Effectiveness and safety of segmentectomy vs. wedge resection for the treatment of patients with operable non­small cell lung cancer: A meta­analysis and systematic review.

The present study compared the differences in effectiveness and safety between segmentectomy (ST) and wedge resection (WR) in patients with operable non-small cell lung cancer (NSCLC). The PubMed, EMBASE, Cochrane Library and Web of Science databases were searched for papers published from inception until July 2023. The inclusion criteria were based on the population, intervention, comparator, outcomes and study designs. ROBINS-I was selected to assess the risk of bias and quality of evidence in the included non-randomised studies. Appropriate effect sizes were selected, and subgroup analyses, heterogeneity tests, sensitivity analyses and publication bias were applied. A total of 18 retrospective studies were included, involving 19,381 patients with operable NSCLC. The 5-year overall survival rate [hazard ratio (HR), 0.19; 95% confidence interval (CI), 0.04, 0.34; P=0.014; I2=76.3%], lung cancer-specific survival rate (HR, 0.3; 95% CI, 0.21, 0.38; P<0.01; I2=13.8%) and metastasis rate [odds ratio (OR), 1.56; 95% CI, 1.03, 2.38; P=0.037] in patients with operable NSCLC treated with WR were worse than those in patients treated with ST. The incidence of postoperative complications (OR, 0.44; 95% CI, 0.23, 0.82) in the WR group was lower than in the ST treatment group. There was no difference in postoperative recurrence (OR, 2.15; 95% CI, 0.97, 4.74; P=0.058) and mortality (risk difference, 0.04; 95% CI, -0.03, 0.11; P=0.287) between groups. Based on current evidence, patients with NSCLC treated with ST surgery have better postoperative survival but more complications than those patients treated with WT, while the effect of WR and ST on the recurrence rate and distant metastasis rate remains controversial.

Multi-cohort validation: A comprehensive exploration of prognostic marker in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common form of RCC. It is characterized by resistance to traditional radiotherapy and chemotherapy, as well as an unfavorable clinical prognosis. Although TYMP is implicated in the advancement of tumor progression, the role of TYMP in ccRCC is still not understood. Heightened TYMP expression was identified in ccRCC through database mining and confirmed in RCC cell lines. Indeed, TYMP knockdown impacted RCC cell proliferation, migration, and invasion in vitro. TYMP showed a positive correlation with clinicopathological parameters (histological grade, pathological stage). Moreover, patients with high TYMP expression were indicative of poor prognosis in TCGA-ccRCC and external cohorts. The results of single-cell analysis showed that the distribution of TYMP was predominantly observed in monocytes and macrophages. Furthermore, there is a significant association between TYMP and immune status. Methylation analysis further elucidated the relationship between TYMP expression and multiple methylation sites. Drug sensitivity analysis unveiled potential pharmaceutical options. Additionally, mutation analyses identified an association between TYMP and the ccRCC driver genes like BAP1 and ROS1. In summary, TYMP may serve as a reliable prognostic indicator for ccRCC.

Multilevel design and construction in nanomembrane rolling for three-dimensional angle-sensitive photodetection.

Releasing pre-strained two-dimensional nanomembranes to assemble on-chip three-dimensional devices is crucial for upcoming advanced electronic and optoelectronic applications. However, the release process is affected by many unclear factors, hindering the transition from laboratory to industrial applications. Here, we propose a quasistatic multilevel finite element modeling to assemble three-dimensional structures from two-dimensional nanomembranes and offer verification results by various bilayer nanomembranes. Take Si/Cr nanomembrane as an example, we confirm that the three-dimensional structural formation is governed by both the minimum energy state and the geometric constraints imposed by the edges of the sacrificial layer. Large-scale, high-yield fabrication of three-dimensional structures is achieved, and two distinct three-dimensional structures are assembled from the same precursor. Six types of three-dimensional Si/Cr photodetectors are then prepared to resolve the incident angle of light with a deep neural network model, opening up possibilities for the design and manufacturing methods of More-than-Moore-era devices.

Recent advances in implantable sensors and electronics using printable materials for advanced healthcare.

