Longitudinal dynamic single-cell mass cytometry analysis of peripheral blood mononuclear cells in COVID-19 patients within 6 months after viral RNA clearance.

This study investigates the longitudinal dynamic changes in immune cells in COVID-19 patients over an extended period after recovery, as well as the interplay between immune cells and antibodies. Leveraging single-cell mass spectrometry, we selected six COVID-19 patients and four healthy controls, dissecting the evolving landscape within six months post-viral RNA clearance, alongside the levels of anti-spike protein antibodies. The T cell immunophenotype ascertained via single-cell mass spectrometry underwent validation through flow cytometry in 37 samples. Our findings illuminate that CD8 + T cells, gamma-delta (gd) T cells, and NK cells witnessed an increase, in contrast to the reduction observed in monocytes, B cells, and double-negative T (DNT) cells over time. The proportion of monocytes remained significantly elevated in COVID-19 patients compared to controls even after six-month. Subpopulation-wise, an upsurge manifested within various T effector memory subsets, CD45RA + T effector memory, gdT, and NK cells, whereas declines marked the populations of DNT, naive and memory B cells, and classical as well as non-classical monocytes. Noteworthy associations surfaced between DNT, gdT, CD4 + T, NK cells, and the anti-S antibody titer. This study reveals the changes in peripheral blood mononuclear cells of COVID-19 patients within 6 months after viral RNA clearance and sheds light on the interactions between immune cells and antibodies. The findings from this research contribute to a better understanding of immune transformations during the recovery from COVID-19 and offer guidance for protective measures against reinfection in the context of viral variants.

Weighted thyroid-stimulating hormone disturbance in prognosis of hepatitis B virus-related acute-on-chronic liver failure.

AIM: To weight the prognostic value of thyroid hormones in catastrophic acute-on-chronic liver failure (ACLF). METHODS: A retrospective cohort (n = 635) and two prospective cohorts (n = 353, and 198) were enrolled in this study. The performance of a novel developed prognostic score was assessed from aspects of reliability, discrimination, and clinical net benefit. RESULTS: Thyroid-stimulating hormone (TSH) was identified to have the most potential as a prognostic predictor for hepatitis B virus-related ACLF among thyroid hormones. The novel score (modified chronic liver failure-organ failure score [mCLIF-OFs]) was developed with weighted TSH and other scored organs in the CLIF-OFs using the retrospective cohort (n = 635). The predicted risk and observed probabilities of death were comparable across the deciles of mCLIF-OFs (Hosmer-Lemeshow χ2  = 4.28, p = 0.83; Brier scaled = 11.9). The C-index of mCLIF-OFs (0.885 [0.883-0.887]) for 30-day mortality was significantly higher than that of the CLIF-OFs, chronic liver failure-sequential organ failure assessment score (CLIF-SOFAs), CLIF-C ACLFs, Model of End-stage Liver Disease (MELD), and Child-Pugh (all p < 0.001). The absolute improvements of prediction error rates of the mCLIF-OFs compared to the above five scores were from 19.0% to 61.1%. After the analysis of probability density function, the mCLIF-OFs showed the least overlapping coefficients (27.9%) among the above prognostic scores. Additionally, the mCLIF-OFs showed greater net benefit than the above five prognostic scores over a wide range of risk threshold of death. Similar results were validated in two prospective ACLF cohorts with HBV and non-HBV etiologies. CONCLUSION: Weighted TSH portended the outcome of ACLF patients, which could be treated as a "damaged organ" of the hypothalamic-pituitary-thyroid axis. The novel mCLIF-OFs is a reliable prognostic score with better discrimination power and clinical net benefit than CLIF-OFs, CLIF-SOFAs, CLIF-C ACLFs, MELD, and Child-Pugh.

Binocular Visual Measurement Method Based on Feature Matching.

