Acta Biomaterialia
·
2023
·
IF 9.7
Xue Bai,Dan Wang,Bin Wang,Xiao Zhang,Yan Bai,Xinying Zhang,Ruoyuan Tian,Caihua Li,Qiying Yi,Yao Cheng,Sirong He
Islet transplantation is regarded as the most promising therapy for type 1 diabetes. However, both hypoxia and immune attack impair the grafted islets after transplantation, eventually failing the islet graft. Although many studies showed that biomaterials with nanoscale pores, like hydrogels, could protect islets from immune cells , the pores on biomaterials inhibited vascular endothelial cells (VECs) to creep in, which resulted in poor revascularization. Thus, a hydrogel device that can facilitate in situ immune modulations without the cost of poor revascularization should be put forward. Accordingly, we designed a spA-modified hydrogel capturing anti-HMGB1 mAB (mAB-spA Gel): the Staphylococcus aureus protein A (spA) was conjugated on the network of hydrogel to capture anti-HMGB1mAB which can inactivate immune cells, while the pore sizes of the hydrogel were more than 100μm which allows vascular endothelial cells (VECs) to creep in. In this study, we screened the optimal spA concentration in mAB-spA Gel according to the physical properties and antibody binding capability, then demonstrated that it could facilitate in situ immunomodulation without decreasing the vessel reconstruction in vitro . Further, we transplanted islet graft in vivo and showed that the survival of islets was elongated. In conclusion, mAB-spA Gel provided an alternative islet encapsulation strategy for type 1 diabetes. Statement of significance Although various studies have shown that the backbone of the hydrogels can isolate islets grafts from immune cells and the survival of the islets can be prolonged by this way, it is also reported that when the pore size of the backbone is too small the revascularization will be adversely affected. According to this point, it is hard to adjust hydrogel's pore size to protect the islets from the immune attack while allowing endothelial vascular cells to creep in. To solve this dilemma, we designed an immunomodulatory hydrogel inhibiting the activation of T cells by immunosuppressive IgGs instead of the backbone network, so the hydrogel can prolong the survival of islets without the sacrifice of revascularization.
研究领域:
生物医学工程
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免疫学
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糖尿病研究
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组织工程
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DOI
PubMed
高影响因子
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2025
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IF 4.6
Xuewa Jiang,Shaoyan Yi,Pingping Shen,Richa Raj,Jian Zhang,Haixia Ge
Chronic low-grade inflammation, driven by elevated levels of circulating high mobility group box1 (HMGB1), plays a crucial role in the pathogenesis of multiple chronic diseases. Glycyrrhetinic acid (GA) and isoliquiritigenin (ISL) are representative metabolites in licorice, exhibit potent regulatory effects on HMGB1-mediated chronic inflammation. In this research, we investigated the interactions of GA and ISL with HMGB1 using multi-spectroscopy, surface plasmon resonance (SPR), and molecular docking. Fluorescence spectroscopy revealed that GA or ISL binds to HMGB1, leading to static fluorescence quenching of the protein. Additionally, the binding of GA or ISL altered the microenvironment of tryptophan and decreased the α-helix content of HMGB1 to varying extents. Dynamic light scattering (DLS) showed that GA induced aggregation of the HMGB1 complex into large particles, while ISL reduced the particle size of HMGB1. SPR analysis confirmed that GA and ISL bound reversibly to HMGB1 with K d values of 53.0 ± 3.6 and 16.3 ± 0.5 μM, respectively. Molecular docking further elucidated the binding modes and sites of GA and ISL on HMGB1, showing that GA binds to the B-box and ISL binds to the A-box of HMGB1, with hydrogen bonding and hydrophobic interactions as the primary driving forces. Isobologram analysis demonstrated that the combination of GA and ISL exhibited a significant synergistic inhibitory effect on HMGB1-induced inflammation on RAW264.7 cells, with an optimal combination ratio of 1:1. This study reveals that GA and ISL synergistically exert anti-inflammatory effect by modulating HMGB1 conformation, offering new insights into licorice extracts for preventing chronic inflammatory diseases.