This review article focuses on the recent printing technological progress in healthcare, underscoring the significant potential of implantable devices across diverse applications. Printing technologies have widespread use in developing health monitoring devices, diagnostic systems, and surgical devices. Recent years have witnessed remarkable progress in fabricating low-profile implantable devices, driven by advancements in printing technologies and nanomaterials. The importance of implantable biosensors and bioelectronics is highlighted, specifically exploring printing tools using bio-printable inks for practical applications, including a detailed examination of fabrication processes and essential parameters. This review also justifies the need for mechanical and electrical compatibility between bioelectronics and biological tissues. In addition to technological aspects, this article delves into the importance of appropriate packaging methods to enhance implantable devices' performance, compatibility, and longevity, which are made possible by integrating cutting-edge printing technology. Collectively, we aim to shed light on the holistic landscape of implantable biosensors and bioelectronics, showcasing their evolving role in advancing healthcare through innovative printing technologies.

Thin-Film Composite Membrane Compaction: Exploring the Interplay among Support Compressive Modulus, Structural Characteristics, and Overall Transport Efficiency.

Water scarcity has driven the demand for water production from unconventional sources and the reuse of industrial wastewater. Pressure-driven membranes, notably thin-film composite (TFC) membranes, stand as energy-efficient alternatives to the water scarcity challenge and various wastewater treatments. While pressure drives solvent movement, it concurrently triggers membrane compaction and flux deterioration. This necessitates a profound comprehension of the intricate interplay among compressive modulus, structural properties, and transport efficacy amid the compaction process. In this study, we present an all-encompassing compaction model for TFC membranes, applying authentic structural and mechanical variables, achieved by coupling viscoelasticity with Monte Carlo flux calculations based on the resistance-in-series model. Through validation against experimental data for multiple commercial membranes, we evaluated the influence of diverse physical parameters. We find that support polymers with a higher compressive modulus (lower compliance), supports with higher densities of "finger-like" pores, and "sponge-like" pores with optimum void fractions will be preferred to mitigate compaction. More importantly, we uncover a trade-off correlation between steady-state permeability and the modulus for identical support polymers displaying varying porosities. This model holds the potential as a valuable guide in shaping the design and optimization for further TFC applications and extending its utility to biological scaffolds and hydrogels with thin-film coatings in tissue engineering.

Human-robot facial coexpression.

Large language models are enabling rapid progress in robotic verbal communication, but nonverbal communication is not keeping pace. Physical humanoid robots struggle to express and communicate using facial movement, relying primarily on voice. The challenge is twofold: First, the actuation of an expressively versatile robotic face is mechanically challenging. A second challenge is knowing what expression to generate so that the robot appears natural, timely, and genuine. Here, we propose that both barriers can be alleviated by training a robot to anticipate future facial expressions and execute them simultaneously with a human. Whereas delayed facial mimicry looks disingenuous, facial coexpression feels more genuine because it requires correct inference of the human's emotional state for timely execution. We found that a robot can learn to predict a forthcoming smile about 839 milliseconds before the human smiles and, using a learned inverse kinematic facial self-model, coexpress the smile simultaneously with the human. We demonstrated this ability using a robot face comprising 26 degrees of freedom. We believe that the ability to coexpress simultaneous facial expressions could improve human-robot interaction.

The m6A modification-mediated positive feedback between glycolytic lncRNA SLC2A1-DT and c-Myc promotes tumorigenesis of hepatocellular carcinoma.