To address the issues of low measurement accuracy and unstable results when using binocular cameras to detect objects with sparse surface textures, weak surface textures, occluded surfaces, low-contrast surfaces, and surfaces with intense lighting variations, a three-dimensional measurement method based on an improved feature matching algorithm is proposed. Initially, features are extracted from the left and right images obtained by the binocular camera. The extracted feature points serve as seed points, and a one-dimensional search space is established accurately based on the disparity continuity and epipolar constraints. The optimal search range and seed point quantity are obtained using the particle swarm optimization algorithm. The zero-mean normalized cross-correlation coefficient is employed as a similarity measure function for region growing. Subsequently, the left and right images are matched based on the grayscale information of the feature regions, and seed point matching is performed within each matching region. Finally, the obtained matching pairs are used to calculate the three-dimensional information of the target object using the triangulation formula. The proposed algorithm significantly enhances matching accuracy while reducing algorithm complexity. Experimental results on the Middlebury dataset show an average relative error of 0.75% and an average measurement time of 0.82 s. The error matching rate of the proposed image matching algorithm is 2.02%, and the PSNR is 34 dB. The algorithm improves the measurement accuracy for objects with sparse or weak textures, demonstrating robustness against brightness variations and noise interference.

I2 -Catalyzed Cycloisomerization of Ynamides: Chemoselective and Divergent Access to Indole Derivatives.

Herein, an I2 -catalyzed unprecedented cycloisomerization of ynamides is developed, furnishing various functionalized bis(indole) derivatives in generally good to excellent yields with wide substrate scope and excellent atom-economy. This protocol not only represents the first molecular-iodine-catalyzed tandem complex alkyne cycloisomerizations, but also constitutes the first chemoselective cycloisomerization of tryptamine-ynamides involving distinctively different C(sp3 )-C(sp3 ) bond cleavage and rearrangement. Moreover, chiral tetrahydropyridine frameworks containing two stereocenters are obtained with moderate to excellent diastereoselectivities and excellent enantioselectivities. Meanwhile, cycloisomerization and aromatization of ynamides produce pyrrolyl indoles with high efficiency enabled by I2 . Additionally, control experiments and theoretical calculations reveal that this reaction probably undergoes a tandem 5-exo-dig cyclization/rearrangement process.

Dynamic Alterations of Plasma Metabolites in the Progression of Liver Regeneration after Partial Hepatectomy.

To elucidate the dynamic alterations of metabolites in rat plasma during liver regeneration and search for potential biomarkers of liver regeneration, 65 male Sprague-Dawley rats were divided into three groups: 70% partial hepatectomy group (PHx, n = 30), sham-operated group (Sham, n = 30), and pre-PHx group (pre-PHx, n = 5). Rats in the Sham and PHx groups were sacrificed after 30 min (min), 6 h (h), 24, 48, 72, and 168 h of surgery (n = 5 per time point). The gas chromatography-mass spectrometry-based metabolomic approach was used to identify the dynamic metabolites. Liver regeneration in the rats was evidenced by an increase in the liver weight/body weight ratio, expression of proliferating cell nuclear antigen, and yes-associated protein-1. Thirty-four differentially abundant metabolites between the Sham and PHx groups were identified, which were involved in arginine and proline metabolism, aminoacyl-tRNA biosynthesis, and cysteine and methionine metabolism pathways. Of these metabolites, low 1,5-anhydroglucitol may indicate proliferation of liver parenchymal cells during liver regeneration. Thus, a series of metabolic changes occurred with the progression of liver regeneration, and 1,5-anhydroglucitol could function as a novel hallmark of proliferation of liver parenchymal cells.

A prognostic model for hepatitis B acute-on-chronic liver failure patients treated using a plasma exchange-centered liver support system.

AIM: To determine the prognostic risk factors of patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) treated with plasma exchange (PE)-based artificial liver support system (ALSS), and create a prognostic predictive model. METHODS: A total of 304 HBV-ACLF patients who received PE-based ALSS were retrospectively analyzed. Potential prognostic factors on admission associated with survival were investigated. Of note, 101 additional patients were analyzed to validate the performance of the prognostic models. RESULTS: According to 28-day survival, a total of 207 patients who survived and 97 non-survivors were identified in the derivation group. Overall, 268 (88.2%) ACLF cases were caused by reactivation of HBV. Cox proportional hazards regression model revealed that age, total bilirubin, ln (alpha-fetoprotein [AFP]), encephalopathy (HE) score, sodium level, and international normalized ratio (INR) were independent risk factors of short-term prognosis. We built a model named ALSS-prognosis model (APM) to predict the 28-day survival of HBV-ACLF patients with ALSS; the model APM showed potentially better predictive performance for both the derivation and validation groups than MELD, MELD-Na, and CLIF-C ACLF score. CONCLUSIONS: Low AFP was found to be an independent risk factor for high mortality in HBV-ACLF patients treated with PE-based ALSS. We generated a new model containing AFP, namely APM, which showed potentially better prediction performance than MELD, MELD-Na, and CLIF-C ACLF score for short-term outcomes, and could aid physicians in making optimal therapeutic decisions.

