PHYSIOLOGICAL RESEARCH
·
2023
·
IF 2.1
T Wang,Q Wang,G Pan,G Jia,X Li,C Wang,L Zhang,C Zuo
The acidic tumor microenvironment (TME) of pancreatic cancer affects the physiological function of pancreatic stellate cells (PSCs), which in turn promotes cancer progression. Acid-sensing ion channel 1a (ASIC1a) is responsible for acidosis-related physiopathological processes. In this study, we investigated the effect of acid exposure on the activation and autophagy of PSCs, and the role of ASIC1a in these events. The results showed that acidic medium upregulated the expression of ASIC1a, induced PSCs activation and autophagy, which can be suppressed by inhibiting ASIC1a using PcTx1 or ASIC1a knockdown, suggesting that ASIC1a involves these two processes. In addition, the acid-induced activation of PSCs was impaired after the application of autophagy inhibitor alone or in combination with ASIC1a siRNA, meaning a connection between autophagy and activation. Collectively, our study provides evidence for the involvement of ASIC1a in the acid-caused PSCs activation, which may be associated with autophagy induction.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
·
免疫学
·
病理学
✓ 已验证
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
·
炎症性疾病
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 3
Jianbin Xiong,Jian Song,Xing Jiang,Zhuanzhuan Huang,Yijie Zhang
Chronic pancreatitis (CP) is a progressive inflammatory disorder with no effective treatment, which underscores the urgent need for novel therapeutic strategies. In this study, single-cell sequencing data retrieved from the Gene Expression Omnibus (GEO) database revealed that Prkcq and IL-4 were highly induced in group 2 innate lymphoid cells (ILC2s), while Mitf and Tgm2 were highly expressed in tissue-resident macrophages (TRMs). A mouse model of CP was established using dibutyltin dichloride (DBTC), and pathological evaluations via H&E, Masson, and Sirius Red staining confirmed typical features of CP, including acinar atrophy, inflammatory cell infiltration, and increased fibrosis. Notably, the numbers of ILC2s and TRMs in pancreatic tissues were significantly elevated in DBTC-treated mice. Functional experiments showed that the Prkcq knockdown in ILC2s suppressed the expression of IL-4, IL-5 and IL-13, while in TRMs, the transcription factor Mitf upregulated Tgm2 expression. In CP mice, Prkcq knockdown reduced TRM abundance, ultimately alleviating pancreatic fibrosis. Collectively, this study identifies Prkcq as a key regulator of CP by modulating TRM populations.
研究领域:
免疫学
·
细胞生物学
·
分子生物学
·
病理学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 4
·1209
·
IF 4.927
Jiacheng He,Xianhua Lin,Fanhui Meng,Yumiao Zhao,Wei Wang,Yao Zhang,Xiaolei Chai,Ying Zhang,Weiwei Yu,Junjie Yang,Guichao Li,Xuekui Du,Hankun Zhang,Mingyao Liu,Weiqiang Lu
Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2(PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP’s activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4–YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.Keywords:pancreatic cancer;metastasis;EP4;small molecule;YAP
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 17
·9667-9681
·
IF 4.486
Li-Juan Wang,Lin He,Lu Hao,Hong-Lei Guo,Xiang-Peng Zeng,Ya-Wei Bi,Guo-Tao Lu,Zhao-Shen Li,Liang-Hao Hu
Chronic pancreatitis (CP) is characterized by persistent inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Currently, the clinical therapeutic scheme of CP is mainly symptomatic treatment including pancreatic enzyme replacement, glycaemic control and nutritional support therapy, lacking of specific therapeutic drugs for prevention and suppression of inflammation and fibrosis aggravating in CP. Here, we investigated the effect of isoliquiritigenin (ILG), a chalcone-type dietary compound derived from licorice, on pancreatic fibrosis and inflammation in a model of caerulein-induced murine CP, and the results indicated that ILG notably alleviated pancreatic fibrosis and infiltration of macrophages. Further in vitro studies in human pancreatic stellate cells (hPSCs) showed that ILG exerted significant inhibition on the proliferation and activation of hPSCs, which may be due to negative regulation of the ERK1/2 and JNK1/2 activities. Moreover, ILG significantly restrained the M1 polarization of macrophages (RAW 264.7) via attenuation of the NF-κB signalling pathway, whereas the M2 polarization was hardly affected. These findings indicated that ILG might be a potential anti-inflammatory and anti-fibrotic therapeutic agent for CP.