研究领域:
药理学
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生物化学
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分子生物学
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免疫学
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药物化学
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DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 9
·7925-7934
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IF 4.171
Yi-Chao Du,Li Lai,Hao Zhang,Fu-Rui Zhong,Huan-Li Cheng,Bao-Lin Qian,Peng Tan,Xian-Ming Xia,Wen-Guang Fu
Acetaminophen (APAP) is one of the safest and most effective over-the-counter (OTC) analgesics and antipyretics, but excessive doses of APAP will induce hepatotoxicity with high morbidity and mortality worldwide. Kaempferol (KA), a flavonoid compound derived from the medicinal and edible plant of Penthorum chinense Pursh, has been reported to exert a profound anti-inflammatory and antioxidant activity. In this study, we explored the protective effect and novel mechanism of KA against APAP-induced hepatotoxicity. The results revealed that KA pretreatment significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), relieved hepatocellular damage and apoptosis, attenuated the exhaustion of glutathione (GSH) and accumulation of malondialdehyde (MDA), increased the expression of antioxidative enzymes (e.g., heme oxygenase 1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1)), and thus restrained APAP-induced oxidative damage in the liver. KA suppressed the expression of NLRP3 and reduced the levels of pro-inflammatory factors, including interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Moreover, KA remarkably inhibited high-mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) expression as well as nuclear factor kappa-B (NF-κB) activation for liver protection against APAP-induced inflammatory responses and apoptosis. Taken together, our findings suggested that KA could effectively protect hepatocytes from APAP hepatotoxicity through the up-regulation of HO-1 and NQO1 expression, the down-regulation of NLRP3 expression, and the inhibition of the HMGB1/TLR4/NF-κB signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Toxics
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2025
·Vol. 13
·期 6
·448
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IF 4.1
Yi-Fang Zhong,Chan Ding,Chun-Ji Yao,Jia-Chun Wang,Min-Qian Feng,Xiao-Xue Gong,Lin Yu,Hua-Dong Xu,Hai-Ling Xia
Malignant mesothelioma (MM) is a highly aggressive cancer strongly associated with asbestos exposure, and accumulating evidence suggests that high mobility group box 1 (HMGB1) plays a central role in its pathogenesis. Our in vitro and in vivo experiments revealed that HMGB1 was highly expressed in MM. Both genetic and pharmacological inhibition of HMGB1 markedly suppressed MM cell viability, migration, and invasion, while inducing G1-phase cell cycle arrest and enhancing apoptosis. Interestingly, the inhibition of Toll-like receptor 4 (TLR4), achieved through both siRNA and TAK-242 treatment, not only suppressed tumor-promoting signals but also reduced HMGB1 expression, suggesting a self-amplifying HMGB1-TLR4 loop. Mechanistically, in vitro experiments indicated that suppression of HMGB1 and TLR4 was associated with decreased activation of NF-κB, AKT, and ERK pathways, which are involved in regulating MM cell survival and motility. In xenograft models, treatment with ethyl pyruvate (EP) and TAK-242 significantly suppressed tumor growth and HMGB1 expression, reinforcing their therapeutic potential. Given HMGB1’s influence on both tumor cell behavior and the immune microenvironment, targeting the HMGB1-TLR4 axis may not only provide a novel therapeutic strategy for MM but also offer insights into the mechanisms underlying asbestos-induced tumorigenesis, potentially guiding future prevention and intervention strategies in asbestos-exposed populations.
