查找使用阿拉丁产品的科研文献

Anti-adipogenesis effect of indole-3-acrylic acid on human preadipocytes and HFD-induced zebrafish

Zhang Ling,Zhao Jing,Peng Zhou,Zhang Zhongxiao,Huang Shan,Dong Xiaohua,Gao Jianfang,Guo Xirong

Background Obesity, defined as excessive or abnormal body fat accumulation, which could significantly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) diseases and seriously affect people’s quality of life. More than 2 billion people are overweight, and the incidence of obesity is increasing rapidly worldwide, it has become a widely concerned public health issue in the world. Diverse evidence show that active metabolites are involved in the pathophysiological processes of obesity. Aims However, whether the downstream catabolite of tryptophan, 3-indole acrylic acid (IA), is involved in obesity remains unclear. Methods We collected the samples of serum from peripheral blood of obesity and health controls, and liquid chromatography–mass spectrometry (LC-MS) was performed to identify the plasma levels of IA. Additionally, we verified the potential benefits of IA on human preadipocytes and HFD- induced zebrafish by cell viability assay, flow cytometry assay, Oil red O staining, total cholesterol (T-CHO), triglyceride (TG) and nonesterified free fatty acids (NEFA) measurements and Nile Red staining. RNA-Seq, functional analysis and western blot revealed the mechanisms underlying the function of IA. Results We found that the content of IA in peripheral blood serum of overweight people was significantly lower than that of normal people. In addition, supplementation with IA in zebrafish larvae induced by a high fat diet (HFD) dramatically reduced HFD induced lipid accumulation. IA had no effect on proliferation and apoptosis of preadipocytes, but significantly inhibited adipogenesis of preadipocytes by down-regulate CEBPα and PPARγ. RNA-Seq and functional analysis revealed that IA regulated the adipogenesis of preadipocytes through stimulate the phosphorylation of STAT1. Conclusions Taken together, IA has been identified as a potent metabolite for the prevention or treatment of obesity. Graphic Abstract

Therapeutic potential of formononetin in cirrhotic portal hypertension: modulating hepatic fibrosis, macrophage polarization, and lymphangiogenesis

Zhenghao Wu,Guqing Luo,Hongjie Li,Min Chen,Guangbo Wu,Qiang Fan,Chihao Zhang,Jiwei Yu,Jiayun Lin,Jinbo Zhao,Xiaoliang Qi,Haizhong Huo,Meng Luo,Lei Zheng

Introduction: Formononetin regulates intrahepatic fibrogenesis and macrophage polarization to improve portal pressure and liver function in rats with cirrhotic PHT through SMAD3, STAT1, STAT3 and GSK-3β signaling pathways, and modulates lymphangiogenesis through direct action and macrophage polarization-mediated indirect effects. Formononetin has the potential function of treating cirrhotic PHT.Background and aims: Formononetin (FN) has been reported to have anti-fibrotic effects in the kidneys and anti-M1 polarization effects on macrophages. Lymphangiogenesis is closely associated with macrophages, but its role in cirrhosis and portal hypertension (PHT) remains unclear. This study aims to explore the effects of FN on cirrhotic PHT and the disease-related intrahepatic lymphangiogenesis.Methods: In vivo experiments, bile duct ligation (BDL) induced PHT models were conducted in rats, followed by a 4-week FN treatment (50 mg/kg/day) administered via gavage. Hemodynamics, liver fibrosis, infiltration and polarization of intrahepatic macrophages, as well as intrahepatic lymphangiogenesis, were observed. For in vitro experiments, hepatic stellate cells, macrophages and lymphatic endothelial cells were used to observe the multiple effects of FN.Results: FN significantly ameliorated portal pressure in cirrhosis-induced PHT, improved liver function, and reduced liver fibrosis and hepatic stellate cell activation with decreased SMAD3 protein expression. The intrahepatic macrophage infiltration were markedly decreased, and M1-type macrophage polarization was suppressed by FN, accompanied by inhibition of STAT1, STAT3 and GSK-3β signaling pathways. In PHT models, FN reduced VEGF-C and VEGF-D levels in both the liver and blood, inhibiting intrahepatic lymphangiogenesis in portal area. In vitro, high-dose FN significantly inhibited lymphatic endothelial cell proliferation, while the pro-lymphangiogenic effect of conditioned medium from FN-treated M1 macrophages was diminished.Conclusions: FN significantly ameliorates cirrhotic PHT while reducing fibrosis, suppressing macrophage M1 polarization and inhibiting lymphangiogenesis. This may result from its modulation of multiple signaling pathways (SMAD3, STAT1, STAT3 and GSK-3β).

