VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY
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2025
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IF 1.4
Chanyu Wu,Xiaohan Wang,Xincan Li,Hexian Li,Qiuyue Peng,Xiaoxin Niu,Yutong Wu,Zhiying Wang,Zuoyong Zhou
Corynebacterium pseudotuberculosis , a zoonotic intracellular bacteria, is responsible for abscesses and pyogranuloma formation of the infected host, which is essentially a chronic inflammatory response. Tripartite motif-containing protein 21 (TRIM21) negatively regulates pro-inflammatory cytokines production during C . pseudotuberculosis infection, the mechanism of which remains unclear. This study found that C . pseudotuberculosis infection in macrophages induced phosphorylation of IκB and p65. TRIM21 interacted with IκBα by PRY/SPRY domain, stabilizes IκBα and negatively regulates IκBα phosphorylation in macrophages during C. pseudotuberculosis infection. In addition, TRIM21 positively regulates the ubiquitination of IκBα via K48 linkage rather than K63 linkage in C. pseudotuberculosis -infected macrophages. In brief, our research confirmed that TRIM21 negatively regulates canonical NF-κB activation by interacting with IκBα and decreasing IκBα phosphorylation in macrophages during C. pseudotuberculosis infection. Preventing inflammation induced by C. pseudotuberculosis infection through regulation of the NF-κB pathway is a potential way to control this pathogen.
研究领域:
免疫学
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微生物学
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分子生物学
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PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
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2025
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IF 4
Ling Zhu,Congyan Liu,Yang Wang,Xuanang Zhu,Lei Wu,Lvan Chen,Jing Zhou,Fan Wang
Background Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. Method Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N 6 -methyladenosine (m 6 A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. Results Stimulation with Aβ 1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m 6 A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. Conclusion Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
研究领域:
神经生物学
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医学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
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IF 12.6
Wu Shujuan,Zhou Mengqi,Zhou Huimin,Han Lu,Liu Huifan
This study explored the novel mechanism of Astragaloside IV (As) in treating sepsis and its application through a biomimetic nano-delivery system (As@ZM). Sepsis, a condition of organ dysfunction caused by an abnormal host response to infection, poses a significant threat to global health due to its high mortality rate. Our findings revealed a new mechanism for As in treating sepsis, which involved the reduction of neutrophil extracellular traps (NETs) release, potentially related to As binding with IκBα to inhibit the activation of the NF-κB pathway. As treated neutrophils also improved the immune microenvironment by crosstalk with endothelial cells and lung epithelial cells. However, the stability and bioavailability of As limited its clinical application. To address this issue, we had developed a ZIF-8-based nano-delivery system that achieved targeted delivery through neutrophil membrane coating, significantly enhancing the therapeutic efficacy of As. The innovative design of As@ZM offered a new strategy for sepsis treatment, with the potential to improve clinical outcomes. Graphical abstract
研究领域:
免疫学
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药剂学
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感染性疾病
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PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
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2023
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IF 5.9
Meixia Xie,Jiale Cai,Xiaoting Zhong,Jiayin Liang,Shengwang Liang,Minghua Xian,Chunyan Yan,Shumei Wang
Rehmannia glutinosa Libosch is a useful crop for both industrial and medical use. Polysaccharide is one of the rich components, while its separation, purification and structural characteristics are rarely reported. In this work, two new natural polysaccharides, RGP90–1–1 and RGP90–1–2 (molecular weights 13.2 kDa and 6.2 kDa, respectively), were obtained from Rehmannia glutinosa . The structural characteristics, including monosaccharide composition, linkage, and configuration, were analyzed by HPLC, FT-IR, GC-MS NMR spectroscopy , and so on. The main component of RGP90–1–1 was arabinose , with trace amounts of glucose and xylose , with the linkages L-Ara f -(1→, →3)-L-Ara f -(1→, →5)-L-Ara f -(1→, D-Glc p -(1→, →3, 5)-L-Ara f -(1→, →2, 5)-L-Ara f -(1→, →6)-D-Glc p -(1→ and →2, 3, 4)-D-Xyl p -(1→. RGP90–1–2 consisted of large amounts of arabinose and a small amount of glucose, with linkages including L-Ara f -(1→, →3)-L-Ara f -(1→, →5)-L-Ara f -(1→, →3,5)-L-Ara f -(1→ and →6)-D-Glc p -(1→. Furthermore, inhibition experiments of α-glucosidase and α-amylase activities showed that RGP90–1–1 and RGP90–1–2 had potential hypoglycemic effects. In vitro, RGP90–1–2 dose-dependently attenuated the secretion of nitric oxide and the expression of iNOS in LPS-induced RAW264.7 inflammation model and exerted significant anti-inflammatory effects via NF-κB/IκBα pathway. The findings suggest that RGP90–1–1 and RGP90–1–2 have the potential for development into new hypoglycemic drugs or health food . It offers a scientific foundation for increasing the planting applications and public awareness of Rehmannia glutinosa .
