Single-cell RNA-seq reveals the role of YAP1 in prefrontal cortex microglia in depression.

BACKGROUND: Depression is a complex mood disorder whose pathogenesis involves multiple cell types and molecular pathways. The prefrontal cortex, as a key brain region for emotional regulation, plays a crucial role in depression. Microglia, as immune cells of the central nervous system, have been closely linked to the development and progression of depression through their dysfunctional states. This study aims to utilize single-cell RNA-seq technology to reveal the pathogenic mechanism of YAP1 in prefrontal cortex microglia in depression. METHODS: Firstly, we performed cell type identification and differential analysis on normal and depressed prefrontal cortex tissues by mining single-cell RNA-seq datasets from public databases. Focusing on microglia, we conducted sub-clustering, differential gene KEGG enrichment analysis, intercellular interaction analysis, and pseudotime analysis. Additionally, a cross-species analysis was performed to explore the similarities and differences between human and rhesus monkey prefrontal cortex microglia. To validate our findings, we combined bulk RNA-Seq and WGCNA analysis to reveal key genes associated with depression and verified the relationship between YAP1 and depression using clinical samples. RESULTS: Our study found significant changes in the proportion and transcriptional profiles of microglia in depressed prefrontal cortex tissues. Further analysis revealed multiple subpopulations of microglia and their associated differential genes and signaling pathways related to depression. YAP1 was identified as a key molecule contributing to the development of depression and was significantly elevated in depression patients. Moreover, the expression level of YAP1 was positively correlated with HAMD scores, suggesting its potential as a biomarker for predicting the onset of depression. CONCLUSION: This study utilized single-cell RNA-seq technology to reveal the pathogenic mechanism of YAP1 in prefrontal cortex microglia in depression, providing a new perspective for a deeper understanding of the pathophysiology of depression and identifying potential targets for developing novel treatment strategies.

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.

Case report: Paralytic ileus resulted from nirmatrelvir/ritonavir-tacrolimus drug-drug interaction in a systemic lupus erythematosus patient with COVID-19.

Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus.

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.

The workload change and depression among emergency medical staff after the open policy during COVID-19: a cross-sectional survey in Shandong, China.

Introduction: In the middle of December 2022, the Chinese government adjusted the lockdown policy on coronavirus disease 2019 (COVID-19), a large number of infected patients flooded into the emergency department. The emergency medical staff encountered significant working and mental stress while fighting the COVID-19 pandemic. We aimed to investigate the workload change, and the prevalence and associated factors for depression symptoms among emergency medical staff after the policy adjustment. Methods: We conducted a cross-sectional online survey of emergency medical staff who fought against COVID-19 in Shandong Province during January 16 to 31, 2023. The respondents' sociodemographic and work information were collected, and they were asked to complete the 9-item Patient Health Questionnaire (PHQ-9) then. Univariate and multivariate logistic regression analyses were applied to identify the potential associated factors for major depression. Results: Nine hundred and sixteen emergency medical personnel from 108 hospitals responded to this survey. The respondents' weekly working hours (53.65 ± 17.36 vs 49.68 ± 14.84) and monthly night shifts (7.25 ± 3.85 vs 6.80 ± 3.77) increased after the open policy. About 54.3% of the respondents scored more than 10 points on the PHQ-9 standardized test, which is associated with depressive symptoms. In univariate analysis, being doctors, living with family members aged ≤16 or ≥ 65 years old, COVID-19 infection and increased weekly working hours after the open policy were significantly associated with a PHQ-9 score ≥ 10 points. In the multivariate analysis, only increased weekly working hours showed significant association with scoring ≥10 points. Conclusion: Emergency medical staff' workload had increased after the open policy announcement, which was strongly associated with a higher PHQ-9 scores, indicating a very high risk for major depression. Emergency medical staff working as doctors or with an intermediate title from grade-A tertiary hospitals had higher PHQ-9 scores, while COVID-19 infection and weekly working hours of 60 or more after the open policy were associated with higher PHQ-9 scores for those from grade-B tertiary hospitals. Hospital administrators should reinforce the importance of targeted emergency medical staff support during future outbreaks.

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.

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.

Hypertension May Reduce the Infection Risk but Increase the Severity of COVID-19: Based on the Current Data in China.

