INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Haihua Zhang,Jing Wang,Wuying Lang,Hongli Liu,Zhiqiang Zhang,Tonglei Wu,Hongqiang Li,Liya Bai,Qiumei Shi
Methotrexate (MTX) treats various diseases but also damages intestinal barrier and leads to enteritis. Albiflorin (ALB) has a variety of pharmacological effects, including antioxidant, anti-inflammation and anti-apoptosis. In the present study, we evaluated the therapeutic effect of ALB on MTX-induced enteritis and investigated the possible mechanisms involved. Male SD rats were intraperitoneally injected with 7 mg/kg MTX for three consecutive days to establish the enteritis model. ALB (20 or 40 mg/kg/day) was intragastrically administrated since two days prior MTX treatment and lasted for six days. We found that ALB treatment increased body weight and intestinal weight of rats with MTX injection. The disease activity index (DAI) score was also decreased after ALB administration. In histological examination, ALB treatment attenuated inflammatory cells infiltration and promoted survival of goblet cells. In detection of inflammatory-associated factors, ALB treatment decreased CD68 + cells infiltration, inhibited myeloperoxidase activity, and suppressed intercellular cell adhesion molecule-1 and cyclooxygenase-2 expression. Additionally, ALB reduced malondialdehyde, glutathione levels, inhibited superoxide dismutase activity and suppressed reactive oxygen species production. Moreover, ALB treatment effectively inhibited NLRP3, as well as caspase 1 p20 and interleukin (IL)-1β and 18 expression. Finally, nuclear factor-κB (NF-κB) p65 phosphorylation and nuclear translocation were also demonstrated to be blocked upon ALB treatment. In conclusion, our findings indicated that ALB alleviated MTX-induced enteritis via inhibiting the NF-κB/NLRP3 pathway.
研究领域:
药理学
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免疫学
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胃肠病学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-17
·
IF 8.9
Xu Teng,Wang Yaning,Zhao Zechen,Wang Jinsong,Zhao Zhenyuan,Yang Yuemei,Song Xiaomeng,Lai Qingguo
Background Tumor dissemination is a life-threatening event which confers to most cancer-related deaths with limited effective therapeutic option. TNFα-induced protein 2 (TNFAIP2) reveals pro-metastasis potential in several cancers. However, its definite role and underlying mechanism in oral squamous cell carcinoma (OSCC) is largely unknown. Methods The impact of TNFAIP2 on tumor metastasis was assessed based on the conditional knockout mouse with 4-nitroquinoline-1-oxide (4NQO) induced OSCC model through feature and immunohistochemistry analysis. To explore the specific mechanism, enrichment analysis and co-immunoprecipitation were applied. Meanwhile, the nano-hydroxyapatite (nHAp) and poly-L-lysine (PLL) based RNA interference delivery system was designed to restrict tumor dissemination. Results The conditional knockout Tnfaip2 in epithelium reduced tumor initiation rate, differentiation degree and cervical lymph node metastasis (LNM) in mouse exposed to 4NQO. Enrichment analysis suggested nuclear factor-kappa B (NF-κB) signaling was associated with these effects. Western blot proved that TNFAIP2 prevented the ubiquitin proteasome degradation of inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKKβ), a classical transcriptional activator protein in NF-κB signaling. Mechanistically, TNFAIP2 was demonstrated to competitively interact with kelch-like ECH-associated protein 1 (KEAP1) to avoid IKKβ from ubiquitination at K63 and proteasomal degradation subsequently, which finally sustained NF-κB signaling and facilitated tumor metastasis by enhancing epithelial-mesenchymal transition (EMT) and lymphangiogenesis. Notably, the synthetic small interfering RNA delivery systems nHAp@PLL-siTnfaip2 showed significant effect in attenuating tumor progression of OSCC mouse. Conclusion Above results showed TNFAIP2 promoted EMT and lymphangiogenesis of OSCC by regulating NF-κB signaling, a mechanism that was dependent on the interaction with KEAP1 competitively. The nHAp based TNFAIP2 interference might serve as a novel therapeutic in limiting OSCC metastasis.