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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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Jujie Pan,Ruixia Bao,Qian Chen,Yuzheng Wu,Beibei Chen,Zicheng Zhu,Jing Xie,Yi Zhang,Tao Wang,Dan Wang
Hyperuricemia (HUA) is a chronic metabolic disease which has been previously observed to be associated with cortisol metabolism disorders (pseudohypoadrenalism). In this study, we aimed to investigate the efficacy as well as mechanism of Eurycoma longifolia Jack (TkA) on alleviating cortisol metabolism. Oral administration of TkA significantly decreased serum uric acid levels and urinary cortisol in HUA mice. TkA improved HPA axis function and upregulated the levels of adrenal Hsd3b2 , Cyp21a1 and Cyp11b1 . In the liver, TkA upregulated the expression of Srd5a1 and Akr1c4 , promoting the conversion from cortisol to 5α-tetrahydrocortisol ( P < 0.001). TNFα was found to be the principal driver of reduced SRD5A1. By activating NF-κB pathway, recruited DNA methyltransferase (DNMT) binding with the CpG islands increased methylation level of Srd5a1 . Our findings highlight that eurycomanol significantly inhibited the activation of IKKβ/IκBα/NF-κB/DNMT pathway as well as up-regulated hepatic SRD5A1, thereby restoring the systemic cortisol metabolic homeostasis under HUA.
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高影响因子
CARBOHYDRATE POLYMERS
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2026
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IF 13.2
Jia-Mei Geng,Pei-Feng Zhu,Lu-Shuang Xu,Ji-Lai Liu,Zheng-Qing Yang,Zhu-Ya Yang,Qiong Jin,Lu Liu
The medicinal moss Rhodobryum giganteum is rich in polysaccharides, whose structural and biofunctional properties remain largely unexplored. In this study, a novel glucose-rich polysaccharide fraction (named RGP, 29.8 kDa) was isolated and characterized from R. giganteum . Structural analysis revealed a unique α -1,6-linked glucan backbone with C-2 acetylation, along with side chains composed of →4)- α - d -glucopyranosyl-(1 → and terminal α - d -glucopyranose units. RGP significantly promoted proliferation, phagocytosis, and cytokine (TNF- α , IL-6) secretion via the TLR4/PI3K-Akt/IκB α pathway in RAW264.7 cells. In immunosuppressed mice, RGP restored immune function, as shown by improved organ indices, elevated serum immunoglobulins (IgA, IgG, IgM), and alleviated splenic damage. Molecular docking revealed that RGP binds the hydrophobic pocket of the TLR4/PI3K-Akt/IκB α complex via its glucose chain, and dynamics simulations confirmed the stability of this interaction. These findings reveal the bioactivity of bryophyte polysaccharides and suggest RGP as a potential immunomodulatory agent.