Increasing evidence has shown an unusual relationship between hypertension and COVID-19, which may not be as simple as previously thought. The purpose of our study was to determine the association of hypertension with the onset and development of COVID-19. A meta-analysis was performed to summarize the prevalence of hypertension in COVID-19 patients, as well as the usage of ACEIs/ARBs. Metaregression analyses were used to evaluate the association of hypertension with disease severity and mortality. PubMed and Google Scholar were searched for relevant studies. A total of 42 studies including 14138 patients were enrolled in the study. The proportion of hypertension in COVID-19 patients in China was 17.7% according to the enrolled studies, while it was 6.0% in a study containing 72314 confirmed cases, which are both much lower than in the general population. All of the data from the 11 provinces in China showed the same tendency. The proportions of hypertension were higher in severe/ICU patients and nonsurvivors than in nonsevere/ICU patients and survivors. The metaregression analyses suggested that both disease severity and risk of death were associated with the incidence of hypertension. A total of 27.6% of COVID-19 patients with hypertension received ACEI/ARB therapy. The proportion of deaths in COVID-19 patients with hypertension treated with ACEIs/ARBs was significantly lower than that in nonuse patients treated with ACEIs/ARBs. In conclusion, hypertension may reduce the infection risk of COVID-19 but increase the risk of developing worse clinical outcomes. The use of ACEIs/ARBs may benefit COVID-19 patients with hypertension.

HBeAg mediates inflammatory functions of macrophages by TLR2 contributing to hepatic fibrosis.

BACKGROUND: We and others have confirmed activation of macrophages plays a critical role in liver injury and fibrogenesis during HBV infection. And we have also proved HBeAg can obviously induce the production of macrophage inflammatory cytokines compared with HBsAg and HBcAg. However, the receptor and functional domain of HBeAg in macrophage activation and its effects and mechanisms on hepatic fibrosis remain elusive. METHODS: The potentially direct binding receptors of HBeAg were screened and verified by Co-IP assay. Meanwhile, the function domain and accessible peptides of HBeAg for macrophage activation were analyzed by prediction of surface accessible peptide, construction, and synthesis of truncated fragments. Furthermore, effects and mechanisms of the activation of hepatic stellate cells induced by HBeAg-treated macrophages were investigated by Transwell, CCK-8, Gel contraction assay, Phospho Explorer antibody microarray, and Luminex assay. Finally, the effect of HBeAg in hepatic inflammation and fibrosis was evaluated in both human and murine tissues by immunohistochemistry, immunofluorescence, ELISA, and detection of liver enzymes. RESULTS: Herein, we verified TLR-2 was the direct binding receptor of HBeAg. Meanwhile, C-terminal peptide (122-143 aa.) of core domain in HBeAg was critical for macrophage activation. But arginine-rich domain of HBcAg hided this function, although HBcAg and HBeAg shared the same core domain. Furthermore, HBeAg promoted the proliferation, motility, and contraction of hepatic stellate cells (HSCs) in a macrophage-dependent manner, but not alone. PI3K-AKT-mTOR and p38 MAPK signaling pathway were responsible for motility phenotype of HSCs, while the Smad-dependent TGF-ß signaling pathway for proliferation and contraction of them. Additionally, multiple chemokines and cytokines, such as CCL2, CCL5, CXCL10, and TNF-α, might be key mediators of HSC activation. Consistently, HBeAg induced transient inflammation response and promoted early fibrogenesis via TLR-2 in mice. Finally, clinical investigations suggested that the level of HBeAg is associated with inflammation and fibrosis degrees in patients infected with HBV. CONCLUSIONS: HBeAg activated macrophages via the TLR-2/NF-κB signal pathway and further exacerbated hepatic fibrosis by facilitating motility, proliferation, and contraction of HSCs with the help of macrophages.

Functional role of miR­155 in physiological and pathological processes of liver injury (Review).

There are several types of liver injury, including alcohol­induced liver injury, drug­induced liver injury, infectious liver injury, cirrhosis, liver ischemia/reperfusion injury and liver failure. In recent years, accumulated data have demonstrated that microRNAs (miRNAs/miRs) may be involved in the occurrence and development of a variety of systemic diseases, such as immune diseases, tumors and nervous system diseases. miR­155 is a key miRNA, which has been studied extensively and has been shown to target different genes. In the present review, the potential effects and mechanisms of miR­155 on the physiological and pathological processes of liver injury were reviewed from the perspective of cell stress, inflammation and activation of fibrosis. In addition, the potential benefits of miR­155 as a therapeutic target and predictor of liver injury were summarized.

Current directions, conceptions and viewpoints on 2019-nCoV (Review).

On December 31, 2019, the first case of a novel coronavirus infection was reported in Wuhan, China. The ongoing outbreak of the 2019 novel coronavirus (2019-nCoV) has caused immense global concern. According to the recommendations of the International Health Regulations Emergency Committee and the facts and cases that 215 other countries have also reported to date, the World Health Organization Director-General announced that the outbreak of 2019-nCoV constitutes a public health emergency of international concern and a severe threat to the human health worldwide. To date, the prevalence of the virus has continued in waves and is increasing globally. The present review briefly introduces the epidemiology of 2019-nCoV, as well as viral structural characteristics, and receptors and cells that may act after entering the body, laboratory examinations, imaging and pathological features, clinical manifestations, complications, treatment and management.