Knockdown of IFIT3 ameliorates multiple sclerosis via selectively regulating M1 polarization of microglia in an experimental autoimmune encephalomyelitis model

Ran Sun,Yan-Fang Wang,Xue Yang

The key to the treatment of multiple sclerosis (MS) is to promote the transition from inflammation-induced demyelination to remyelination. Polarization of microglia towards M1 or M2 phenotype is critical in this transition. Interferon induced protein with tetratricopeptide repeats 3 (IFIT3) is involved in inflammatory reaction and up-regulated in M1-polarized macrophages. However, its effect on microglia during MS has not been reported. In this paper, we demonstrated the important role of IFIT3 in selectively regulating microglia polarization. The expression of IFIT3 was increased when microglia were polarized towards M1, but did not change under M2 polarization. The knockdown of IFIT3 selectively inhibited M1 polarization, while M2 polarization was not affected by IFIT3 silencing. Furthermore, the activation of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa-B (NF-ĸB) signaling in M1 polarized microglia was suppressed by downregulating IFIT3. In experimental autoimmune encephalitis (EAE) mice, an animal model of MS, IFIT3 expression was upregulated. The disease progression, inflammatory infiltration and demyelination in the EAE mice were alleviated by silencing IFIT3. The inhibitory effects of IFIT3 knockdown on M1 polarization and STAT1 and NF-ĸB pathways were also confirmed in the spinal cord of EAE mice. In summary, our findings suggest that IFIT3 selectively intensified microglia polarization towards the pro-inflammatory M1 phenotype, and may contribute to the progression of MS.

Bioactivity-Oriented Separation of “Pepper Alkaloids” from Piper sintenense Hatusima with Potential Antigouty Arthritis Activity

Zhiren Yao,Tian Li,Meiling Jin,Siyang Fang,Jie Wang,Jiaming Zheng,Ke Pan,Jian Zhang,Guoqing Zhao,Zhiqi Yin,Yaping Huang

Piper sintenense Hatusima (PsH) is a member of the Piper genus used as food and folk medicine in China. However, the detailed chemical ingredients and potential pharmacological effects are still underexploited. In this study, we evaluated the anti-inflammatory and antigouty arthritis effect of the ethanolic extract of P. sintenense. Active compounds were isolated from the petroleum ether fraction resulting in six novel amide alkaloids (1–6) and 13 known analogues (7–19). All of the compounds exhibited excellent anti-inflammatory activities. Bioinformatics analysis and in vitro experiments showed that compound 4 had anti-inflammatory properties (IC50 = 4.86 ± 0.32 μM) and antigouty arthritis activity. Mechanistic studies revealed that compound 4 exerted its favorable efficacy by regulating macrophage polarization by inhibiting P-STAT1/4. These findings provide new insights into the chemical composition and function of P. sintenense and expand its promising application as a functional food in the prevention and treatment of gouty arthritis.

Mucin2 regulated by Ho1/p38/IL-10 axis plays a protective role in polystyrene nanoplastics-mediated intestinal toxicity

Mengxing Cui,Qianmei He,Ziwei Wang,Yongjiang Yu,Huan Gao,Ziqi Liu,Honghao Peng,Han Wang,Xue Zhang,Daochuan Li,Liping Chen,Xiumei Xing,Yongmei Xiao,Wen Chen,Qing Wang

Micro/nano-plastics (MPs/NPs) are a newly discovered environmental pollutant that can be ingested by humans through food and drinking water. In this study we evaluated the impact of MPs/NPs on the intestinal barrier and its mechanism. Doses of MPs/NPs were used to treat Caco-2/HT29-MTX in-vitro model and in-vivo model. In in-vitro model, 20 nm polystyrene nanoplastics (PS-NPs) had higher cytotoxicity than larger particles (200 nm and 2000 nm), and led to the increase of the permeability along with the decreased expression of tight junction proteins. Intriguingly, 20 nm PS-NPs elevated the expression of MUC2 simultaneously. Further studies revealed that PS-NPs increased the expression of HO1 through ROS generation, and then activated p38 to elevate IL-10 secretion in Caco-2 cell. The IL-10 secreted by Caco-2 cell promoted the expression of MUC2 in HT29-MTX cell through STAT1/3. Elevated MUC2 expression alleviates the cytotoxicity of PS-NPs. Besides, increased intestinal permeability and up-regulation of MUC2 through Ho1/p38/IL-10 pathway was also observed in 20 nm PS-NPs treated mouse model. In conclusion, PS-NPs can induce the intestinal toxicity and result in the increased adaptive expression of MUC2 to resist this adverse effect. People with inadequate mucin expression need to pay more attention to the toxicity of PS-NPs. This study provided a valuable insight for clarifying the mechanism and potential risk of intestinal toxicity induced by nanoplastics.

Inhibition of Long Noncoding RNA SNHG15 Ameliorates Hypoxia/Ischemia-Induced Neuronal Damage by Regulating miR-302a-3p/STAT1/NF-κB Axis

Chunting Hu,Chen Li,Qiaoya Ma,Ruili Wang,Ya He,Hui Wang,Guogang Luo

Purpose Ischemic brain injury results in high mortality and serious neurologic morbidity. Here, we explored the role of SNHG15 in modulating neuronal damage and microglial inflammation after ischemia stroke. Materials and Methods The hypoxia/ischemia models were induced by middle cerebral artery occlusion in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Quantitative real-time PCR (qRT-PCR) and Western blot were conducted to determine the levels of SNHG15, miR-302a-3p, and STAT1/NF-κB. Moreover, gain- or loss-of functional assays of SNHG15 and miR-302a-3p were conducted. MTT assay was used to evaluate the viability of HT22 cells, and the apoptotic level was determined by flow cytometry. Furthermore, enzyme-linked immunosorbent assay was performed to detect oxidative stress and inflammatory mediators in the ischemia cortex and OGD/R-treated BV2 microglia. Results The SNHG15 and STAT1/NF-κB pathways were both distinctly up-regulated, while miR-302a-3p was notably down-regulated in the ischemia cortex. Additionally, overexpressing SNHG15 dramatically enhanced OGD/R-mediated neuronal apoptosis as well as the expression of oxidative stress and inflammation factors from microglia. In contrast, knocking down SNHG15 or overexpressing miR-302a-3p relieved OGD/R-mediated neuronal apoptosis and microglial activation. Moreover, the rescue experiment testified that overexpressing miR-302a-3p also attenuated SNHG15 up-regulation-induced effects. In terms of the mechanisms, SNHG15 sponged miR-302a-3p and activated STAT1/NF-κB as a competitive endogenous RNA, while miR-302a-3p targeted STAT1 and negatively regulated the STAT1/NF-κB pathway. Conclusion SNHG15 was up-regulated in the hypoxia/ischemia mouse or cell model. The inhibition of SNHG15 ameliorates ischemia/hypoxia-induced neuronal damage and microglial inflammation by regulating the miR-302a-3p/STAT1/NF-κB pathway.

Myricitrin Modulates NADPH Oxidase-Dependent ROS Production to Inhibit Endotoxin-Mediated Inflammation by Blocking the JAK/STAT1 and NOX2/p47phox Pathways

