Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Construction and characterization of a new hepatitis C virus genotype 6a subgenomic replicon that is prone to render the sofosbuvir resistance.

Hepatitis C virus (HCV) infection remains a challenge to human public health despite the development of highly effective direct-acting antivirals (DAAs). Sofosbuvir (SOF), a key component in most DAA-based anti-HCV cocktail regimens, is a potent viral RNA polymerase (NS5B) inhibitor with a high barrier to drug resistance. The serine-to-threonine mutation at NS5B 282 (S282T) confers the SOF resistance, but severely impairs viral replication in most HCV genotypes (GTs) and cannot be stably maintained after the termination of the SOF-based therapies. In this study, we first developed a new HCV GT-6a subgenomic replicon PR58D6. Next, we selected SOF-resistant PR58D6 variants by culturing the replicon cells in the presence of SOF. Interestingly, unlike many other HCV replicons which require additional mutations to compensate for the S282T-inducing fitness loss, S282T alone in PR58D6 is genetically stable and confers the SOF resistance without significantly impairing viral replication. Furthermore, we showed that amino acid residue at NS5B 74 (R74) and 556 (D556) which are conserved in GT 6a HCV contribute to efficient replication of PR58D6 containing S282T. Finally, we showed that the G556D mutation in NS5B could rescue the replication deficiency of the S282T in JFH1, a GT-2a replicon. In conclusion, we showed that a novel GT-6a HCV replicon may easily render SOF resistance, which may call for attention to potential drug resistance during DAA therapies of HCV GT-6a patients.

Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models.

The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulated necrotic areas during immune-mediated liver injury and that this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the Jagged1/notch homolog protein 2 (JAG1/NOTCH2) axis to induce cell death-resistant SRY-box transcription factor 9+ (SOX9+) hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q-positive (C1q+) MoMFs that promoted necrotic removal and liver repair, while Pdgfb+ MoMFs activated hepatic stellate cells (HSCs) to express α-smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions, not only by removing necrotic tissues, but also by inducing cell death-resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth muscle actin-expressing HSCs to facilitate necrotic lesion resolution.

Clinic-radiomics model using liver magnetic resonance imaging helps predict chronicity of drug-induced liver injury.

BACKGROUND AND AIMS: Some drug-induced liver injury (DILI) cases may become chronic, even after drug withdrawal. Radiomics can predict liver disease progression. We established and validated a predictive model incorporating the clinical characteristics and radiomics features for predicting chronic DILI. METHODS: One hundred sixty-eight DILI patients who underwent liver gadolinium-diethylenetriamine pentaacetate-enhanced magnetic resonance imaging were recruited. The patients were clinically diagnosed using the Roussel Uclaf causality assessment method. Patients who progressed to chronicity or recovery were randomly divided into the training (70%) and validation (30%) cohorts, respectively. Hepatic T1-weighted images were segmented to extract 1672 radiomics features. Least absolute shrinkage and selection operator regression was used for feature selection, and Rad-score was constructed using support vector machines. Multivariable logistic regression analysis was performed to build a clinic-radiomics model incorporating clinical characteristics and Rad-scores. The clinic-radiomics model was evaluated for its discrimination, calibration, and clinical usefulness in the independent validation set. RESULTS: Of 1672 radiomics features, 28 were selected to develop the Rad-score. Cholestatic/mixed patterns and Rad-score were independent risk factors of chronic DILI. The clinic-radiomics model, including the Rad-score and injury patterns, distinguished chronic from recovered DILI patients in the training (area under the receiver operating characteristic curve [AUROC]: 0.89, 95% confidence interval [95% CI]: 0.87-0.92) and validation (AUROC: 0.88, 95% CI: 0.83-0.91) cohorts with good calibration and great clinical utility. CONCLUSION: The clinic-radiomics model yielded sufficient accuracy for predicting chronic DILI, providing a practical and non-invasive tool for managing DILI patients.