Glycolysis exerts a key role in the metabolic reprogramming of cancer. Specific long non-coding RNAs (lncRNAs) have been identified to exhibit oncogenic glycolysis regulation. Nevertheless, the precise mechanisms by which glycolysis-related lncRNAs control hepatocellular carcinoma (HCC) are still unknown. We profiled and analyzed glycolysis-associated lncRNA signatures using HCC specimens from The Cancer Genome Atlas (TCGA) dataset. Considerable upregulation of the glycolysis-related lncRNA SLC2A1-DT was noted in HCC tissues; this upregulation was strongly linked with advanced tumor stage and poor prognosis. Cell culture and animal-related studies indicated that knockdown or overexpression of SLC2A1-DT obviously restrained or promoted glycolysis, propagation, and metastasis in HCC cells. Mechanistically, SLC2A1-DT enhanced the interaction of protein between ß-catenin and YWHAZ, suppressing the binding between ß-catenin and ß-TrCP, an E3 ubiquitin ligase. Thereby, SLC2A1-DT impeded the ß-TrCP-dependent ubiquitination and ß-catenin degradation. The upregulated ß-catenin activated the transcription of c-Myc, which then increased the transcription of glycolytic genes including SLC2A1, LDHA, and HK2. Additionally, we revealed that c-Myc transcriptionally induced the expression of methyltransferase 3 (METTL3), which increased N6-methyladenosine (m6A) modification and stability of SLC2A1-DT in a YTHDF1 dependent manner. Collectively, we show that the lncRNA SLC2A1-DT promotes glycolysis and HCC tumorigenesis by a m6A modification-mediated positive feedback mechanism with glycolytic regulator c-Myc and suggested as an innovative treatment option and indicator for HCC.

Epidemiology and Clinical Characteristics of Pediatric Sepsis in PICUs in Southwest China: A Prospective Multicenter Study.

OBJECTIVES: To describe the epidemiological characteristics of pediatric sepsis in Southwest China PICUs. DESIGN: A prospective, multicenter, and observational study. SETTING: Twelve PICUs in Southwest China. PATIENTS: The patients admitted to the PICU from April 1, 2022, to March 31, 2023. The age ranged from 28 days to 18 years. All patients met the criteria of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 31 PICUs invited to participate, 12 PICUs (capacity of 292 beds) enrolled patients in the study. During the study period, 11,238 children were admitted to the participating PICUs, 367 (3.3%) of whom met the diagnosis of severe sepsis or septic shock. The most prevalent sites of infection were the respiratory system (55%) and the digestive system (15%). The primary treatments administered to these patients included antibiotics (100%), albumin (61.3%), invasive mechanical ventilation (58.7%), glucocorticoids (55.6%), blood products (51%), gammaglobulin (51%), and vasoactive medications (46.6%). Sepsis-related mortality in the PICU was 11.2% (41/367). Nearly half of the sepsis deaths occurred within the first 3 days of PICU admission (22/41, 53.7%). The mortality rate of septic shock (32/167, 19.2%) was significantly higher than that of severe sepsis (9/200, 4.5%; p < 0.001). The outcomes of a multivariate logistic regression analysis suggested that a higher pediatric Sequential Organ Failure Assessment score, and the use of invasive mechanical ventilation and vasoactive medications were independently associated with PICU mortality in children with sepsis. CONCLUSIONS: This report updates the epidemiological data of pediatric sepsis in PICUs in Southwest China. Sepsis is still a life-threatening disease in children.

Structural Consequences of Introducing Bioactive Domains to Designer ß-Sheet Peptide Self-Assemblies.

We applied solid- and solution-state nuclear magnetic resonance spectroscopy to examine the structure of multidomain peptides composed of self-assembling ß-sheet domains linked to bioactive domains. Bioactive domains can be selected to stimulate specific biological responses (e.g., via receptor binding), while the ß-sheets provide the desirable nanoscale properties. Although previous work has established the efficacy of multidomain peptides, molecular-level characterization is lacking. The bioactive domains are intended to remain solvent-accessible without being incorporated into the ß-sheet structure. We tested for three possible anticipated molecular-level consequences of introducing bioactive domains to ß-sheet-forming peptides: (1) the bioactive domain has no effect on the self-assembling peptide structure; (2) the bioactive domain is incorporated into the ß-sheet nanofiber; and (3) the bioactive domain interferes with self-assembly such that nanofibers are not formed. The peptides involved in this study incorporated self-assembling domains based on the (SL)6 motif and bioactive domains including a VEGF-A mimic (QK), an IGF-mimic (IGF-1c), and a de novo SARS-CoV-2 binding peptide (SBP3). We observed all three of the anticipated outcomes from our examination of peptides, illustrating the unintended structural effects that could adversely affect the desired biofunctionality and biomaterial properties of the resulting peptide hydrogel. This work is the first attempt to evaluate the structural effects of incorporating bioactive domains into a set of peptides unified by a similar self-assembling peptide domain. These structural insights reveal unmet challenges in the design of highly tunable bioactive self-assembling peptide hydrogels.