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高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Xu Gao,Xiaofeng Zhu,Yibin Lin,Chengkuan Liu,Qingwen Wang,Xian Lin
Background Developing novel therapeutic targets and innovative drugs for rheumatoid arthritis (RA) remains highly challenging. Despite the involvement of 5-methylcytosine (m5C) RNA methylation in various biological processes, its specific roles in RA and potential applications in drug development remain unclear. Additionally, the role of CX26 in RA progression and its inflammatory effects on fibroblast-like synoviocytes (FLSs) have not been elucidated. Salvianolic acid B (SAB), a bioactive component derived from Salvia miltiorrhiza , possesses anti-inflammatory properties, but its potential in RA treatment has not been completely explored. Purpose This study aimed to clarify the role of m5C-methylated gene CX26 in RA-FLSs and evaluate the therapeutic potential of SAB for RA therapy. Methods Multi-omics analysis was used to determine the contribution of m5C RNA methylation to RA pathogenesis and characterize m5C-methylated genes during RA progression. Methylated RNA immunoprecipitation sequencing and RNA sequencing were employed to analyze the effect of SAB on m5C methylation of CX26 in RA-FLSs. Immunohistochemistry, quantitative real-time PCR, Western blot, Cell Counting Kit-8, 5-Ethynyl-2′-deoxyuridine, and Transwell assays were applied to assess the effects of CX26 and SAB on RA-FLSs. The anti-arthritic activity of SAB was validated in a collagen-induced arthritis (CIA) mouse model. Results This study demonstrated a vital role of m5C RNA methylation in RA progression. CX26 was identified as an m5C-methylated gene that was selectively overexpressed in RA-FLSs. The CX26 levels in the synovium of patients with RA demonstrated significant associations with an activated immuno-inflammatory phenotype, clinical features, and treatment outcomes. Moreover, the CX26 mRNA m5C methylation, stability and expression were elevated by TNF. CX26 augmented inflammation-induced proliferation, migration, and invasion of RA-FLSs via activating the IκBα/NF-κB signaling. SAB reduced m5C methylation of CX26 mRNA and impair CX26 expression, thus abrogating CX26/IκBα/NF-κB signaling–induced pathological phenotypes of RA-FLSs. Furthermore, computational modeling and the CIA model confirmed that SAB alleviated RA progression. Conclusions This cross-validated study, based on multi-omics analysis, outlines the potential of CX26 as a highly selective target and SAB as a novel therapeutic candidate for RA treatment.
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高影响因子
JOURNAL OF TOXICOLOGICAL SCIENCES
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2021
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IF 2.196
Chunsong Yang,Mengqing Si,Jing Zhou
Excessive use of Ketamine (KET) has a neurotoxic effect on the brain. This study explored the effect of Transient Receptor Potential Vanilloid 4 (TRPV4) on KET-induced neurotoxicity in the hippocampus. We extracted and identified rat hippocampal neuronal cells. The hippocampal neurons were treated with different concentrations (0, 0.1, 1, 10, 100, 300 and 1000 μmol/L) of KET (6, 12 and 24 hr). Cell viability was detected by cell counting Kit-8 (CCK-8), and TRPV4 expression was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and western blot. After silencing TRPV4, we tested cell viability and apoptosis. The contents of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and catalase (CAT) were detected by colorimetry, and the contents of TNF-α, IL-1β, IL-6 and reactive oxygen species (ROS) were detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Finally, the expression levels of apoptosis-related proteins Bcl-2, Bax and Cleaved caspase-3, and phosphorylated-p65 (p-65), p65, phosphorylated-IκBα (p-IκBα) and IκBα were detected by qRT-PCR and western blot. KET inhibited the viability of hippocampal neurons in a dose-dependent manner, and up-regulated TRPV4 expression. SiTRPV4 inhibits KET-induced decrease in cell viability and promotes apoptosis. SiTRPV4 reduced MDA and ROS content, increased SOD, GSH and CAT levels. The release of proinflammatory factors TNF-α, IL-1β and IL-6 was also inhibited by siTRPV4. In addition, siTRPV4 up-regulated KET-induced Bcl-2 expression in hippocampal neurons, down-regulated Bax and Cleaved caspase-3, and inhibited the activation of the inflammatory pathway. Silencing TRPV4 partially reverses the neurotoxic effects induced by KET through regulating apoptosis-related proteins and p65/IκBα pathway.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
