Treatment of severe alcoholic hepatitis: A systematic review

Melkebeke, Lukas Van; Korf, Hannelie; Tsochatzis, Emmanuel; Merwe, Schalk van der; Nevens, Frederik; Verbeek, Jef

doi:10.1016/j.coph.2021.06.011

Cited by 12 publications

(9 citation statements)

References 61 publications

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“…ALD is the most frequent cause of advanced chronic liver disease worldwide, contributing to 47.9% of all liver cirrhosis‐related deaths globally (Sarin & Sharma, 2020). Severe alcoholic hepatitis the most severe form of ALD, is a source of morbidity and mortality worldwide and has become a major economic burden and nonnegligible public health issues (Van Melkebeke et al, 2021). Growing evidence has demonstrated a liver protective role of autophagy in mediating the fat accumulation that causes alcoholic hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Quercetin alleviates ethanol‐induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy

Zhao

Xue

Wang

et al. 2022

Phytotherapy Research

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This study aimed to investigate the therapeutic effect of quercetin on ethanol‐induced hepatic steatosis in L02 cells and elucidate the potential mechanism. In brief, L02 cells were pretreated with or without ethanol (3%) for 24 h, then treated quercetin (80, 40, 20 μM) for 24 h. The transfection procedure was performed with transcription factor EB (TFEB) small interfering RNA (siRNA TFEB) for 24 h. Our results showed that quercetin autophagic flux in the L02 cells, via upregulating of microtubule associated protein light chain 3B (LC3‐II) and lysosome‐associated membrane protein 1 (LAMP1), then downregulating of protein sequestosome 1 (SQSTM1/p62). Mechanistically, quercetin activated TFEB nuclear translocation, contributing to lysosomal biogenesis and autophagic activation. Accordingly, the genetic inhibition of TFEB‐dependent autophagy decreased ethanol‐induced fat accumulation in L02 cells via regulating fatty acid β oxidation and lipid synthesis. Subsequently, quercetin‐induced TFEB‐dependent autophagic activation was also linked to inhibit oxidative stress via suppressing reactive oxygen species (ROS), enhancing activities of antioxidant enzymes, and promoting nuclear transfer of the nuclear factor E2‐related factor 2 (Nrf2) translocation. Thus, we uncovered a novel protective mechanism against ethanol‐induced hepatic steatosis and oxidative stress through TFEB‐mediated lysosomal biogenesis and discovered insufficient autophagy as a novel previously unappreciated autophagic flux.

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Section: Discussionmentioning

confidence: 99%

Quercetin alleviates ethanol‐induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy

Zhao

Xue

Wang

et al. 2022

Phytotherapy Research

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“…Aside from treating the excessive systemic inflammatory response, modulation of the gut-liver axis by transplantation of healthy donor faecal microbiota offers an additional therapeutic approach in AH-ACLF 11,87 . With promising results in small steroid-ineligible patient samples, improving survival rates up to 548 days after administration as well as an ongoing trial comparing microbiota transplantation to steroid J o u r n a l P r e -p r o o f therapy (NCT03091010) in severe AH, microbiota transplantation might in the future prove to be an effective treatment 88 .…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Alcohol and Acute-on-Chronic Liver Failure

Ballester

Sittner

Jalan

2022

Journal of Clinical and Experimental Hepatology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…8 Therefore, corticosteroids, which reduce immune activation, block cytotoxicity, and mitigate inflammation, have been employed as the sole pharmacological treatment option in the medical treatment of severe ALD, 9,10 but they are still considered suboptimal due to their marginal short-term survival benefit. 10,11 Given these circumstances, there is a critical need to develop novel, safer, and more effective therapeutic drugs for the treatment of both AUD and ALD. 12,13 Phosphodiesterases (PDEs), a class of regulatory hydrolase enzymes, centrally modulate cellular levels of the key second messenger molecules, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP).…”

Section: ■ Introductionmentioning

confidence: 99%

“…Prolonged and heavy alcohol consumption can lead to liver cell damage, resulting in the release of extracellular vesicles (EV) that activate inflammatory cells such as macrophages, subsequently leading to the release of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 . Therefore, corticosteroids, which reduce immune activation, block cytotoxicity, and mitigate inflammation, have been employed as the sole pharmacological treatment option in the medical treatment of severe ALD, , but they are still considered suboptimal due to their marginal short-term survival benefit. , Given these circumstances, there is a critical need to develop novel, safer, and more effective therapeutic drugs for the treatment of both AUD and ALD. , …”

Section: Introductionmentioning

confidence: 99%

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

Zheng,

Aimaiti,

Long

et al. 2023

J. Med. Chem.

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Alcohol use disorder (AUD) results in numerous disabilities and approximately 3 million deaths annually, caused mainly by alcoholic liver disease (ALD). Phosphodiesterase IV (PDE4) has emerged as an attractive molecular target for a new treatment for AUD and ALD. In this study, we describe the identification of 5-azaindazole analogues as PDE4 inhibitors against AUD and ALD. System optimization studies led to the discovery of ZL40 (IC 50 = 37.4 nM) with a remarkable oral bioavailability (F = 94%), satisfactory safety, and a lower emetogenic potency than the approved PDE4 inhibitors roflumilast and apremilast. Encouragingly, ZL40 exhibited AUD therapeutic effects by decreasing alcohol intake and improving acute alcohol-induced sedation and motor impairment. Meanwhile, ZL40 displayed the potential to alleviate alcoholic liver injury and attenuate inflammation in the NIAAA mice model. These results showed that ZL40 is a promising compound for future drug development to treat alcohol-related diseases.

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Treatment of severe alcoholic hepatitis: A systematic review

Cited by 12 publications

References 61 publications

Quercetin alleviates ethanol‐induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy

Quercetin alleviates ethanol‐induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy

Alcohol and Acute-on-Chronic Liver Failure

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

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