Cell Death & Disease
·
2018
·Vol. 9
·期 7
·1-16
·
IF 5.638
Wang Zhe,Zhao Simeng,Song Lihua,Pu Yuzhi,Wang Qiang,Zeng Guangzhi,Liu Xing,Bai Ming,Li Shao,Gao Fabao,Chen Lijuan,Wang Chen,Tan Ninghua
Rubiaceae-type cyclopeptides (RAs) are a type of plant cyclopeptides from the Rubia that have garnered significant attention owing to their unique bicyclic structures and amazing antitumour activities. Our recent work has shown that RAs suppress inflammation and angiogenesis and induce apoptosis. However, the underlying mechanism and targets remained unknown. Nuclear factor κB (NF-κB) signaling pathway plays a critical role in these biological processes, prompting us to investigate whether and how RAs affect this pathway. By screening compound libraries using NF-κB-dependent luciferase reporter, we observed that RA-V is the best NF-κB inhibitor. Further experiments demonstrated that RA-V interrupted the TAK1–TAB2 interaction and targeted TAK1 in this pathway. Moreover, RA-V prevented endotoxin shock and inhibited NF-κB activation and tumor growth in vivo. These findings clarify the mechanism of RA-V on NF-κB pathway and might account for the majority of known bioactivities of RA-V, which will help RA-V develop as new antiinflammatory and antitumour therapies.
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Aging-US
·
2020
·
IF 4.831
Ke Lin,Wu Luo,Jueqian Yan,Siyuan Shen,Qirui Shen,Jun Wang,Xinfu Guan,Gaojun Wu,Weijian Huang,Guang Liang
Excessive vascular remodeling has been shown in hypertensive patients. In experimental models of hypertensive vascular injury, such as angiotensin II (Ang II) challenged mice, toll like receptor 2 (TLR2) initiates inflammatory responses. More recently, studies have reported atypical endothelial to mesenchymal transition (EndMT) in vascular injuries and inflammatory conditions. Here, we aimed to investigate whether TLR2 mediates Ang II-induced vascular inflammation and initiates EndMT. In a mouse model of angiotensin II-induced hypertension, we show that aortas exhibit increased medial thickening, fibrosis, and features of EndMT. These alterations were not observed in TLR2 knockout mice in response to Ang II. TLR2 silencing in cultured endothelial cells confirmed the essential role of TLR2 in Ang II-induced inflammatory factor induction, and EndMT-associated phenotypic change. Mechanistically, we found Ang II activates nuclear factor-κB signaling, inducing pro-inflammatory cytokine production, and mediates EndMT in both cultured endothelial cells and in mice. These studies illustrate a novel role of TLR2 in regulating Ang II-induced deleterious vascular remodeling through the induction of EndMT. The studies also suggest that TLR2 may be targeted to alleviate hypertension-associated vascular injury.
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BIOCHEMICAL PHARMACOLOGY
·
2016
·
IF 5.091
Shan Liu,Lingxin Zhu,Jie Zhang,Jingjing Yu,Xue Cheng,Bin Peng
Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-κB (NF-κB) during anti-osteoclastogenic effects by ISL in vitro and in vivo . We observed that ISL inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-κB expression and nuclear translocation, whereas the NF-κB inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K , autophagic LC3, and NF-κB expression to protect against inflammatory calvarial bone erosion in vivo . Our findings highlight the inhibition of NF-κB-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity.
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IMMUNOLOGY LETTERS
·
2025
·
IF 2.8
Rui Kong,Jun Bai,Qing Yao,Xiaoqing Xu
Allergic asthma is characterized by persistent chronic airway inflammation, leading to mucus hypersecretion and airway hyperresponsiveness. Dual-specificity phosphatase 14 (DUSP14), a member of the DUSP family, is a key regulator in various biological processes. However, the function of DUSP14 in allergic asthma remains to be elucidated. In this study, we aim to explore the function and mechanism of DUSP14 in asthma-related airway inflammation. In an ovalbumin (OVA) asthma mouse model, DUSP14 was found to be significantly diminished. DUSP14 overexpression relieved airway inflammation and attenuated airway mucus production. In vitro , overexpression of DUSP14 attenuated IL-13-induced cellular inflammation and mucus hypersecretion in bronchial epithelial cells (BEAS-2B). Afterwards, we used the co-immunoprecipitation assay to confirm that DUSP14 interacted with TAK1. DUSP14 overexpression restrained the activation of TAK1 and NF-κB signaling pathway in vitro and in vivo . Taken together, our findings clearly showed that DUSP14 could alleviate airway inflammation by inhibiting TAK1 activity and NF-κB signaling pathway, positioning the DUSP14-TAK1-NF-κB regulatory axis as a potential therapeutic target for allergic asthma.