The progress to establish optimal animal models for the study of acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) defines a complicated and multifaceted syndrome characterized by acute liver dysfunction following an acute insult on the basis of chronic liver diseases. It is usually concurrent with bacterial infection and multi-organ failure resulting in high short-term mortality. Based on the cohort studies in ACLF worldwide, the clinical course of ACLF was demonstrated to comprise three major stages including chronic liver injury, acute hepatic/extrahepatic insult, and systemic inflammatory response caused by over-reactive immune system especially bacterial infection. However, due to the lack of optimal experimental animal models for ACLF, the progress of basic study on ACLF is limping. Though several experimental ACLF models were established, none of them can recapitulate and simulate the whole pathological process of ACLF patients. Recently, we have developed a novel mouse model for ACLF combining chronic liver injury [injection of carbon tetrachloride (CCl4) for 8 weeks], acute hepatic insult (injection of a double dose CCl4), and bacterial infection (intraperitoneal injection of Klebsiella pneumoniae), which could recapitulate the major clinical features of patients with ACLF worsened by bacterial infection.

Clinical characteristics and pathogen spectra of parasitic infections in a tertiary hospital of Shanghai: A 13-year retrospective study.

Background: This study performed a follow-up investigation of parasitic infections and the evolution of the infection spectra in Shanghai and its surrounding areas in Eastern China. The current study was conducted in the Shanghai Ruijin Hospital, a tertiary hospital affiliated with Shanghai Jiao Tong University School of Medicine. Methods: This retrospective investigation reviewed a total of 412 parasitic infections in patients admitted to the Department of Infectious Diseases, Ruijin Hospital from January 1, 2010 to July 31, 2022. Detailed information for these patients was retrieved from the Electronic Medical Record System. Analysis was performed using GraphPad Prism 5.0 and SPSS Statistics 26. Results: Overall, 17 species of parasites were detected from the 412 admissions. Over the 13 years, the number of patients peaked in 2021 and food-born parasites (FBPs) were the primary species. During the most recent 5 years, Clonorchis sinensis, replacing Paragonimus westermani, has become the primary parasite detected among the patients, consistent with the observation that eating uncooked fish has turned into the most common route of transmission. Paragonimus westermani infections declined with age, but Cysticercus increased with age. The periods from the onset of symptoms to definite diagnosis for some patients infected with Sparganum mansoni, Paragonimus westermani, and Cysticercus were more than 6 months. Interestingly, eosinophilia was only detected in 51.83% of parasite-infected patients. In addition, superinfections of parasites were common in our study. Conclusion: Our study demonstrates the transitional change in the prevalence of parasitic infection over the latest 13 years in a single center in Eastern China. The incidence of parasitic infections peaked in 2021, and the dominant parasitic species switched from a soil origin to foodborne. The direction for the diagnosis and prevention of parasitic infection among different age groups should alter according to age. It is difficult to diagnose parasitic infections and superinfections that occur in some patients. Thus, more sensitive and efficient detection methods should be developed. In addition, although eosinophilia and elevated IgE are still reliable indicators for initiating screening of parasitic infection, the development of novel parasitic diagnostic kits is still in urgent need for occult infection.

Human Umbilical Cord Blood Mononuclear Cells Ameliorate CCl4-Induced Acute Liver Injury in Mice via Inhibiting Inflammatory Responses and Upregulating Peripheral Interleukin-22.

