CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Weili Yang,Hui Liu,Xiaowei Liu,Yuxin Cao,Xuemei Wang,Xinxin Wang,Wenwen Cao,Chunjing Guo,Daquan Chen
Acute lung injury (ALI) is a complex acute respiratory illness with a high mortality rate. Reactive oxygen species (ROS) play a pivotal role in ALI, inducing cellular damage, inflammation, and oxidative stress, thereby exacerbating the severity of the injury. In this study, inspired by the “subtractive” strategy, we developed a fucoidan-based macrophage membrane bio-nanosystem, abbreviated as MF@CB, designed as an anti-inflammatory and antioxidant agent to alleviate lipopolysaccharide (LPS)-induced inflammation in ALI. MF@CB coated with macrophage membrane for effective targeting and accumulation in ALI lesions. In addition, MF@CB activates Nrf2 transcriptional activity in macrophages, inhibiting ROS synthesis at its origin while effectively removing ROS already present in the ALI. This dual-pronged approach demonstrates robust antioxidant properties and restores the macrophage antioxidant defense barrier. In the LPS-induced ALI mouse model, MF@CB significantly mitigated lung inflammatory damage by modulating lung macrophage polarization and inhibiting the over-secretion of pro-inflammatory cytokines by activated immune cells. More importantly, unlike most surface modification strategies because it remove the molecule, this approach is easier to apply and potentially safer and may provide useful insights into the development of more effective therapeutic strategies for ALI.
研究领域:
纳米技术
·
药理学
·
免疫学
·
呼吸医学
✓ 已验证
DOI
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Hu Cheng-hong,Chen Yue,Jin Tian-yang,Wang Zhe,Jin Bo,Liao Jing,Ding Chun-yong,Zhang Ao,Tang Wei-yang,Zhang Ling-xi,Xu Lei-yu,Ning Fang-min,Liang Guang,Wei Xiao-hong,Wang Yi
Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma , possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg −1 ·d −1 ) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg −1 ·d −1 , i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
炎症性肠病
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
PLoS One
·
2024
·Vol. 19
·期 8
·e0308132
·
IF 2.9
Qingting Yu,Linyuan Zhang,Ting Xu,Jiapeng Shao,Falei Yuan,Zuisu Yang,Yuncheng Wu,Haiyan Lyu
To investigate the sex-dependent differentiation of Sox10 cells and their response to pathological conditions such as lipopolysaccharide (LPS) exposure or ischemia, we utilized Sox10 Cre-ER T2 , tdTomato mice. Tamoxifen administration induced the expression of red fluorescent protein (RFP) in these cells, facilitating their subsequent tracking and analysis after LPS injection and ischemia via immunofluorescence staining. Propidium iodide (PI) was injected to label necrotic cells following LPS administration. We found that the conversion of Sox10 cells to pericytes in female mice was significantly higher than in male mice, especially in those exposed to LPS. After LPS injection, the number of PI + necrotic cells were significantly greater in females than in males. Moreover, RFP + cells did not co-localize with glial fibrillary acidic protein (GFAP) or cluster of differentiation 11b (CD11b). Similarly, after brain ischemia, RFP + cells did not express cluster of differentiation 13 (CD13), neuronal nuclei (NeuN), GFAP, or ionised calcium binding adaptor molecule 1 (Iba-1). These findings indicate that the conversion of Sox10 cells to pericytes following LPS exposure is sex-dependent, with neither male nor female groups showing differentiation into other cell types after LPS exposure or under ischemic conditions. The differences in LPS-induced necrosis of pericytes between sexes may explain the variations in the conversion of Sox10 cells to pericytes in both sexes.
研究领域:
神经科学
·
免疫学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Huiling Tang,Qiuping Li,Zhengqi Zha,Yuzhi Jiao,Baowei Yang,Zhaoyan Cheng,Ting Wang,Hongping Yin
Ulcerative colitis (UC) is a chronic inflammatory disease resulting from abnormal immune response to gut microflora translocating through damaged intestinal barrier. Xylan acetate ester (XylA) can increase colon short-chain fatty acids (SCFAs) levels and alleviate kidney disease by inhibiting inflammation through the G protein-coupled receptor pathway. Here, we synthesized and purified XylA, and then the effects and mechanisms of XylA on dextran sodium sulfate-induced UC in mice were investigated. The results showed that in mice, similar to the positive drug 5-aminosalicylic acid, oral administration of XylA significantly alleviated all UC symptoms, including weight loss, diarrhea, and hematochezia. Further mechanism studies revealed that XylA could repair the damaged colon structure and intestinal barrier function by increasing the expression of tight junction protein zonula occludens 1 and occludin, thus reducing LPS penetration. Moreover, XylA could also restrain intestinal inflammation via inhibiting LPS-TLR4 pathway, downregulating M1 macrophage polarization, and reducing proinflammatory cytokines expression, and in vitro cell experiments showed that these effects may be mediated by XylA derived SCFAs, particularly acetates, propionates and butyrates. All these results suggested that XylA may be a potential improving agent for UC treatment, and natural polysaccharides may represent a novel avenue for drug development of UC.
