BIOMACROMOLECULES
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2026
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IF 5.9
Yuru Chen,Fangjian Shan,Junhan Yuan,Yuchun Pan,Yu Duan,Gaojian Chen
Synthetic glycopolymers are potent immunomodulators, yet the role of programmable interfacial cues in engaging Toll-like receptors (TLRs) remains poorly defined. Here, we investigate the self-assembly behavior of degradable amphiphilic glycopolymers synthesized via radical ring-opening copolymerization. We demonstrate that dendritic cell (DC) maturation exhibits a pronounced nonlinear dependence on backbone hydrophobicity, with an MDO molar fraction between 30 and 40% identified as the “sweet spot” for maximizing DC maturation markers (CD80+/CD86+, MHC II, and CCR7). By integrating ANS fluorescence assays, multiscale DPD simulations, and molecular docking, we confirm that this dependence is primarily dictated by the formation of surface “hydrophobic patches.” Specifically, a surface hydrophobic patch content of ∼29% (exemplified by the PGM-4 formulation) provides the ideal interface for TLR4-associated signaling by optimizing the balance between hydrophobic anchoring and multivalent glycan recognition, as evidenced by inhibition studies with the TLR4-selective antagonist TAK-242. Furthermore, these nanoparticles maintain sufficient structural stability in the short term while exhibiting enzyme-responsive backbone degradation over a longer duration. This study establishes a quantitative framework for designing “patchy” glyco-nanoparticles, where the synergy between hydrophobic domains and glycan clusters dictates potent adjuvant activity.
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2026
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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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DOI
PubMed
高影响因子
Small
·
2026
·
IF 11.8
Junyan Liu,He Ke,Lingyu Su,Zhirou Lin,Chong Liu,Shilong Jiang,Hong Huang,Chengxian Guo,Qinghua Zhang,Huifang Tang,Zhaoqian Liu,Wenhu Zhou,Qi Pei,Qianfei Cui
Osteoarthritis (OA) is a degenerative joint disease, for which effective disease-modifying therapies remain lacking. Here, we report yam-derived nanovesicles (YDNVs) as a plant-derived exosome-like nanoplatform with intrinsic therapeutic activity for OA treatment. YDNVs exhibited typical nanoscale vesicular characteristics and were efficiently internalized by chondrocytes via clathrin-mediated endocytosis. Through enzymatic pretreatment and multi-omics analyses, RNA-particularly microRNAs (miRNAs)-was identified as the primary bioactive component mediating their anti-inflammatory effects. Mechanistic studies further confirmed that aof-miR168a directly binds to the 3′ untranslated regions of TLR4 and TRAF6, thereby suppressing downstream inflammatory signaling. To enhance targeting and therapeutic efficacy, a cartilage-targeting peptide-modified system (YDNVs-CAP) was engineered via membrane insertion of a cholesterol-anchored conjugate. This modification significantly improved cellular uptake, cartilage targeting, and intra-articular retention. Functionally, YDNVs-CAP effectively alleviated inflammation, oxidative stress, and extracellular matrix degradation in vitro, and markedly attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model. Collectively, this study establishes an RNA-mediated therapeutic mechanism for plant-derived nanovesicles and highlights YDNVs-CAP as a promising biomimetic nanoplatform for disease-modifying OA therapy.
