfusion injury (HIRI) following transplantation or resection can lead to irreversible liver dysfunction and even failure, yet current therapeutic interventions are limited. Herein, we introduce a “defend–attack and capture flag” nanotheranostic strategy for the cascade management of HIRI. Firstly, the NIR-II photothermal pretreatment with the developed nanosystem provides preprotection for the liver, acting as “defend”. Subsequently, the pharmacotherapy furnishes direct cure for HIRI via the delivery and controlled release of wedelolactone from the nanosystem, serving as “attack”. Meanwhile, the photoacoustic (PA) imaging ability of the nanosystem enables the real-time monitoring of the inflammatory hypoxia, which is the “flag” to be captured in HIRI treatment. The photothermal preprotection can activate heat shock factor 1 (HSF-1), while the pharmaceutical therapy directly attacks NF-κB, both of which eventually inhibits NLRP3 inflammasome, thus reducing the activity of proinflammatory cytokine IL-1β, ending up with the alleviation of necrosis and apoptosis in HIRI. Such treatment effect can be reported by the real-time PA imaging. By the organic combination of the above three-step mechanism, significantly enhanced therapeutic efficacy was achieved in the animal model of HIRI, providing an effective solution for overcoming the challenge of HIRI.
研究领域:
纳米技术
·
药学
·
医学影像
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移植医学
·
炎症生物学
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产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Minjun Yao,Caihua Zhang,Lingzhi Ni,Xiaoxiao Ji,Jianqiao Hong,Yazhou Chen,Jie Wang,Congsun Li,Jiyan Lin,Tingting Lu,Yihao Sheng,Menghao Sun,Mingmin Shi,Chenhe Zhou,Xunzi Cai
Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha , exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.
研究领域:
药理学
·
风湿病学
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Shilin Zhou,Yuxuan Sun,Kaidi Wang,Xintao Gao,Kehong Dong,Jing Wang,Xiaochen Wu,Chuanlong Guo
Oxaliplatin (OXL) is a first-line drug for the treatment of colon cancer , with excellent efficacy. Intestinal toxicity is a common side effect of OXL, with unclear pathogenesis and a lack of effective treatment strategies. Polydatin (PD) has anti-inflammatory and antioxidant activities and is a potential drug for treating intestinal diseases , but its poor water solubility limits its application. In this study, polyvinylpyrrolidone (PVP) was used as a carrier to prepare nanoparticles loaded with PD (PVP-PD), with a particle size of 92.42 nm and exhibiting sustained release properties. In vitro results showed that PVP-PD protected NCM460 cells from OXL induced injury, mitochondrial membrane potential (MMP) disruption, and accumulation of reactive oxygen species (ROS). The in vivo results demonstrated the protective effect of PVP-PD on intestinal toxicity induced by OXL, such as alleviating weight loss and colon length reduction induced by OXL. Both in vivo and in vitro mechanisms indicated that OXL induced DNA damage and activated the cGAS-STING pathway, further inducing the expression of inflammatory factors such as IL-1β and TNF-α. PVP-PD alleviated the aforementioned changes induced by OXL by inhibiting the DNA damage-cGAS-STING pathway. In summary, our study demonstrated that the DNA damage-cGAS-STING pathway was involved in OXL induced intestinal toxicity, and PVP-PD provided a potential strategy for treating OXL induced intestinal toxicity.
研究领域:
药理学
·
毒理学
·
纳米技术
·
细胞生物学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2023
·
IF 11.4
Tianxiang Wang,Changmei Yang,Zhiqiang Li,Ting Li,Ran Zhang,Yujiao Zhao,Tianyi Cheng,Zhaoyun Zong,Yingying Ma,Dongyuan Zhang,Haiteng Deng
Flavonoids are bioactive natural polyphenolic compounds with health benefits, including anti-tumor, anti-inflammatory and anti-aging effects. Our previous studies revealed that a flavonoid 4,4′-dimethoxychalcone (DMC) induced ferroptosis via inhibiting ferrochelatase (FECH). However, the effect of DMC on cellular senescence is unknown. In the present study, we found that DMC treatment selectively eliminated senescent cells, and DMC alone or a combination of DMC and quercetin or dasatinib showed high efficiency in the clearance of senescent cells. We identified FECH was highly expressed in senescent cells compared to non-senescent cells. Mechanistically, we found that DMC inhibited FECH and induced ferritinophagy, which led to an increase of labile iron pool, triggering ferroptosis of senescent cells. Importantly, we found that DMC treatment prevented hair loss, improved motor coordination, and reduced the expression of several senescence-associated secretory phenotype factors ( IL-6 , IL-1β , CXCL-10 , and MMP12 ) in the liver of old mice. Collectively, we revealed that, through the induction of ferroptosis, DMC holds the promise as a new senolytics to prevent age-related pathologies.
研究领域:
细胞生物学
·
衰老研究
·
药理学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
BMC Complementary Medicine and Therapies
·
2022
·Vol. 22
·期 1
·1-13
·
IF 2.838
Gong Linna,Miao Zhishuo,Zhang Li,Shi Birui,Xiao Zuoqi,Qiu Panzi,Liu Menghua,Zou Wei
Background Penyanqing (PYQ), a traditional Chinese medicine (TCM), has a good clinical efficacy for the treatment of pelvic inflammatory disease (PID). Previously, researches on its anti-inflammatory effect and mechanism in vitro, in silico, and in vivo have been reported by our team. However, the interrelationship between the anti-inflammatory activity and the active compounds in PYQ are not clear. Here, the pharmacokinetics-pharmacodynamics (PK-PD) study was carried out for more proper clinical use.Methods The plasma concentrations of salvianolic acid B (SAB), protocatechualdehyde (PRO), paeoniflorin (PE), astilbin (AST), ferulic acid (FE), and chlorogenic acid (CH) in SD rats after PYQ administration were determined by a selective and rapid HPLC–MS/MS method. In addition, the PK-PD on cell model was used to explore the relationship between the plasma concentration and inflammatory biomarkers (TNF-α, IL-1β).Results The results of this study showed that the six components could reach the peak blood concentration within 0.29 h, indicating the rapid absorption of it. The eliminations of AST, CH, FE, PE, and PRO were relatively fast due to their mean residence times (MRTs) within 3 h, while the elimination of SAB was slower (MRT 5.67 ± 0.66 h). Combined with a THP-1 cell model, there was a significant correlation between inflammatory factors and component plasma concentrations with correlation coefficients in the range of -0.9—-0.746. Correspondingly, the drug-containing plasma obtained at 0.25 h point exhibited the best inhibition effect on production of IL-1β and TNF-α in LPS-induced THP-1 cells.Conclusion The six main components in PYQ could be quickly absorbed, and there was a potential good correlation between their pharmacokinetics and the pharmacodynamics of PYQ.
研究领域:
药理学
·
传统中药
·
炎症研究
·
细胞生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Mengting Li,Lingyu Ma,Jiahao Lv,Zhe Zheng,Wenyu Lu,Xunkai Yin,Weijiang Lin,Ping Wang,Jian Cui,Lihong Hu,Jian Liu
Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin ( Ori ), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950 . However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC 50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori , D6 demonstrated the enhancement of IL-1β inhibitory activity (IC 50 = 41.79 nM), which was better than the parent compound Ori . Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo . Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.
研究领域:
药理学
·
炎症
·
呼吸系统疾病
·
药物设计
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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