Background: Human umbilical cord blood mononuclear cells (hUCBMNCs) show therapeutic effects on many inflammatory diseases. The deterioration of acute liver injury is attributed to excessive inflammatory responses triggered by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Whether hUCBMNCs treatment is a promising strategy for acute liver injury/failure needs to be investigated. Methods: Liver injury mice induced by PAMPs, DAMPs, or DAMPs plus PAMPs were developed. DAMPs included CCl4 (carbon tetrachloride), APAP (acetaminophen), and ConA (Concanavalin A). PAMPs included Klebsiella pneumoniae (K.P.) and Salmonella typhimurium (S. Typhimurium). DAMP plus PAMP-induced liver injury was developed by sequential CCl4 and K.P. administration. hUCBMNCs were injected intravenously. Results: hUCBMNCs significantly prolonged mice survival time in DAMP plus PAMP-induced liver failure but had no benefit in bacteria-infected mice. hUCBMNCs significantly alleviated hepatic necrosis post CCl4/ConA insult. In CCl4-induced acute liver injury, peripheral levels of interleukin (IL)-22 were upregulated and liver regeneration was enhanced after treating with hUCBMNCs at 48h. The levels of p62 and LC3B-II, autophagy markers, were also upregulated in the hUCBMNC-treated group. Conclusion: hUCBMNCs as a kind of cell therapeutic strategy could attenuate acute liver injury in mice, which is executed by enhancing autophagy and regeneration in the liver via inhibiting inflammatory responses and upregulating peripheral IL-22.

Autologous Skin Fibroblast-Based PLGA Nanoparticles for Treating Multiorgan Fibrosis.

Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast-targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic-co-glycolic) acid cores, these nanoparticles, termed fibroblast membrane-camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor-ß, interleukin (IL)-11, IL-13, and IL-17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof-of-concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad-spectrum therapy for fibrosis management.

Alteration of Bile Acids and Omega-6 PUFAs Are Correlated With the Progression and Prognosis of Drug-Induced Liver Injury.

Background & Aims: Drug-induced liver injury (DILI) is one of the leading causes of liver failure with some of the patients progressed to chronic DILI. The mechanisms underlying the severity and chronicity of DILI are poorly elucidated and the biomarkers are limited. Metabolites and gut microbiota played a crucial role in the development of various liver diseases. Herein, a systematic analysis of serum metabolites and gut microbiota was performed in DILI patients, aiming to identify metabolites correlated with the progression and clinical prognosis of DILI. Methods: Various serum metabolites were quantitated using a metabolite array technology in this prospective study. Gut microbiome compositions and the expression profiles of liver genes were determined in patients with DILI and healthy controls. Results: Metabolomic analysis revealed that bile acids (BAs) and polyunsaturated fatty acids (PUFAs) were closely related to DILI severity and chronicity respectively. The ratios of serum primary/secondary BAs and omega-6/omega-3 PUFAs were elevated in DILI patients. A model established by adrenic acid (AdA) and aspartic acid (Asp) exerts good performance for predicting the chronicity of DLIL. Hepatic transcriptome revealed enhanced expression of PUFA peroxidation and supressed expression of BA synthesis related genes in DILI patients. In addition, Lactic acid bacteria and BA converting bacteria were increased in gut of DILI patients. Besides, elevated serum malondialdehyde (MDA) and fibroblast growth factor 19 (FGF19) was observed in DILI patients. Conclusion: BAs and PUFAs could be potent markers for the severity and chronicity of DILI respectively. The panel of AdA and Asp could be ideal predictive model for the risk of chronicity at the acute stage of DILI. Gut microbiota might act as a negative feedback mechanism to maintain the homeostasis of BAs and PUFAs via FGF19 signalling and PUFA saturation, respectively. Our study revealed novel biomarkers for severe and chronic DILI and provided new therapeutic targets for DILI.

COVID-19 vaccines in patients with decompensated cirrhosis: a retrospective cohort on safety data and risk factors associated with unvaccinated status.

