Hepatic fibrosis, primarily driven by the sustained activation of hepatic stellate cells (HSCs), continues to pose a significant global health challenge due to the scarcity of effective therapeutic interventions. Existing single-target approaches are inadequate in addressing the complex multicellular regulatory network within the fibrotic niche, where injured hepatocytes, Kupffer cells (KCs), and capillarized liver sinusoidal endothelial cells (LSECs) collectively perpetuate HSC activation through paracrine signaling mechanisms. To address this challenge, a novel nanoplatform has been developed, comprising a co-delivery system of quercetin (Que) and simvastatin (Sim) within a mesoporous polydopamine (MPDA)-based matrix, designed to achieve the synchronized modulation of multicellular interactions. The MPDA carrier possesses intrinsic liver-targeting and reactive oxygen species (ROS)-scavenging properties, facilitating preferential accumulation in fibrotic lesions and the mitigation of oxidative stress originating from hepatocytes and KCs. In the acidic fibrotic environment, Que and Sim are sustained within the system due to the acid-responsive properties of MPDA. The released Que reprograms pro-inflammatory M1 macrophages into anti-inflammatory M2 phenotypes, while Sim reverses LSEC capillarization, collectively disrupting the microenvironmental factors driving HSC activation. Moreover, all components—MPDA, Que, and Sim—can directly inhibit HSC activation through complementary pathways. This multi-target strategy resulted in a more significant reduction in collagen deposition compared to monotherapies in preclinical models, alongside a notable restoration of liver function. By integrating microenvironmental reprogramming with the interception of multicellular networks, our study establishes a paradigm-shifting nanotherapeutic approach for reversing fibrosis and underscores the potential of engineered multidrug coordination in treating complex stromal diseases.

This file contains Supplementary Tables 1-18, Supplementary Figure 1-2, clinical protocol and notification to attending physicians.

Background and Objectives:The treatment options for hepatitis B surface antigen (HBsAg) clearance are limited for patients who have failed pegylated interferon-α (Peg-IFNα) therapy. Given preclinical evidence that PD-1 blockade boosts antiviral immunity, this study aims to evaluate the efficacy and safety of PD-1 inhibitors in chronic hepatitis B (CHB) patients who have failed interferon therapy. Methods:This non-randomized controlled trial was conducted in CHB patients who failed to achieve HBsAg clearance after 48 weeks of Peg-IFNα therapy. Including two groups: (i) a PD-1 inhibitor plus Peg-IFNα group receiving sintilimab 1 mg/kg/12 weeks plus Peg-IFNα 180 μg/week (n = 33) or (ii) a Peg-IFNα group continuing Peg-IFNα therapy (n = 31). The primary endpoint was HBsAg clearance at week 24. Results:The PD-1 inhibitor plus Peg-IFNα group included 33 patients and the Peg-IFNα group included 31 patients. At week 24, HBsAg clearance occurred in 30.3% of PD-1 inhibitor plus Peg-IFNα group versus 9.7% of Peg-IFNα group (P = 0.047). Median HBsAg declined by -0.916 log10 IU/mL in the PD-1 inhibitor plus Peg-IFNα group compared with -0.067 log10 IU/mL in Peg-IFNα group (P = 0.013). In the PD-1 inhibitor plus Peg-IFNα group, alanine transaminase (ALT) rose transiently at week 12 only among patients who ultimately cleared HBsAg. Sintilimab increased stomatitis (12.1%) and recurrent fever (36.4%), but the frequency of grade ≥ 3 adverse events did not differ from Peg-IFNα group. Enzyme-linked immunosorbent assay (ELISA) profiling showed progressive induction of ISG15 after sintilimab, and patients achieving HBsAg clearance displayed higher baseline and week-12 OAS1 concentrations than non-clearers (both P < 0.05). Conclusions:Quarterly sintilimab add-on therapy triples the short-term HBsAg clearance rate in interferon-refractory CHB without major additional toxicity. A week-12 ALT surge and elevated OAS1 may serve as early biomarkers of response, but confirmation in larger randomized trials is needed.