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DOI
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2025
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IF 4.3
Xinhao Ye,Shiyi Duan,Hao Wang,Shimei Xiao,Mijia Li,Wei Yuan,Yan Zhao,Yiyue Zhang,Keyuan Zhong
The inflammatory response is a core protective physiological process against stimuli like infection or injury, and can be initiated by autoimmune disorders. It is primarily characterized by neutrophil-dominated leukocytosis and may lead to multiple organ dysfunction in severe cases. Environmental factors play an important role in the inflammatory response. Rare earth elements are not essential elements for living organisms. However, owing to large-scale mining and use, their concentrations in the environment have increased. Thus, rare earth elements are now considered emerging environmental pollutants, and the risks that rare earth elements pose to human health need further investigation. In this study, zebrafish were used as experimental animals, and zebrafish embryos were exposed to the different concentrations of lanthanum chloride (0, 5, 15, and 25 mg/L) to analyze its effect on embryo development and immune system. The number and distribution of zebrafish neutrophils as well as changes in oxidative stress and the expression of genes related to inflammation were analyzed. The results indicated that lanthanum chloride exposure reduced the heart rate, shortened the body length, and increased the yolk area of zebrafish embryos. In addition, exposure to lanthanum chloride caused the diffusion of neutrophils, leading to inflammation in zebrafish. Concurrently, the exposure led to the accumulation of reactive oxygen species in zebrafish, which subsequently resulted in the upregulation of malondialdehyde, catalase, and superoxide dismutase levels. Further experiments revealed that exposure to lanthanum chloride led to the upregulation of several inflammation-related genes, such as IL-6 , IL-8 , IL-10 , and cxcl-c1c , as well as certain TLR4/NF-κB signaling-related genes, including TLR4 , MyD88 , NF-κB P65 , IL-1β , and TNF-α . The TLR4/NF-κB signaling pathway inhibitor andrographolide can alleviate the inflammatory response induced by lanthanum chloride exposure. In conclusion, lanthanum chloride induced inflammation in zebrafish by activating the TLR4/NF-κB signaling pathway. The study results can provide a reference for evaluating the health risks of rare earth elements in humans.
研究领域:
毒理学
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环境科学
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免疫学
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分子生物学
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水生毒理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Meimei Zhao,Zhiqi Liu,Yuqi Geng,Xinyu Lv,Jingyi Xu,Xinyi Zhao,Ziteng Yu,Ruijiao Zhu,Mengcong Li,Fang Han,Xiao Ma,Ning Gu
This study aimed to investigate the effects of Boletus edulis Bull: Fr. polysaccharide (BEP), extracted using a deep eutectic solvent based on l -lactic acid and glycine, on glucose and lipid metabolism in high-fat diet (HFD)-fed mice. The primary mechanism by which BEP improves symptoms of glucose and lipid imbalances involves the modulation of gut microbiota. Key beneficial bacteria, including S24–7 , Lachnospiraceae , [Prevotella], and Lactobacillus , were significantly enriched in the intestines of BEP-treated mice, with abundances 2.48-, 1.62-, 6.33- and 2.60-fold higher, respectively, compared to the HFD group. In contrast, the abundance of harmful bacteria, particularly Desulfovibrio , was reduced by 1.81-fold. These microbial shifts contributed to the alleviation of intestinal mucus layer damage and a 50 % reduction in serum lipopolysaccharide (LPS) levels, a key driver of systemic inflammation, compared to the HFD group. As a result, BEP effectively inhibited LPS-induced activation of the hepatic TLR4/Myd88/MAPK signaling pathway, thereby normalizing the expression of proteins related to glucose and lipid metabolism. A fecal microbiota transplantation study further demonstrated that the gut microbiota changes induced by BEP were central to its anti-metabolic syndrome effects. Overall, BEP may serve as a dietary supplement for preventing and treating diet-induced metabolism disorders by targeting the gut microbiota.
研究领域:
营养学
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微生物学
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代谢研究
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2019
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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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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
·
IF 8.2
Shuang Xiao,Peng Zhang,Guowen Zhang,Wenwen Li,Haowen Lin,Xing Hu
The activation of toll-like receptor 4 (TLR4) signaling is crucial for initiating and coordinating the immune response against infections, and is proved as a vital target for inflammatory diseases. Herein, TLR4 with sufficient amount and functional activity was generated by heterologous expression and used to investigate the mechanism of apigenin (Api)/chrysin (Chr) inhibition of TLR4 activation. The results demonstrated that Api/Chr exhibited a strong fluorescence quenching effect through a static quenching and a high binding affinity ( K a > 10 5 L·mol −1 ) with TLR4, indicating the potential of Api/Chr as a TLR4 inhibitor. Additionally, the binding of Api/Chr induced a loose and unstable conformation of TLR4 with evidence like the decreased hydrophobicity of the tryptophan microenvironment, decreased α-helix content and increased free sulfhydryl content, resulting in reduced stability of the TLR4. The computer simulations revealed that Api/Chr occupied the myeloid differentiation factor 2 (MD-2) binding region, preventing MD-2 from binding to TLR4. Furthermore, the accuracy of the binding site between Api/Chr and TLR4 was confirmed through genetic mutations . Overall, the mechanism by which Api/Chr inhibited TLR4 activation was elucidated at the macroscopic and molecular levels, providing the worthful information concerning the future therapeutic application of Api/Chr as a natural TLR4 inhibitor.