研究领域:
免疫学
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呼吸病学
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分子生物学
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MEDIATORS OF INFLAMMATION
·
2016
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IF 3.418
Shuai Wang,Zewei Sun,Wenting Zhao,Zhen Wang,Mingjie Wu,Yanyun Pan,Hui Yan,Jianhua Zhu
CD97/ADGRE5 protein is predominantly expressed on leukocytes and belongs to the EGF-TM7 receptors family. It mediates granulocytes accumulation in the inflammatory tissues and is involved in firm adhesion of PMNC on activated endothelial cells. There have not been any studies exploring the role of CD97 in LPS induced NF-κB activation in macrophages. Therefore, we first measured the CD97 expression in LPS treated human primary macrophages and subsequently analyzed the levels of inflammatory factor TNF-α and transcription factor NF-κB in these macrophages that have been manipulated with either CD97 knockdown or overexpression. We found that a reported anti-inflammatory transcription factor, PPAR-γ, was involved in the CD97 mediated NF-κB suppression. Furthermore, by immunofluorescence staining, we established that CD97 overexpression not only inhibited LPS induced p65 expression in the nucleus but also promoted the PPAR-γ expression. Moreover, using CD97 knockout THP-1 cells, we further demonstrated that CD97 promoted PPAR-γ expression and decreased LPS induced NF-κB activation. In conclusion, CD97 plays a negative role in LPS induced NF-κB activation and TNF-α secretion, partly through PPAR-γ upregulation.
研究领域:
免疫学
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细胞生物学
·
炎症研究
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INFLAMMATION
·
2020
·Vol. 44
·期 2
·645-658
·
IF 3.212
Shao Yun-yun,Guo Yao,Feng Xiao-juan,Liu Jun-jin,Chang Zhuang-peng,Deng Gui-feng,Xu Ding,Gao Jian-ping,Hou Rui-gang
To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1β, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.
研究领域:
药理学
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胃肠病学
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分子生物学
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细胞生物学
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Materials Today Bio
·
2026
·
IF 11
Hongyun Xuan,Zihao Liu,Keyu Lu,Yao Chen,Haonan Gu,Biyun Li,Jingjun Sun,Yan Jin,Yumin Yang,Huihua Yuan
Diabetic wound repair remains a formidable clinical challenge due to impaired healing and heightened infection risks associated with conventional sutures. To address these limitations, this study introduces a novel injectable, self-healing, and antibacterial polysaccharide hydrogel (PGHAA), synthesized from borated peach gum and oxime-modified hyaluronic acid. By leveraging dynamic boronic ester bonds and metal coordination, PGHAA demonstrates enhanced tissue adhesion, self-healing capabilities, and antibacterial activity with immunomodulatory capacity to reprogram chronic wounds into a regenerative state. The incorporation of arginine as a cross-linking agent further improves both biocompatibility and functional performance. In vitro and in vivo evaluations indicate that PGHAA facilitates rapid hemostasis, robust tissue adhesion, and macrophage polarization toward a pro-regenerative phenotype, resulting in accelerated diabetic wound healing. Using an in vivo study with chronic diabetic skin we demonstrated that PGHAA induced wound healing via modulation of IL-17/NF-κB signaling—a pathway repurposed from its classical inflammatory role to drive tissue regeneration. This work redefines diabetic wound therapy by introducing a first-in-class hydrogel that leverages immune modulation for tissue repair, offering a transformative solution for regenerative medicine.