Assessment of biological functions for C3A cells interacting with adverse environments of liver failure plasma.

BACKGROUND: For its better differentiated hepatocyte phenotype, C3A cell line has been utilized in bioartificial liver system. However, up to now, there are only a few of studies working at the metabolic alternations of C3A cells under the culture conditions with liver failure plasma, which mainly focus on carbohydrate metabolism, total protein synthesis and ureagenesis. In this study, we investigated the effects of acute liver failure plasma on the growth and biological functions of C3A cells, especially on CYP450 enzymes. METHODS: C3A cells were treated with fresh DMEM medium containing 10% FBS, fresh DMEM medium containing 10% normal plasma and acute liver failure plasma, respectively. After incubation, the C3A cells were assessed for cell viabilities, lactate dehydrogenase leakage, gene transcription, protein levels, albumin secretion, ammonia metabolism and CYP450 enzyme activities. RESULTS: Cell viabilities decreased 15%, and lactate dehydrogenase leakage had 1.3-fold elevation in acute liver failure plasma group. Gene transcription exhibited up-regulation, down-regulation or stability for different hepatic genes. In contrast, protein expression levels for several CYP450 enzymes kept constant, while the CYP450 enzyme activities decreased or remained stable. Albumin secretion reduced about 48%, and ammonia accumulation increased approximately 41%. CONCLUSIONS: C3A cells cultured with acute liver failure plasma showed mild inhibition of cell viabilities, reduction of albumin secretion, and increase of ammonia accumulation. Furthermore, CYP450 enzymes demonstrated various alterations on gene transcription, protein expression and enzyme activities.

Metabolomics and Cytokine Analysis for Identification of Severe Drug-Induced Liver Injury.

AIM: To evaluate the levels of metabolites and cytokines in the serum of patients with severe and non-severe idiosyncratic drug-induced liver injury (DILI) and to identify biomarkers of DILI severity. METHODS: Gas chromatography-mass spectrometry (GC-MS) and ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) based metabolomic approaches were used to evaluate the metabolome of serum samples from 29 DILI patients of severity grade 3 (non-severe), 27 of severity grade 4 (severe), and 36 healthy control (HC). The levels of total keratin-18 (K18), fragment K18, and 27 cytokines were determined by enzyme-linked immunosorbent assay. RESULTS: The alkaline phosphatase activity ( p = 0.021) and international normalized ratio (INR) ( p < 0.001) differed significantly between the severe and non-severe groups. The severe group had a higher serum fragment K18 level than the non-severe group. A multivariate analysis showed good separation between all pairs of the HC, non-severe, and severe groups. According to the orthogonal partial least-squares-discriminant analysis (OPLS-DA) model, 14 metabolites were selected by GC-MS and 17 by UPLC-MS. Among these metabolites, the levels of 16 were increased and of 15 were decreased in the severe group. A pathway analysis revealed major changes in the primary bile acid biosynthesis and alpha-linolenic acid metabolic pathways. The levels of PDGF-bb, IP-10, IL-1Rα, MIP-1ß, and TNF-α differed significantly between the severe and non-severe groups, and the levels of most of the metabolites were negatively correlated with those of these cytokines. An OPLS-DA model that included the detected metabolites and cytokines revealed clear separation of the severe and non-severe groups. CONCLUSION: We identified 31 metabolites and 5 cytokines related to the severity of idiosyncratic DILI. The primary bile acid biosynthesis and alpha-linolenic acid metabolism pathways were also related to the severity of DILI. A model that incorporated the metabolites and cytokines showed clear separation between patients with severe and non-severe DILI, suggesting that these biomarkers have potential as indicators of DILI severity.

Advanced oxidation protein products play critical roles in liver diseases.

