JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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2024
·Vol. 388
·期 3
·813-826
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IF 3.1
Peter Thornton,Valérie Reader,Zsofia Digby,Pamela Smolak,Nicola Lindsay,David Harrison,Nick Clarke,Alan P. Watt
Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism.
研究领域:
免疫学
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代谢疾病
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF RADIATION BIOLOGY
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2024
·
IF 2.1
Lingyu Zhang,Lina Cai,Yashi Cai,Weiyi Ke,Linqian Zhou,Yuhua Yang,Weixu Huang,Jianming Zou,Huifeng Chen
Purpose To investigate the role of moderate doses of ionizing radiation-induced cellular senescence in mouse lung tissue and whole-body inflammation levels.Material and methods Forty-two C57BL/6J mice were randomly divided into the control group, the 1, 3, and 7 days after 2 Gy irradiation group, and the 1, 3, and 7 days after 4 Gy irradiation group, with six mice in each group. The histopathology, cellular senescence, oxidative-antioxidant, DNA damage repair, and inflammation-related indicators of irradiated mice were examined.Results Compared with the control group, the histopathological scores, the positive area of senescence-associated-β-galactosidase (SA-β-Gal) staining, and the mRNA levels of senescence-related genes in the lung tissues in all dose groups increased on 1, 3, and 7 days after irradiation. In peripheral blood, erythrocytes, leukocytes, platelets, hemoglobin, 8-hydroxydeoxyguanosine (8-OHdG), C-reactive protein, and other indicators showed a different trend in all dose groups. The levels of malondialdehyde(MDA), superoxide dismutase (SOD), glutathione (GSH), and 8-OHdG in the lung tissue showed different trends after 2 Gy and 4 Gy irradiation. The 8-Oxoguanine DNA glycosylase 1 (hOGG1) and O-6-methylguanine-DNA methyltransferase (MGMT) mRNA levels showed a trend of increasing and then decreasing. The levels of whole-body inflammation were significantly correlated with the levels of indicators related to cellular senescence and damage repair in the lung tissue of mice.Conclusions The moderate doses of ionizing radiation induce oxidative stress, and DNA damage and increase DNA repair gene expression in mouse lung tissue. The lung tissue cellular senescence correlates with the level of whole-body inflammation.
研究领域:
放射生物学
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分子生物学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2024
·
IF 21.8
Wu Xiaoxia,Zhao Xiaoming,Li Fang,Wang Yang,Ou Yangjing,Zhang Haiwei,Li Xiaoming,Wu Xuanhui,Wang Lingxia,Li Ming,Zhang Yue,Liu Jianling,Xing Mingyan,Liu Han,Tan Yongchang,Wang Yangyang,Xie Yangyang,Zhang Hanwen,Luo Yan,Li Hong,Wang Jing,Sun Liming,Li Yu,Zhang Haibing
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT ), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
研究领域:
免疫学
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病理生理学
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细胞生物学
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炎症
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血管生物学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL CHEMISTRY JOURNAL
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2024
·Vol. 57
·期 12
·1872-1882
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IF 0.8
Guo Haihua,Li Meng,Lin Yue,Zhai Zizhao,Wang Guanlin,Zhao Suqing
The diterpenoid isosteviol is one of the stevia derivatives that have reported various activities . In mice inhaling isosteviol, OVA- and ACh-induced bronchial asthma showed a dose-dependent improvement of a decline in the expression of inflammatory cytokines and the infiltration of basophils. Compared with inhalation of budesonide 0.6 mg/kg, sensitized mice inhaling 1.0 mg/kg dosage of isosteviol performed a higher tolerate against the ACh stimulation. In behavior tests, the 1.0 mg/kg isosteviol nebulization reached almost 80% of the level of budesonide with regard to the ameliorative effects on depression-like behavior and improvement in sport ability. In addition, lung and systemic inflammation were markedly prevented by isosteviol with a dosage of more than 0.6 mg/kg, which exhibited limited expression of IL-1β and TNF-α, less infiltration of basophils in lung tissues, and a low level of systemic immunocytes, which showed in hematoxylin and eosin staining, RT-PCR, and ELISA results. On the other hand, none of the abnormal pathology was found in both peripheral and central organs of all the administration groups. Generally, this study implicated that the mechanism could involve effects of isosteviol inhalation on the suppression of IL-1β and TNF-α to restrict a systemic upsurge of immunocytes and infiltration into the lung that prevents the occurrence of depression-like behavior and hypokinesia.
研究领域:
药理学
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免疫学
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呼吸医学
✓ 已验证
产品关联
DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-15
·
IF 14.7
Yu Tingting,Bai Rushui,Wang Zeming,Qin Yuting,Wang Jingwei,Wei Yaohua,Zhao Ruifang,Nie Guangjun,Han Bing
The potential for mitigating intestinal inflammation through the gut-bone axis in the treatment of osteoporosis is significant. While various gut-derived postbiotics or bacterial metabolites have been created as dietary supplements to prevent or reverse bone loss, their efficacy and safety still need improvement. Herein, a colon-targeted drug delivery system is developed using surface engineering of polyvinyl butyrate nanoparticles by shellac resin to achieve sustained release of postbiotics butyric acid at the colorectal site. These engineered postbiotics nanoparticles can effectively suppress macrophage inflammatory activation, modulate the redox balance, and regulate the composition of the gut microbiota, thereby restoring epithelial barriers, inhibiting bacterial invasion, and down-regulating pro-inflammatory responses. As a result, the remission of systemic inflammation is accompanied by a rebalancing of osteoblast and osteoclast activity, alleviating inflammatory bowel disease-related and post-menopausal bone loss. Specifically, the treatment of engineered postbiotics nanoparticles can also improve the quality and quantity of bone with restoration of deteriorative mechanical properties, which indicating a therapeutic potential on fracture prevention. This study provides valuable insights into the gut-bone axis and establishes a promising and safe therapeutic strategy for osteoporosis.
研究领域:
药理学
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生物材料
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微生物学
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免疫学
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骨骼生物学
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药物递送系统
✓ 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）