研究领域:
肿瘤学
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分子生物学
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口腔医学
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生物化学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Tiantian Wang,Ruihe Zheng,Song Sun
Acute lung injury (ALI) is a significant cause of morbidity and mortality worldwide. To search for a new treatment for acute lung injury, we investigated the effect of escitalopram on lipopolysaccharide (LPS)-induced ALI. Our results showed that escitalopram inhibited salt-inducible kinase 2 (SIK2) activity (IC 50 = 6.36 ± 0.93 μM) and triggered histone deacetylase 4 (HDAC4) dephosphorylation . Following its dephosphorylation, HDAC4 translocated into the nucleus, promoted deacetylation and cytoplasmic shuttling of p65, thus inhibited LPS-induced pro-inflammatory cytokine production. Moreover, escitalopram markedly ameliorated the inflammatory responses, reduced neutrophils infiltration and attenuated LPS-induced pulmonary injury in mice. Taken together, we identified a previously unexplored role for escitalopram in SIK2/HDAC4/NF-κB pathway, therefore escitalopram may be considered as a new treatment for ALI.
研究领域:
药理学
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免疫学
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肺病学
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药物再利用
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2023
·Vol. 29
·期 2
·1-11
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IF 3.4
Xiaoqian Guo,Guangwei Qiao,Jingjiao Wang,Changyi Yang,Min Zhao,Qian Zhang,Yingbiao Wan
Diabetic periodontitis (DP) refers to destruction of periodontal tissue and absorption of bone tissue in diabetic patients. Tumor necrosis factor receptor‑associated factor (TRAF)‑interacting protein with forkhead‑associated domain (TIFA) as a crucial regulator of inflammation activates the NF‑κB signaling pathway to regulate cell biological behavior. However, the function and mechanism of TIFA on DP suffer from a lack of research. In the present study, TIFA was upregulated in the periodontal tissue of a DP mouse model. In addition, the expression of TIFA in RAW264.7 cells was induced by high glucose (HG) culture and increased by lipopolysaccharide (LPS) from Porphyromonas gingivalis treatment in a time‑dependent manner. Knockdown of TIFA significantly reduced the levels of inflammatory cytokines, including TNF‑α, IL‑6, IL‑1β and monocyte chemoattractant protein‑1, in HG and LPS‑induced RAW264.7 cells. The nuclear translocation of NF‑κB p65 was induced by HG and LPS and was clearly suppressed by absence of TIFA. The expression of downstream factors Nod‑like receptor family pyrin domain‑containing 3 and apoptosis‑associated speck‑like protein was inhibited by silencing TIFA. Moreover, TIFA was increased by receptor activator of NF‑κB (RANK) ligand (RANKL) in a concentration dependent manner. The expression of cathepsin K, MMP9 and nuclear factor of activated T cells cytoplasmic 1 was downregulated by depletion of TIFA. RANKL‑induced osteoclast differentiation was inhibited by silencing of TIFA. Meanwhile, the decrease of TIFA blocked activation of the NF‑κB pathway in RANKL‑treated RAW264.7 cells. In conclusion, TIFA as a promoter regulates the inflammation and osteoclast differentiation via activating the NF‑κB signaling pathway.
研究领域:
牙科
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分子生物学
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免疫学
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PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2025
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IF 7.3
Zixu Li,Yacan Gong,Emmanuel Sunday Okeke,Dan Li,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
Typical plasticizer dibutyl phthalate (DBP) has been demonstrated to induce hepatotoxicity in zebrafish, but the underlying molecular mechanisms remain incompletely elucidated. Numerous studies have shown that ferroptosis is involved in the pathophysiological progression of hepatic disease. However, it remains unclear whether ferroptosis is involved in the DBP-induced hepatotoxicity in zebrafish. Initially, histopathological analyses have preliminarily confirmed that DBP can activate inflammatory responses in the zebrafish liver. Further investigation revealed that DBP induces ferroptosis in the zebrafish liver, characterized by iron overload, lipid peroxidation, and aberrant activation of ferroptosis pathways. Furthermore, DBP exposure induced ferroptosis, disrupting cell membranes and subsequent release of HMGB1, which are sensed by immunocytes TLR4/NF-κB signaling pathways, thereby activating the innate immune response in a context-dependent manner. Moreover, the ferroptosis inhibitor Fer-1 effectively rescues the activation of HMGB1-TLR4/NF-κB-mediated immune processes. Overall, this work enriches the molecular mechanism of DBP-induced zebrafish liver inflammatory damage and provides a reliable biomarker for future environmental risk assessment of DBP.