There is a complex oxidant and antioxidant system that maintains the redox homoeostasis in the liver. While suffering from exogenous or endogenous risk factors, the balance between oxidants and antioxidants is disturbed and excessive reactive oxygen species are generated, resulting in oxidative stress. Oxidative stress is prevalent in various liver diseases and is thought to be involved in their pathophysiology. Advanced oxidation protein products are generated under conditions of oxidative damage and are newly described protein markers of oxidative stress. Previous studies have underscored the universal pathogenic roles of oxidation protein products in various diseases. However, investigations into how these products participate in the development of liver diseases have been superficial and insufficient. In this review, we highlight the current understanding of the roles of advanced oxidation protein products in liver disease pathogenesis and the underlying mechanisms. Moreover, we summarize the current studies on advanced oxidation protein products in infectious and noninfectious, acute and chronic liver diseases. Different strategies for targeting these advanced oxidation protein products and future perspectives, which may pave the way for developing new therapeutic strategies, will also be discussed here.

Proteomic Signature of Acute Liver Failure: From Discovery and Verification in a Pig Model to Confirmation in Humans.

Acute liver failure (ALF) is a fatal condition hallmarked by rapid development. The present study aimed to describe the dynamic alterations of serum proteins associated with ALF development, and to seek for novel biomarkers of ALF. Miniature pigs (n = 38) were employed to establish ALF models by infusing d-galactosamine (GALN, 1.3 g/kg). A total of 1310 serum proteins were compared in pooled serum samples (n = 10) before and 36 h after GALN administration through label-free quantitation (LFQ) based shotgun proteomics. Functional analysis suggested a significant enrichment of ALF-related proteins involved in energy metabolism. Temporal changes of 20 energy metabolism related proteins were investigated in individual pigs (n = 8) via parallel reaction monitoring (PRM) based targeted proteomics. In addition, mitochondrion degeneration and gene expression alteration of aerobic metabolism genes were confirmed in GALN-insulted pig liver. In clinical validation study enrolled 34 ALF patients and 40 healthy controls, fructose-1,6-bisphosphatase 1 (FBP1) showed a prognostic value for short-term survival (30 days) equal to that of the Model of End-stage Liver Disease score (ROC-AUC = 0.778). Survival analysis suggested significantly higher death-related hazard in ALF patients with higher FBP1 levels (>16.89 µg/dL) than in those with lower FBP1 levels (p = 0.002). Additionally, serum retinol binding protein 4 (RBP4) level was found decreased prior to ALT elevation in GALN-insulted pig model. We also confirmed that serum level of RBP4 is significantly lower in ALF patients (p < 0.001) as compared with healthy controls. In summary, this translational study, displayed by multistaged proteomics techniques, unveiled underlying functional changes related to the development of ALF and facilitated the discovery of novel ALF markers.

Tectorigenin protects against experimental fulminant hepatic failure by regulating the TLR4/mitogen-activated protein kinase and TLR4/nuclear factor-κB pathways and autophagy.

Tectorigenin has received attention due to its antiproliferation, anti-inflammatory, and antioxidant activities. In this study, we investigated the effects of tectorigenin on lipopolysaccharide (LPS)/D-galactosamine(D-GalN)-induced fulminant hepatic failure (FHF) in mice and LPS-stimulated macrophages (RAW 264.7 cells). Pretreatment with tectorigenin significantly reduced the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), histological injury, apoptosis, and the mortality of FHF mice, by suppressing the production of inflammatory cytokines such as TNF-α and IL-6. Tectorigenin also suppressed the activation of the inflammatory response in LPS-stimulated RAW 264.7 cells. Tectorigenin-induced protection is mediated through its mitigation of TLR4 expression, inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway activation, and promotion of autophagy in FHF mice and LPS-stimulated RAW 264.7 cells. Therefore, tectorigenin has therapeutic potential for FHF in mice via the regulation of TLR4/MAPK and TLR4/NF-κB pathways and autophagy.

Development and validation of a novel score for fibrosis staging in patients with chronic hepatitis B.

