Novel ASK1 Inhibitor AGI-1067 Attenuates AGE-Induced Fibrotic Response by Suppressing the MKKs/p38 MAPK Pathway in Human Coronary Arterial Smooth Muscle Cells

Liu, Zhongwei; Shi, Shuang; Zhu, Haitao; Chen, Yunfei; Zhang, Yong; Zhang, Zheng; Wang, Xi

doi:10.1536/ihj.17-625

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Figure 5 shows that the LPS-induced decline of DUSP8 was significantly inhibited by EP. MKK6 is a regulatory kinase in the upstream of p38MAPK, which mainly promotes phosphorylation of p38 [42,43]. In our results, EP reduced MKK6 expression induced by LPS ( Figure 5).…”

Section: Discussionsupporting

confidence: 58%

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Dong

Xue

et al. 2019

Cell Cycle

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The endotoxin of Gram-negative bacteria threatens the intestinal health of livestock. Ethyl pyruvate (EP) has been shown to regulate intestinal immunity and protect against cell and tissue damage. In this study, it was first verified that EP could reduce the secretion of IL-8, TNF-α, IL-6 and IL-1β in LPS-induced IPEC-J2 cells. Then, we used RNA sequencing (RNA-seq) to analyze the differentially expressed genes (DEGs) of inflammatory factors induced by LPS in IPEC-J2 cells. It was found that LPS induced the upregulation of 377 genes and the downregulation of 477 genes compared to Vehicle; LPS+EP induced the upregulation of 258 genes and the downregulation of 240 genes compared to Vehicle; and LPS+EP induced the upregulation of 373 genes and the downregulation of 188 genes compared to LPS (fold change > 1.5 and FDR < 0.01). Their enrichment pathways included the MAPK signaling pathway, PI3K-Akt signaling pathway, Tolllike receptor signaling pathway, and other pathways. Furthermore, the mRNA level of cytokines associated with inflammation and apoptosis enriched in the MAPK pathway was verified by qRT-PCR. Western blots and immunofluorescence revealed that EP significantly inhibited phosphorylated p38 and phosphorylated-ERK1/2 protein expression levels (P < 0.05). The apoptosis due to LPS reduced by EP was significantly inhibited, as shown by Annexin V-FITC/PI staining. According to the results, EP inhibited the expression of IL-8, TNF-α, IL-6 and IL-1β as well as apoptosis by inhibiting the phosphorylation of p38 and ERK1/2 in LPS-induced IPEC-J2 cells.

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Section: Discussionsupporting

confidence: 58%

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Dong

Xue

et al. 2019

Cell Cycle

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“…AGI-1067 was welltolerated and significantly attenuated liver injury, inflammation, and fibrosis. Since AGI-1067 is also known as an anti-oxidative and anti-inflammatory agent (29,30), other mechanisms than VCAM-1 inhibition might have contributed to the beneficial effect observed. Improvement of insulin sensitivity as indicated by HOMA-IR reduction in AGI-1067-treated mice might be due to an extrahepatic effect or multi-functional property of this drug.…”

Section: Discussionmentioning

confidence: 99%

“…and fibrosis in FFC-fed mice. AGI-1067, also called succinobucol, has broad anti-oxidative and anti-inflammatory properties (29,30), and is known to reduce VCAM-1 expression (31). AGI-1067 has been employed in clinical trials for atherosclerosis and type 2 diabetes (32,33).…”

Section: The Vcam1 Pharmacological Inhibitor (Agi-1067) Attenuates Hepatic Inflammation Injurymentioning

confidence: 99%

Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis

Furuta¹,

Guo²,

Pavelko³

et al. 2021

Journal of Clinical Investigation

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“…The reported beneficial effects of ASK1 deficiency are widespread, indicating that ASK1 inhibition may be a particularly useful therapy in multi-system disorders, such as diabetesinduced tissue damage. Indeed, ASK1 inhibition is beneficial in models of diabetes or high-fat diet-related damage of the cardiovasculature [85,119], liver [85], kidney [58], and brain [45]. Furthermore, ASK1 inhibition or deficiency has repeatedly limited pathologic activation of P38 or JNK in a diseasespecific manner [46-48, 50, 55, 59].…”

Section: Discussionmentioning

confidence: 99%

ASK1 inhibition: a therapeutic strategy with multi-system benefits

2020

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p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species-induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38-and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38-and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders. Keywords Apoptosis signal-regulating kinase 1. MAP3K5. Clinical trial. ROS. MAPK. p38. JNK Mitogen-activated protein kinase kinase kinase 5 (MAP3K5), commonly known as apoptosis signal-regulating kinase 1 (ASK1), has emerged as a target for preventing p38 mitogen-activated protein kinase (MAPK14, 11, and 12/ P38α, β, and γ) and c-Jun N-terminal kinase (MAPK8, 9, and 10/JNK1, 2, and 3)-mediated cell death and disease. Both P38 and JNK are associated with reactive oxygen species (ROS)-induced disease 1 , and numerous studies have demonstrated that P38 and JNK inhibition ameliorates cell death [3-7]. However, complete inhibition of P38 or JNK in vivo is problematic, given that these ubiquitously expressed proteins are also critical for cell survival and homeostatic and/ or metabolic functions [8-11]. This is highlighted by the embryonic lethality of homozygous P38α and Jnk1/2 knockout mice [12, 13]. In addition, homozygous P38β knockout mice exhibit defective skeletal development [14] and homozygous Jnk1 knockout mice spontaneously develop intestinal tumours [15]. Negative outcomes have also been reported due to partial P38 or Jnk expression, with heterozygous P38α knockout mice developing progressive renal dysfunction [16] and heterozygous Jnk1 knockout mice exhibiting altered weight gain, hyperinsulinaemia, insulin resistance, inflammatory cytokine disruption, and reduced viability [17]. Serious side effects have also been observed when pharmacological inhibition of P38 or JNK is pursued in vivo [14, 18, 19]. For example, pamapimod, a P38 (α and β) inhibitor, did not significantly reduce joint swelling or improve mobility in individuals with rheumatoid arthritis in a phase II clinical trial. However, 35% of the participants receiving daily pamapimod (300 mg) experienced infection, 20% developed a skin rash, 15% became dizzy, and 13% had e...

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Novel ASK1 Inhibitor AGI-1067 Attenuates AGE-Induced Fibrotic Response by Suppressing the MKKs/p38 MAPK Pathway in Human Coronary Arterial Smooth Muscle Cells

Cited by 10 publications

References 44 publications

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis

ASK1 inhibition: a therapeutic strategy with multi-system benefits

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