Negative feedback loop of ERK/CREB/miR-212-3p inhibits HBeAg-induced macrophage activation.

The activation of liver macrophages is closely related to liver injury after HBV infection. Our previous results demonstrated that HBeAg played a key role in inducing macrophage activation. As we all know, miRNAs are involved in the regulation of multiple immune cell functions. Meanwhile, we have shown that miR-155 positively regulates HBeAg-induced macrophage activation and accelerates liver injury. Subsequently, based on our previous miRNA sequencing results, we further evaluated the role of miR-212-3p called 'neurimmiR' in HBeAg-induced macrophages in this study. First, miR-212-3p expression was significantly elevated in HBeAg-treated macrophages. Meanwhile, we found up-regulation of miR-212-3p significantly decreased the production of cytokines, whereas knockdown of miR-212-3p held the opposite effect by gains and losses of function. Mechanically, although MAPK signal pathway, including ERK, JNK and p38, was activated in HBeAg-induced macrophages, only ERK promoted the expression of miR-212-3p via transcription factor CREB, which was able to bind to the promoter of miR-212-3p verified by ChIP assay. Moreover, we further indicated that up-regulated miR-212-3p inhibited HBeAg-induced inflammatory cytokine production through targeting MAPK1. In conclusion, miR-212-3p was augmented in HBeAg-stimulated macrophages via ERK/CREB signal pathway and the elevated miR-212-3p suppressed inflammatory cytokine production induced by HBeAg through targeting MAPK1.

Long non-coding RNA MIAT/miR-148b/PAPPA axis modifies cell proliferation and migration in ox-LDL-induced human aorta vascular smooth muscle cells.

AIMS: Atherosclerosis (AS) performs the important pathogenesis which refers to coronaryheart and vascular diseases. Long non-coding RNAs (lncRNAs) was reported to be related to the AS progression. We aimed to probe the role and potential mechanism of Myocardial Infarction Associated Transcript (MIAT) in AS. MATERIALS AND METHODS: Levels of MIAT, microRNA-148b (miR-148b) and pregnancy-associated plasma protein A (PAPPA) were detected by quantitative Real-time polymerase chain reaction (qRT-PCR) in oxidized low-density lipoprotein (ox-LDL)-induced human aorta vascular smooth muscle cells (HA-VSMCs). Proliferation and migration were examined by Cell counting kit-8 (CCK-8) and wound-healing assays, respectively. Protein levels of Ki-67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase (MMP)-2, MMP-9 and PAPPA were examined by western blot assay. Ki-67 and PCNA level was detected by flow cytometry. The interaction among MIAT, miR-148b and PAPPA was confirmed via dual-luciferase reporter and RNA immunoprecipitation (RIP). The biology role of MIAT was detected by an AS model in vivo. KEY FINDINGS: The levels of MIAT and PAPPA were augmented, whereas mature miR-148b level was repressed in ox-LDL-induced AS model. The inhibitory effects of knockdown of MIAT on proliferation and migration were relieved by miR-148b inhibitor. Additionally, miR-148b regulated proliferation and migration by targeting PAPPA. Mechanically, MIAT functioned as sponge of miR-148b to impact PAPPA expression. MIAT knockdown protected AS mice against lipid metabolic disorders in vivo. SIGNIFICANCE: Proliferation and migration were modified by MIAT/miR-148b/PAPPA axis in ox-LDL induced AS cell model, supplying a novel insight into the underlying application of MIAT in the clinical treatment of AS.

The functions and targets of miR-212 as a potential biomarker of cancer diagnosis and therapy.

Cancer is a major health problem worldwide. An increasing number of researchers are studying the diagnosis, therapy and mechanisms underlying the development and progression of cancer. The study of noncoding RNA has attracted a lot of attention in recent years. It was found that frequent alterations of miRNA expression not only have various functions in cancer but also that miRNAs can act as clinical markers of diagnosis, stage and progression of cancer. MiR-212 is an important example of miRNAs involved in cancer. According to recent studies, miR-212 may serve as an oncogene or tumour suppressor by influencing different targets or pathways during the oncogenesis and the development and metastasis of cancer. Its deregulation may serve as a marker for the diagnosis or prognosis of cancer. In addition, it was recently reported that miR-212 was related to the sensitivity or resistance of cancer cells to chemotherapy or radiotherapy. Here, we summarize the current understanding of miR-212 functions in cancer by describing the relevant signalling pathways and targets. The role of miR-212 as a biomarker and its therapeutic potential in cancer is also described. The aim of this review was to identify new methods for the diagnosis and treatment of human cancers.

The latest progress on miR-374 and its functional implications in physiological and pathological processes.