BACKGROUND & AIMS: Non-invasive assessment methods for liver fibrosis are urgently needed. The present study aimed to develop a novel diagnostic model for fibrosis staging in patients with chronic hepatitis B. METHODS: A cross-sectional set of 417 chronic hepatitis B patients who underwent liver biopsy was enrolled and the METAVIR score was adopted as the reference of fibrosis staging. RESULTS: Among thyroid hormones, only the level of free tetraiodothyronine (FT4) decreased gradually with the METAVIR fibrosis score (P < .001). FibroStage, a novel diagnosis model that incorporates data on FT4, platelets, cholinesterase, gamma-glutamyl transpeptidase, and age, was developed using the deriving set (n = 219). For the diagnosis of significant fibrosis, the FibroStage model had a significantly higher area under the receiver operating curve than did the FibroIndex, Forn, and Lok models (all of P < .01) and tended to better than the fibrosis-4 (P = .0791) but comparable with the aspartate transaminase-to-platelet ratio index model (P = .1694). For the diagnosis of advanced fibrosis, FibroStage had a higher area under the receiver operating curve than did the aspartate transaminase-to-platelet ratio index, FibroIndex, Forn, and Lok models (all of P < .05) and had a comparable area under the receiver operating curve with the fibrosis-4 model (P = .2109). For the diagnosis of cirrhosis, the area under the receiver operating curve of FibroStage was higher than those of the aspartate transaminase-to-platelet ratio index, fibrosis-4, FibroIndex, and Lok (all of P < .05) models and was comparable with Forn (P = .1649). These results was validated by a validation set (n = 198). CONCLUSION: FT4 may be an indicator for fibrosis staging in chronic hepatitis B patients. FibroStage is a better model than aspartate transaminase-to-platelet ratio index, fibrosis-4, FibroIndex, Forn, and Lok for the comprehensively diagnosis of significant and advanced fibrosis and cirrhosis.

High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid.

BACKGROUND: Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of thrombocytopenia in patients with acute-on-chronic liver failure (ACLF) who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocytopenia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients. METHODS: Thirty-five patients with ACLF who had been subjected to intravenous administration of 600 mg linezolid every 12 hours for more than 7 days were categorized as a ACLF treatment (ACLF-T) group, 72 patients without ACLF treated with the same dosage of linezolid were recruited as a non-ACLF treatment (NACLF-T) group, and 70 patients with ACLF without linezolid treatment served as an ACLF control (ACLF-C) group. The incidences of thrombocytopenia in different groups were compared at day 14. Risk factors were investigated using logistic regression analysis. RESULTS: The incidence of thrombocytopenia at day 14 was significantly higher in the ACLF-T group than in the ACLF-C group (20/35 vs 24/70, P=0.025) and in the NACLF-T group (20/35 vs 9/72, P<0.001). Multivariate analysis showed that the ratio of platelet count (day 7/day 0)<1 (OR=10.021; P=0.012) and the baseline platelet count (OR=0.985; P=0.036) were independent risk factors of thrombocytopenia at day 14 of linezolid therapy. CONCLUSIONS: The benefits of linezolid treatment should outweigh the risk of thrombocytopenia in patients with ACLF. Moreover, it is necessary to closely monitor the platelet count during linezolid therapy especially in the patients with decreased platelet count at day 7 of linezolid therapy.

Investigation of the Association between Air Pollution and Non-Alcoholic Fatty Liver Disease in the European Population: A Mendelian Randomization Study.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease worldwide. At the same time, the relationship between air pollution and the likelihood of developing NAFLD has been a subject of debate due to conflicting findings in previous observational research. Our objective was to examine the potential correlation between air pollutant levels and the risk of NAFLD in the European population by employing a two-sample Mendelian randomization (MR) analysis. The UK Biobank Consortium provided the summary statistics for various air pollution indicators (PM2.5, PM2.5 absorbance, PM2.5-10, PM10, NO2, and NOx). Additionally, information on NAFLD was obtained from three studies, including one derivation set and two validation sets. Heterogeneity, pleiotropy, and sensitivity analyses were performed under different MR frameworks, and instrumental variables associated with confounders (such as education, smoking, alcohol, and BMI) were detected by tools. In the derivation set, causal relationships between PM2.5, NO2, and NAFLD were observed in univariable Mendelian randomization (UVMR) (Odds Ratio (OR) = 1.99, 95% confidence interval (95% CI) = [1.22-3.22], p = 0.005; OR = 2.08, 95% CI = [1.27-3.40], p = 0.004, respectively). After adjustment for air pollutants or alcohol intake frequency in multivariable Mendelian randomization (MVMR), the above genetic correlations disappeared. In validation sets, the null associations remained in UVMR. Our findings from MR analysis using genetic data did not provide evidence for a causal association between air pollution and NAFLD in the European population. The associations observed in epidemiological studies could be partly attributed to confounders.