BACKGROUND: Safety data reported from the large-scale clinical trials of the coronavirus disease 2019 (COVID-19) vaccine are extremely limited in patients with decompensated cirrhosis. The vaccination campaign in this specific population could be difficult due to uncertainty about the adverse events following vaccination. We aimed to assessed the COVID-19 vaccination rate, factors associated with unvaccinated status, and the adverse events following vaccination in patients with decompensated cirrhosis. METHODS: This is a retrospective study from Ruijin Hospial (Shanghai, China) on an ongoing prospective cohort designed for long-term survival analysis of decompensated cirrhotic patients who recovered from decompensating events or acute-on-chronic liver failure (ACLF) between 2016 and 2018. We assessed the COVID-19 vaccination rate, the number of doses, type of vaccine, safety data, patient-reported reasons for remaining unvaccinated, factors associated with unvaccinated status, and the adverse events of COVID-19 vaccine. Binary logistic regression was used for identifying factors associated with unvaccinated status. RESULTS: A total of 229 patients with decompensated cirrhosis without previous SARS-CoV-2 infection participated (mean age, 56 ± 12.2 years, 75% male, 65% viral-related cirrhosis). Mode of decompensation were grade II‒III ascites (82.5%), gastroesophageal varices bleeding (7.9%), hepatic encephalopathy (7.9%). Eighty-five participants (37.1%) received at least one dose of vaccination (1 dose: n = 1, 2 doses: n = 65, 3 doses: n = 19) while 62.9% remained unvaccinated. Patient-reported reasons for remaining unvaccinated were mainly fear of adverse events (37.5%) and lack of positive advice from healthcare providers (52.1%). The experience of hepatic encephalopathy (OR = 5.61, 95% CI: 1.24-25.4) or ACLF (OR = 3.13, 95% CI: 1.12-8.69) and post-liver transplantation status (OR = 2.47, 95% CI: 1.06-5.76) were risk factors of remaining unvaccinated independent of residential areas. The safety analysis demonstrated that 75.3% had no adverse events, 23.6% had non-severe reactions (20% injection-site pain, 1.2% fatigue, 2.4% rash) and 1.2% had a severe event (development of acute decompensation requiring hospitalization). CONCLUSIONS: Patients with decompensated cirrhosis in eastern China are largely remained at unvaccinated status, particularly those with previous episodes of ACLF or hepatic encephalopathy and liver transplantation recipients. Vaccination against COVID-19 in this population is safe.

Genetic Variations of ALDH (rs671) Are Associated With the Persistence of HBV Infection Among the Chinese Han Population.

Alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), members of the alcohol dehydrogenase family, have important roles in liver diseases. The roles of the polymorphisms of ADH1B rs1229984 and ALDH2 rs671 in hepatitis B virus (HBV) susceptibility and persistent infection were investigated in the present study. Total 1,034 patients with hepatitis B [99 acute hepatitis B (AHB), 521 chronic hepatitis B (CHB), 158 acute-on-chronic liver failure (ACLF), 159 liver cirrhosis (LC), and 97 hepatocellular carcinoma (HCC)] and 1,262 healthy controls (HCs) of the Chinese Han population were recruited, and single nucleotide polymorphisms (SNPs) of rs671 and rs1229984 were genotyped. Independent and joint roles of rs671 and rs1229984 in HBV infection were analyzed. The results showed that rs671 genotypes had a significantly different distribution among different subgroups. Compared with HCs, the frequency of rs671-AA genotype was higher in hepatitis B individuals, especially in the CHB group [adjusted OR (95%CI) = 1.899 (1.232-2.928), p = 0.003, in the co-dominant model], which showed a significant positive association. It was further confirmed that CHB individuals who carried ALDH2 rs671-AA genotype had a higher risk of persistent HBV infection and higher HBV-DNA quantitation compared with those with GG/GA genotype. In addition, the rs671-AA genotype might predict HCC incidence in patients with CHB. There were no different distributions of alleles or genotypes in rs671 mutant among AHB, ACLF, LC, or HCC groups compared with HCs. These data suggested the possible hazardous role of rs671-AA variant in HBV infection and persistence.

Identification of a novel replication-competent hepatitis C virus variant that confers the sofosbuvir resistance.

