SH-Alb inhibits phenotype remodeling of pro-fibrotic macrophage to attenuate liver fibrosis through SIRT3-SOD2 axis.

Albumin has a variety of biological functions, such as immunomodulatory and antioxidant activity, which depends largely on its thiol activity. However, in clinical trials, the treatment of albumin by injection of commercial human serum albumin (HSA) did not achieve the desired results. Here, we constructed reduced modified albumin (SH-Alb) for in vivo and in vitro experiments to investigate the reasons why HSA did not achieve the expected effects. SH-Alb was found to delay the progression of liver fibrosis in mice by alleviating liver inflammation and oxidative stress. Although R-Alb also has some of the above roles, the effect of SH-Alb is more remarkable. Mechanism studies have shown that SH-Alb reduces the release of pro-inflammatory and pro-fibrotic cytokine through the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, SH-Alb deacetylates SOD2, a key enzyme of mitochondrial reactive oxygen species (ROS) production, by promoting the expression of SIRT3, thereby reducing the accumulation of ROS. Finally, macrophages altered by R-Alb or SH-Alb can inhibit the activation of hepatic stellate cells and endothelial cells, further delaying the progression of liver fibrosis. These results indicate that SH-Alb can remodel the phenotype of macrophages, thereby affecting the intrahepatic microenvironment and delaying the process of liver fibrosis. It provides a good foundation for the application of albumin in clinical treatment.

Phosphorylation of RGS16 at Tyr168 promote HBeAg-mediated macrophage activation by ERK pathway to accelerate liver injury.

Liver injury is closely associated with macrophage activation following HBV infection. Our previous study showed that only HBeAg, but not HBsAg and HBcAg, stably enhances inflammatory cytokine production in macrophages. And we also indicated that HBeAg could induce macrophage activation via TLR2 and thus aggravate the progression of liver fibrosis. However, the specific molecular mechanism of HBeAg in macrophage activation is not clear. We screened significantly overexpressed RGS16 from RNASeq results of HBeAg-stimulated macrophages and validated them with cellular assays, GSE83148 microarray dataset, and in clinical samples. Meanwhile, small interference, plasmid, and lentivirus transfection assays were used to establish cell models for knockdown and overexpression of RGS16, and q-PCR, ELISA, Transwell, and CCK-8 assays were used to analyze the role of RGS16 in HBeAg-induced macrophage activation. In addition, the upstream and downstream mechanisms of RGS16 in HBeAg-treated macrophage activation were explored using inhibitors, phostag gels, and RGS16 phosphorylation mutant plasmids. Finally, the effect of RGS16 on hepatic inflammation in murine tissues was evaluated by H&E staining, liver enzyme assay and immunofluorescence. RGS16 was significantly upregulated in HBeAg-induced macrophage activation, and its expression was enhanced with increasing HBeAg content and treatment time. Functional experiments showed that overexpression of RGS16 promoted the production of inflammatory factors TNF-α and IL-6 and boosted macrophage proliferation and migration, while knockdown of RGS16 exhibited the opposite effect. Mechanistically, we discovered that RGS16 is regulated by the TLR2/P38/STAT5 signaling pathway. Meanwhile, RGS16 enhanced ERK phosphorylation via its own Tyr168 phosphorylation to contribute to macrophage activation, thereby accelerating liver injury. Finally, in mice, overexpression of RGS16 markedly strengthened liver inflammation. HBeAg upregulates RGS16 expression through the TLR2-P38-STAT5 axis, and the upregulated expression of RGS16 enhances macrophage activation and accelerates liver injury by promoting ERK phosphorylation. In this process, phosphorylation of Tyr168 is necessary for RGS16 to function. KEY MESSAGES: RGS16 boosted HBeAg-induced macrophage inflammation, proliferation, and migration. Tyr168 phosphorylation of RGS16 affected by ERK promoted macrophage activation. HBeAg upregulated the expression of RGS16 through TLR2/P38/STAT5 signal pathway. RGS16 promoted liver injury by regulating macrophage functions in mouse model.

Albumin, an interesting and functionally diverse protein, varies from 'native' to 'effective' (Review).

Human serum albumins (HSAs) are synthesized in the liver and are the most abundant proteins in plasma of healthy human. They play an important role in the pathophysiological processes of the liver and even the whole organism. Previous studies have mainly focused on the regulation of HSAs' expression. However, with the progress of research in recent years, it has been found that the content of circulating albumin cannot fully reflect the biological function of albumin itself. Given the aforementioned fact, the concept of serum 'effective albumin concentration' has been proposed. It refers to the content of albumin that is structurally and functionally intact. Alterations in the molecular structure and function of albumin have been reported in a variety of diseases, including liver disease. Moreover, these changes have been verified to affect the progression of oxidative stress­related diseases. However, the link between albumin structure and function has not been fully elaborated, and the mechanisms by which different forms of albumin affect disease also need to be further investigated. In this context, the present review mainly expounded the biological characteristics and functions of albumin, summarized the different types of post­translational modification of albumin, and discussed their functional changes and possible mechanisms in non­alcoholic fatty liver disease, alcoholic hepatitis, viral hepatitis and different stages of cirrhosis. This will help to improve understanding of the role of albumin in disease development and provide a more comprehensive physiological basis for it in disease treatment.