Cytolysin-positive Enterococcus faecalis is a key pathogen in severe alcoholic hepatitis, yet the mechanisms through which it worsens disease and possible therapeutic strategies remain poorly understood. This study aimed to clarify the pathogenic effects of E. faecalis in acute alcohol-associated liver disease (ALD) and to assess the protective potential of Akkermansia muciniphila (Akk11) against this pathogen. Using a mouse model of acute ethanol gavage, animals received E. faecalis and/or Akk11 under prophylactic or therapeutic regimens. Assessments included liver injury markers, histopathology, lipid profiles, inflammatory cytokines, gut barrier integrity, and gut microbiota composition. E. faecalis exacerbated ethanol-induced hepatic steatosis and injury, showing a paradoxical effect: it increased histological damage while lowering circulating LPS and transaminases. This was linked to upregulated hepatic autophagy (increased Atg7) and reduced cholesterol, yet it promoted neutral lipid accumulation. Importantly, E. faecalis aggravated gut dysbiosis by markedly enriching the pro-inflammatory pathobiont Helicobacter typhlonius and impairing colonic barrier function. Intervention with Akk11 alleviated liver injury, reduced lipid accumulation and oxidative stress, and restored cytokine balance. Akk11 also strengthened gut barrier integrity, lowered serum endotoxin, and beneficially reshaped the microbiota. Prophylactic administration was particularly effective, normalizing the Firmicutes/Bacteroidota ratio, suppressing H. typhlonius, and enriching beneficial Bacteroides sartorii. This study confirms the pathogenic role of E. faecalis in acute ALD and establishes A. muciniphila (Akk11) as a promising microbiota-targeted therapy, which protects against liver injury by reinforcing the gut barrier, selectively modulating microbiota, and reducing inflammation, with prophylactic administration showing superior efficacy.

The red cell distribution width-to-albumin ratio (RAR) integrates inflammation and nutritional compromise - two hallmarks of lung cancer progression. This study validates RAR as a predictor of long-term mortality in critically ill lung cancer patients, addressing gaps in conventional ICU prognostication. In this MIMIC-IV-based retrospective cohort, 973 lung cancer patients meeting ICU criteria were stratified by RAR quartiles (calculated as RDW-CV (%) / albumin (g/dL)). Primary and secondary endpoints were 180-day and 365-day all-cause mortality. Multivariable Cox regression (adjusted for demographics, severity scores, and interventions), restricted cubic splines (RCS), and ROC analysis (at the specified endpoint) evaluated RAR's predictive utility. Subgroup analysis tested interactions with disease severity. Among 973 critically ill lung cancer patients, those in the highest RAR quartile (6 ≤ RAR < 14.29) exhibited substantially elevated mortality compared to the lowest quartile: 66.4% versus 31.1% at 180 days (P < 0.001) and 73.4% versus 43.2% at 365 days (P < 0.001). Multivariable Cox regression confirmed RAR as an independent mortality predictor, with each unit increase in continuous RAR associated with 20% higher 180-day risk (HR = 1.20, 95%CI 1.14-1.27) and 19% higher 365-day risk (HR = 1.19, 95%CI 1.13-1.25), while patients in the highest quartile faced more than doubled mortality hazard versus the lowest quartile (180-day HR = 2.32, 95%CI 1.74-3.09; 365-day HR = 2.07, 95%CI 1.60-2.67). Restricted cubic spline analysis demonstrated a linear dose-response relationship between rising RAR and mortality risk (P < 0.001). RAR significantly outperformed SOFA in discriminative accuracy for both endpoints (180-day AUC 0.65 (95%CI 0.62-0.69) vs. 0.56 (95%CI 0.53-0.60); 365-day AUC 0.64 (95%CI 0.60-0.67) vs. 0.55 (95%CI 0.51-0.59)). Subgroup analyses revealed diminished predictive utility in high-severity patients (SOFA ≥ 5; P = 0.006), though robustness persisted across other clinical strata. RAR is a robust, accessible predictor of long-term mortality in lung cancer ICU patients. Its strong discriminative ability (> 65% mortality at 6 ≤ RAR < 14.29) supports clinical utility for early risk stratification, particularly before multi-organ failure develops.

Background:Liver cancer poses a significant global health burden, characterized by substantial regional disparities. We analyzed liver cancer incidence and mortality across 204 countries and territories from 1990 to 2021 and projected trends from 2021 to 2041. Materials and methods:Data from the Global Burden of Disease (GBD) Study 2021 were used to calculate age-standardized rate (ASR), average annual percentage change (AAPC), and estimated annual percentage change (EAPC). Risk factors, human development index (HDI), and sociodemographic index (SDI) were evaluated. The Nordpred and Bayesian Age-Period-Cohort (BAPC) models projected future trends. Results:Globally, according to the analysis of AAPC, the ASR of liver cancer incidence rose by 0.115% (95% CI: 0.07-0.159) annually, while the mortality ASR trend remains stable (-0.113%, 95% CI: -0.35-0.124). Viral hepatitis B and C remained primary causes, but non-alcoholic steatohepatitis (NASH) contributions increased. The summary exposure value (SEV) for drug use increased by 12% globally, with a dramatic increase of 308% in North America. High-HDI/SDI countries exhibited higher ASR than expected, which may be attributed to aging populations and the rising incidence of metabolic diseases. Projections indicated a rising number of cases but declining ASR for both males and females by 2041. Conclusions:Tailored prevention strategies are needed to address region-specific risk factors and mitigate the growing burden of liver cancer.