Despite the excellent antiviral potency of direct-acting antivirals (DAAs) against hepatitis C virus (HCV), emergence of drug-resistant viral mutations remains a potential challenge. Sofobuvir (SOF), a nucleotide analog targeting HCV NS5B - RNA-dependent RNA polymerase (RdRp), constitutes a key component of many anti-HCV cocktail regimens and confers a high barrier for developing drug resistance. The serine to threonine mutation at the amino acid position 282 of NS5B (S282T) is the mostly documented SOF resistance-associated substitution (RAS), but severely hampers the virus fitness. In this study, we first developed new genotype 1b (GT1b) subgenomic replicon cells, denoted PR52D4 and PR52D9, directly from a GT1b clinical isolate. Next, we obtained SOF-resistant and replication-competent PR52D4 replicon by culturing the replicon cells in the presence of SOF. Sequencing analysis showed that the selected replicon harbored two mutations K74R and S282T in NS5B. Reverse genetics analysis showed that while PR52D4 consisting of either single mutation K74R or S282T could not replicate efficiently, the engineering of the both mutations led to a replication-competent and SOF-resistant PR52D4 replicon. Furthermore, we showed that the K74R mutation could also rescue the replication deficiency of the S282T mutation in Con1, another GT1b replicon as well as in JFH1, a GT2a replicon. Structural modeling analysis suggested that K74R might help maintain an active catalytic conformation of S282T by engaging with Y296. In conclusion, we identified the combination of two NS5B mutations S282T and K74R as a novel RAS that confers a substantial resistance to SOF while retains the HCV replication capacity.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection.

BACKGROUND: This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. METHODS: In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. RESULTS: In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14-1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. CONCLUSION: The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.

Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections.

The coronavirus disease 2019 (COVID-19) has caused global public health and economic crises. Thus, new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic. The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the attractive treatment strategies for COVID-19. Currently, the receptor-binding domain (RBD) of the spike (S) protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells. A single monoclonal antibody (mAb) treatment is prone to selective pressure due to increased possibility of targeted epitope mutation, leading to viral escape. In addition, the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection. These risks can be reduced using multiple mAbs that target nonoverlapping epitopes. Thus, a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.

Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes.

BACKGROUND & AIMS: Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. METHODS: Il20 knockout (Il20-/-) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. RESULTS: Il20-/- mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20-/- mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. CONCLUSIONS: IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. LAY SUMMARY: Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.

Risk factors for myocardial injury in patients with coronavirus disease 2019 in China.

AIMS: In patients with coronavirus disease 2019 (COVID-19), the involvement of the cardiovascular system significantly relates to poor prognosis. However, the risk factors for acute myocardial injury have not been sufficiently studied. Thus, we aimed to determine the characteristics of myocardial injury and define the association between routine blood markers and cardiac troponin I, in order to perform a predictive model. METHODS AND RESULTS: This retrospective cohort study included patients with confirmed COVID-19 from Wuhan Tongji Hospital (Wuhan, China). Data were compared between those with and without myocardial injury. Kaplan-Meier analysis and Cox regression models were used to describe the association between myocardial injury and poor prognosis. Simple correlation analyses were used to find factors associated with high-sensitivity cardiac troponin I levels. Univariate and multivariate logistic regression methods were used to explore the risk factors associated with myocardial injury. The area under the receiver operating characteristic curve was used to determine the predictive value of the model. Of 353 patients included in the study, 79 presented myocardial injury. Patients with myocardial injury had higher levels of inflammation markers, poorer liver and kidney function, and more complications compared with patients without myocardial injury. High-sensitivity cardiac troponin I levels were significantly associated with neutrophil/lymphocyte ratio, creatinine, d-dimer, lactate dehydrogenase, and inflammatory cytokines and negatively associated with oxygen saturation. It was significantly associated with poor prognosis after adjusting for age, sex, and complications. Multivariate regression showed that myocardial injury was associated with a high neutrophil/lymphocyte ratio (odds ratio 2.30, 95% CI 1.11-4.75, per standard deviation increase, P = 0.02), creatinine (3.58, 1.35-8.06, P = 0.01), and lactate dehydrogenase (3.39, 1.42-8.06, P = 0.01) levels. Using a predictive model, the area under the receiver operating characteristic curve was 0.92 (0.88-0.96). CONCLUSIONS: In patients with COVID-19, neutrophil/lymphocyte ratio, creatinine, and lactate dehydrogenase are blood markers that could help identify patients with a high risk of myocardial injury at an early stage.

