Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation

Abstract

BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined. AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism. METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1. RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1. CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.

Unveiling the potential anti‐cancer activity of calycosin against multivarious cancers with molecular insights: A promising frontier in cancer research

“…In contrast, it was found that the expression of snail, vimentin, and CD31 was increased in the Balb/C nude mice model, suggesting that calycosin may act as an anti‐cancer therapeutic agent by preventing pancreatic cancer cell proliferation 79 . According to an in vivo study conducted on male C57BL/6N mice, calycosin (25–50 mg/kg) blocks HMGB1/NF‐β signaling with decreasing production of pro‐inflammatory cytokines and chemokines, notably TNF‐α, IL‐6, IL‐1, CXCL‐1, and HMGB1 80 . Calycosin (25–200 μM) prevented the growth and viability of pancreatic cancer cells (PaCa‐2, PANC1) by triggering p21Waf1/Cip1‐induced cell cycle arrest at S phase and caspase‐dependent apoptosis via caspase‐3,8,9 activation, elevating Bax expression while lowering Bcl‐2, consequently increasing the ratio of Bcl‐2 to Bax 81 .…”

“…79 According to an in vivo study conducted on male C57BL/6N mice, calycosin (25-50 mg/kg) blocks HMGB1/NF-β signaling with decreasing production of pro-inflammatory cytokines and chemokines, notably TNF-α, IL-6, IL-1, CXCL-1, and HMGB1. 80 Calycosin (25-200 μM) prevented the growth and viability of pancreatic cancer cells (PaCa-2, PANC1) by triggering p21Waf1/Cip1-induced cell cycle arrest at S phase and caspase-dependent apoptosis via caspase-3,8,9 activation, elevating Bax expression while lowering Bcl-2, consequently increasing the ratio of Bcl-2 to Bax. 81 Calycosin (100 μM) diminished cyclin A1 and the related cyclin-dependent kinase CDK2 expression while increasing Snail, MMP-2, -9, and p21 gene expression and regulated Raf/MEK/ERK pathway in the pancreatic cell line MIA PaCa-2.…”

Intestinal Microbiota - An Unmissable Bridge to Severe Acute Pancreatitis-Associated Acute Lung Injury

“…Elevated HMGB1 levels in lung tissue and bronchoalveolar lavage fluid (BALF) are demonstrated to be positively correlated with the level of pro-inflammatory cytokines using the PALI mice model. The PALI mice model was established by giving them 4g/kg intraperitoneal injection of L-arginine every hour for 2 hours, and the underlying mechanisms are linked to the activation of the TLR4/MyD88/NF-κB pathway and release of NLRP3 inflammasomes ( 93 – 96 ).…”

Fighting Fire with Fire: Exosomes and Acute Pancreatitis-Associated Acute Lung Injury

“…HMGB1 has been implicated in SAP-induced intestinal barrier injury via the activation of the TLR4/9/NF-κB signaling pathway, disruption of intestinal flora, and disruption of intestinal tight junctions, according to several research findings [ 116 , 117 , 118 ]. Similarly, AP-associated ALI is exacerbated by HMGB1, which promotes inflammation by triggering nuclear translocation of NF-κB and inflammasome formation [ 119 , 120 ]. SAP may cause myocardial injury, which is an uncommon yet life-threatening consequence.…”