Ginsenoside Rg3 promotes hepatic stellate cell ferroptosis by epigenetically regulating ACSL4 to suppress liver fibrosis progression.

BACKGROUND: Ginsenoside Rg3 (G-Rg3), extracted from Panax notoginseng, possesses hepatoprotective properties. Hepatic stellate cells (HSCs) activation is responsible for liver fibrosis. Recent studies have reported the suppressive effects of G-Rg3 on HSC activation and proliferation. Ferroptosis is a novel iron regulated cell death. ACSL4, a key indicator of ferroptosis, is commonly methylated in various diseases. PURPOSE: However, the role of ACSL4 methylation-mediated HSC ferroptosis in G-Rg3 inhibition of hepatic fibrosis needs to be explored. METHODS: Effects of G-Rg3 on inhibiting fibrosis were evaluated in vivo and in vitro. The impact of G-Rg3 on HSC ferroptosis was assessed in vitro. Furthermore, the expression of ACSL4, ACSL4 methylation and microRNA-6945-3p (miR-6945-3p) levels were determined. RESULTS: G-Rg3 significantly alleviated CCl4-induced liver fibrosis, accompanied by collagen downregulation. In vitro, G-Rg3 contributed to HSC inactivation, leading to decreased collagen production. G-Rg3 induced HSC ferroptosis, characterized by increased iron accumulation, depletion of glutathione, malondialdehyde levels, and generation of lipid reactive oxygen species. Moreover, G-Rg3 promoted ACSL4 demethylation and restored its expression. Notably, DNMT3B counteracted the effect of G-Rg3-mediated inhibition of ACSL4 methylation and was targeted by miR-6945-3p. Further investigations revealed that G-Rg3 suppressed ACSL4 methylation through miR-6945-3p-mediated DNMT3B inhibition. Consistent with this, miR-6945-3p inhibition reversed G-Rg3-induced ACSL4 expression and HSC ferroptosis. CONCLUSION: G-Rg3 inhibits ACSL4 methylation by miR-6945-3p-mediated DNMT3B inhibition, thereby promoting HSC ferroptosis and mitigating liver fibrosis.

Comparison between percutaneous short-segment fixation and percutaneous vertebroplasty in treating Kummell's disease: A minimum 2-year follow-up retrospective study.

BACKGROUND: Percutaneous kyphoplasty (PKP) or percutaneous short-segment fixation (PSSF) is often used to treat Kummell's disease. However, it is not clear which treatment is better for patients. OBJECTIVE: To retrospectively compare the clinical efficacy of PVP and PSSF for the treatment of Kummell's disease. METHOD: 60 patients were involved in this research and the period of follow-up was at least 2 years. 27 of them were treated with PVP (Group I) and the rest who received PSSF (Group II). The visual analog scale (VAS) and radiographic indexes of each participant had been measured preoperatively as well as 1 week, 3 months, and 2 years postoperatively. Additionally, the Oswestry Disability Index (ODI) scores were assessed at the last time point. RESULTS: Comparing the two groups, no statistical significance was found among all parameters preoperatively. The time of operations and blood loss is less in Group I. At each time point after operation, the imaging indices in Group II are lower (P< 0.05). One week after treatments, the VAS scores are lower in Group I, and similarly, 3 months are the same (P< 0.05), while VAS are similar at the last time point. In the aspect of ODI scores, they are lower in Group II during long-term follow-up. CONCLUSION: For the treatment of Kummell's disease, both PVP and PSSF have been found to be effective. PVP can provide rapid pain relief with a shorter operation time. However, in cases with severe kyphosis deformity, PSSF should be given priority.

Self-Assembling Peptides with Insulin-Like Growth Factor Mimicry.

