BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Xiaohua Lu,Ge Yan,Sabine M. Klauck,Edmond Fleischer,Anette Klinger,Yoshikazu Sugimoto,Letian Shan,Thomas Efferth
After decades of research, multidrug resistance (MDR) remains a huge challenge in cancer treatment. In this study, the cytotoxic of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide (MCC1734) has been investigated towards multidrug-resistant cancer cell lines. MCC1734 exerted cytotoxicity on cell lines expressing different mechanisms of drug resistance (P-glycoprotein, BCRP, ABCB5, EGFR, p53 knockout) to a different extent. Interestingly, sensitive CCRF-CEM cells and multidrug-resistant P-gp-overexpressing CEM/ADR5000 cells represented similar sensitivity towards MCC1734, indicating MCC1734 can bypass P-gp-mediated resistance. Microarray-based mRNA expression revealed that MCC1734 affected cells by multiple pathways, including cell cycle regulation, mitochondrial dysfunction, apoptosis signaling, and EIF2 signaling. MCC1734 stimulated the generation of excessive reactive oxygen species and the collapse of mitochondria membrane potential in CCRF-CEM cells, companied by the arrest of the cell cycle in the G 2 M phase and apoptosis induction as determined by flow cytometry. In addition, our immunoblotting analysis highlighted that MCC1734 triggered endoplasmic reticulum (ER) stress, evidenced by the activation of p-PERK, p-eIF2α, ATF4 and CHOP. The anti-cancer effects of MCC1734 were further observed in vivo using human xenograft tumors transplanted to zebrafish, providing further support for MCC1734 as a promising new candidate for cancer drug development.
研究领域:
肿瘤学
·
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
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yassmin Raafat Hassan,Riham A. El-Shiekh,Hala M. El Hefnawy,Osama G. Mohamed,Karema Abu-Elfotuh,Ahmed M. Hamdan,Alshaymaa Darwish,Ayah M.H. Gowifel,Ashootosh Tripathi,Camilia George Michael
Ethnopharmacological relevance Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as “African mango” or “bush mango”, belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. Aim of the study The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction . Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat , metformin , and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. Materials and methods Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. Results More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. Conclusion Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.
研究领域:
民族药理学
·
药理学
·
神经科学
·
代谢组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2019
·Vol. 14
·期 1
·1-7
·
IF 1.907
Xiong Guirun,Chen Hui,Wan Qi,Dai Jihang,Sun Yu,Wang Jingcheng,Li Xiaolei
Background Laminectomy is usually classed as a common orthopedic surgery, but postoperative epidural fibrosis often leads to less-than-desirable clinical outcomes. As demonstrated by prior studies, emodin (EMO) exerts an anti-fibrotic effect. Here, we carried out investigation into the inhibitory effect created by EMO application on epidural fibrosis after laminectomy in rats.Methods The paper conducts a series of experiment. In vitro, we observed the effect of EMO on fibroblasts by Cell Counting Kit-8 (CCK-8) assay. Apoptosis of fibroblasts induced by EMO was detected by western blot, TUNEL assay, and flow cytometry. The results revealed that EMO was capable of inducing fibroblast apoptosis, and the proteins of PERK pathway also changed accordingly. In vivo, the effect of EMO on epidural fibrosis in 12 male Sprague-Dawley rats was observed by histological staining.Results CCK-8 assay indicated that EMO was effective in reducing fibroblast viability in a time- and a dose-dependent manner. TUNEL assay and flow cytometry analysis have demonstrated that the apoptotic rate of fibroblasts increased as the EMO concentration rose. Western blot analysis proved that EMO promoted the relative expression of p-perk and p-eIF2α and that the expression of its downstream proteins CHOP and GRP78 was also enhanced. The expression of apoptotic protein Bax and cleaved PARP was upregulated, whereas the expression of anti-apoptotic protein Bcl-2 was downregulated. In addition, histological and immunohistochemical analysis demonstrated that EMO functioned to inhibit epidural fibrosis and increase GRP78 expression in fibrous tissue by promoting apoptosis of fibroblasts.Conclusion sEMO could have inhibitory effect on epidural fibrosis in a concentration-dependent manner. The potential mechanism might be through PERK signaling pathway to promote fibroblast apoptosis. It has a possibility to be taken as a novel method for the treatment of epidural fibrosis.