研究领域:
环境毒理学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2022
·Vol. 45
·期 12
·1733-1742
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IF 2.264
Yongbin Jing,Mingkun Jia,Jinpeng Zhuang,Dong Han,Changlong Zhou,Jinglong Yan
Osteosarcoma (OS) is the most common primary malignant bone tumor and is mainly diagnosed in children. Toll-like receptor 9 (TLR9) is expressed in various tumor cells and was correlated with cancer progression. However, the underlying mechanism of TLR9 on the OS progression remains unclear. Our previous study demonstrated that the expression of TLR9 was positively correlated with the development stage of OS. Herein, we further evaluated the actual roles and the molecular mechanism of TLR9 on regulating OS cell proliferation and metastasis. Our data showed that TLR9 was upregulated in OS cells compared to normal osteoblastic cells, and knockdown of TLR9 inhibited OS cell proliferation and induced cell cycle arrest by the decreased expression of cyclin D1, CDK2, and p-Rb, while TLR9 overexpression exerted the inverse effects. Furthermore, TLR9 overexpression could enhance the migration and invasion activities of the OS cells by the upregulation of matrix metalloproteinases 2 (MMP2) and MMP9, and the opposite result was observed in TLR9-silenced cells. Moreover, the nuclear factor kappa B (NF-κB) signaling pathway was activated by TLR9, and TLR9-induced malignant phenotype of OS cells was abrogated by the NF-κB antagonist BAY11-7082. Our study indicated that TLR9 might play a critical role in facilitating OS progression by activating the NF-κB signaling pathway, which may provide a valuable therapeutic target for OS.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 10
·8682
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IF 5.6
Zijiao Zhang,Juhan Song,Seung-Hee Kwon,Zhao Wang,Suk-Gyun Park,Xianyu Piao,Je-Hwang Ryu,Nacksung Kim,Ok-Su Kim,Sun-Hun Kim,Jeong-Tae Koh
There has been increasing interest in adjunctive use of anti-inflammatory drugs to control periodontitis. This study was performed to examine the effects of pirfenidone (PFD) on alveolar bone loss in ligature-induced periodontitis in mice and identify the relevant mechanisms. Experimental periodontitis was established by ligating the unilateral maxillary second molar for 7 days in mice (n = 8 per group), and PFD was administered daily via intraperitoneal injection. The micro-computed tomography and histology analyses were performed to determine changes in the alveolar bone following the PFD administration. For in vitro analysis, bone marrow macrophages (BMMs) were isolated from mice and cultured with PFD in the presence of RANKL or LPS. The effectiveness of PFD on osteoclastogenesis, inflammatory cytokine expression, and NF-κB activation was determined with RT-PCR, Western blot, and immunofluorescence analyses. PFD treatment significantly inhibited the ligature-induced alveolar bone loss, with decreases in TRAP-positive osteoclasts and expression of inflammatory cytokines in mice. In cultured BMM cells, PFD also inhibited RANKL-induced osteoclast differentiation and LPS-induced proinflammatory cytokine (IL-1β, IL-6, TNF-a) expression via suppressing the NF-κB signal pathway. These results suggest that PFD can suppress periodontitis progression by inhibiting osteoclastogenesis and inflammatory cytokine production via inhibiting the NF-κB signal pathway, and it may be a promising candidate for controlling periodontitis.Keywords:pirfenidone;periodontitis;osteoclast differentiation;alveolar bone loss;inflammation;NF-κB pathway
研究领域:
牙科学
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药理学
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免疫学
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PubMed
高影响因子
RESEARCH IN VETERINARY SCIENCE
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2023
·
IF 2.4
Jirao Shen,Feng Yang,Guibo Wang,Xiaoqing Mou,Jinyu Li,Xuezhi Ding,Xurong Wang,Hongsheng Li
