Etomidate elicits anti-tumor capacity by disrupting the JAK2/STAT3 signaling pathway in hepatocellular carcinoma

Xu, Jiali; Zhang, Liren; Li, Nana; Dai, Jingjing; Hua, Dongxu; Wu, Zifeng; Zhou, Huixuan; Zhou, Lian; Zhang, Ruizhi; Yao, Feifan; Li, Qing; Wang, Xuehao; Liu, Cunming

doi:10.1016/j.canlet.2022.215970

“…The binding affinity was calculated as Kcal/mol. The resulting models were visualized using PyMOL 2.3.0 and BIOVIA Discovery Studio 2016 [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Remimazolam Attenuates LPS-Derived Cognitive Dysfunction via Subdiaphragmatic Vagus Nerve Target α7nAChR-Mediated Nrf2/HO-1 Signal Pathway

Zhou,

Yang,

Wei

et al. 2024

Neurochem Res

1

0

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Sepsis-induced neuroinflammation is significantly associated with sepsis-related brain dysfunction. Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic with multiple organ protective effects. However, it is unknown whether remimazolam can ameliorate LPS-induced brain impairment. In this study, Lipopolysaccharide (5 mg/kg, LPS) severely impaired Sprague-Dawley rats spatial learning ability, memory, and cognitive function. However, remimazolam treatment showed a protective effect on LPS-induced cognitive dysfunction. Remimazolam partly reversed LPS-induced splenomegaly, decreased serum cytokine expression, suppressed hippocampal M1 microglial activation, and mitigated oxidative stress injury and neuroinflammation. Electroacupuncture (EA) or PNU282987 treatment improved LPS-induced cognitive dysfunction and also significantly inhibited neuroinflammation and systemic inflammation. However, MLA, ML385, or subdiaphragmatic vagus nerve (SDV) treatment abolished the protective effects of remimazolam. Further mechanistic studies showed that remimazolam induces protective effects by activating subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signaling pathway. These results demonstrate that remimazolam can up-regulate α7nAChR, Cyto-Nrf2, HO-1, and cognitive-related (CREB, BDNF, PSD95) protein expressions, suppress M1 microglia, ameliorate neuroinflammation or systemic inflammation, and reverse cognitive dysfunction. Therefore, this study provides insight into a new therapeutic target for the treatment of sepsis-induced cerebral dysfunction. Graphical Abstract

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“…Etomidate inhibits phosphorylation and activation of JAK2 by competing with ATP for binding to the ATP-binding pocket of JAK2. Application of etomidate to HCC cells (HepG2 and Huh-7) suppressed phosphorylation of JAK2 and STAT3, resulting in the inhibition of cell proliferation, migration, and invasion, coupled with enhanced apoptosis [ 152 ]. Similarly, momelotinib, another small-molecule JAK2 inhibitor, suppressed phosphorylated JAK2 and STAT3 levels upon treatment of HCC cells (SNU-378 and SNU-475), subsequently leading to reduced cell viability, migration, and invasion [ 153 ].…”

Section: In Vitro and In Vivo Studies Targeting The Jak/stat Signalin...mentioning

confidence: 99%

“…Overexpression of miR-515-5p inhibited migration and invasion of HepG2 cells that were transplanted into nude mice [ 160 ]. Similarly, in xenograft mice transplanted with HepG2 cells, treatment with etomidate, an inhibitor of JAK2, led to the inhibition of tumor growth and subsequent increases in animal survival ( Table 3 ) [ 152 ].…”

Section: In Vitro and In Vivo Studies Targeting The Jak/stat Signalin...mentioning

confidence: 99%

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Park,

Lee,

Lee

et al. 2023

IJMS

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

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“…Etomidate inhibits phosphorylation and activation of JAK2 by competing with ATP for binding to the ATP-binding pocket of JAK2. Application of etomidate to HCC cells (HepG2 and Huh-7) suppressed phosphorylation of JAK2 and STAT3, resulting in the inhibition of cell proliferation, migration, and invasion, coupled with enhanced apoptosis [128]. Similarly, momelotinib, another small-molecule JAK2 inhibitor, suppressed phosphorylated JAK2 and STAT3 levels upon treatment of HCC cells (SNU-378 and SNU-475), subsequently leading to reduced cell viability, migration, and invasion [129].…”

Section: In Vitro Studies Targeting the Jak/stat Signaling Pathway In...mentioning

confidence: 99%

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Park,

Lee,

Lee

et al. 2023

Preprint

3

0

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Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

show abstract

Etomidate elicits anti-tumor capacity by disrupting the JAK2/STAT3 signaling pathway in hepatocellular carcinoma

Cited by 10 publications

References 37 publications

Remimazolam Attenuates LPS-Derived Cognitive Dysfunction via Subdiaphragmatic Vagus Nerve Target α7nAChR-Mediated Nrf2/HO-1 Signal Pathway

Remimazolam Attenuates LPS-Derived Cognitive Dysfunction via Subdiaphragmatic Vagus Nerve Target α7nAChR-Mediated Nrf2/HO-1 Signal Pathway

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications

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