研究领域:
免疫学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
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2023
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IF 2
Qian Hu,Ran Tao,Xiaoyun Hu,Haibo Wu,Jianjun Xu
Acute pancreatitis is an inflammatory response in the pancreas, involving activation of pancreatic enzymes. Severe acute pancreatitis (SAP) often causes systemic complications that affect distant organs, including the lungs. The aim of this study was to explore the therapeutic potential of piperlonguminine on SAP-induced lung injury in rat models. Acute pancreatitis was induced in rats by repetitive injections with 4% sodium taurocholate. Histological examination and biochemical assays were used to assess the severity of lung injury, including tissue damage, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), reactive oxygen species (ROS), and inflammatory cytokines. We found that piperlonguminine significantly ameliorated pulmonary architectural distortion, hemorrhage, interstitial edema, and alveolar thickening in rats with SAP. In addition, NOX2, NOX4, ROS, and inflammatory cytokine levels in pulmonary tissues were notably decreased in piperlonguminine- treated rats. Piperlonguminine also attenuated the expression levels of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). Together, our findings demonstrate for the first time that piperlonguminine can ameliorate acute pancreatitis-induced lung injury via inhibitory modulation of inflammatory responses by suppression of the TLR4/NF-κB signaling pathway.
研究领域:
药理学
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炎症
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肺医学
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胃肠病学
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DOI
PubMed
高影响因子
Nano Today
·
2026
·
IF 10.9
Tianwei Lan,Xiaoping Guo,Chang Liu,Pai Wang,Shichen Zhang,Lei Guo,Siyuan Wang,Lu Wang,Rui Zhou,Xinran Yan,Baiqiao Chen,Mujie Kan,Fang Wang,Caina Xu
Allergic asthma (AAS) is a chronic inflammatory airway disease. While zileuton (ZIL) has the efficient ability to relieve AAS symptoms, its systemic, untargeted administration could lead to adverse neurological effects. Thus, we constructed a drug combination nanomicelle (NMs) platform, H(BZP)-NMs, to reach synergistic effect therapy. It was comprised of a hydrophilic end formed from methoxy poly(ethylene glycol) (mPEG) and poly( L -glutamic acid) (PGlu), and a ROS/pH dual-sensitive hydrophobic core. The core was created by coupling 4-(hydroxymethyl)phenylboronic acid (HPBA) to betamethasone (BMZ). Zileuton (ZIL) was strategically loaded in the core. Hyaluronic acid (HA) functionalization further enabled CD44-targeting ability. In pathological microenvironments, the boronate ester bonds undergo responsive cleavage, causing the parallel delivery of the drugs. The slow-release profile addressed the need for rapid early-stage control and prolonged late-stage relief. In vivo, H(BZP)-NMs significantly decreased Penh values, lowered the IL-4, IL-5, IL-13, and LTB4 levels, and ameliorated airway pathological injuries. Given the molecular docking and verification of network pharmacology, these effects were associated with the dual-drug synergistic inhibition of the TLR4-MyD88-NF-κB p65 signals. Collectively, this study shows that H(BZP)-NMs are an inventive nanomedicine approach that unifies targeted delivery and extended co-release, offering promise for accurate and synergistic treatment of AAS.
