BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Yelin Tang,Wenxin Zhang,Liqin Wu,Bin Bai,Bin Zheng,Mengying Li,Yue Tang,Xiaona Zhu,Yali Zhang,Yi Wang,Bing Zhang
Purpose Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. Methods In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance , ELISA and immunoprecipitation assay. Results It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines , and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization . Conclusions As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
研究领域:
药理学
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免疫学
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肺医学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 2
·e70047
·
IF 4.2
Kangmin Chen,Yanni Zhao,Tianyang Jin,Tingxin Xu,Conglun Zhu,Hui Shen,Xiaohong Xu,Yongsheng Jiang,Yi Wang,Shihang Xue
Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Miaomiao Sun,Honghong Zhan,Xiaoliang Long,Ali M. Alsayed,Zhe Wang,Fancheng Meng,Guowei Wang,Jingxin Mao,Zhihua Liao,Min Chen
Background Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. Purpose The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. Methods The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo . And DHL on reducing inflammatory response and regulating TLR4/NF‐κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. Results DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. Conclusion This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
研究领域:
药理学
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免疫学
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肿瘤学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
BASIC RESEARCH IN CARDIOLOGY
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2016
·Vol. 112
·期 1
·1-15
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IF 6.038
Han Jibo,Zou Chunpeng,Mei Liqin,Zhang Yali,Qian Yuanyuan,You Shengban,Pan Yong,Xu Zheng,Bai Bin,Huang Weijian,Liang Guang
Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and pro-fibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subcutaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.
研究领域:
心脏病学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR THERAPY
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2023
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IF 12.4
Jiaxin Li,Yuqi Chen,Rui Li,Xianglong Zhang,Tao Chen,Fengyi Mei,Ruofan Liu,Meiling Chen,Yue Ge,Hongbin Hu,Rongjuan Wei,Zhenfeng Chen,Hongying Fan,Zhenhua Zeng,Yongqiang Deng,Haihua Luo,Shuiwang Hu,Shumin Cai,Feng Wu,Nengxian Shi,Zhang Wang,Yunong Zeng,Ming Xie,Yong Jiang,Zhongqing Chen,Wei Jia,Peng Chen
Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.
研究领域:
免疫学
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传染病学
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药理学
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2025
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IF 4.6
Yufang Lu,Ruiying Zhou,Ruyi Zhu,Xue Wu,Jin Liu,Yue Ma,Xin Zhang,Yaling Zhang,Luting Yang,Yanhua Li,Yuan Zhang,Yaping Yan,Qian Zhang
This study aims to elucidate the target and mechanism of baicalin, a clinically utilized drug, in the treatment of neuroinflammatory diseases. Neuroinflammation, characterized by the activation of glial cells and the release of various pro-inflammatory cytokines, plays a critical role in the pathogenesis of various diseases, including spinal cord injury (SCI). The remission of such diseases is significantly dependent on the improvement of inflammatory microenvironment. Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2) complex plays an important role in pathogen recognition and innate immune activation. baicalin, a natural flavonoid, is renowned for its potent anti-inflammatory property. In this study, we discovered that baicalin significantly reduced the activation of glial cells and the levels of pro-inflammatory cytokines at the lesion site of SCI mice, thereby mitigating demyelination and neuronal damage. By directly occupying the active pocket of TLR4/MD2 complex on microglia, baicalin inhibited PI3K/AKT/NF-κB pathway, thereby exerting its anti-inflammatory effect. These findings were corroborated in mice induced by lipopolysaccharide, a TLR4 agonist. Furthermore, baicalin indirectly altered phenotype of astrocytes by reducing secretion of TNF-α, IL-1α, and C1q levels from microglia. Our work demonstrated that baicalin effectively alleviated neuroinflammation by directly targeting microglia and indirectly modulating astrocytes phenotype. As a natural flavonoid, baicalin holds significant potential as a therapeutic candidate for diseases characterized by neuroinflammation.