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PHYTOMEDICINE
·
2026
·
IF 8.3
Xueling He,Chen Wang,Ruihao Zhang,Yuanyuan Wang,Ying Zhang,Tong Yang,Junzhe Zhang,Shuan Rao,Huan Tang,Xin Peng,Jigang Wang
Background Sepsis, a life-threatening condition, arises from an aberrant or uncontrolled immune response of the host to severe infection. Timely and precise control of this inflammatory response is of paramount importance in sepsis prevention and constitutes the core of sepsis prevention efforts. Parthenolide (PA), recognized as an NF-κB inhibitor, has previously demonstrated its capacity to mitigate the inflammatory response. This study aimed to investigate whether and how PA can inhibit inflammation, thereby alleviating sepsis, and to profile functional target proteins using chemoproteomics strategy. Methods The cecal ligation and puncture (CLP) procedure was performed to induce a mouse model of sepsis, and lipopolysaccharide (LPS) was employed to establish a model of cellular inflammation in mouse mononuclear macrophage cells (RAW264.7) in vitro . Enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin (H&E) staining were utilized to evaluate the therapeutic effects of PA on septic mice. In the in vitro experiments, streamlined cysteine activity-based protein profiling (SLC-ABPP) and proteomics techniques were employed to identify potential protein targets and molecular pathways responsible for the anti-inflammatory properties of PA. Results We demonstrated that PA could enhance the survival rate, reduce inflammatory cytokines release, ameliorate histopathological changes, and balance macrophage polarization in a sepsis model. Similarly, PA could effectively alleviate the inflammatory response in LPS-stimulated RAW264.7 cells. Chemoproteomics profiling revealed that Trim33 protein was a potential covalent target of PA via cysteine engagement, and the expression changes of global proteins indicated by proteomics analysis suggested that PA mitigated inflammation by inhibiting the NF-κB pathway. Finally, through a series of molecular biology experiments, we confirmed that PA suppresses the NF-κB pathway by functionally binding to Trim33 and subsequently reducing the ubiquitin dependent degradation of Smad4, thereby exhibiting anti-inflammatory activity. Conclusion Our findings demonstrated that PA significantly mitigated inflammation in sepsis by targeting the Trim33 protein and consequently suppressing ubiquitination on Smad4 as well inhibiting the NF-κB pathway, thus providing new insights into the clinical use of PA in treatment of inflammation related diseases.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2026
·
IF 5.2
Ming Yue,Keying Zhu,Kunyu Zhan,Jinjie Zhang,Yuanbin Zhang,Kun Tian,Wenbiao Zheng,Xiaogang Chen,Hongfeng Ruan
Chlorpyrifos (CPF), a widely used pesticide, poses significant risks to human and animal health through environmental and food exposure. While its detrimental effects on the nervous, cardiovascular, and endocrine systems are well-documented, its impact on knee joint health remains poorly understood. In this study, 4-week-old male C57BL/6 mice were exposed to CPF via intragastric administration at doses of 3 and 6 mg/kg for durations of 4 and 8 weeks. Osteoarthritis (OA) severity and associated molecular alterations in knee joints were evaluated by hematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, immunohistochemistry, and immunofluorescence. Our results showed that CPF exposure led to knee joint injury, characterized by articular cartilage degeneration and subchondral bone loss. Notably, CPF induced both apoptosis and pyroptosis of chondrocytes via activation of the NF-κB signaling pathway, with pyroptosis appearing to be the predominant mechanism at lower doses and shorter exposure durations. Collectively, our findings provide novel insights into CPF's role in exacerbating articular cartilage degeneration by activating chondrocyte pyroptosis, underscoring its contribution to knee joint damage and OA-like progression.
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American Journal of Translational Research
·
2024
·Vol. 16
·期 10
·5385
·
IF 1.7
Hui Huang,Guanhua Wang,Dali Zeng
Objective: To investigate the protective effect of Peimine (PM) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the underlying mechanisms. Methods: KM mice were randomly divided into five groups: Control, LPS, Peimine low-dose (PM-L, 0.1 mg/kg), medium-dose (PM-M, 1 mg/kg), and high-dose (PM-H, 10 mg/kg) groups. Mice in the PM treatment groups received intraperitoneal injection of Peimine at different doses, while the mice in control and LPS groups received physiological saline. Afterwards, mice in the LPS and PM groups were subjected to intranasal instillation of LPS to establish the model of acute lung injury. The wet-to-dry (W/D) weight ratio of lung tissues was calculated, and H&E staining was performed to observe pathological changes in the lung tissues. Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and MDA were measured using ELISA kits. Western blot was employed to assess the expression of NF-κB, IκBα, phospho-IκBα, Nrf2, HO-1, and SOD2 in lung tissues. RT-PCR quantified the mRNA levels of Nrf2 and its downstream genes HO-1 and NQO1. Additionally, RAW264.7 cells were treated with various drug concentrations for 24 hours followed by LPS exposure (100 ng/mL) for another 24 hours. Prior to treatment of RAW264.7 cells with PM and LPS, the ML385+PM group was pre-treated with ML385 (3 μM) for 4 hours. ELISA kits were used to measure TNF-α, IL-6, IL-1β, and MDA in cell supernatants, while ROS levels were determined using a ROS assay kit. Results: Compared with the model group, pretreatment with PM significantly reduced the lung tissue W/D weight ratio, ameliorated lung tissue pathological changes, and inhibited the secretion of TNF-α, IL-6, and IL-1β in bronchoalveolar lavage fluid. PM inhibited the LPS-induced elevation in lung tissue MDA levels, SOD2 consumption, and ROS levels. Furthermore, PM suppressed LPS-induced NF-κB activation and nuclear translocation, while significantly enhancing the protein expression of Nrf2 and HO-1 and increasing the mRNA levels of Nrf2 and its downstream genes, such as HO-1 and NQO1. In RAW264.7 cells, LPS induction led to elevated IL-1β, IL-6, TNF-α, MDA, and ROS levels, which were significantly suppressed by PM treatment. However, the antioxidative and anti-inflammatory effects of PM were effectively blocked by inhibiting the Nrf2 pathway. Conclusion: PM effectively ameliorates LPS-induced lung injury, primarily through inhibition of the NF-κB pathway, and activation of the Nrf2 pathway, alongside a reduction in the release of inflammatory factors.