Growth factor (GF) mimicry involves recapitulating the signaling of larger molecules or cells. Although GF mimicry holds considerable promise in tissue engineering and drug design applications, difficulties in targeting the signaling molecule to the site of delivery and dissociation of mimicking peptides from their target receptors continue to limit its clinical application. To address these challenges, we utilized a self-assembling peptide (SAP) platform to generate synthetic insulin-like growth factor (IGF)-signaling, self-assembling GFs. Our peptide hydrogels are biocompatible and bind target IGF receptors in a dose-dependent fashion, activate proangiogenic signaling, and facilitate formation of angiogenic microtubules in vitro. Furthermore, infiltrated hydrogels are stable for weeks to months. We conclude that the enhanced targeting and long-term stability of our SAP/GF mimicry implants may improve the efficacy and safety of future GF mimic therapeutics.

Schisandrin B Promotes Hepatic Stellate Cell Ferroptosis via Wnt Pathway-Mediated Ly6Clo Macrophages.

A key event in liver fibrosis is the activation of the hepatic stellate cell (HSC). Schisandrin B (Sch B), a major component extracted from Schisandra chinensis, has been shown to inhibit HSC activation. Recently, ferroptosis (FPT) has been reported to be involved in HSC activation. However, whether Sch B has an effect on the HSC FPT remains unclear. Herein, we explored the effects of Sch B on liver fibrosis in vivo and in vitro and the roles of Wnt agonist 1 and ferrostatin-1 in the antifibrotic effects of Sch B. Sch B effectively alleviated CCl4-induced liver fibrosis, with decreased collagen deposition and α-SMA level. Additionally, Sch B resulted in an increase in lymphocyte antigen 6 complex locus C low (Ly6Clo) macrophages, contributing to a reduced level of TIMP1 and increased MMP2. Notably, the Wnt pathway was involved in Sch B-mediated Ly6C macrophage phenotypic transformation. Further studies demonstrated that Sch B-treated macrophages had an inhibitory effect on HSC activation, which was associated with HSC FPT. GPX4, a negative regulator of FPT, was induced by Sch B and found to be involved in the crosstalk between macrophage and HSC FPT. Furthermore, HSC inactivation as well as FPT induced by Sch B-treated macrophages was blocked down by Wnt pathway agonist 1. Collectively, we demonstrate that Sch B inhibits liver fibrosis, at least partially, through mediating Ly6Clo macrophages and HSC FPT. Sch B enhances Wnt pathway inactivation, leading to the increase in Ly6Clo macrophages, which contributes to HSC FPT. Sch B may be a promising drug for liver fibrosis treatment.

Diagnostic value of peripheral blood eosinophils for benign and malignant pulmonary nodule.

This retrospective study aims to assess the diagnostic utility of peripheral blood eosinophil counts in distinguishing between benign and malignant pulmonary nodules (PNs) prior to surgical intervention. We involved patients presenting with PNs measuring ≤30 mm as the primary CT imaging finding prior to surgical procedures at the General Hospital of Northern Theater Command in Shenyang, China, during the period spanning 2021 to 2022. Multivariable logistic regression analysis and receiver operator characteristic curve analysis, along with area under the curve (AUC) calculations, were used to determine the diagnostic value of eosinophil. A total of 361 patients with PN were included, consisting of 135 with benign PN and 226 with malignant PN. Multivariable logistic regression analysis showed that eosinophil percentage (OR = 1.909, 95% CI: 1.323-2.844, P < .001), absolute eosinophil value (OR = 0.001, 95% CI: 0.000-0.452, P = .033), tumor diameter (OR = 0.918, 95% CI: 0.877-0.959, P < .001), nodule type (OR = 0.227, 95% CI: 0.125-0.400, P < .001), sex (OR = 2.577, 95% CI: 1.554-4.329, P < .001), and age (OR = 0.967, 95% CI: 0.945-0.989, P = .004) were independently associated with malignant PN. The diagnostic value of regression model (AUC [95% CI]: 0.775 [0.725-0.825]; sensitivity: 74.3%; specificity: 71.1%) was superior to eosinophil percentage (AUC [95% CI]: 0.616 [0.556-0.677]; specificity: 66.8%; specificity: 51.1%) (Delong test: P < .001). Peripheral blood eosinophil percentage might be useful for early malignant PN diagnosis, and combining that with other characteristics might improve the diagnostic performance.