CELL BIOLOGY INTERNATIONAL
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2022
·Vol. 46
·期 5
·806-818
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IF 4.473
Zhi Cui,Shiqun Sun,Jia Li,Jianing Li,Tong Sha,Jie He,Linjing Zuo
Oral squamous cell carcinoma (OSCC) and hypopharyngeal squamous cell carcinoma (HSCC) are representative of head and neck squamous cell carcinoma (HNSCC) and the molecular pathogenesis has not been completely clarified. Ubiquitin-conjugating enzyme E2 L3 (UBE2L3) is the key member of the E2 family that encodes 153 amino acid residues. Previous studies demonstrate that UBE2L3 is aberrantly overexpressed in various types of human cancers, suggesting that UBE2L3 may function as an oncogene. However, its functional role and the potential mechanisms in the OSCC and HSCC remain unclear. In the present study, we found that UBE2L3 was significantly upregulated in clinical HNSCC samples and HNSCC cell lines, and patients with lower UBE2L3 expression have a higher survival rate. Two HNSCC cell lines FaDu (HSCC cells) and CAL-27 (OSCC cells) with moderate expression of UBE2L3 were selected for in vitro experiments. We proved that UBE2L3 overexpression was positively associated with cellular malignant phenotypes in vitro, including proliferation, invasion, migration, and tumor growth in vivo. Conversely, UBE2L3 suppression diametrically yielded opposing results. Our further study demonstrated that overexpression of UBE2L3 significantly activated the nuclear factor kappa B (NF-κB) signaling pathway through promoting NF-κB p65 nuclear translocation and the ubiquitination and degradation of IκBα protein. Additionally, UBE2L3 was proved to be targeted and negatively regulated by miR-378a-5p, and UBE2L3 overexpression reversed the effects of miR-378a-5p upregulation. Collectively, the present study indicates that UBE2L3 may promote OSCC and HSCC progression via activating the NF-κB signaling by increasing IκBα degradation, indicating that UBE2L3 may be a potential therapeutic target for the treatment of HNSCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Haiying Liu,Yuqi Liu,Xiaoxi Lin,Jianhui Fan,Zhao Huang,Ao Li
Background Lipopolysaccharide (LPS) triggers the activation of nuclear factor kappa B (NF-κB) by interacting with Toll-like receptor 4 (TLR4), leading to the production of various proinflammatory enzymes and cytokines that are crucial in the development of acute lung injury (ALI). Mitoxantrone (MTX) has been demonstrated to mitigate the inflammatory response caused by LPS; however, its precise function in the context of ALI is not fully comprehended. Purpose This study aimed to investigate the inhibitory effects and underlying mechanisms of MTX against LPS-induced ALI. Methods ALI was induced in C57BL/6 mice via a single intratracheal administration of LPS (5 mg/kg), followed by an intraperitoneal injection of MTX to evaluate its therapeutic potential. The effects of MTX on lung injury and the progression of inflammation in ALI mice were assessed using a comprehensive range of techniques, including hematoxylin-eosin (H&E) staining, immunohistochemistry (IHC), myeloperoxidase activity measurement, cell enumeration in bronchoalveolar lavage fluid (BALF), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Additionally, IHC, Western blotting, and co-immunoprecipitation were used to elucidate the specific signaling pathways and molecular mechanisms by which MTX exerted its anti-inflammatory effects in ALI mice. Surface plasmon resonance (SPR) and molecular docking were used to examine the target to which MTX binds directly to reduce inflammation. We also established a lung epithelial cell injury model using LPS-treated A549 cells. The polyubiquitination of IκBα and TRAF6 