研究领域:
药理学
·
病理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Wei Yao,Yihui Wang,Xin Zhang,Yuhe Lin
Pancreatic cancer (PC) is one of the most lethal malignancies and new therapeutic strategies are urgently needed. β1,3-N-acetylglucosaminyltransferase V (B3GNT5) may be a potential option for cancer treatment, but its role in PC remains unknown. In this study, we first demonstrated through bioinformatics analysis that B3GNT5 was high expression in PC and predicted poor prognosis. We further constructed B3GNT5 overexpression or knockdown cell lines by employing lentivirus packaging techniques and confirmed that B3GNT5 could promote tumor cell viability and autonomous growth using cultured cells and vivo xenograft models. In addition, we found that knockdown of B3GNT5 in PC cells inhibited cell migration, invasion, and angiogenesis, as well as stemness of cancer stem cells and enhanced chemotherapy sensitivity to gemcitabine. Mechanistically, overexpression of the transcription factor STAT5B in PC cells enhanced the transcriptional activity of the B3GNT5 promoter. Our work confirmed a tumor-promotive role of B3GNT5 in PC pathogenesis.
研究领域:
肿瘤学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2019
·Vol. 24
·期 5
·833-848
·
IF 2.214
Gui-xin Zhang,Chen Zhan,Kai Wang,Jian Han,Dong Shang,Hai-long Chen
Acute biliary pancreatitis (ABP) is a potentially life-threatening disease that is induced by the common bile duct (CBD) sludge or stones. This study aimed to investigate protective effects of Qingyi Decoction (QYT) on deoxycholic-acid-sodium salt (DCA) induced ABP in rats. Gpbar1 is a G-protein coupled receptor that can be activated by DCA. Both Gpbar1 overexpression vector and Gpbar1 RNAi were constructed and transfected into ABP cell models. Functional assays reveal that DCA significantly induced AR42J apoptosis and triggered Gpbar1 expression. Gpbar1 significantly activated caspase 8 and caspase 9 as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 significantly triggered apoptosis associated inflammatory factors as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 significantly induced calcium flux as compared to LV5-NC and LV3-NC (p<0.05). Gpbar1 up-regulated caspases and inflammatory factors in DCA treated pancreatic acinar cells. QYT reversed DCA induced apoptosis and inflammatory response. QYT significantly reduced Gpbar1 levels compared to no-QTY treated cells (p<0.05). In conclusion, QYT protects against DCA induced pancreatic acinar cell damage in ABP by inhibiting Gpbar1/NF-kB/p-RIP signaling pathway.
研究领域:
药理学
·
胃肠病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 12
·2988
·
IF 4.183
Xiuliang Zhu,Nan Lu,Ying Zhou,Shaoyan Xuan,Jiaojiao Zhang,Francesca Giampieri,Yongping Zhang,Fangfang Yang,Risheng Yu,Maurizio Battino,Zuhua Wang
Pancreatic cancer is a concealed and highly malignant tumor, and its early diagnosis plays an increasingly weighty role during the course of cancer treatment. In this study, we developed a polymeric magnetic resonance imaging (MRI) nanoplatform for MRI contrast agents. To improve tumor-targeting delivery of MRI contrast agents, we employed a pancreatic cancer targeting CKAAKN peptide to prepare a peptide-functionalized amphiphilic hyaluronic acid–vitamin E succinate polymer (CKAAKN–HA–VES) for delivering ultra-small superparamagnetic iron oxide (USPIO), namely, CKAAKN–HA–VES@USPIO. With the modification of the CKAAKN peptide, CKAAKN–HA–VES@USPIO could specifically internalize into CKAAKN-positive BxPC-3 cells. The CKAAKN–HA–VES@USPIO nanoparticles presented a more specific accumulation into pancreatic cancer cells than normal pancreatic cells, and an obvious decrease in signal intensity was observed in CKAAKN-positive BxPC-3 cells, compared with CKAAKN-negative HPDE6-C7 cells and non-targeting HA–VES@USPIO nanoparticles. The results demonstrated that our polymeric MRI nanoplatform could selectively internalize into CKAAKN-positive pancreatic cancer cells by the specific binding of CKAAKN peptide with pancreatic cancer cell membrane receptors, which provided a novel polymeric MRI contrast agent with high specificity for pancreatic cancer diagnosis, and makes it a very promising candidate for magnetic resonance imaging contrast enhancement.Keywords:pancreatic cancer;CKAAKN peptide;MRI contrast agent;polymer
研究领域:
肿瘤学
·
医学影像学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2017
·
IF 13.942
Tianjiao Ji,Jiayan Lang,Jing Wang,Rong Cai,Yinlong Zhang,Feifei Qi,Lijing Zhang,Xiao Zhao,Wenjing Wu,Jihui Hao,Zhihai Qin,Ying Zhao,Guangjun Nie
During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was constructed via coassembly of a tailor-designed MMP-2 responsive amphiphilic peptide and phospholipids. By utilizing the MMP-2-rich pathological environment, the pirfenidone (PFD) loaded MRPL (MRPL-PFD) can specifically release PFD at the pancreatic tumor site and down-regulate the multiple components of ECM expressed by the PSCs. This resulted in a significant increase in the penetration of gemcitabine into the tumor tissue and enhanced the efficacy of gemcitabine for pancreatic tumor. Our design tailored for antifibrosis of pancreatic cancer may provide a practical approach to build functional liposomes through supramolecular assembly, and regulation of ECM may be a promising adjuvant therapeutic strategy for pancreatic and other ECM-rich tumors.
研究领域:
药学
·
肿瘤学
·
生物材料
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zhongcheng Zhu,Xiaolin Dou,Qizhen Chen,Yebin Lu
Acute pancreatitis (AP) has a high mortality, involving oxidative stress and mitochondrial damage. Nuclear receptor subfamily 4 group A member 3 (Nr4a3) and BTG anti-proliferation factor 2 (Btg2) have a close connection with mitochondrial damage. Here, we found that Nr4a3 expression was upregulated in pancreatic tissues of AP mice induced by cerulein. To elucidate Nr4a3's role, we injected adeno-associated virus 9 (AAV9) carrying Nr4a3-targeting short hairpin RNA into the pancreatic duct. This intervention reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis by suppressing pancreatic enzyme activation. Moreover, Nr4a3 knockdown improved mitochondrial function in pancreatic acinar cells, evidenced by increased mitochondrial membrane potential, enhanced ATP production, and decreased superoxide levels. It also inhibited cell apoptosis by suppressing the activation of the caspase pathway. In vitro, Nr4a3 knockdown in CCK-treated pancreatic acinar cells decreased oxidative stress, mitigated mitochondrial damage, and suppressed apoptosis, while Nr4a3 overexpression exacerbated cell injury. Further investigation identified Btg2 as a downstream target of Nr4a3. Btg2 expression was elevated in pancreatic acinar cells of AP mice, and siRNA-mediated Btg2 knockdown alleviated CCK-induced cell injury. Mechanistically, Nr4a3 promoted Btg2 transcription, thereby promoting mitochondrial damage in pancreatic acinar cells and leading to cell apoptosis. Btg2 overexpression reversed the protective effects of Nr4a3 knockdown. Overall, our findings demonstrate that downregulation of Nr4a3 exerts anti-AP effects by regulating Btg2, providing potential therapeutic targets for AP.
研究领域:
分子生物学
·
细胞生物学
·
生物化学
·
医学研究
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2016
·
IF 7.145
Tianjiao Ji,Suping Li,Yinlong Zhang,Jiayan Lang,Yanping Ding,Xiao Zhao,Ruifang Zhao,Yiye Li,Jian Shi,Jihui Hao,Ying Zhao,Guangjun Nie
Fibrotic stroma, a critical character of pancreatic tumor microenvironment, provides a critical barrier against the penetration and efficacy of various antitumor drugs. Therefore, new strategies are urgently needed to alleviate the fibrotic mass and increase the drug perfusion within pancreatic cancer tissue. In our current work, we developed a β-cyclodextrin (β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive liposome, integrating antifibrosis and chemotherapeutic drugs for regulation of pancreatic stellate cells (PSCs), a key source of the fibrosis, and targeted delivery of cytotoxic drugs for pancreatic cancer therapy. These liposomes disassembed into two functional parts upon MMP-2 cleavage at the tumor site. One part was constituted by the β-CDs and the antifibrosis drug pirfenidone, which was kept in the stroma and inhibited the expression of collagen I and TGF-β in PSCs, down-regulating the fibrosis and decreasing the stromal barrier. The other segment, the RGD peptide-modified-liposome loading the chemotherapeutic drug gemcitabine, targeted and killed pancreatic tumor cells. This integrated nanomedicine, showing an increased drug perfusion without any overt side effects, may provide a potential strategy for improvement of the pancreatic cancer therapy.
研究领域:
癌症生物学
·
药学
·
纳米技术
·
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）