Non-coding RNAs (ncRNAs) have been emerging players in cell development, differentiation, proliferation and apoptosis. Based on their differences in length and structure, they are subdivided into several categories including long non-coding RNAs (lncRNAs >200nt), stable non-coding RNAs (60-300nt), microRNAs (miRs or miRNAs, 18-24nt), circular RNAs, piwi-interacting RNAs (26-31nt) and small interfering RNAs (about 21nt). Therein, miRNAs not only directly regulate gene expression through pairing of nucleotide bases between the miRNA sequence and a specific mRNA that leads to the translational repression or degradation of the target mRNA, but also indirectly affect the function of downstream genes through interactions with lncRNAs and circRNAs. The latest studies have highlighted their importance in physiological and pathological processes. MiR-374 family member are located at the X-chromosome inactivation center. In recent years, numerous researches have uncovered that miR-374 family members play an indispensable regulatory role, such as in reproductive disorders, cell growth and differentiation, calcium handling in the kidney, various cancers and epilepsy. In this review, we mainly focus on the role of miR-374 family members in multiple physiological and pathological processes. More specifically, we also summarize their promising potential as novel prognostic biomarkers and therapeutic targets from bench to bedside.

HBV infection suppresses the expression of inflammatory macrophage miR­210.

It has been previously reported that hepatitis B e­antigen (HBeAg) induces microRNA (miR)­155 expression and promotes liver injury by increasing inflammatory cytokine production in macrophages. Moreover, it was previously demonstrated that miR­210 alleviates lipopolysaccharide­stimulated proinflammatory cytokine production in macrophages. In addition, accumulating evidence suggests that miR­210 is able to suppress hepatitis B virus (HBV) replication in HepG2.2.15 cells. However, it remains unclear whether miR­210, similar to miR­155, affects the progress of hepatitis B by regulating macrophage function. Reverse transcription­quantitative polymerase chain reaction analysis was used to detect miR­210 levels in serum and cells. HBV­associated antigens stimulated different types of macrophages and facilitated the observation of the effects of these antigens on miR­210 expression in macrophages. Co­culture of peripheral blood monocytes from healthy controls and the serum of patients with chronic hepatitis B (CHB) was conducted to evaluate the effect of HBV­associated elements in the serum on the expression of the macrophage miR­210 in vivo. It was observed that miR­210 expression levels were decreased in the peripheral blood monocytes (PBMs) and serum of patients with CHB and negatively associated with serum alanine aminotransferase and aspartate aminotransferase, but not other clinical parameters including hepatitis B surface antigen (HBsAg), HBeAg, anti­HBe antibody (HBeAb) and hepatitis B core antibody (HBcAb) and HBV­DNA. Notably, it was demonstrated that miR­210 expression was not affected by treatment with HBV­associated antigens in different types of macrophages. Notably, the serum of patients with CHB was able to markedly downregulate the miR­210 expression of PBMs in healthy controls. These findings suggested that, unlike the induction of miR­155 by HBeAg, there may be certain other elements, apart from HBV­associated antigens, regulating miR­210 levels in the serum and PBMs of patients with CHB that affect macrophage activation.

The E3 ubiquitin ligase MuRF2 attenuates LPS-induced macrophage activation by inhibiting production of inflammatory cytokines and migration.

Muscle RING-finger (MuRF) proteins are E3 ubiquitin ligases that are expressed in striated muscle. MuRF2 is an important member of this family, but whether it is expressed in tissues other than striated muscle has not been thoroughly elucidated to date. In this study, we determined that MuRF2 is also expressed in other vital organs, including liver, lung, brain, spleen and kidney. Moreover, we show that the level of MuRF2 expression is significantly decreased in hepatic mononuclear cells of mice with lipopolysaccharide (LPS)/d-galactosamine-induced hepatitis and negatively correlated with the serum levels of alanine aminotransferase and aspartate aminotransferase in these mice. Furthermore, the expression of MuRF2 was down-regulated in RAW264.7 cells activated with LPS but not in cells treated with polyinosinic-polycytidylic acid (Poly(I:C)) or with lipidosome plus Poly(I:C). We also found that MuRF2 was able to translocate from the cytoplasm to the nucleus in RAW264.7 cells activated with LPS but not in cells treated with Poly(I:C). In addition, we demonstrated that interleukin 6 and tumour necrosis factor α production and macrophage migration were inhibited after MuRF2 was overexpressed in RAW264.7 cells. We further verified that nuclear factor-κB p65 subunit level was greatly reduced in RAW264.7 macrophage nuclei by gain of function. Taken together, these findings indicate that MuRF2 may rescue LPS-induced macrophage activation by suppressing the production of proinflammatory cytokines and cell migration. We also identify a novel function of MuRF2 in non-muscle tissues and cells.