Staphylococcus haemolyticus ( S. haemolyticus ) is one of the most common coagulase-negative staphylococci (CoNS) isolates from bovine mastitis . Paeoniflorin (PF) shows anti-inflammatory effects on different inflammatory diseases in vitro studies and in vivo animal experiments. In this study, the viability of bovine mammary epithelial cells (bMECs) was detected by the cell counting kit-8 experiment. Subsequently, bMECs were induced with S. haemolyticus , and the induction dosage was determined. The expression of pro-inflammatory cytokines and toll-like receptor (TLR2) and nuclear factor kappa-B (NF-κB) signaling pathway-related genes were investigated by quantitative real-time PCR. The critical pathway proteins were detected by western blot . The results showed that the multiplicity of infection (MOI; the ratio of bacteria to bMECs) 5:1 of S. haemolyticus for 12 h could cause cellular inflammation, which was selected to establish the inflammatory model. Incubation with 50 μg/ml PF for 12 h was the best intervention condition for cells stimulated by S. hemolyticus . Quantitative real-time PCR and western blot analysis showed that PF inhibited the activation of TLR2 and NF-κB pathway-related genes and the expression of related proteins. Western blot results showed that PF suppressed the expression of NF-κB unit p65, NF-κB unit p50, and MyD88 in bMECs stimulated by S. haemolyticus . The inflammatory response pathway and molecular mechanism caused by S. haemolyticus on bMECs are related to TLR2-mediated NF-κB signaling pathways. The anti-inflammatory mechanism of PF may also be through this pathway. Therefore, PF is expected to develop potential drugs against CoNS-induced bovine mastitis.
研究领域:
兽医学
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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
Food & Function
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2025
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IF 5.4
Xiaoran Kong,Li Zhao,He Huang,Qiaozhen Kang,Jike Lu,Jia-Qing Zhu
Hyperuricemia is chronic metabolic disease with a high incidence, and it has become the “fourth highest” health risk in modern times. Isorhamnetin is a natural flavonoid found in a variety of plants, especially fruits such as buckthorn. In vivo hyperuricemia ameliorating effect of isorhamnetin and the specific molecular mechanism were profoundly investigated through a hyperuricemia mice model in the present study. The results demonstrated that isorhamnetin showed a significant uric acid-lowering effect in mice. Isorhamnetin was able to reduce uric acid production by inhibiting XOD activity. On the other hand, it reduced the expression of GLUT9 to inhibit uric acid reabsorption and enhanced the expression of ABCG2, OAT1, and OAT3 to promote uric acid excretion. Metabolomics analysis revealed that isorhamnetin gavage restored the purine metabolism and riboflavin metabolism disorders, and thus significantly alleviated the hyperuricemia in mice. Further, the alleviating effect of isorhamnetin on hyperuricemia-induced renal inflammation and its specific mechanism were explored through network pharmacology and molecular validation experiments. Network pharmacology predicted that seven targets were enriched in the PI3K/AKT pathway (CDK6, SYK, KDR, RELA, PIK3CG, IGF1R, MCL1) and four targets were enriched in the NF-κB pathway (SYK, PARP1, PTGS2, RELA). Western blot validated that isorhamnetin inhibited the phosphorylation of PI3K and AKT and down-regulated the expression of NF-κB p65. It indicated that isorhamnetin could inhibit the PI3K/AKT/NF-κB signaling pathway to reduce the levels of renal inflammatory factors (TNF-α, IL-β and IL-6) and ultimately ameliorate the hyperuricemia-induced renal inflammation in mice. This study will provide comprehensive and penetrating theoretical basis for the application of isorhamnetin in the field of functional foods or dietary supplements to improve hyperuricemia.