Interleukin-22 in alcoholic hepatitis and beyond.

Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of excess alcohol consumption and recent heavy alcohol abuse. Severe AH is a life-threatening form of alcohol-associated liver disease with a high short-term mortality rate around 30-50% at one month from the initial presentation. A large number of pro-inflammatory mediators, metabolic pathways, transcriptional factors and epigenetic factors have been suggested to be associated with the development and progression of AH. Several factors may contribute to liver failure and mortality in patients with severe AH including hepatocyte death, inflammation, and impaired liver regeneration. Although the pathogeneses of AH have been extensively investigated and many therapeutic targets have been identified over the last five decades, no new drugs for AH have been successfully developed. In this review, we discuss interleukin-22 (IL-22) biology and its roles of anti-apoptosis, anti-fibrosis, anti-oxidation, anti-bacterial infection and regenerative stimulation in protecting against liver injury in many preclinical models including several recently developed models such as chronic-plus-binge ethanol feeding, acute-on-chronic liver failure, C-X-C motif chemokine ligand 1 plus high-fat diet-induced nonalcoholic steatohepatitis. Finally, clinical trials of IL-22 for the treatment of AH are also discussed, which showed some promising benefits for AH patients.

The Use of NACSELD and EASL-CLIF Classification Systems of ACLF in the Prediction of Prognosis in Hospitalized Patients With Cirrhosis.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium and the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) as an acute deterioration of cirrhosis with multiple organ failures and high short-term mortality. However, their diagnostic criteria differ. We aimed to compare these 2 criteria in the prediction of prognosis in hospitalized cirrhosis. METHODS: This was a prospective study of nonelectively hospitalized patients with cirrhosis (N = 468) from a single tertiary hospital between 2016 and 2018. Baseline characteristics, incidence, and types of organ failure and survival data at 7, 28, and 90 days were collected. Prognostic utilities of the 2 criteria were compared. RESULTS: One hundred thirty-seven of 468 patients (29.3%) had EASL-CLIF ACLF, and 35 of 468 (7.4%) had NACSELD ACLF. The 28-day transplant-free survival of ACLF was 58.4% using EASL-CLIF and 37.1% using the NACSELD criteria. In predicting 28-day mortality, the NACSELD criteria demonstrated significantly higher overall accuracy (92.0% vs 85.3%, P < 0.01), specificity (99.7% vs 84.0%, P < 0.001), and positive predictive value (97.1% vs 50.4%, P < 0.001) but lower sensitivity (49.3% vs 92.5%, P < 0.001) and negative predictive value (91.6% vs 98.5%, P < 0.001) than those of EASL-CLIF. The results were similar in predicting 7-day outcome. However, the overall accuracy became similar between NACSELD and EASL-CLIF ACLF criteria in predicting 90-day mortality (86.3% vs 88.7%, P = 0.27) because of the decrease of sensitivity and negative predictive value of NACSELD ACLF criteria. The prognostic performance of these 2 ACLF criteria was similar when applied to patients with or without hepatitis B virus infection as an etiology of cirrhosis. DISCUSSION: There are both caveats and utilities of NACSELD and EASL-CLIF ACLF criteria in prognosis prediction in patients with cirrhosis. NACSED criteria is highly accurate in predicting morality, whereas the EASL-CLIF criteria is more sensitive to identify patients who would benefit from liver transplantation.