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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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2026
·
IF 5.9
Jiangjiang Fu,Gangchen Cheng,Zhongxi Lyu,Zezhi Fan,Feiyang Li,Zhifang Xu,Bo Chen,Yongming Guo,Yuhan Liu,Hui Zhang,Yuan Xu,Yi Guo
Introduction: The acupuncture acupoint is the critical initial site for the therapeutic efficacy of electroacupuncture (EA). Previous studies have confirmed that the NF-κB pathway within the acupoint region mediates the therapeutic effects of acupuncture. Therefore, this study focuses on an in-depth investigation of the MD2/TLR4/NF-κB axis. Methods: The mouse model of adjuvant-induced arthritis (AIA) was established via intraplantar injection of Complete Freund’s Adjuvant (CFA). EA intervention was applied bilaterally to the Zusanli (ST36) acupoints, and behavioral, molecular, and immunological approaches were integrated to investigate the role of MD2 in EA-mediated analgesia. Results: EA increased paw thermal withdrawal thresholds (PTWTs) in AIA mice (P < 0.05), accompanied by higher levels of MD2, TLR4, p65, and the phosphorylated form of p65 (p-p65) at the acupoint. Co-immunoprecipitation (Co-IP) confirmed binding between MD2 and TLR4 in ST36 acupoint, while immunofluorescence (IF) revealed co-localization of TLR4 with fibroblasts and mast cells in ST36, suggesting these immune cells are critical targets for signal activation. Lentivirus-mediated knockdown of MD2 in the acupoint partially reversed EA’s analgesic effects and suppressed downstream TLR4/NF-κB pathway activation, whereas MD2 overexpression elicited a partial analgesic effect and promoted pathway activation. Together with spinal cord proteomics data, these findings indicate that modulating MD2 in the acupoint can regulate spinal cord-related signaling pathways. Mechanistically, EA dynamically regulates the equilibrium of the Grem1/BMP4/COX2 axis in the spinal dorsal horn via activation of the MD2/TLR4/NF-κB pathway cascade, achieving systemic analgesia. Conclusion: This study provides molecular evidence supporting the "acupoint priming" theory in acupuncture and highlights MD2 as a potential therapeutic target for pain management.
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2019
·
IF 4.18
Hongjin Chen,Yali Zhang,Wenxin Zhang,Hui Liu,Chuchu Sun,Bing Zhang,Bin Bai,Di Wu,Zhongxiang Xiao,Hazel Lum,Jianmin Zhou,Ruijie Chen,Guang Liang
Background ALI/ARDS is characterized by severe hypoxemic respiratory failure attributed to inflammatory tissue injury. There are no treatment modalities able to prevent/reverse the dire pathological sequelae in these patients . Evidence links the inflammatory lung injury to uncontrolled activation of the immune signaling complex, TLR4-MD2 (Toll-like receptor-myeloid differentiation factor 2). Baicalein , a natural flavonoid , is reported to have robust anti-inflammatory properties, but its inhibition mechanism remains unclear. Hypothesis/Purpose This study investigated the protective mechanisms of baicalein on ALI/ARDS. Methods We used two experimental mouse models of LPS-induced ALI , pulmonary infection model (intratracheal LPS), and systemic infection model (intravenous LPS). Blood, BALF , lung and liver tissues were analyzed using routine methods. In vitro studies using peritoneal mouse macrophages or recombinant proteins were designed to elucidate inhibition mechanisms of baicalein. Results Our critical new findings revealed that Baicalein was an MD2 inhibitor, directly bound to MD2, effectively suppressing TLR4-MD2 activation and the subsequent MAPK and NF-κB signaling. The inhibited MD2 prevented development of inflammatory tissue injury and improved survival. The importance of MD2 in the inflammatory injury in ALI was corroborated by data obtained from MD2 −/− mice, which did not develop the characteristic LPS-induced lung tissue damage. Thus, the findings indicated that MD2 was critical for development of ALI, functioning as an early upstream signal driving the progression of inflammatory injury. Conclusion Baicalein, as a direct and selective MD2 inhibitor, inhibited the early upstream TLR4-MD2 signaling and is a promising therapeutic agent for the treatment of ALI/ARDS.
研究领域:
免疫学
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药理学
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肺科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2022
·Vol. 180
·期 8
·1114-1131
·
IF 9.473
Weiwei Zhu,Minxiu Wang,Leiming Jin,Bin Yang,Bin Bai,Rumbidzai Natasha Mutsinze,Wei Zuo,Nipon Chattipakorn,Joo Young Huh,Guang Liang,Yi Wang
Background and Purpose Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. Experimental Approach A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. Key Results Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo , licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. Conclusion and Implications In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy. Graphical Licochalcone A directly binds with MD2 whereas LEU61 and PHE151 are two key residues for conformational stabilization. This interaction blocks the biological function of MD2 in transducing the signalling from the LPS-induced TLR4 pathway, subsequently restrains both TBK1/IRF3 and TAK1/MAPKs/NF-κB activation and inflammatory cytokines, chemokines, interferons, and so on overexpression, thus decreasing the immune cell infiltration in lung tissue and improving the acute lung injury.