研究领域:
药理学
·
骨科手术
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-15
·
IF 10.2
Jin Nianqiang,Wang Binhang,Liu Xinyao,Yin Chengcheng,Li Xing,Wang Zilin,Chen Xi,Liu Yunling,Bu Wenhuan,Sun Hongchen
Background The implementation of pyroptosis exhibits significant potential as a tactic to enhance tumor immune microenvironments. Previous applications of pyroptosis inducers have encountered various limitations, such as the development of drug resistance, manifestation of toxic side effects, and a deficiency in targeting capabilities. As a result, there is a growing demand for tumor therapeutic molecules that can overcome these obstacles. Therefore, the objective of this study is to develop a multifunctional nanospheres that addresses these challenges by enabling high-precision targeting of tumor cells and inducing effective pyroptosis. Results We prepared a mannose-modified MOF called mannose-doped Fe 3 O 4 @NH 2 -MIL-100 (M-FNM). M-FNM could enter CAL27 cells through MR-mediated endocytosis, which caused in a significant increase in the level of intracellular ROS. This increase subsequently triggered ER stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway. CHOP then mediated the downstream cascade of Caspase-1, inducing pyroptosis. In in vivo experiments, M-FNM demonstrated excellent targeting ability and exhibited anti-tumor effects. Additionally, M-FNM reshaped the immune microenvironment by promoting the infiltration of anti-tumor immune cells, primarily T lymphocytes. Conclusions M-FNM significantly decreased tumor growth. This novel approach to induce pyroptosis in tumor cells using M-FNM may offer new avenues for the development of effective immunotherapies against cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2026
·
IF 5
Minlei Dong,Ping Li,Jun Luo,Yingqiong Zhang,Xiaoyi Pan,Hui Zhou,Nengming Lin,Yun Gao,Ningning Li,Jing Zhu,Zhongjian Chen,Huidi Jiang
Higher serum bilirubin is associated with improved prognosis in ESCC. • Bilirubin suppresses ESCC growth both in vitro and in vivo . • Bilirubin induces endoplasmic reticulum stress and selectively activates the PERK axis. • Bilirubin binds PERK to activate PERK–eIF2α–mediated translational repression. Bilirubin, an endogenous heme catabolite with potent antioxidant properties, has been inversely associated with cancer risk across multiple malignancies; however, its clinical relevance and the underlying molecular mechanisms in esophageal squamous cell carcinoma (ESCC) remain incompletely understood. Here, we retrospectively analyzed a cohort of 2011 patients with ESCC and found that higher serum bilirubin levels were associated with improved overall survival and served as an independent favorable prognostic factor. Mechanistically, physiological bilirubin directly engaged protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and activated the PERK–eIF2α signaling axis, resulting in translational repression and suppression of ESCC proliferation. This translational repression was associated with altered cell cycle progression in vitro . In xenograft models, bilirubin treatment inhibited tumor growth and was accompanied by increased eIF2α phosphorylation and reduced proliferative activity. Together, these findings demonstrate that higher physiological bilirubin is associated with favorable prognosis in ESCC and bilirubin suppresses tumor progression via PERK-mediated translational repression, providing mechanistic insights into the role of the PERK–eIF2α axis in bilirubin-mediated tumor suppression. Download: Download high-res image (145KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2026
·
IF 13.6
Sun Ya-Zhou,Li Xin-Yan,Wang Jia,Zeng Meng-Liu,Qu Wei-Yi,Cheng Xu,Luo Lei,Wang Wei,Yang Juan,Zhang Jun,Tian Han,Zhang Peng,She Zhi-Gang,Li Hongliang,Zhang Xiao-Jing
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions lacking specific pharmacological treatments. Endoplasmic reticulum (ER) stress plays a pivotal role in their pathophysiology, yet the precise regulatory mechanisms remain elusive. In this study, we identify the E3 ubiquitin ligase ring finger protein 5 (RNF5) as a critical driver of ALI/ARDS. RNF5 is markedly upregulated in response to ALI and significantly exacerbates lung injury by stabilizing HSPA5 (heat shock protein family A member 5), a master regulator of the unfolded protein response (UPR). Notably, in vivo Rnf5 ablation effectively attenuated pulmonary edema, inflammatory cell infiltration, and apoptosis, whereas lung-specific Rnf5 overexpression worsened inflammation and cell death in mice. Mechanistically, RNF5 interacts with HSPA5 and competitively blocks its binding to PERK, facilitating PERK release. Furthermore, RNF5 promotes the retro-translocation of HSPA5 from the ER lumen to the cytosol. In the cytosol, RNF5 mediates the K6- and K63-linked polyubiquitination of HSPA5, enhancing its thermal stability and preventing its re-entry into the ER. This spatial sequestration sustains the persistent dissociation of the PERK-HSPA5 complex, leading to the hyperactivation of the pro-apoptotic and pro-inflammatory PERK-eIF2α-CHOP signaling cascade. The ability of RNF5 to promote ALI is strictly dependent on its E3 ligase activity. In conclusion, our findings uncover a compartment-specific regulatory mechanism of HSPA5, suggesting that the RNF5-HSPA5-PERK axis represents a promising therapeutic target for ALI/ARDS.
✓ 已验证
产品关联
DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2018
·
IF 3.974
Peng Chen,Na Geng,Dong Zhou,Yiran Zhu,Yuliang Xu,Kangping Liu,Yongxia Liu,Jianzhu Liu
Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Exposure of Cr(VI) can lead to cell autophagy, but the preventive measures for diminishing Cr(VI)-induced autophagy need further study. COX-2 can be induced by several heavy metals and can lead to endoplasmic reticulum (ER) stress and autophagy; thus, COX-2, ER stress, and autophagy may be related. This study mainly investigated the role of COX-2 in the eIF2α-ATF4 pathway, which is a major pathway in cell autophagy. In this study, Cr(VI) was used as a xenobiotic to determine changes in the parameters of ER stress, autophagy, and COX-2 levels. At the same time, a clear contrast was obtained by assigning positive and negative controls of ER stress and autophagy. The results showed that during Cr(VI) invasion, the parameters of ER stress and autophagy (such as BiP, PERK, p62, LC3-II, and mTOR) were enhanced, similarly to the positive control of ER stress and/or the autophagy controls. Such enhancement is a protective mechanism for cell survival. Additionally, the COX-2 levels increased. Moreover, when COX-2 was inhibited, the PERK level remained high, whereas the LC3-II level decreased. This finding suggests that COX-2 specifically affects the interaction between ER stress and autophagy. Notably, this study reveals that Cr(VI) can induce ER stress and autophagy in DF-1 cells and that COX-2 plays an essential role in the interaction between ER stress and autophagy.
研究领域:
毒理学
·
细胞生物学
·
环境科学
✓ 已验证
DOI
PubMed
高影响因子
Nature Chemical Biology
·
2024
·
IF 12.9
Gan Lu,Jiang Qiwei,Huang Dong,Wu Xueji,Zhu Xinying,Wang Lei,Xie Wei,Huang Jialuo,Fan Runzhu,Jing Yihang,Tang Guihua,Li Xiang David,Guo Jianping,Yin Sheng
Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.
研究领域:
药理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yi Li,Wenyan She,Tangxi Guo,Tianhe Huang,Yixin liu,Pan Liu,Xiaoran Xu,Xinyu Wang,Miao Wang,Chaochao Yu,Yi Liu,Yongchang Wei
Developing novel drugs for gastric cancer (GC) is greatly needed, and a reactive oxygen species (ROS)-modulating strategy has been demonstrated to be useful for cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated apoptosis and autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated apoptosis and autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2022
·
IF 4.336
Xueru Wang,Ruiming Hu,Chang Wang,Zejing Wei,Shaoxing Pi,Yong Li,Guyue Li,Fan Yang,Caiying Zhang
Excessive molybdenum (Mo) and cadmium (Cd) have toxic effects on animals. However, hepatotoxicity co-induced by Mo and Cd in ducks is still unclear. To evaluate the effects of Cd and Mo co-exposure on autophagy by nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant defense and endoplasmic reticulum stress (ERS) in duck livers, 40 healthy 7-day-old ducks were randomly assigned to 4 groups and fed diets containing different doses of Mo and/or Cd for 16 weeks, respectively. The results verified that Mo and/or Cd induced oxidative stress via decreasing glutathione peroxidase (GSH-Px), catalase (CAT), and total-superoxide dismutase (T-SOD) activities and increasing hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) concentrations; inhibited Nrf2 axis by downregulating the pathway-related genes and proteins expression levels , and activated ERS through upregulating the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2a (eIF2a), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) pathway-related genes and proteins expression levels, which triggered autophagy via increasing autophagosomes , light chain 3 (LC3) puncta, LC3A, LC3B, autophagy-related gene 5 (Atg5), Bcl-2-interacting protein (Beclin-1) mRNA levels and Beclin-1, microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein levels, decreasing Dynein, p62 , mammalian target of rapamycin (mTOR) mRNA levels and p62 protein level. Additionally, the changes in Mo and Cd group were the most obvious. Briefly, our study reveals that autophagy induced by Mo and/or Cd may be associated with the activation of crosstalk between Nrf2-mediated antioxidant defense response and ERS in duck livers. Mo and Cd may aggravate toxic damage to the liver.