研究领域:
肿瘤学
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分子生物学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Journal of the American Heart Association
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2022
·
IF 6.106
Xin‐Lin Zhang,Ting‐Yu Wang,Zheng Chen,Hong‐Wei Wang,Yong Yin,Lian Wang,Yong Wang,Biao Xu,Wei Xu
BackgroundHeart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown.Methods and ResultsSerum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice.ConclusionsNETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
研究领域:
心脏病学
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免疫学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION
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2024
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IF 2.2
Wenyue Qiu,Wenxin Jiang,Yiman Su,Hui Huang,Jiali Ye,Rongmei Wang,Zhaoxin Tang,Rongsheng Su
Lipopolysaccharides (LPS) is the major compoent of Gram-negative bacteria and an important factor in inducing inflammation, which usually leads to multiple organ failure in broilers, seriously affecting the growth performance of broilers and hindering the development of poultry farming. Under the policy of prohibiting antibiotics in feed, it has become more urgent to find natural drugs to prevent liver damage caused by LPS in broilers. Asiatic acid (AA) is a pentacyclic triterpene that has been proven to have anti-inflammatory and antioxidant effects. However, the protective effects of AA in LPS-induced liver damage in broilers still need to be clarified. This study aims to explore the complete mechanism of AA against LPS-induced acute liver injury (ALI) in broilers. A total of 60 broilers (1 day old) were randomly divided into the control group, LPS group, LPS+AA (15, 30 and 60 mg/kg) group and control+AA (60 mg/kg) group. At 16, 18 and 20 days of age, the broilers were attacked with LPS (0.5 mg/kg) to construct liver injury model. H&E staining assessed liver pathological changes. The mRNA and protein expression levels related to the HMGB1/TLR4/NF-κB pathway, pyroptosis, and ERS-mediated apoptosis in the liver tissue were detected. Our results founded that intraperitoneal injection of LPS in broilers increased the activities of AST and ALT, as well as raising the related gene and protein expression of the HMGB1/TLR4/NF-κB pathway, pyroptosis, and ERS-mediated apoptosis. Interestingly, AA improved LPS-induced liver damage and decreased the activities of AST and ALT in broilers. Additionally, AA mitigated LPS-induced ALI by reducing the mRNA levels and protein expressions of the HMGB1/TLR4/NF-κB pathway, pyroptosis and ERS-mediated apoptosis. In conclusion, the present study investigated that AA mitigated LPS-induced ALI in broilers by reducing pyroptosis and ERS-mediated apoptosis via inhibition of the HMGB1/TLR4/NF-κB pathway. Therefore, AA may serve as a potential feed additive for the prevention of LPS-induced ALI in broilers.
研究领域:
兽医学
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药理学
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免疫学
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动物科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION
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2023
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IF 2.7
Wenyue Qiu,Xinting Zhang,Xiaoyue Pang,Jianjia Huang,Shuilian Zhou,Ruixia Wu,Rongmei Wang,Zhaoxin Tang,Rongsheng Su
Inflammatory response induced by biological stress usually occurs in weaning piglets, it reduces the production performance of piglets and even causes death. Tert-butylhydroquinone (TBHQ) is a food additive that has the effect of anti-inflammation and anti-oxidation. However, there are few reports related to the protective mechanisms of TBHQ on lipopolysaccharide (LPS) induced injury in intestinal porcine epithelial (IPEC-J2) cells. Quantitative real-time polymerase chain reaction and western blot analysis, respectively, detected the mRNA levels and protein expressions related to pyroptosis, tight junction (TJ) protein and high-mobility group box 1/toll-like receptor 4/nuclear factor kappa-B (HMGB1/TLR4/NF-κB) axis. Localisation and expression of NOD-like receptor pyrin domain containing 3 (NLRP3), HMGB1 and P-NF-κB proteins detected by immunofluorescence. The results showed that TBHQ (12.5 and 25 μM) can increase cell activity and reduce intracellular lactate dehydrogenase (LDH) levels in a dose-dependent manner. LPS significantly decreases cell viability and increases the LDH level. However, pretreatment with TBHQ evidently increases cell viability and decreases the LDH level of IPEC-J2 cells. In addition, treatment with LPS decreased the mRNA level and protein expression of zonula occludens-1, occludin and claudin-1, and increased the mRNA level and protein expression of pyroptosis and HMGB1/TLR4/NF-κB axis. Interestingly, pretreatment with TBHQ increased the TJ protein expressions as well as decreased the mRNA level and protein expressions of pyroptosis and HMGB1/TLR4/NF-κB axis. Moreover, the results of immunofluorescence showed that TBHQ significantly reduced the expression of NLRP3, HMGB1 and P-NF-κB in LPS-induced injury of IPEC-J2 cells. Therefore, we come to the conclusion that TBHQ attenuates LPS-induced pyroptosis in IPEC-J2 cells through downregulation of the HMGB1/TLR4/NF-κB axis, TBHQ may become a potential feed additive for preventing inflammatory diarrhoea in piglets.
