The role of interleukin-20 in liver disease: Functions, mechanisms and clinical applications.

Liver disease is a severe public health concern worldwide. There is a close relationship between the liver and cytokines, and liver inflammation from a variety of causes leads to the release and activation of cytokines. The functions of cytokines are complex and variable, and are closely related to their cellular origin, target molecules and mode of action. Interleukin (IL)-20 has been studied as a pro-inflammatory cytokine that is expressed and regulated in some diseases. Furthermore, accumulating evidences has shown that IL-20 is highly expressed in clinical samples from patients with liver disease, promoting the production of pro-inflammatory molecules involved in liver disease progression, and antagonists of IL-20 can effectively inhibit liver injury and produce protective effects. This review highlights the potential of targeting IL-20 in liver diseases, elucidates the potential mechanisms of IL-20 inducing liver injury, and suggests multiple viable strategies to mitigate the pro-inflammatory response to IL-20. Genomic CRISPR/Cas9-based screens may be a feasible way to further explore the signaling pathways and regulation of IL-20 in liver diseases. Nanovector systems targeting IL-20 offer new possibilities for the treatment and prevention of liver diseases.

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

Research Progress on the Correlation between Acetaldehyde Dehydrogenase 2 and Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is the predominant pathologic type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation. Increasing evidence suggests that ALDH2 is a crucial regulator of human tumor development, including HCC. Therefore, clarifying the relationship between ALDH2 and HCC is helpful for formulating rational treatment strategies. This review highlights the regulatory roles of ALDH2 in the development of HCC, elucidates the multiple potential mechanisms by which ALDH2 regulates the development of HCC, and summarizes the progress of research on ALDH2 gene polymorphisms and HCC susceptibility. Meanwhile, we envision viable strategies for targeting ALDH2 in the treatment of HCC SIGNIFICANCE STATEMENT: Numerous studies have aimed to explore novel therapeutic targets for HCC, and ALDH2 has been reported to be a critical regulator of HCC progression. This review discusses the functions, molecular mechanisms, and clinical significance of ALDH2 in the development of HCC and examines the prospects of ALDH2-based therapy for HCC.

Recent advances of Phosphodiesterase 4B in cancer.

INTRODUCTION: Phosphodiesterase 4B (PDE4B) is a crucial enzyme in the phosphodiesterases (PDEs), acting as a regulator of cyclic adenosine monophosphate (cAMP). It is involved in cancer process through PDE4B/cAMP signaling pathway. Cancer occurs and develops with the regulation of PDE4B in the body, suggesting that PDE4B is a promising therapeutic target. AREAS COVERED: This review covereed the function and mechanism of PDE4B in cancer. We summarized the possible clinical applications of PDE4B, and highlighted the possible ways to develop clinical applications of PDE4B inhibitors. We also discussed some common PDEs inhibitors, and expected the development of combined targeting PDE4B and other PDEs drugs in the future. EXPERT OPINION: The existing research and clinical data can strongly prove the role of PDE4B in cancer. PDE4B inhibition can effectively increase cell apoptosis, inhibit cell proliferation, transformation, migration, etc., indicating that PDE4B inhibition can effectively inhibit the development of cancer. Other PDEs may antagonize or coordinate this effect. As for the further study on the relationship between PDE4B and other PDEs in cancer, it is still a challenge to develop multi-targeted PDEs inhibitors.

Research progress on the role of cholesterol in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is often diagnosed at advanced stages with no effective treatment options. Mechanistically, it is a complex biological process. Recently, the main cause of its incidence is changing from viral to non-viral. It has been shown that high cholesterol levels can cause the further transformation of non-alcoholic fatty liver disease (NAFLD) to HCC, but some investigations have found that serum cholesterol levels are negatively correlated with morbidity and mortality. Conflicting experimental results and epidemiological investigations illustrate the complex mechanisms of HCC. Cholesterol is essential for the survival of the body and tumors, although research on the function of cholesterol in tumors is evolving, the use of lowering cholesterol drugs in treating HCC remains limited. In this review, the cholesterol-involved mechanisms that cause the development of HCC or reduce the mortality and the latest progress in the use of cholesterol in the treatment of HCC and prospects for prevention and diagnosis have been summarized.

The role of acetaldehyde dehydrogenase 2 in the pathogenesis of liver diseases.

Common liver tissue damage is mainly due to the accumulation of toxic aldehydes in lipid peroxidation under oxidative stress. Cumulative toxic aldehydes in the liver can be effectively metabolized by acetaldehyde dehydrogenase 2 (ALDH2), thereby alleviating various liver diseases. Notably, gene mutation of ALDH2 leads to impaired ALDH2 enzyme activity, thus aggravating the progress of liver diseases. However, the relationship and specific mechanism between ALDH2 and liver diseases are not clear. Consequently, the review explains the relationship between ALDH2 and liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). In addition, this review also discusses ALDH2 as a potential therapeutic target for various liver diseases,and focuses on summarizing the regulatory mechanism of ALDH2 in these liver diseases.

Emerging role of the cGAS-STING signaling pathway in autoimmune diseases: Biologic function, mechanisms and clinical prospection.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, as vital component of innate immune system, acts a vital role in distinguishing invasive pathogens and cytosolic DNA. Cytosolic DNA sensor cGAS first binds to cytosolic DNA and catalyzes synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which is known as the second messenger. Next, cGAMP activates the adaptor protein STING, triggering a molecular chain reaction to stimulate cytokines including interferons (IFNs). Recently, many researches have revealed that the regulatory role of cGAS-STING signaling pathway in autoimmune diseases (AIDs) such as Rheumatoid arthritis (RA), Aicardi Goutières syndrome (AGS) and systemic lupus erythematosus (SLE). Moreover, accumulated evidence have showed inhibition of the cGAS-STING signaling pathway could remarkably suppress the joint swelling and inflammatory cell infiltration in RA mice. Therefore, in this review, we describe the molecular properties, biologic function and mechanisms of the cGAS-STING signaling pathway in AIDs. In addition, potential clinical applications especially selective small molecule inhibitors targeting the cGAS-STING signaling pathway are also discussed.