LncRNA FTO-IT1 promotes glycolysis and progression of hepatocellular carcinoma through modulating FTO-mediated N6-methyladenosine modification on GLUT1 and PKM2.

BACKGROUND: Long non-coding RNAs (LncRNAs) have been extensively studied to play essential roles in tumor progression. However, more in-depth studies are waiting to be solved on how lncRNAs regulate the progression of hepatocellular carcinoma (HCC). METHODS: Different expression levels of lncRNAs in HCC cells were compared by analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases. The effects of lncRNA FTO Intronic Transcript 1 (FTO-IT1) on HCC cells were assessed by gain- and loss-of-function experiments. Colony formation assay, Edu assay, glucose uptake and lactic acid production assay were performed to evaluate the regulation of proliferation and glycolysis of HCC cells by FTO-IT1. The binding between protein interleukin enhancer binding factor 2/3 (ILF2/ILF3) and FTO-IT1 was determined by RNA pull-down, mass spectroscopy and RNA immunoprecipitation experiments. RNA stability assay, quantitative reverse transcription PCR and Western blot were employed to determine the regulatory mechanisms of FTO-IT1 on fat mass and obesity-associated (FTO). Methylated RNA immunoprecipitation assay was used to assessed the regulation of key enzymes of glycolysis by FTO. The role of FTO-IT1/FTO in vivo was confirmed via xenograft tumor model. RESULTS: LncRNA FTO-IT1, an intronic region transcript of FTO gene, was highly expressed in HCC and associated with poor prognosis of patients with HCC. FTO-IT1 was related to proliferation and glycolysis of HCC cells, and contributed to the malignant progression of HCC by promoting glycolysis. Mechanistically, FTO-IT1 induced stabilization of FTO mRNA by recruiting ILF2/ILF3 protein complex to 3'UTR of FTO mRNA. As a demethylase for N6-methyladenosine (m6A), FTO decreased m6A modification on mRNAs of glycolysis associated genes including GLUT1, PKM2, and c-Myc which alleviated the YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated mRNA degradation. Therefore, the upregulated expression of FTO-IT1 leaded to overexpression of GLUT1, PKM2, and c-Myc by which enhanced glycolysis of HCC. Meanwhile, it was found that c-Myc transcriptional regulated expression of FTO-IT1 by binding to its promoter area under hypo-glucose condition, forming a reciprocal loop between c-Myc and FTO-IT1. CONCLUSIONS: This study identified an important role of the FTO-IT1/FTO axis mediated m6A modification of glycolytic genes contributed to glycolysis and tumorigenesis of HCC, and FTO-IT1 might be served as a new therapeutic target for HCC.

Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells.

BACKGROUND & AIMS: Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS: Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS: SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS: The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.

Hepatocyte-derived exosomal miR-146a-5p inhibits hepatic stellate cell EMT process: a crosstalk between hepatocytes and hepatic stellate cells.

Recently, Salidroside (Sal) has been demonstrated to suppress hepatic stellate cell (HSC) activation, a crucial event for liver fibrosis. Moreover, Sal has been reported to decrease hepatocyte injury. A growing number of reports have indicated that the crosstalk between hepatocytes and HSCs is very crucial for liver fibrosis development. Whether Sal-treated hepatocytes could inhibit HSC activation is unclear. Exosomes, as vital vehicles of intercellular communication, have been shown to transfer cargos between hepatocytes and HSCs. Herein, we aimed to investigate the roles of exosomal miRNAs from Sal-treated hepatocytes in HSC activation as well as liver fibrosis. Our results showed that Sal suppressed carbon tetrachloride (CCl4)-induced liver fibrosis in vivo. HSC activation as well as cell proliferation was repressed in HSCs co-cultured with Sal-treated hepatocytes. Interestingly, miR-146a-5p was up-regulated by Sal in CCl4-treated mice. Also, enhanced miR-146a-5p was found in hepatocytes isolated from Sal-treated CCl4 mice and hepatocyte-derived exosomes. Notably, hepatocyte exosomal miR-146a-5p contributed to HSC inactivation. Inhibiting miR-146a-5p in hepatocyte exosomes resulted in reduced E-cadherin (E-cad) and increased desmin in HSCs, indicating that miR-146a-5p caused HSC inactivation via epithelial-mesenchymal transition (EMT). miR-146a-5p inhibition-mediated HSC activation and EMT process were blocked down by loss of EIF5A2. Further studies revealed that EIF5A2 was a target of miR-146a-5p. Furthermore, exosomes with miR-146a-5p overexpression inhibited liver fibrosis in CCl4 mice. Collectively, exosomal miR-146a-5p from Sal-treated hepatocytes inhibits HSC activation and liver fibrosis, at least in part, by suppressing EIF5A2 and EMT process.