Cellular Senescence in Acute Liver Injury: What Happens to the Young Liver?

Cellular senescence, characterized by irreversible cell cycle arrest, not only exists in age-related physiological states, but has been found to exist in various diseases. It plays a crucial role in both physiological and pathological processes and has become a trending topic in global research in recent years. Acute liver injury (ALI) has a high incidence worldwide, and recent studies have shown that hepatic senescence can be induced following ALI. Therefore, we reviewed the significance of cellular senescence in ALI. To minimize the potential confounding effects of aging on cellular senescence and ALI outcomes, we selected studies involving young individuals to identify the characteristics of senescent cells, the value of cellular senescence in liver repair, its regulation mechanisms in ALI, its potential as a biomarker for ALI, the prospect of treatment, and future research directions.

The 90-Day Survival Threshold: A Pivotal Determinant of Long-Term Prognosis in HBV-ACLF Patients - Insights from a Prospective Longitudinal Cohort Study.

This work aims to explore the long-term prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). In this prospective study, eligible inpatients with HBV-ACLF are enrolled and followed up from December 2012 to February 2023, for clinical events, laboratory tests at least every 6 months. Overall, the survival rates at 28 days, 90 days, 1 year, 5 years, and 8 years are 64.7%, 48.8%, 46.1%, 43.8%, and 42.2%, respectively. Among the 8-year mortality and liver transplant cases, ACLF survivors (who survived over 90 days) accounted for 7.8% (9/115). Among 101 patients who survived for more than 90 days, 97.9% of patients achieve virologic response at 1 year. For HBeAg-positive patients, the HBeAg seroconversion are 25.5%, 63.6%, and 76.9% at 1, 5, and 8 years, respectively. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, INR, white blood cell count, and albumin levels gradually improve within the first year. Fibrosis biomarkers APRI, FIB-4 and Chitinase-3-like protein 1 (CHI3L1) levels decreases within the first 5 years. The Cox proportional hazards regression reveal that high total bilirubin (HR = 1.008, p = 0.021) is the independent risk factor for 8-year survival of ALCF survivors. The 90-day period following of HBV-ACLF represented a critical juncture for long-term prognosis, revealing favorable outcomes beyond this timeframe.

Identification and analysis of C17orf53 as a prognostic signature for hepatocellular carcinoma.

C17orf53 is a novel gene for DNA synthesis and homologous recombination. However, the exact role of C17orf53 in hepatocellular carcinoma (HCC) remains unclear. In this study, we analyzed it using a set of public datasets. UALCAN, Human Protein Atlas (HPA), Kaplan‒Meier Plotter, Tumor Immune Estimation Resource (TIMER), cBioPortal, GEPIA, GeneMANIA, and LinkedOmics were used. Functional analysis was conducted in SK-Hep-1 cells by using small interfering RNA (siRNA). C17orf53 was highly expressed and predicted unfavorable survival in HCC patients. Moreover, it showed positive correlations with the abundance of B cells, macrophages and dendritic cells. In addition, we identified 126 genes that were positively correlated with C17orf53 and its coeffector minichromosome maintenance 8 (MCM8). These genes were mainly enriched in the cell cycle, DNA replication and Fanconi anemia pathways. Knockdown of C17orf53 significantly inhibited the proliferation of SK-Hep-1 cells and decreased the expression of MCM8, cyclin D1 and proliferating cell nuclear antigen (PCNA). Overall, C17orf53 is a novel prognostic signature for HCC.

Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway in vivo and in vitro.

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.

Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition for construction of C─N axially chiral indoles and pyrroles.

Here, an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines was developed, forging various functionalized C─N axially chiral indoles and pyrroles in generally good to excellent yields (up to 99%), excellent chemoselectivities, and high enantioselectivities (up to 98% enantiomeric excess) with wide substrate scope. This cocatalyzed strategy not only provided an alternative promising and reliable way for asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle but also settled the issues of previous [Rh(COD)2]BF4-catalyzed system on the construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. In addition, control experiments and theoretical calculations disclosed that Zn(OTf)2 markedly reduced the barrier of migration insertion to significantly increase reaction efficiency, which was distinctly different from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination.