Isoliquiritigenin ameliorates caerulein‐induced chronic pancreatitis by inhibiting the activation of PSCs and pancreatic infiltration of macrophages

Wang, Li-Juan; He, Lin; Liang, Hao; Guo, Hong-Lei; Zeng, Xiang-Peng; Bi, Yang; Lu, Guotao; Li, Zhao‐Shen; Hu, Liang‐Hao

doi:10.1111/jcmm.15498

Cited by 22 publications

(14 citation statements)

References 42 publications

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“…In immunofluorescence, iNOS and CD206 were used to mark M1 and M2 macrophages, respectively. In quantitative real-time PCR, the markers of M1 ( Inos, Cd86, Il-12a , and Tnf-α ) and M2 ( Cd163, Cd206 , and Ym-1 ) macrophages were consistent with previous studies [ 6 , 30 , 42 – 45 ]. Compared with the control group (Con), conditioned medium from WT and Mlkl -/- mouse-derived, PBS-treated pancreatic acinar cells (CM-WT-PBS, CM- Mlkl -/- -PBS) exhibited weak pro-M1 ability, although significant differences were found only in CD86 and YM-1 mRNA levels (Fig.…”

Section: Resultssupporting

confidence: 90%

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

Pan

Wang

et al. 2023

Cell Death Dis

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Acute pancreatitis (AP) is a disease characterized by local and systemic inflammation with an increasing incidence worldwide. Receptor-interacting serine/threonine protein kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), and innate immune cell macrophages have been reported to be involved in the pathogenesis of AP. However, the mechanisms by which RIPK3 and MLKL regulate pancreatic injury, as well as the interactions between injured pancreatic acinar cells and infiltrating macrophages in AP, remain poorly defined. In the present study, experimental pancreatitis was induced in C57BL/6J, Ripk3-/- and Mlkl-/- mice by cerulein plus lipopolysaccharide in vivo, and primary pancreatic acinar cells were also isolated to uncover cellular mechanisms during cerulein stimulation in vitro. The results showed that MLKL and its phosphorylated protein p-MLKL were upregulated in the pancreas of the mouse AP model and cerulein-treated pancreatic acinar cells, independent of its canonical upstream molecule Ripk3, and appeared to function in a cell death-independent manner. Knockout of Mlkl attenuated AP in mice by reducing the polarization of pancreatic macrophages toward the M1 phenotype, and this protective effect was partly achieved by reducing the secretion of CXCL10 from pancreatic acinar cells, whereas knockout of Ripk3 did not. In vitro neutralization of CXCL10 impaired the pro-M1 ability of the conditioned medium of cerulein-treated pancreatic acinar cells, whereas in vivo neutralization of CXCL10 reduced the polarization of pancreatic macrophages toward M1 and the severity of AP in mice. These findings suggested that targeting the MLKL-CXCL10-macrophage axis might be a promising strategy for the treatment of AP.

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Section: Resultssupporting

confidence: 90%

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

Pan

Wang

et al. 2023

Cell Death Dis

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“…In addition, ILG weakens the M1 polarization trend of macrophages by affecting the NF-κB signaling pathway, but does not affect M2 polarization. The above experimental results suggest that ILG is a candidate drug for CP worthy of further study ( 88 ).…”

Section: Research Progress Of Anti-inflammatory and Anti-fibrotic The...mentioning

confidence: 89%

The research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis

Liu

Mao

et al. 2022

Front. Oncol.

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Chronic pancreatitis (CP) is a chronic progressive inflammatory disease of the pancreas, caused by multiple factors and accompanied by irreversible impairment of pancreatic internal and external secretory functions. Pathologically, atrophy of the pancreatic acini, tissue fibrosis or calcification, focal edema, inflammation, and necrosis are observed. Clinical manifestations include recurrent or persistent abdominal pain, diarrhea, emaciation, and diabetes. In addition, CP is prone to develop into pancreatic cancer(PC) due to persistent inflammation and fibrosis. The disease course is prolonged and the clinical prognosis is poor. Currently, clinical treatment of CP is still based on symptomatic treatment and there is a lack of effective etiological treatment. Encouragingly, experiments have shown that a variety of active substances have great potential in the etiological treatment of chronic pancreatitis. In this paper, we will review the pathogenesis of CP, as well as the research progress on anti-inflammatory and anti-fibrotic therapies, which will provide new ideas for the development of subsequent clinical studies and formulation of effective treatment programs, and help prevent CP from developing into pancreatic cancer and reduce the prevalence of PC as much as possible.

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“…Furthermore, recent studies showed that multiple miRs (miR-301, miR-200c, miR-149, miR-139, miR-34b) can affect the activity of PSCs during chronic pancreatitis, and modulation of their levels leads to PSCs apoptosis [ 70 , 71 , 72 , 73 , 74 ]. Moreover, studies demonstrated that targeting PSCs with antifibrotic or anti-inflammatory compounds in a form of siRNA or small molecules could prevent chronic pancreatitis progression [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ]. YAP1 has been shown to induce the activity of PSCs and stimulate pancreatic fibrosis during chronic pancreatitis [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro

Almanzar

Shah

LaComb

et al. 2023

IJMS

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Chronic pancreatitis is characterized by chronic inflammation and fibrosis, processes heightened by activated pancreatic stellate cells (PSCs). Recent publications have demonstrated that miR-15a, which targets YAP1 and BCL-2, is significantly downregulated in patients with chronic pancreatitis compared to healthy controls. We have utilized a miRNA modification strategy to enhance the therapeutic efficacy of miR-15a by replacing uracil with 5-fluorouracil (5-FU). We demonstrated increased levels of YAP1 and BCL-2 (both targets of miR-15a) in pancreatic tissues obtained from Ptf1aCreERTM and Ptf1aCreERTM;LSL-KrasG12D mice after chronic pancreatitis induction as compared to controls. In vitro studies showed that delivery of 5-FU-miR-15a significantly decreased viability, proliferation, and migration of PSCs over six days compared to 5-FU, TGFβ1, control miR, and miR-15a. In addition, treatment of PSCs with 5-FU-miR-15a in the context of TGFβ1 treatment exerted a more substantial effect than TGFβ1 alone or when combined with other miRs. Conditioned medium obtained from PSC cells treated with 5-FU-miR-15a significantly inhibits the invasion of pancreatic cancer cells compared to controls. Importantly, we demonstrated that treatment with 5-FU-miR-15a reduced the levels of YAP1 and BCL-2 observed in PSCs. Our results strongly suggest that ectopic delivery of miR mimetics is a promising therapeutic approach for pancreatic fibrosis and that 5-FU-miR-15a shows specific promise.

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Isoliquiritigenin ameliorates caerulein‐induced chronic pancreatitis by inhibiting the activation of PSCs and pancreatic infiltration of macrophages

Cited by 22 publications

References 42 publications

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

MLKL signaling regulates macrophage polarization in acute pancreatitis through CXCL10

The research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis

5-FU-miR-15a Inhibits Activation of Pancreatic Stellate Cells by Reducing YAP1 and BCL-2 Levels In Vitro

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