Race between virus and inflammasomes: inhibition or escape, intervention and therapy.

The inflammasome is a multiprotein complex that further regulates cell pyroptosis and inflammation by activating caspase-1. The assembly and activation of inflammasome are associated with a variety of diseases. Accumulative studies have shown that inflammasome is a key modulator of the host's defense response to viral infection. Indeed, it has been established that activation of inflammasome occurs during viral infection. At the same time, the host has evolved a variety of corresponding mechanisms to inhibit unnecessary inflammasome activation. Therefore, here, we review and summarize the latest research progress on the interaction between inflammosomes and viruses, highlight the assembly and activation of inflammosome in related cells after viral infection, as well as the corresponding molecular regulatory mechanisms, and elucidate the effects of this activation on virus immune escape and host innate and adaptive immune defenses. Finally, we also discuss the potential therapeutic strategies to prevent and/or ameliorate viral infection-related diseases via targeting inflammasomes and its products.

FNDC3B protects steatosis and ferroptosis via the AMPK pathway in alcoholic fatty liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is a leading cause of chronic liver disease worldwide with limited therapeutic options. The role of fibronectin type III domain-containing protein 3B (FNDC3B), an important regulator of metabolism, in ALD, and the underlying mechanism as well as its potential implication in ALD therapeutic strategies remain unknown. METHODS: Hepatocyte-specific FNDC3B knockdown or control C57BL/6 N mice received a Lieber-DeCarli diet for four weeks, followed by oral gavage (chronic-binge). Primary mouse hepatocytes and cell lines were used for in vitro studies. Liver injury, hepatic steatosis, and lipid peroxidation were assessed. RESULTS: In cultured cells and mouse livers, alcohol exposure increased FNDC3B expression. Hepatocyte-specific FNDC3B deletion aggravated alcohol-induced liver steatosis via AMP-activated protein kinase (AMPK) inhibition. In vitro, FNDC3B expression was negatively regulated by miR-192-5p. Furthermore, FNDC3B deletion significantly exacerbated ethanol-mediated lipid peroxidation. The RNA sequence assay revealed a connection between FNDC3B and ferroptosis, which was verified by the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Additionally, FNDC3B inhibition-mediated AMPK inactivation downregulated transferrin expression, which was associated with marked iron overload and ferroptosis. CONCLUSIONS: This study elucidated the critical role of FNDC3B in preventing hepatic steatosis and ferroptosis in response to chronic alcohol consumption. Our findings indicate that FNDC3B is a potential therapeutic target for ALD.

Functions of regulators of G protein signaling 16 in immunity, inflammation, and other diseases.

Regulators of G protein signaling (RGS) act as guanosine triphosphatase activating proteins to accelerate guanosine triphosphate hydrolysis of the G protein α subunit, leading to the termination of the G protein-coupled receptor (GPCR) downstream signaling pathway. RGS16, which is expressed in a number of cells and tissues, belongs to one of the small B/R4 subfamilies of RGS proteins and consists of a conserved RGS structural domain with short, disordered amino- and carboxy-terminal extensions and an α-helix that classically binds and de-activates heterotrimeric G proteins. However, with the deepening of research, it has been revealed that RGS16 protein not only regulates the classical GPCR pathway, but also affects immune, inflammatory, tumor and metabolic processes through other signaling pathways including the mitogen-activated protein kinase, phosphoinositide 3-kinase/protein kinase B, Ras homolog family member A and stromal cell-derived factor 1/C-X-C motif chemokine receptor 4 pathways. Additionally, the RGS16 protein may be involved in the Hepatitis B Virus -induced inflammatory response. Therefore, given the continuous expansion of knowledge regarding its role and mechanism, the structure, characteristics, regulatory mechanisms and known functions of the small RGS proteinRGS16 are reviewed in this paper to prepare for diagnosis, treatment, and prognostic evaluation of different diseases such as inflammation, tumor, and metabolic disorders and to better study its function in other diseases.

SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms.

As of April 1, 2022, over 468 million COVID-19 cases and over 6 million deaths have been confirmed globally. Unlike the common coronavirus, SARS-CoV-2 has highly contagious and attracted a high level of concern worldwide. Through the analysis of SARS-CoV-2 structural, non-structural, and accessory proteins, we can gain a deeper understanding of structure-function relationships, viral infection mechanisms, and viable strategies for antiviral therapy. Angiotensin-converting enzyme 2 (ACE2) is the first widely acknowledged SARS-CoV-2 receptor, but researches have shown that there are additional co-receptors that can facilitate the entry of SARS-CoV-2 to infect humans. We have performed an in-depth review of published papers, searching for co-receptors or other auxiliary membrane proteins that enhance viral infection, and analyzing pertinent pathogenic mechanisms. The genome, and especially the spike gene, undergoes mutations at an abnormally high frequency during virus replication and/or when it is transmitted from one individual to another. We summarized the main mutant strains currently circulating global, and elaborated the structural feature for increased infectivity and immune evasion of variants. Meanwhile, the principal purpose of the review is to update information on the COVID-19 outbreak. Many countries have novel findings on the early stage of the epidemic, and accruing evidence has rewritten the timeline of the outbreak, triggering new thinking about the origin and spread of COVID-19. It is anticipated that this can provide further insights for future research and global epidemic prevention and control.