研究领域:
药理学
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免疫学
·
分子生物学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2024
·
IF 3.5
Shipeng Li,Ping Yang,Zhenghan Wu,Wenqiang Huang,Xiaofeng Zhu,Lianmei Zhong
Objective Research has shown that cerebral ischemia-reperfusion injury (CIRI) involves a series of physiological and pathological mechanisms, including inflammation, oxidative stress, and cell apoptosis. The cannabinoid receptor 2 agonist AM1241 has been found to have anti-inflammatory and anti-oxidative stress effects. However, it is unclear whether AM1241 has a protective effect against brain ischemia-reperfusion injury, and its underlying mechanisms are not yet known. Methods In this study, we investigated the anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects of AM1241 and its mechanisms in BV2 cells stimulated with H 2 O 2 and in a C57BL/6 mouse model of CIRI in vitro and in vivo , respectively. Results In vitro , AM1241 significantly inhibited the release of pro-inflammatory cytokines TNF-α and IL-6, reactive oxygen species (ROS), and the increase in Toll-like receptor 4/myeloid differentiation protein 2 (MD2/TLR4) complex induced by H 2 O 2 . Under H 2 O 2 stimulation, MD2 overexpression resulted in increased levels of MD2/TLR4 complex, TNF-α, IL-6, NOX2, BAX, and Cleaved-Caspase3 (C-Caspase3), as well as the activation of the MAPK pathway and NF-κB, which were reversed by AM1241. In addition, molecular docking experiments showed that AM1241 directly interacted with MD2. Surface Plasmon Resonance (SPR) experiments further confirmed the binding of AM1241 to MD2. In vivo , AM1241 significantly attenuated neurofunctional impairment, brain edema, increased infarct volume, oxidative stress levels, and neuronal apoptosis in CIRI mice overexpressing MD2. Conclusion Our study demonstrates for the first time that AM1241 alleviates mouse CIRI by inhibiting the MD2/TLR4 complex, exerting anti-inflammatory, anti-oxidative stress and anti-apoptotic effects.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
DOI
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Jianjun Lin,Ke Lin,Lijiang Huang,Yongsheng Jiang,Xiaoxiao Ding,Wu Luo,Aleksandr V. Samorodov,Valentin N. Pavlov,Guang Liang,Jianchang Qian,Yi Wang
Heme, as an essential component of hemoproteins , is a prosthetic co-factor found in many cells, which is essential for physiologically vital oxygen transport. However, extracellular or circulatory heme is cytotoxic and triggers inflammation. Although the proinflammatory role of heme has been reported to be associated with Toll-like receptor 4 (TLR4) signaling, the exact mechanism remains unknown. Here, we show that heme promotes TLR4 signaling and inflammation via directly physically interacting with TLR4 and its adaptor protein myeloid differentiation protein 2 (MD2). Genetic loss of MD2 ameliorates heme-induced inflammation and inflammatory cytokine production in the spleen of MD2 knockout (MD2 -/- ) mice. Using mouse macrophage RAW 264.7 cell line, we show that heme induces TLR4 dimerization and MD2/TLR4/MyD88 activation by physically interacting with TLR4 and MD2 in vitro . Genetic loss of MD2 inhibits heme-induced inflammation and MAPK/NF-κB pathway in mouse primary macrophages extracted from MD2 -/- mice. Furthermore, pharmacological inhibition of MD2 by L6H9 ameliorates heme-induced inflammation in macrophages. These findings demonstrate that heme causes inflammation by directly binding to MD2/TLR4 complex, leading to activation of TLR4/MAPK/NF-κB signaling pathway and production of downstream effectors of inflammation.
研究领域:
免疫学
·
细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2023
·Vol. 20
·期 6
·e202201145
·
IF 2.9
Huiying Bai,Zhen Cao,Sha Meng,Rui Ge,Shurong Ban,Yuanlin Zhang,Li Tang,Qing-Shan Li
Myeloid differentiation protein 2 (MD2), a key TLR4 adaptor protein for sensing LPS, plays an important role in inflammatory process and has been identified as a promising target for the treatment of a variety of inflammatory diseases. In our study, a series of benzoxazolone derivatives were synthesized, characterized and tested for anti-inflammatory activity in vitro . The compounds 3c , 3d and 3g demonstrated the greatest anti-inflammatory activity against IL-6 with IC 50 values of 10.14±0.08, 5.43±0.51 and 5.09±0.88 μM, respectively. Furthermore, the bis-ANS displacement assay revealed that these compounds competitively inhibited the binding between the probe bis-ANS and the MD2 protein. The most active compound 3g , revealed a directly bind with MD2 protein via Arg90 binding and a dissociation constant value of 1.52×10 −6 mol L −1 as determined by the biological layer interference (BLI) assay. Our finding suggested that compounds 3g could be a promising lead compound as MD2 inhibitor for further anti-inflammatory agent development.
研究领域:
药理学
·
药物化学
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炎症研究
✓ 已验证
DOI
PubMed
高影响因子
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