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Bioactive Materials
·
2021
·
IF 14.593
Yujuan Tian,Ying Li,Jialin Liu,Yi Lin,Jian Jiao,Bo Chen,Wanmeng Wang,Shuilin Wu,Changyi Li
Periodontitis is an inflammatory disease initiated by bacterial infection, developed by excessive immune response, and aggravated by high level of reactive oxygen species (ROS). Hence, herein, a versatile metal-organic framework (MOF)-based nanoplatform is prepared using mesoporous Prussian blue (MPB) nanoparticles to load BA, denoted as MPB-BA. The established MPB-BA nanoplatform serves as a shelter and reservoir for vulnerable immunomodulatory drug BA, which possesses antioxidant, anti-inflammatory and anti-bacterial effects. Thus, MPB-BA can exert its antioxidant, anti-inflammatory functions through scavenging intracellular ROS to switch macrophages from M1 to M2 phenotype so as to relieve inflammation. The underlying molecular mechanism lies in the upregulation of phosphorylated nuclear factor erythroid 2-related factor 2 (Nrf2) to scavenge ROS and subsequently inhibit the nuclear factor kappa-B (NF-κB) signal pathway. Moreover, MPB-BA also exhibited efficient photothermal antibacterial activity against periodontal pathogens under near-infrared (NIR) light irradiation. In vivo RNA sequencing results revealed the high involvement of both antioxidant and anti-inflammatory pathways after MPB-BA application. Meanwhile, micro-CT and immunohistochemical staining of p -Nrf2 and p-P65 further confirmed the superior therapeutic effects of MPB-BA than minocycline hydrochloride. This work may provide an insight into the treatment of periodontitis by regulating Nrf2/NF-κB signaling pathway through photothermal bioplatform-assisted immunotherapy.
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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分子生物学
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JCI Insight
·
2022
·
IF 9.484
Jing Yang,Hongxia Li,Chi Zhang,Yafeng Zhou
There is a high prevalence of ventricular arrhythmias related to sudden cardiac death in patients with chronic kidney disease (CKD). To explored the possible mechanism of CKD-related ventricular arrhythmias, a CKD rat model was created, and indoxyl sulfate (IS) was further used in vivo and in vitro. This project used the following methods: patch clamp, electrocardiogram, and some molecular biology experimental techniques. IS was found to be significantly elevated in the serum of CKD rats. Interestingly, the expression levels of the fast transient outward potassium current–related (I to,f -related) proteins (Kv4.2, Kv4.3, and KChIP2) in the heart of CKD rats and rats treated with IS decreased. IS dose-dependently reduced I to,f density, accompanied by the decreases in Kv4.2, Kv4.3, and KChIP2 proteins in vitro. IS also prolonged the action potential duration and QT interval, and paroxysmal ventricular tachycardia could be induced by IS. In-depth studies have shown that ROS/p38MAPK, ROS–p44/42 MAPK, and NF-κB signaling pathways play key roles in the reduction of I to,f density and I to,f -related proteins caused by IS. These data suggest that IS reduces I to,f -related proteins and I to,f density by activating ROS/MAPK and NF-κB signaling pathways, and the action potential duration and QT interval are subsequently prolonged, which contributes to increasing the susceptibility to arrhythmia in CKD.
研究领域:
心脏病学
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肾病学
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分子生物学
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电生理学
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