GAS5-inhibited hepatocyte pyroptosis contributes to hepatic stellate cell inactivation via microRNA-684 and AHR.

Hepatocyte pyroptosis has been shown to be involved in liver damage progression. Previously, we found that growth arrest-specific 5 (GAS5) is a regulator of hepatic stellate cell (HSC) activation. However, whether GAS5 plays a role in hepatocyte pyroptosis remains unclear. In this study, reduced GAS5 was shown in CCl4-treated mice and restoration of GAS5-inhibited liver fibrosis in vivo. Hepatocyte pyroptosis participated in the effects of GAS5-inhibited liver fibrosis, associated with reduced caspase-1, NLRP3, and IL-1ß (hepatocyte pyroptosis markers). Notably, AHR expression, a suppressor of NLRP3, was enhanced by GAS5. Silencing AHR inhibited GAS5-mediated hepatocyte pyroptosis. GAS5 and AHR were targets of microRNA-684 (miR-684). In addition, the effects of GAS5 on hepatocyte pyroptosis could be inhibited by miR-684. Interestingly, GAS5-mediated hepatocyte pyroptosis contributed to HSC inactivation. In conclusion, we demonstrate that GAS5 inhibits hepatocyte pyroptosis and HSC activation, at least in part, via regulation of miR-684 and AHR.

Ginsenoside Rh2 promotes hepatic stellate cell ferroptosis and inactivation via regulation of IRF1-inhibited SLC7A11.

BACKGROUND: Sustained liver fibrosis may lead to cirrhosis. Activated hepatic stellate cells (HSCs) are crucial for liver fibrosis development. Ferroptosis, a newly iron-dependent regulated cell death, has been demonstrated to be involved in HSC inactivation. PURPOSE: Ginsenoside Rh2 (GRh2), a natural bioactive product derived from ginseng, has been shown to promote HSC inactivation. However, the effect of GRh2 on HSC ferroptosis remains unclear. METHODS: We explored the effects of GRh2 on liver fibrosis in vivo and in vitro. RNA-sequence analysis was performed in HSCs after GRh2 treatment. The crosstalk between ferroptotic HSCs and macrophages was also explored. RESULTS: GRh2 alleviated liver fibrosis in vivo. In vitro, GRh2 reduced HSC proliferation and activation via ferroptosis, with increased intracellular iron, reactive oxygen species, malondialdehyde and glutathione depletion. The expression of SLC7A11, a negative regulator of ferroptosis, was obviously reduced by GRh2. Interestingly, interferon regulatory factor 1 (IRF1), a transcription factor, was predicted to bind the promoter region of SCL7A11. The interaction between IRF1 and SCL7A11 was further confirmed by the results of chromatin immunoprecipitation and luciferase reporter assays. Furthermore, loss of IRF1 led to an increase in SCL7A11, which contributed to the suppression of HSC ferroptosis and the enhancement of HSC activation in GRh2-treated HSCs. Further studies revealed that GRh2-induced HSC ferroptosis contributed to the inhibition of macrophage recruitment via regulation of inflammation-related genes. Moreover, GRh2 caused a reduction in liver inflammation in vivo. CONCLUSION: Collectively, GRh2 up-regulates IRF1 expression, resulting in the suppression of SLC7A11, which contributes to HSC ferroptosis and inactivation. GRh2 ameliorates liver fibrosis through enhancing HSC ferroptosis and inhibiting liver inflammation. GRh2 may be a promising drug for treating liver fibrosis.