GENES AND IMMUNITY
·
2025
·
IF 4.5
Lin Shizhao,Liang Feihong,Chen Changgan,Lin Jiajing,Wu Yuwei,Hou Zelin,Huang Heguang,Fang Haizong,Pan Yu
Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.
研究领域:
医学
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免疫学
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病理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
Marine Drugs
·
2023
·Vol. 21
·期 1
·39
·
IF 5.4
Hong-Yu Zou,Hui-Juan Zhang,Ying-Cai Zhao,Xiao-Yue Li,Yu-Ming Wang,Tian-Tian Zhang,Chang-Hu Xue
It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional β-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA β-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA β-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet β-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.Keywords:streptozotocin;polyunsaturated fatty acid;pancreas injury;oxidative stress;inflammation;apoptosis;mouse
研究领域:
营养学
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内分泌学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Ying Ren,Xiangka Hu,Mushuang Qi,Wanjun Zhu,Jin Li,Shuyu Yang,Chunmei Dai
Background Diabetes is a metabolic disease characterized by hyperglycaemia. Tangningtongluo Tablet (TNTL) is an inpatient formula extensively utilized to treat diabetes mellitus (DM), but the protective mechanism is not clear. This study aimed to investigate the relevant mechanisms by which TNTL affects pancreatic damage in diabetic mice and autophagy. Methods The impact of TNTL on pancreatic damage in diabetic mice in vitro and in vivo was investigated via glucose and lipid metabolism analyses, HE staining, CCK-8, TUNEL staining, Annexin V/PI, and Western blotting. Molecular docking and Western blotting were used to verify the results of network pharmacological analysis, which was carried out to explore the mechanism by which TNTL affects DM. The autophagosome levels were visualized via RFP-GFP-LC3 and transmission electron microscopy, and lysosomal function was evaluated via Lysotracker red staining. Western blot, immunohistochemistry and immunofluorescence staining were used to detect the expression of the autophagy proteins LC3, p62 and LAMP2. Results Compared with the model group, TNTL protected pancreas from oxidative stress, decreased the level of MDA, increased the levels of SOD and GSH-px, induced the occurrence of autophagy and decreased the levels of apoptotic factors. Moreover, TNTL inhibited the protein expression of p-PI3K, p-Akt and p-mTOR, increased the levels of LC3 and LAMP2 and decreased the level of p62, and the autophagy inhibitor CQ blocked the protective effect of TNTL on pancreatic damage in diabetic mice. Conclusion These results demonstrated that TNTL ameliorated pancreatic damage in diabetic mice by inhibiting the PI3K/Akt/mTOR signaling and regulating autophagy.
研究领域:
药理学
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糖尿病
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Foods
·
2024
·Vol. 13
·期 23
·3797
·
IF 4.7
Chenmeng Song,Wei Zheng,Chengyi Song,Houfeng Zhou,Jengyuan Yao
Background: Kaempferol (KPF), a flavonoid abundant in edible plants, possesses potent anti-inflammatory and antioxidant properties beneficial with notable health benefits. Objective: To evaluate the protective effects of KPF on metabolic disturbances and pancreatic damage in a Type 1 diabetes mellitus (T1DM) mouse model. Methods: Male C57BL/6 mice were divided into normal, T1DM, T1DM + KPF 25 mg/kg, and T1DM + KPF 50 mg/kg groups. T1DM was induced by streptozotocin (STZ). KPF was administered via intraperitoneal injection for 2 weeks. After 4 weeks from the start, metabolic parameters, pancreatic histology, and plasma metabolites were analyzed. Network pharmacology and molecular docking identified key targets and pathways. In vitro, INS-1 cells were used to assess reactive oxygen species (ROS) production and apoptosis. Results: KPF significantly reduced blood glucose (GLU) and triglyceride (TG) levels, increased high-density lipoprotein (HDL) levels, and preserved pancreatic β-cell structure. Metabolomics revealed changes in energy metabolism and oxidative stress-related metabolites. Network analysis highlighted the PI3K/AKT/mTOR pathway, with strong binding affinities to targets such as AKT1. In vitro, KPF decreased ROS production in INS-1 cells; this effect was reversed by a PI3K/AKT inhibitor. KPF also reduced apoptosis in INS-1 cells. Conclusions: KPF ameliorates metabolic disturbances and pancreatic damage in T1DM mice, suggesting potential as a functional food ingredient for diabetes management.
研究领域:
药理学
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糖尿病研究
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分子生物学
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代谢组学
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网络药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
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2020
·
IF 3.641
Keyan Wu,Guanghuai Yao,Xiaolei Shi,Huan Zhang,Qingtian Zhu,Xinnong Liu,Guotao Lu,Lianghao Hu,Weijuan Gong,Qi Yang,Yanbing Ding
Acinar cell necrosis is one of the most prominent pathophysiological changes of acute pancreatitis (AP). Asiaticoside (AS) is a triterpene compound with confirmed apoptosis-and necrosis-related activities. However, the specific effects of AS on AP have not been determined. In this study, we aimed to investigate the protective effect of AS on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, We found that AS administration reduced serum amylase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. And the levels of toll-like receptor 4 (TLR4) and necrotic related proteins (RIP3 and p-MLKL) of pancreatic tissue were reduced after AS administration. In addition, TLR4 deficiency eliminated the protective effect of AS on AP induced by caerulein in mice. Correspondingly, we elucidated the effect of AS in vitro and found that AS protected against pancreatic acinar cells necrosis and TAK-242 counteracted this protective effect. Meanwhile, we found that AS ameliorated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by l -arginine. Furthermore, Molecular docking results revealed interaction between AS and TLR4. Taken together, our data for the first time confirmed the protective effects of AS on AP in mice via TLR4 pathway.
研究领域:
药理学
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病理生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cellular and Molecular Gastroenterology and Hepatology
·
2022
·
IF 8.797
Xin Liu,Wu Luo,Jiahao Chen,Chenghong Hu,Rumbidzai N. Mutsinze,Xu Wang,Yanmei Zhang,Lijiang Huang,Wei Zuo,Guang Liang,Yi Wang
Background & Aims Severe acute pancreatitis can easily lead to systemic inflammatory response syndrome and death. Macrophages are known to be involved in the pathophysiology of acute pancreatitis (AP), and macrophage activation correlates with disease severity. In this study, we examined the role of ubiquitin-specific protease 25, a deubiquitinating enzyme and known regulator of macrophages, in the pathogenesis of AP. Methods We used L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP in Usp25 -/- mice and wild-type mice. We also generated bone marrow Usp25 -/- chimeric mice and initiated L-arginine–mediated AP. Primary acinar cells and bone marrow–derived macrophages were isolated from wild-type and Usp25 -/- mice to dissect molecular mechanisms. Results Our results show that Usp25 deficiency exacerbates pancreatic and lung injury, neutrophil and macrophage infiltration, and systemic inflammatory responses in L-arginine, cerulein, and choline-deficient ethionine-supplemented diet–induced models of AP. Bone marrow Usp25 -/- chimeric mice challenged with L-arginine show that Usp25 deficiency in macrophages exaggerates AP by up-regulating the TANK-binding kinase 1 (TBK1)–nuclear factor-κB (NF-κB) signaling pathway. Similarly, in vitro data confirm that Usp25 deficiency enhances the TBK1–NF-κB pathway, leading to increased expression of inflammatory cytokines in bone marrow–derived macrophages. Conclusions Usp25 deficiency in macrophages enhances TBK1–NF-κB signaling, and the induction of inflammatory chemokines and type I interferon-related genes exacerbates pancreatic and lung injury in AP.
研究领域:
免疫学
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胃肠病学
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炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Zhang Man,Wu Yan-Qing,Xie Ling,Wu Jiang,Xu Ke,Xiao Jian,Chen Da-Qing
Severe acute pancreatitis (SAP) is a digestive system disease that is associated with a range of complications including intestinal dysfunction. In this study, we determined that the chalcone compound, isoliquiritigenin (ISL), reduces pancreatic and intestinal injury in a mouse model of SAP. These effects were achieved by suppressing oxidative stress and the inflammatory responses to SAP. This was evidenced by a reduction in histological score, and malondialdehyde (MDA), interleukin (IL)-6, tumor necrosis factor (TNF)-α and cleaved-caspase-3 (c-caspase-3) protein along with an increase in Nrf2, hemeoxygenase-1 (HO-1), quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD). We then used Nrf2-/- mice to test the protective effect of Nrf2 during ISL treatment of SAP. Our results indicated that Nrf2-/- mice had greater pancreatic injury and intestinal dysfunction than wild-type mice. They also had reduced adherens junctions (P120-catenin) and tight junctions (occludin), and increased activated nuclear factor-κB (NF-κB) protein. In Nrf2-/- mice, ISL was less effective at these functions than in the WT mice. In conclusion, this study demonstrated that ISL exerts its protective effects against oxidative stress and inflammatory injury after SAP via regulation of the Nrf2/NF-κB pathway. It also showed that the efficacy of ISL in repairing the intestinal barrier damage caused by SAP is closely related to the Nrf2 protein. Our findings demonstrated that Nrf2 is an important protective factor against SAP-induced injuries in the pancreas and intestines.
研究领域:
药理学
·
胃肠病学
·
分子生物学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Zeyu Wu,Jiting Gao,Chongwei Yu,Wei Zhao,Nan Chen,Teresa G. Valencak,Daxi Ren
Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia, with its prevalence escalating. It exerts a profound impact on human health care and socio-economic development. Probiotics, known as natural, safe, and minimal side effects, have emerged as promising intervention agents to manage chronic diabetes. Our study aimed to explore the therapeutic potential of Lactobacillus rhamnosus ZJUIDS07 for mitigating T2D in mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Administration of L. rhamnosus ZJUIDS07 led to a reduction in diabetic symptoms, including reversal of weight loss, improvement in hyperglycemia and insulin resistance, mitigation of disruptions in glucose and lipid metabolism, alleviation of pancreatic pathological damage, and reduction in oxidative stress and inflammation. Moreover, treatment with L. rhamnosus ZJUIDS07 could restore intestinal microbiota balance in T2D mice by altering the structure and composition of intestinal microbiota, and increased short-chain fatty acids (SCFAs) levels. Specifically, L. rhamnosus ZJUIDS07 significantly decreased the abundance of harmful bacteria like Staphylococcus , Corynebacterium , and Odoribacte , while increasing the abundance of beneficial bacteria (especially SCFAs-producing bacteria) such as Muribaculaceae_norank, Dubosiella , Clostridium sensu stricto 1, Lactobacillus , and Faecalibaculum . Our findings highlight that L. rhamnosus ZJUIDS07 represents a promising probiotic strategy for future treatment of T2D, and that the modulation of gut microbiota and their metabolites through the microbiome-gut-pancreas axis play a pivotal role for the antidiabetic effects of L. rhamnosus ZJUIDS07.
研究领域:
微生物学
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糖尿病研究
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营养科学
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胃肠病学
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免疫学
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产品关联
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2021
·
IF 6.53
Yaoxing Dou,Ronglei Huang,Qiaoping Li,Yuhong Liu,Yucui Li,Hanbin Chen,Gaoxiang Ai,Jianhui Xie,Huifang Zeng,Jiannan Chen,Chaodan Luo,Ziren Su
Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo . The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.
研究领域:
药理学
·
糖尿病研究
·
代谢组学
·
胃肠病学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2021
·
IF 4.451
Zhenfeng Huang,You Luo,Xuesen Xia,Anping Wu,Zhenqiang Wu
Fermentation results in the release and biotransformation of phenolic compounds in guava leaves. This study aimed to evaluate the bioaccessibility, safety and antidiabetic effect of phenolic-rich extract from fermented guava leaves (PE-fgl) using Monascus anka and Bacillus sp. BS2. The total phenolics and flavonoids were 51.18% and 16.60% bioaccessible after gastrointestinal digestion, respectively. High bioaccessibility was observed, particularly for ellagic acid, isoquercitrin, quercetin-3-O-β-D-xylopyranoside, quercetin-3-O-α-L-arabinofuranoside and avicularin, resulted in high recovery of α-glucosidase inhibition activity and antioxidant capacity. Moreover, PE-fgl was practically nontoxic with a median lethal dose (LD 50 ) greater than 5000 mg/kg and was without evidence of toxicity following subchronic administration up to the dose limit of 2000 mg/kg. Furthermore, PE-fgl significantly improved serum glucose and lipid levels as well as antioxidant capacity in diabetic mice. Liver, kidney and pancreas damage was also significantly alleviated. These results suggested that PE-fgl could be a nontoxic candidate for diabetes treatment.
研究领域:
药理学
·
营养学
·
糖尿病研究
·
食品科学
·
毒理学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）