研究领域:
兽医学
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细胞生物学
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免疫学
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动物营养学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2022
·
IF 16.874
Lulu Jin,Zhixin Zhu,Liangjie Hong,Zhefeng Qian,Fang Wang,Zhengwei Mao
Ischemic stroke is an acute and serious cerebral vascular disease, which greatly affects people's health and brings huge economic burden to society. Microglia, as important innate immune components in central nervous system (CNS), are double-edged swords in the battle of nerve injury, considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes. High mobility group box 1 (HMGB1) is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia. 18β-glycyrrhetinic acid (GA) is an effective intracellular inhibitor of HMGB1, but of poor water solubility and dose-dependent toxicity. To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy, herein, we designed reactive oxygen species (ROS) responsive polymer-drug conjugate nanoparticles (DGA) to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1. DGA presented excellent therapeutic efficacy in stroke mice, as evidenced by the reduction of infarct volume, recovery of motor function, suppressed of M1 microglia activation and enhanced M2 activation, and induction of neurogenesis. Altogether, our work demonstrates a close association between HMGB1 and microglia polarization, suggesting potential strategies for coping with inflammatory microglia-related diseases.
研究领域:
神经科学
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药学
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纳米技术
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炎症生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Immunology Research
·
2023
·
IF 4.1
Hui Du,Shiwen Tong,Ge Kuang,Xia Gong,Ningman Jiang,Xian Yang,Hao Liu,Nana Li,Yao Xie,Yang Xiang,Jiashi Guo,Zhenhan Li,Yinglin Yuan,Shengwang Wu,Jingyuan Wan
Acetaminophen (APAP) overdose would lead to liver toxicity and even acute liver failure in severe cases by triggering an inflammatory response and oxidative stress. Sesamin has been reported to possess anti-inflammatory and antioxidant actions in several animal disease models. In the present study, the effects and mechanisms of sesamin on APAP-induced acute liver injury (ALI) were explored. The results showed that pretreatment with sesamin significantly alleviated APAP-induced ALI, as indicated by decreased serum aminotransferase activities, hepatic pathological damages, and hepatic cellular apoptosis. But sesamin has no significant effects on the expression of cytochrome P450 2E1 (CYP2E1), APAP-cysteine adducts (APAP-CYS) production, and glutathione content in the liver of APAP-administered mice. Moreover, APAP-induced liver oxidative stress and inflammatory response also were remarkedly attenuated by sesamin, including reducing hepatic reactive oxygen species levels, promoting antioxidant generation, and inhibiting the expression of TNF-α and IL-1β, as well as decreasing inflammatory cell recruitment. Notably, sesamin inhibited serum high-mobility group box 1 (HMGB1) releases and blocked hepatic activation of Toll-like receptor 4 (TLR4)-interleukin 1 receptor-associated kinase 3-nuclear factor kappa B (NF-κB) signaling pathway in APAP-administered mice. These findings indicated that sesamin could mitigate APAP-induced ALI through suppression of oxidative stress and inflammatory response, which might be mediated by the deactivation of HMGB1/TLR4/NF-κB signaling in mice.
研究领域:
肝病学
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药理学
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免疫学
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DOI
PubMed
高影响因子
BRAIN BEHAVIOR AND IMMUNITY
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2020
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IF 6.633
Jinfeng Xie,Bingtian Bi,Yunyun Qin,Wenli Dong,Jiahong Zhong,Mengfan Li,Yufang Cheng,Jiangping Xu,Haitao Wang
Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g. ) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.
