Xiaofeng Li’s research while affiliated with Anhui Medical University and other places

Kupffer cells (KCs), as residents and sentinels of the liver, are involved in the formation of hepatic fibrosis (HF). However, the biological functions of circular RNAs (circRNAs) in KCs to HF have not been determined. In this study, the expression levels of circRNAs, microRNAs, and messenger RNAs (mRNAs) in KCs from a mouse model of HF mice were investigated using microarray and circRNA-Seq analyses. circDcbld2 was identified as a candidate circRNA in HF, as evidenced by its up-regulation in KCs. Silver staining and mass spectrometry showed that Wtap and Igf2bp2 bind to cirDcbld2. The suppression of circDcbld2 expression decreased the KC inflammatory response and oxidative stress and inhibited hepatic stellate cell (HSCs) activation, attenuating mouse liver fibrogenesis. Mechanistically, Wtap mediated the N⁶-methyladenosine (m6A) methylation of circDcbld2, and Igf2bp2 recognized m6A-modified circDcbld2 and increased its stability. circDcbld2 contributes to the occurrence of HF by binding miR-144-3p/Et-1 to regulate the inflammatory response and oxidative stress. These findings indicate that circDcbld2 functions via the m6A/circDcbld2/miR-144-3p/Et-1 axis and may act as a potential biomarker for HF treatment.

Background aims: The common characteristics for alcohol-associated liver injury (ALI) include abnormal liver function, infiltration of inflammatory cells, and generation of oxidative stress. The gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, gastrin-releasing peptide (GRP). GRP/GRPR appears to induce the production of cytokines in immune cells and promotes neutrophil migration. However, the effects of GRP/GRPR in ALI are unknown. Approach results: We found high GRPR expression in the liver of patients with alcoholic steatohepatitis and increased pro-GRP levels in peripheral blood mononuclear cells of these patients compared to that of the control. Increased expression of GRP may be associated with histone H3 lysine 27 acetylation induced by alcohol, which promotes the expression of GRP and then GRPR binding. Grpr-/- and Grprflox/floxLysMCre mice alleviated ethanol-induced liver injury with relieved steatosis, lower serum alanine aminotransferase, aspartate aminotransferase, triglycerides, malondialdehyde, and superoxide dismutase levels, reduced neutrophil influx, and decreased expression and release of inflammatory cytokines and chemokines. Conversely, overexpression of GRPR showed opposite effects. The pro-inflammatory and oxidative stress roles of GRPR might be dependent on IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified the therapeutic and preventive effects of RH-1402, a novel GRPR antagonist, for ALI. Conclusions: A knockout or antagonist of GRPR during excess alcohol intake could have anti-inflammatory and antioxidative roles, as well as provide a platform for histone modification-based therapy for ALI.

Since the discovery of the first miRNA in 1993, numerous studies have focused on their biogenesis, their functions on regulating a diversity of cellular processes, and the molecular mechanisms underlying their regulatory activity. The critical roles they play during pathogenesis have also been explored. With the advancement on next-generation sequencing, new classes of small RNA with distinct functions have been discovered. Among them, tRNA derived fragment (tsRNAs) have become a center of studies due to their similarity to miRNA. In this review, we summarized the biogenesis of miRNA and tsRNAs, the molecular mechanisms of their functions, and their important roles during the development of diseases. The similarity and difference between miRNA and tsRNAs were also discussed.

N6-methyladenosine (m6A) is a dynamic and reversible epigenetic regulation. As the most prevalent internal post-transcriptional modification in eukaryotic RNA, it participates in the regulation of gene expression through various mechanisms, such as mRNA splicing, nuclear export, localization, translation efficiency, mRNA stability, and structural transformation. The involvement of m6A in the regulation of gene expression depends on the specific recognition of m6A-modified RNA by reader proteins. In the pathogenesis and treatment of liver disease, studies have found that the expression levels of key genes that promote or inhibit the development of liver disease are regulated by m6A modification, in which abnormal expression of reader proteins determines the fate of these gene transcripts. In this review, we introduce m6A readers, summarize the recognition and regulatory mechanisms of m6A readers on mRNA, and focus on the biological functions and mechanisms of m6A readers in liver cancer, viral hepatitis, non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis (HF), acute liver injury (ALI), and other liver diseases. This information is expected to be of high value to researchers deciphering the links between m6A readers and human liver diseases.