Shimei Qi,Zunyong Feng,Qiang Li,Zhilin Qi,Yao Zhang

Myricitrin, a naturally occurring polyphenol hydroxy flavonoid, has been reported to possess anti-inflammatory properties. However, the precise molecular mechanism of myricitrin’s effects on LPS-induced inflammation is unclear. In the present study, myricitrin significantly alleviated acute lung injury in mice. Myricitrin also markedly suppressed the production of NO, TNF-α, IL-6, and MCP-1 in RAW264.7 macrophage cells. The inhibition of NO was concomitant with a decrease in the protein and mRNA levels of iNOS. The phosphorylation of JAKs and STAT-1 was abrogated by myricitrin. Furthermore, myricitrin inhibited the nuclear transfer and DNA binding activity of STAT1. The JAK-specific inhibitor ruxolitinib simulated the anti-inflammatory effect of myricitrin. However, myricitrin had no impact on the MAPK signalling pathway. Myricitrin attenuated the generation of intracellular ROS by inhibiting the assembly of components of the gp91phox and p47phox. Suppression of ROS generation using NAC or apocynin or by silencing gp91phox and p47phox all demonstrated that decreasing the level of ROS inhibited the LPS-induced inflammatory response. Collectively, these results confirmed that myricitrin exhibited anti-inflammatory activity by blocking the activation of JAKs and the downstream transcription factor STAT1, which may result from the downregulation of NOX2-dependent ROS production mediated by myricitrin.

Cannabinoid CB2 receptor controls chronic itch by regulating spinal microglial activation and synaptic transmission

Kangtai Xu,Xuefei Liu,Qian Zeng,Yaqi Liu,Leyan Shan,Luyao Ji,Yifei Wu,Jiawei Wu,Yiming Chen,Yitong Li,Songqiang Huang,Changyu Jiang,Xin Hong,Chaoran Wu,Zilong Wang

Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal cannabinoid receptor type 2 (CB 2 R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB 2 R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA sequencing and molecular mechanistic studies suggest that CB 2 R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB 2 R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB 2 R activation in microglia alleviates chronic itch via neuro-immune interactions.

Tyrosine kinase nonreceptor 1 (TNK1) knockdown ameliorates hemorrhage shock-induced kidney injury via inhibiting macrophage M1 polarization

Tang Miaolong,Cai Jimin,Wang Yan,Huan Zhirong,Yao Hao,Xu Ce,Ge Xin,Song Sheng

Hemorrhage shock (HS) is a major threat to patients with trauma and spontaneous bleeding, resulting in multi-organ failure including the kidney. Tyrosine kinase nonreceptor 1 (TNK1) has been shown to be upregulated in the kidney of experimental HS and patients with severe trauma . The study aims to investigate the role of TNK1 and the underlying mechanism in HS-induced kidney injury. A model of HS was established with femoral artery bloodletting, followed by resuscitation in Sprague–Dawley rats. Renal expression of TNK1 was abnormally induced by HS in rats. Knockdown of TNK1 alleviated HS-induced cell apoptosis and the level of proinflammatory cytokines (TNF-α, IL-6 and IL-1β) in the kidney. The expression of M1 macrophage markers (CD86 and iNOS) and the activation of STAT1 were inhibited by TNK1 knockdown in HS rats. In vitro, human monocyte THP-1 cells were treated with 20 ng/mL interferon-gamma plus 100 ng/mL lipopolysaccharide to induce M1 polarization. TNK1 knockdown exerted inhibitory effect on macrophage M1 polarization, M1-type inflammatory cytokine production and STAT1 activation in THP-1 cells. In conclusion, downregulation of TNK1 alleviates HS-induced kidney injury by suppressing macrophage M1 polarization, inflammation and kidney cell apoptosis, in which the deactivation of STAT1 signaling may be involved.

β-hydroxybutyrate regulates microglia M1/M2 polarization and phagocytosis through the JAK1/STAT1 pathway to reduce neuroinflammation and exert anti-epileptic effects

Yang Hui,Wang Huifen

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity

Li Liu,Shengxiang Fu,Wencheng Zhu,Zhongyuan Cai,Yingzi Cao,Yubing Huang,Li Yang,Xiaomin Fu,Rongrong Jin,Chunchao Xia,Yunjiao Zhang,Su Lui,Qiyong Gong,Bin Song,Longping Wen,James M. Anderson,Hua Ai

Carbohydrates have emerged as promising candidates for immunomodulation , however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles , comparing to mannose and galactose . In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK , and STAT1 signaling pathways . Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy .

Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1

Liu Nian,Zhang Jianglin,Yan Mingjie,Chen Lihui,Wu Jie,Tao Qian,Yan Bei,Chen Xiang,Peng Cong

Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.