研究领域:
神经科学
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药理学
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免疫学
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精神病学
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产品关联
DOI
PubMed
高影响因子
Journal of Hard Tissue Biology
·
2022
·
IF 0.593
Jie Zhang,Yongli Wang,Jianzhong Zhang,Shaoyan Huang
We investigated the anti-inflammatory effect of hydroxyethyl starch (HES) 6% 200/0.5 on lipopolysaccharide (LPS)-induced RAW264.7 cells based on the high mobility group protein B1/nuclear transcription factor-κB (HMGB1/NF-κB) signaling pathway. The mouse monocyte macrophage RAW264.7 cells were divided into control group (no additional treatment), LPS group (0.2 pg/ml LPS), LPS+HES group (0.2 pg/ml LPS+6% HES) and LPS+TAK-242 (HMGB1/NF-κB signal pathway blocker) group (0.2 pg/ml LPS The LPS+HES+TAK-242 group (0.2 pg/ml LPS+6% HES+1 μ mol/l TAK-242) was cultured for 48 hours. Griess method and ELISA were used to detect the levels of nitric oxide (NO), tumor necrosis factor α (TNF-α), interleukin (IL)-6 and IL-1β in cell supernatant. The level of intracellular reactive oxygen species (ROS) was detected by flow cytometry. The mitochondrial membrane potential was detected by immunofluorescence. The mRNA expressions of inducible nitric oxide synthase (iNOS), HMGB1, Toll-like receptor 4 (TLR4), nuclear factor-κ b inhibitory protein α (IκBα) and NF-κB were detected by qRT-PCR. The expressions of HMGB1, TLR4, IκBα, phosphorylated IκBα (p-IκBα), NF-κB and phosphorylated NF-κB (p-NF-κB) were detected by western blotting. Compared with the control group, the expression levels of NO, TNF-α, IL-6, IL-1β, ROS, iNOS, HMGB1, TLR4, NF-κB mRNA, HMGB1, TLR4 and p-NF-κB proteins in the LPS group, LPS+HES group, LPS+TAK-242 group and LPS+HES+TAK-242 group increased (P<0.05), the expression levels of mitochondrial membrane potential, IκBα mRNA and p-IκBα protein decreased (P<0.05). Compared with LPS group, the expression levels of NO, TNF-α, IL-6, IL-1β, ROS, iNOS, HMGB1, TLR4, NF-κB mRNA, HMGB1, TLR4 and p-NF-κB proteins in the LPS+HES group, LPS+TAK-242 group and LPS+HES+TAK-242 group increased (P<0.05), the expression levels of mitochondrial membrane potential, IκBα mRNA and p-IκBα protein decreased (P<0.05). The expression levels of mitochondrial membrane potential, IκBα mRNA and p-IκBα protein increased (P<0.05). Six % HES 200/0.5 could down-regulate the expression of molecules related to HMGB1/NF-кB signaling pathway, and reduce the inflammatory response of RAW264.7 cells induced by LPS.
研究领域:
药理学
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免疫学
·
细胞生物学
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分子生物学
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产品关联
DOI
高影响因子
Journal of Environmental Sciences
·
2026
·
IF 6.3
Fu-Wei Jiang,Jing-Han Lin,Jia-Xin Wang,Ming- Shan Chen,Shuo Liu,Hong-Mei Zhu,Yu-Sheng Shi,Ming Lou,Zi-Yan Hu,Yi Zhao,Jin-Long Li
As a widely used brominated flame retardant, tetrabromobisphenol A (TBBPA) is heavily utilized and has led to major concerns about its environmental and health implications. Although TBBPA has been detected in various environmental and biological matrices globally, its impact on the spleen and the underlying mechanisms remain poorly understood. HMGB1 is a protein released during pyroptosis which can trigger inflammation by activating the TLR4/MyD88/NF-κB pathway, leading to the production of inflammatory cytokines and chemokines. Nonetheless, its impact of HMGB1 on spleen damage caused by TBBPA is still uncertain. This study aims to explore the effect of TBBPA on spleen injury in mice and elucidates the role of HMGB1 in this process. In this study, male ICR mice were treated with TBBPA (50 mg/(kg·day)) for 28 days. Results showed that TBBPA induced splenic injury, characterized by white pulp reduction, red pulp congestion, lymphatic hyperplasia, and inflammatory infiltration. Moreover, vacuolation was observed in the mitochondria of the TBBPA exposed group, with the majority of mitochondrial cristae either disrupted or had vanished. Mechanistically, TBBPA upregulates HMGB1, which activates the TLR4/MyD88/NF-κB pathway and subsequently promotes NLRP3-mediated pyroptosis, ultimately exacerbating the inflammatory response. Our findings indicate that HMGB1 could be an effective target for addressing inflammatory and immune disorders.
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高影响因子
危险品化学品经营许可证（带存储）