研究领域:
药理学
·
免疫学
·
胃肠病学
·
炎症性肠病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Jiahui Wang,Wei Liu,Jia Lu,Mengyue Zhu,Yanni Wu,Wenhui Pan,Boyi Fan,Yan Song,Wenli Wang,Guangtong Chen
The prevalence of neurodegenerative diseases has increased in recent decades. Its exact pathogenesis is not yet fully understood, and only a few drugs can be used clinically to alleviate disease symptoms. Increasing evidence highlights plant-derived compounds are becoming a promising resource for mitigating the onset and progression of neurodegenerative diseases. Uvaol (1) is an ursane-type triterpenoid commonly found in olive leaves, fruits, and virgin olive oil. It is one of the rare compounds in olive oil that can penetrate the blood–brain barrier. Despite its potential neuroprotective activity, research on its structural variations and antineuroinflammatory properties remains sparse. This study explored the biotransformation of uvaol using three fungal species: Actinomucor elegans, Aspergillus flavus, and Circinella muscae. This process yielded 15 new compounds along with seven known ones. Their structures were determined through comprehensive spectroscopic analysis. Furthermore, the antineuroinflammatory activities of compounds were evaluated by using MTT and Griess assays. Notably, compound 9 was found to markedly suppress the transcriptional levels of inflammation-associated elements such as TNF-α, IL-1β, IL-6, iNOS, and COX-2 in BV-2 cells stimulated by lipopolysaccharides (LPS). Moreover, compound 9 also facilitated autophagy by upregulating ULK1 mRNA expression and downregulating the p62 protein. These results suggested that biotransformation was an effective approach for rapidly diversifying uvaol and providing a basal material for the discovery of candidates in treating neurodegenerative diseases.
研究领域:
药理学
·
神经科学
·
药物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Chongchong Liu,Jiangyan Sun,Xiaoming Shen,Shefang Li,Sha Luo,Na Chen,Yunke Zhang
Epilepsy is a chronic neurological disorder. Drug-resistant epilepsy (DRE) accounts for about one-third of epilepsy patients worldwide. Peimine, a main active component of Fritillaria, has been reported to show anti-inflammatory effects. However, its potential therapeutic role in DRE is not yet fully understood. In this work, a DRE rat model was established by injecting 1 μg kainic acid (KA), followed by a 250 mg/kg administration of valproic acid (VPA) from day 4–31. Rats were treated with different doses of peimine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) daily from day 32–62. In vitro, BV-2 microglia were exposed to different doses of peimine (7.5 μg/ml, 15 μg/ml, and 30 μg/ml) in presence of LPS. The aim of this study was to investigate the potential therapeutic effects of peimine on DRE. The results showed that peimine efficiently suppressed the KA-induced epileptic behaviors of rats in a dose-dependent manner, as recorded by electroencephalography. Furthermore, peimine ameliorated hippocampal neuron injury in DRE rats, and promoted an M1-to-M2 microglial phenotype shift in a dose-dependent manner. Mechanistically, peimine inhibited the TLR4/NF-κB/HIF-1α signaling pathway both in vivo and in vitro. Additionally, peimine suppressed the apoptosis of primary neurons induced by LPS-treated microglia. In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-κB/HIF-1α signaling pathway, thereby attenuating DRE.
研究领域:
神经病学
·
药理学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
eLife
·
2024
·
IF 6.4
Zeina Salloum,Kristin Dauner,Yun-feng Li,Neha Verma,David Valdivieso-González,Víctor Almendro-Vedia,John D Zhang,Kiran Nakka,Mei Xi Chen,Jeffrey McDonald,Chase D Corley,Alexander Sorisky,Bao-Liang Song,Iván López-Montero,Jie Luo,Jeffrey F Dilworth,Xiaohui Zha
Statins are known to be anti-inflammatory, but the mechanism remains poorly understood. Here, we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the adenosine triphosphate (ATP) synthase in the inner mitochondrial membrane and changes the proton gradient in the mitochondria. This activates nuclear factor kappa-B (NF-κB) and Jmjd3 expression, which removes the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus lipopolysaccharide (M1), macrophages, either treated with statins in vitro or isolated from statin-fed mice, express lower levels proinflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL-4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.