研究领域:
药理学
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代谢生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yasi Deng,Yuxin Chen,Hao Zheng,Bin Li,Ling Liang,Wei Su,Bilal Ahmad,Yupei Yang,Hanwen Yuan,Wei Wang,Huanghe Yu
Ethnopharmacological relevance Synovial inflammatory hyperplasia is the key pathological process that leads to further joint damage in rheumatoid arthritis (RA) progress. Kadsura heteroclita (Roxb) Craib, also called Xuetong in Chinese Tujia ethnomedicine, is utilized for its medicinal properties, including promoting blood circulation, dispelling “wind evil”, and relieving “damp evil”. It has been used in the treatment of arthralgia and RA, within Tujia ethnomedicinal practices. Xuetongsu (XTS), the main component of Xuetong, has been shown to inhibit the proliferation of RA fibroblast-like synovial cells (RAFLS) cells. However, the molecular mechanism of XTS in RA treatment requires further investigation. Aim of the study To observe the therapeutic effect of XTS on synovial inflammatory hyperplasia in rheumatoid arthritis, focusing on its underlying molecular mechanisms involving the janus kinase 2 (JAK2)/transducer/activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways. Materials and methods Protein-protein interaction (PPI) and molecular docking were used to find the main targets of XTS treatment for RA. In lipopolysaccharide (LPS)-induced RAFLS and RAW264.7 cells in vitro models, the levels of inflammatory cytokines were analyzed using enzyme linked immunosorbent assay (ELISA), and the expression of JAK2, STAT3, and NF-κB signaling pathways, as well as cyclooxygenase-2 (COX-2), were analyzed through western blotting test. A hemolysis assay was used to certify the biosecurity of XTS. A model of adjuvant arthritis (AIA) was established in 40 male rats, and different doses of XTS were administered, followed by an automatic blood routine, ELISA assay, hematoxylin and eosin (H&E) staining, and radiological analysis of the effect of no XTS on blood cytokines, histological changes, and improvement of posterior paw bone destruction in AIA rats. The protein levels of inflammatory cytokines were analyzed by immunofluorescence, immunohistochemistry, or western blot. Finally, H&E staining was used to detect the damage of XTS on the heart, liver, spleen, lung, and kidney of AIA rats. Results Our results demonstrate that XTS effectively inhibited LPS-induced inflammatory responses in RAFLS and RAW264.7 cells by modulating the JAK2/STAT3 and NF-κB signaling pathways. Moreover, XTS administration in the AIA rats model significantly ameliorated paw swelling. Histological analysis revealed that XTS also suppressed the inflammatory response in paw tissue by modulating the JAK2/STAT3 and NF-κB signaling pathways. Importantly, during the treatment, XTS exhibited excellent safety profiles, as it did not induce any abnormalities in blood routine parameters or cause organ damage in the rats. Conclusions Our findings highlight XTS as a promising natural agent for inhibiting synovial hyperplasia in RA. XTS holds great potential as an unprecedented natural agent for developing novel therapeutic strategies to target synovial hyperplasia in RA.
研究领域:
药理学
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免疫学
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民族药理学
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分子生物学
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DOI
PubMed
高影响因子
Cells
·
2022
·Vol. 11
·期 22
·3588
·
IF 7.666
Tuo Li,Lei Li,Ruilong Peng,Hongying Hao,Hejun Zhang,Yalong Gao,Cong Wang,Fanjian Li,Xilei Liu,Fanglian Chen,Shu Zhang,Jianning Zhang
Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib’s effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.Keywords:TBI;abrocitinib;neuroinflammation;JAK1/STAT1/NF-κB
研究领域:
神经科学
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药理学
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炎症
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创伤
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 3
·1252
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IF 6.208
Jing Yang,Xujiao Tang,Xue Ke,Yutong Dai,Jinsong Shi
Triptolide (TP), the main active ingredient ofTripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.Keywords:acute pancreatitis;triptolide;inflammatory responses;oxidative stress
研究领域:
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
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