in LPS-induced A549 cells was detected through Western blotting following immunoprecipitation. Results In mice with LPS-induced ALI, MTX exhibits anti-inflammatory effects by ameliorating histopathological abnormalities caused by LPS, reducing inflammatory cell infiltration, and decreasing the production of proinflammatory enzymes and cytokines. It has been observed that MTX directly binds to the NEDD8 activating enzyme (NAE), thereby inhibiting the transfer of NEDD8 to the substrates UBC12, Cul1, and Cul5. Consequently, the polyubiquitination of IκBα and TRAF6 is disrupted, leading to the suppression of TAK1 activation by TRAF6. This suppression of TAK1 activity hindered the phosphorylation of IKK and MAPK. By stabilizing IκBα through dephosphorylation via IKK inhibition and preventing polyubiquitination, NF-κB activation is reduced. This cascade of events ultimately leads to a reduction in the production of proinflammatory enzymes and cytokines, effectively mitigating the inflammatory response in ALI. In A549 cells, MTX reduces the LPS-induced K48-linked polyubiquitination of IκBα and K63-linked polyubiquitination of TRAF6. This process can be reversed by the overexpression of NEDD8. Additionally, treatment with MG-132, a proteasome inhibitor, can restore the polyubiquitination of IκBα that was inhibited by MTX. Conclusions These findings confirm the essential role of Cul1/5 neddylation in ALI and suggest that MTX could be a promising therapeutic agent for 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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分子生物学
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PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2023
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IF 3.9
Yinzhong Chen,Wei Guo,Weizhao Lu,Xiucheng Guo,Weilu Gao,Zongsheng Yin
Osteoarthritis (OA), the most common joint disease, is characterized by inflammation and cartilage degradation. Previous studies illustrated that Smad nuclear-interacting protein 1 (SNIP1) is an inhibitor of the TGF-β signal transduction pathway and SNIP1 has been reported as an anti-inflammatory factor. This study aimed to explore the role of SNIP1 in OA progression. In this study, the SNIP1 expression was evaluated in OA human and OA mice tissue and interleukin-1 beta (IL-1β)-induced chondrocytes . The Safranin-O (SO) staining and osteoarthritis research society international (OARSI) scoring system was used to evaluate cartilage injury. The gain- and loss-of-function studies for SNIP1 were performed in chondrocytes. The SNIP1 overexpression adenovirus was injected into mice by intra-articular injection. The SNIP1 expression was decreased in OA patients, OA mice, and IL-1β-stimulated chondrocytes. The cartilage injury of medial meniscus-induced OA (DMM-OA) mice at 8 weeks showed more severe than that at 4 weeks. The expression of SNIP1 was lower at 8 weeks than that at 4 weeks. In IL-1β-stimulated chondrocytes, SNIP1 overexpression reduced the expression of TNF-α and IL-6, alleviated ECM degradation, reduced the phosphorylation levels of p65 and IκBα , and decreased the p65 level in nuclear. Moreover, overexpression of SNIP1 alleviated cartilage injury in DMM-OA mice. In brief, our study suggested that SNIP1 alleviated OA and repressed inflammation by inhibiting the activation of NF-κB. This study might provide a new insight into OA treatment.
研究领域:
风湿病学
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分子生物学
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炎症
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软骨生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 6.7
Yihang Wu,Zixiu Liu,Zhenxiu He,Jumei Yi,Xingfang Qiao,Chunbin Tan,Yajing Xing,Yaobo Zeng,Dajian Yang,Junlin Yin,Baomin Fan,Guangzhi Zeng
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα , and NF-κB p65 , and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.
研究领域:
药理学
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炎症
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药物发现
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胃肠病学
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PubMed
高影响因子
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