研究领域:
免疫学
·
药理学
·
细胞生物学
·
表观遗传学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Qiong Liu,Aizhen Zhao,Xiaopeng Wu,Xin Zhang,Xiaoru Li,Wenwen Yang,Wangrui Lei,Hui Liu,Huadong Zhao,Shuai Jiang,Yang Yang,Mingzhi Shen
Background Septic heart failure has been recognized as a puzzle since antiquity and poses a major challenge to modern medicine. Our previous work has demonstrated the potential effects of lycorine (LYC) on sepsis and septic myocardial injury. Nonetheless, further exploration is needed to elucidate the underlying cellular and molecular mechanisms. Methods In this study, we conducted transcriptome analysis and weighted gene co-expression network analysis (WGCNA) to identify the key genes and reveal the mechanism of LYC against septic heart failure. Purpose This study aims to apply bioinformatic analysis and experimental validations to explore the protective effects and underlying mechanism of LYC on the cecal ligation and puncture (CLP)-induced sepsis model mice. Results Transcriptome analysis revealed the differentially expressed genes (DEGs) following LYC treatment. WGCNA analysis identified gene modules associated with LYC-mediated protection, with BCL3 emerging as a core gene within these modules. Notably, BCL3 was an overlapping gene of DEGs and WGCNA core genes induced by LYC treatment, and is highly negatively correlated with cardiac function indicator. In vivo and in vitro study further prove that LYC exerted a protective effect against septic myocardial injury through inhibiting BCL3. BCL3 siRNA ameliorated LPS-induced cardiac injury and inflammation, while BCL3 overexpression reversed the protective effect of LYC against LPS injury. Conclusion In summary, our findings demonstrate the significant attenuation of septic myocardial disorder by LYC, with the identification of BCL3 as a pivotal target gene. This study is the first to report the role of BCL3 in sepsis and septic myocardial injury. Furthermore, the strategy for hub genes screening used in our study facilitates a comprehensive exploration of septic targets and reveals the potential targets for LYC effect. These findings may offer a new therapeutic strategy for the management of septic heart failure, highlighting the cardioprotective effect of LYC as adjunctive therapy for sepsis management.
研究领域:
心脏病学
·
药理学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNOBIOLOGY
·
2024
·
IF 2.5
Min Li,Wenjia Tong,Chao Dai,Guoping Lu,Danqun Jin,Fang Deng
Sepsis-associated acute kidney injury (S-AKI) is a prevalent and life-threatening complication in hospitalized and critically ill patients. Recent researches indicates that immunoproteasome, especially proteasome 20S subunit beta 8 (PSMB8), is highly associated with various kidney diseases. This study aims to investigate the potential involvement of PSMB8 in S-AKI and its impact on apoptosis and inflammation. The model of S-AKI induced by LPS (10 mg/kg) was assessed by histological examination. ELISA and Real-time PCR were used to detect the levels of inflammatory cytokines in the renal cortex. The role of shPSMB8 in LPS-induced apoptosis was detected by flow cytometry. Finally, western blot was performed to assess the NF-κB signaling pathway related proteins, and the nuclear translocation of NF-kB P65 was detected by immunofluorescence microscopy. PSMB8 knockdown substantially protected against renal injury by reducing blood urea nitrogen and creatinine levels and ameliorating inflammation. PSMB8 knockdown inhibited renal expression of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and COX-2 to improve inflammatory response. Mechanistic studies demonstrated that downregulation of PSMB8 blocked LPS-induced S-AKI phosphorylation and nuclear translocation of NF-κB P65. Collectively, our results suggest that inhibition of PSMB8 significantly contributes to S-AKI via regulation of NF-κB. These findings reveal the pathogenic role of PSMB8 in AKI and suggest a novel therapeutic target for the condition.
研究领域:
免疫学
·
肾病学
·
炎症研究
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Mengting Li,Lingyu Ma,Jiahao Lv,Zhe Zheng,Wenyu Lu,Xunkai Yin,Weijiang Lin,Ping Wang,Jian Cui,Lihong Hu,Jian Liu
Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin ( Ori ), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950 . However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC 50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori , D6 demonstrated the enhancement of IL-1β inhibitory activity (IC 50 = 41.79 nM), which was better than the parent compound Ori . Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo . Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.