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产品关联
DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Fei Fang,Bo Peng,Yanjuan Zhu,Wenping Xu,Yang Zhang,Jiagao Cheng
Comprehensive understanding the toxic effects of pesticide with relative long half-life properties are always hot research topics in the world. In this study, the immunotoxic effects of Bixafen (BIX), a prominent Succinate Dehydrogenase Inhibitor (SDHI) fungicide, were systematically assessed at concentrations of 0.05, 0.1, and 0.2 μM, using a zebrafish ( Danio rerio ) larval model. Neutral red staining and confocal microscopy quantification showed that BIX exposure reduced immune cell numbers in a concentration-dependent manner. qPCR and Western blot validation revealed upregulated pro-inflammatory factors ( IL-1β , IL-8 , TNF-α ) and TLR4 gene expression, while the lymphocyte marker gene rag1 was downregulated. Protein - level detection found significantly increased p-p65/p65 and TLR4 expression. Molecular docking experiments showed that BIX forms multiple interactions with the TLR4 protein. RNA-Seq analysis further confirmed that BIX interferes with DNA replication and metabolic pathways. Our results suggest that BIX may activate proinflammatory responses and disrupt immune cell homeostasis via the TLR4 signaling pathway, posing a potential immunotoxicity risk to non-target organisms. These findings provide insights into the molecular mechanisms of BIX-induced immunotoxicity and are critical for assessing the environmental safety and health risks associated with SDHI fungicides.
研究领域:
毒理学
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环境科学
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免疫学
·
分子生物学
·
水生毒理学
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产品关联
DOI
PubMed
高影响因子
FOOD HYDROCOLLOIDS
·
2024
·
IF 11
Zhili Sheng,Hui Liu,Bailin Li,Hong Zhu,Yueming Jiang,Bao Yang
Huangqi (Astragalus membranaceus root) is a widely recognized functional food with impressive health benefits. The primary biomacromolecules in A. membranaceus , polysaccharides, are hypothesized to contribute to these health advantages. However, the precise structure and bioactivity of these polysaccharides remain unclear. In this study, the predominant water-soluble polysaccharides were extracted from A. membranaceus root. A homogeneous fraction with molecular weight of 42.0 kDa, designated APS-I, was purified. The monosaccharides of APS-I comprised arabinose and galacturonic acid in a molar ratio of 34:21. The precise structure of APS-I was elucidated by using nuclear magnetic resonance spectroscopy (NMR) and tandem mass spectrometry (MS). The backbone was identified to be α-(1 → 4)-D-galacturonan, which was substituted at O-3 by α-L-Araf-(1→ [5)-α-L-Araf-(1] n → and α-L-Araf-(1→, respectively. This confirmed it as an arabinogalacturonan. The immunomodulatory activity of APS-I was assessed by using macrophage cells. Our findings indicated that arabinogalacturonan could induce NO, IL-6, TNF-α and IL-1β production, demonstrating their potential as an immunoregulatory compound. Notably, TLR4 receptor was involved in the regulation of immune response and may be a target for APS-I.
研究领域:
药理学
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免疫学
·
食品科学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Ke Lin,Wu Luo,Na Yang,Lan Su,Hao Zhou,Xiang Hu,Yi Wang,Zia A. Khan,Weijian Huang,Gaojun Wu,Guang Liang
Background Kidney damage is a frequent event in the course of hypertension. Recent researches highlighted a critical role of non-hemodynamic activities of angiotensin II (Ang II) in hypertension-associated kidney fibrosis and inflammation. These activities are mediated through toll-like receptors (TLRs) but the mechanisms by which Ang II links TLRs to downstream inflammatory and fibrogenic responses is not fully known. In this study, we investigated the role of TLR adapter protein called myeloid differentiation primary-response protein-88 (MyD88) as the potential link. Methods C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop nephropathy. Mice were treated with small-molecule MyD88 inhibitor LM8. In vitro , MyD88 was blocked using siRNA or LM8 in Ang II-challenged renal tubular epithelial cells. Results We show that MyD88 is mainly located in tubular epithelial cells and Ang II increases the interaction between TLR4 and MyD88. This interaction activates MAPKs and nuclear factor-κB (NF-κB), leading to increased production of inflammatory and fibrogenic factors. Inhibition of MyD88 by siRNA or selective inhibitor LM8 supresses MyD88-TLR4 interaction, NF-κB activation, and elaboration of inflammatory cytokines and fibrosis-associated factors. These protective actions resulted in decreased renal pathological changes and preserved renal function in LM8-treated hypertensive mice, without affecting hypertension. Conclusion These results demonstrate that Ang II induces inflammation and fibrosis in renal tubular epithelial cells through MyD88 and present MyD88 as a potential point of intervention for hypertension-associated kidney disease.
研究领域:
药理学
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肾病学
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）