研究领域:
毒理学
·
分子生物学
·
兽医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·210
·
IF 4.3
Mao Niping,Zheng Yihui,Yuan Junhui,Feng Xiaoli,Ren Yi,Wang Xun,Tao Xiaoyue,Wang Xingyun,Fang Mingchu,Lin Zhenlang
Perinatal hypoxia causes hypoxic-ischemic brain damage (HIBD), which can result in neurological sequelae of varying severity. This syndrome is a major cause of neonatal mortality and pediatric impairment. Although research is ongoing to better understand its origins and develop targeted treatments, endoplasmic reticulum stress (ERS)–mediated apoptosis via the unfolded protein response (UPR) is crucial for the progression of cerebral ischemia injury. Parthenolide (PN), a sesquiterpene lactone derived from the Asteraceae family, exhibits anti-inflammatory, anti-apoptotic, and antioxidant properties that are beneficial in treating central nervous system disorders. To investigate the role of PN in HIBD and its underlying mechanism. In vivo and in vitro experiments were conducted to observe apoptosis and endoplasmic reticulum (ER) hyperactivation in HIBD, followed by a comparison of the neuroprotective effects of PN through modulation of the protein kinase Ribonucleic Acid-like ER kinase (Perk) pathway of ER stress. An in vivo model of HIBD was established using postnatal day 7 rat pups exposed to hypoxia for 2 h after left common carotid artery ligation. The in vitro model involved rat brain astrocyte cells that were depleted of glucose and oxygen for 7 h. Perfusion imaging and 2,3,5-triphenyltetrazolium chloride staining were used to visualize cerebral edema and infarction in HIBD brain tissue. Nissl staining and other histological techniques were used to detect nerve cell loss and destruction in damaged areas. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and CCAAT/enhancer binding protein-homologous protein (CHOP) staining were used to localize sites with high expression of apoptosis-positive cells in the liver. Real-time quantitative polymerase chain reaction and Western blotting were used to observe apoptosis and pathway markers at the transcriptional and translational levels, respectively. Behavioral tests were conducted to evaluate the motor and memory abilities of rats over time. In this study, we observed that phosphorylated Perk/Perk (P-Perk/Perk), glucose-regulated protein-78, activating transcription factor 4 (ATF4), phosphorylated eukaryotic translation initiation factor 2α/eukaryotic translation initiation factor 2α (P-eIf2α/eIf2α), CHOP, and various apoptotic factors were significantly elevated in the cortex of rats with HIBD compared to normal rats. PN acts through the Perk pathway, regulating ERS and reducing apoptosis after HIBD in neonatal rat models. Our findings demonstrate that elevated P-Perk expression activates the UPR-mediated pathway and triggers apoptosis, thereby counteracting the protective effects of PN both in vivo and in vitro. Conversely, PN inhibits Perk and the Perk/eIf2α/ATF4/CHOP pathway, leading to reduced apoptosis and astrocyte activation in neonatal rats. This study highlights the preventive role of PN in HIBD by downregulating apoptotic expression, potentially through the modulation of the Perk/eIf2α/ATF4/CHOP pathway within the disease framework.
研究领域:
神经科学
·
分子生物学
·
药理学
·
新生儿医学
·
细胞凋亡
·
脑缺血
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2023
·Vol. 42
·期 12
·711-719
·
IF 3.1
Shoudi He,Changsheng Huang,Ning Tan,Jianyong Zhang
Oridonin (ORI), derived from Chinese herbs Rabdosia rubescens, has anti-inflammatory, proapoptotic, anticancer effects. Previous studies have found that ORI induces apoptosis in rheumatoid arthritis fibroblast synovial cells (RA-FLSs), but this mechanism is not clear. We will investigate the apoptosis mechanism of ORI on RA-FLSs. RA-FLSs were treated with various concentrations of ORI (0, 5, 10, 15, 20, 25, and 30 μM) for 24 h. CCK8, LDH, and hochest/PI assay determined the viability, cytotoxicity, and death of ORI on RA-FLSs. The endoplasmic reticulum probe was used to observe structural changes of endoplasmic reticulum in RA-FLSs. RNA expression was detected with RNA sequencing analysis and quantitative real-time PCR. The PERK/eIF2α/CHOP pathway protein of the endoplasmic reticulum was verified with Western Blot. Our results show that ORI induced the apoptosis of RA-FLSs from CCK8, LDH, and Hochest/PI. The endoplasmic reticulum distribution was altered in RA-FLSs after being treated with ORI. Bioinformatics analysis of RNA sequencing data found that 1453 genes were elevated. The PERK/eIF2α/CHOP pathway of the endoplasmic reticulum was regulated from the Gene ontology and KEGG analysis. The results of quantitative real-time PCR and Western blot analysis verified the regulation of PERK/eIF2α/CHOP pathway in RA-FLSs. Our data imply that the endoplasmic reticulum's PERK/eIF2α/CHOP signaling pathway is certainly implicated in the induction of RA-FLS apoptosis by ORI. This study has important implications for the pharmacological effects of ORI and the treatment of RA.
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）