Inflammation is a key factor contributing to the progression of alcohol-associated liver disease (ALD). Accumulating data have shown that ethyl alcohol (EtOH) induced liver macrophages activation along with an inflammatory response that contributes to the development of ALD. The liver-specific peroxisomal enzyme hydroxyacid oxidase 1 (HAO1) has been found to be associated with chronic liver disease. But the role of HAO1 remains unknown in ALD. In our study, HAO1 was found to be decreased in ALD patients and EtOH-fed mice. Interestingly, HAO1 expression was reduced in primary hepatocytes, whereas HAO1 was elevated in peripheral blood monocytes from ALD patients and EtOH-fed mice liver macrophages as well as LPS-treated RAW264.7 cells. Moreover, HAO1 knockdown exacerbated the inflammatory response, while HAO1 overexpression inhibited inflammation in LPS-stimulated RAW264.7 cells. Additionally, overexpression or silencing of HAO1 in vitro significantly affected NF-κB signaling pathway. Collectively, the results revealed a key role of HAO1-mediated macrophage activation and may provide a potential target for treating ALD.

Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. The incidences of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Long noncoding RNAs (lncRNAs) wrapped in exosomes can change the expression of their target genes in recipient cells, thereby regulating the behavior of recipient cells. Increasing evidence has demonstrated that there is a correlation between the activation of exosomal lncRNAs and the development of HCC. In this review article, we highlighted the functions of exosomal lncRNAs in the development of HCC, showing that exosomal lncRNAs play a vital role in the growth and progression of HCC and are targets for HCC.

Rheumatoid arthritis (RA), a common autoimmune disease, is extremely damaging to human health. Fibroblast-like synoviocytes (FLSs) have a vital role in the occurrence and development of RA. Methyltransferase-like 3 (METTL3), which is a crucial component of the N6-methyladenosine (m6A) methyltransferase complex, is involved in the progression of many diseases. In this study, we explored the role of METTL3 in the inflammatory response and proliferation, invasion, and migration of FLSs. We used human RA synovial tissues and the adjuvant-induced arthritis (AIA) animal model of RA. Experimental results revealed that METTL3 expression was significantly upregulated in human RA synovial tissues and in the rat AIA model. METTL3 knockdown suppressed interleukin (IL)-6, matrix metalloproteinase (MMP)-3, and MMP-9 levels in human RA-FLSs and rat AIA-FLSs. In contrast, they were increased by METTL3 overexpression. Additionally, we found that, in FLSs, METTL3 may activate the nuclear factor (NF)-κB signaling pathway. The experimental results showed that METTL3 may promote FLS activation and inflammatory response via the NF-κB signaling pathway.

Rheumatoid arthritis (RA) is a persistent autoimmune disease. Fibroblast-like synoviocytes (FLS) are a key component of invasive pannus and a pathogenetic mechanism in RA. Expression of bone morphogenetic protein 3 (BMP3) mRNA is reportedly decreased in the arthritic synovium. We previously showed that BMP3 expression is significantly downregulated in the synovial tissues of RA patients and models of adjuvant-induced arthritis (AIA). In the present study, we explored the association between BMP3 and FLS migration and secretion of proinflammatory factors in RA. We found that inhibition of BMP3 expression using BMP3 siRNA increased the proinflammatory chemokines and migration of FLS stimulated with TNF-α. Inhibition of BMP3 expression also increased expression of IL-6, IL-1β, IL-17A, CCL-2, CCL-3, VCAM-1, MMP-3, and MMP-9, but not TIMP-1, in AIA and RA FLS. Correspondingly, induction of BMP3 overexpression through intra-articular injection of ad-BMP3 diminished arthritis severity in AIA rats. We also found that BMP3 may inhibit activation of TGF-β1/Smad signaling. These data indicate that BMP3 may suppress the proliferation and migration of FLS via the TGF-β1/Smad signaling pathway.