研究领域:
药理学
·
炎症
·
呼吸系统疾病
·
药物设计
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Di Liu,Si Sun,Huanhuan Qiao,Qi Xin,Sufei Zhou,Lingxia Li,Nan Song,Lijie Zhang,Qi Chen,Fangzhen Tian,Xiaoyu Mu,Shaofang Zhang,Jing Zhang,Meili Guo,Hao Wang,Xiao-Dong Zhang,Ruiping Zhang
Artificial enzymes, especially nanozymes, have attracted wide attention due to their controlled catalytic activity, selectivity, and stability. The rising Cerium-based nanozymes exhibit unique SOD-like activity, and Vanadium-based nanozymes always hold excellent GPx-like activity. However, most inflammatory diseases involve polymerase biocatalytic processes that require multi-enzyme activities. The nanocomposite can fulfill multi-enzymatic activity simultaneously, but large nanoparticles (>10 nm) cannot be excreted rapidly, leading to biosafety challenges. Herein, atomically precise Ce 12 V 6 clusters with a size of 2.19 nm are constructed. The Ce 12 V 6 clusters show excellent glutathione peroxidase (GPx) -like activity with a significantly lower Michaelis-Menten constant (K m , 0.0125 mM versus 0.03 mM of natural counterpart) and good activities mimic superoxide dismutase (SOD) and peroxidase (POD). The Ce 12 V 6 clusters exhibit the ability to scavenge the ROS including O 2 ·− and H 2 O 2 via the cascade reactions of multi-enzymatic activities. Further, the Ce 12 V 6 clusters modulate the proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and consequently rescue the multi-organ failure in the lipopolysaccharide (LPS)-induced sepsis mouse model. With excellent biocompatibility, the Ce 12 V 6 clusters show promise in the treatment of sepsis.
研究领域:
纳米技术
·
生物化学
·
药理学
·
免疫学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Li Gao,Ai-ping Zhang,Lei Fu,Qian-wen Li,Xue-mei Qin,Jing Zhao
Background The incidence of neuropathic pain is progressively increasing over time. The activation of M1-type microglia plays a crucial role in the initiation and progression of neuropathic pain. Huangqin Decoction (HQD) is traditionally used to alleviate dysentery and abdominal pain. However, it remains unclear whether HQD can effectively mitigate neuropathic pain and the underlying mechanisms. Purpose The present study aims to investigate the impact of HQD on neuropathic pain induced by spared nerve injury (SNI) in mice, and to elucidate whether the analgesic effect of HQD is associated with microglia polarization. Methods The analgesic effect of HQD on SNI mice was investigated through assessments of mechanical pain threshold, thermal pain threshold, cold pain threshold, and motor ability. We elucidated the molecular mechanisms of HQD in alleviating SNI-induced neuropathic pain by focusing on microglia polarization and intestinal metabolite abnormalities. The expression levels of markers associated with microglia polarization (Iba-1, CD68, CD206, iNOS) was detected by immunofluorescence and Western blot, and the levels of inflammatory factors (IL-4, IL-10, IL-6, TNF-α) were assessed by ELISA. UPLC-QTOF-MS metabolomics was utilized to identify differential metabolites in the intestines of SNI mice. We screened the differential metabolites related to microglial polarization by correlation analysis, subsequently nicotinamide was selected for validation in LPS-induced BV-2 cells. Results Our findings demonstrated that HQD (20 g/kg) significantly enhanced the mechanical pain threshold, thermal pain threshold, and cold pain threshold, and protected the injured DRG neurons of SNI mice. Moreover, HQD (20 g/kg) obviously suppressed the expression of microglia M1 polarization markers (Iba-1, CD68, iNOS, IL-6, TNF-α), and promoted the expression of microglia M2 polarization markers (CD206, IL-10, IL-4) in the spinal cord of SNI mice. Additionally, HQD (20 g/kg) prominently ameliorated intestinal barrier damage by upregulating Claudin 1 and Occludin expression in the colon of SNI mice. Furthermore, HQD (20 g/kg) rectified 19 metabolite abnormalities in the intestine. Notably, nicotinamide (100 μM), an amide derivative with anti-inflammatory property, effectively suppresses microglia activation and polarization in LPS-induced BV-2 cells by downregulating IL-6 level and CD68 expression while upregulating IL-4 level and CD206 expression. Conclusion In summary, HQD alleviates neuropathic pain in SNI mice by regulating the activation and polarization of microglia, partially mediated through intestinal nicotinamide metabolism.
研究领域:
神经科学
·
药理学
·
代谢组学
·
免疫学
·
疼痛研究
✓ 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）