BackgroundSeveral RET-targeted agents, including highly selective RET inhibitors (SRIs) and multi-kinase inhibitors (MKIs), have been approved for the treatment of advanced medullary thyroid cancer (MTC). Despite these agents targeting the same pathway, direct comparative data is lacking. This study aims to evaluate the relative efficacy and safety of these agents via network meta-analysis (NMA).MethodsWe systematically searched PubMed, Embase, Cochrane Library, Web of Science, and CNKI (up to March 2026) for RCTs evaluating RET-targeted therapies for advanced MTC. The primary outcome was progression-free survival (PFS); secondary outcomes included objective response rate (ORR) and ≥Grade 3 adverse events (AEs). A frequentist random-effects model was employed, and treatments were ranked using P-scores. The study was registered in PROSPERO (CRD420261342793).ResultsFive RCTs (n = 1,076) were included. Selpercatinib demonstrated the most significant PFS benefit (HR = 0.10, 95% CI: 0.05–0.18; P-score = 0.999), outperforming cabozantinib (HR = 0.28) and vandetanib (HR = 0.46). It also ranked first for ORR (OR = 122.6, 95% CI: 34.5–435.6). Regarding safety, selpercatinib showed no significant difference in ≥Grade 3 AEs compared to placebo (OR = 1.34), whereas anlotinib exhibited the highest toxicity (OR = 12.00). Although selpercatinib was associated with hepatotoxicity (OR = 4.20), it avoided the off-target toxicities typical of MKIs, such as hypertension and diarrhea.ConclusionThis network meta-analysis demonstrates that selpercatinib exhibits superior efficacy (PFS and ORR) and a more favorable safety profile compared to MKIs for advanced MTC. These results support its role as a recommended first-line option for advanced MTC. However, due to the heterogeneity of included populations (mixed RET mutation status and therapy lines), clinicians should interpret these findings with caution regarding the generalizability to strictly defined RET-mutant populations. Clinical decisions should be individualized.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/view/CRD420261342793, identifier CRD420261342793.

BACKGROUND/AIMS:A large percentage of patients undergoing esophagogastroduodenoscopy (EGD) screening do not have esophageal varices (EV) or have only small EV. We evaluated a large, international, multicenter cohort to develop a novel score, termed FIB-4plus, by combining the fibrosis-4 (FIB-4) score, liver stiffness measurement (LSM), and spleen stiffness measurement (SSM) to identify high-risk EV (HRV) in compensated cirrhosis. METHODS:This international cohort study involved patients with compensated cirrhosis from 17 Chinese hospitals and one Croatian institution (NCT04546360). Two-dimensional shear wave elastography-derived LSM and SSM values, and components of the FIB-4 score (i.e., age, aspartate aminotransferase, alanine aminotransferase, and platelet count [PLT]) were combined using machine learning algorithms (logistic regression [LR] and extreme gradient boosting [XGBoost]) to develop the LR-FIB-4plus and XGBoost-FIB-4plus models, respectively. Shapley Additive exPlanations method was used to interpret the model predictions. RESULTS:We analyzed data from 502 patients with compensated cirrhosis who underwent EGD screening. The XGBoost-FIB-4plus score demonstrated superior predictive performance for HRV, with an area under the receiver operating characteristic curve (AUROC) of 0.927 (95% confidence interval [CI] 0.897-0.957) in the training cohort (n=268), and 0.919 (95% CI 0.843-0.995) and 0.902 (95% CI 0.820-0.984) in the first (n=118) and second (n=82) external validation cohorts, respectively. Additionally, the XGBoost-FIB-4plus score exhibited high AUROC values for predicting EV across all cohorts. The FIB-4plus score outperformed the individual parameters (LSM, SSM, PLT, and FIB-4). CONCLUSION:The FIB-4plus score effectively predicted EV and HRV in patients with compensated cirrhosis, providing clinicians with a valuable tool for optimizing patient management and outcomes.

Liver fibrosis (LF) is a significant pathological manifestation in various types of chronic liver diseases andis associated withsubstantial global morbidity and mortality. While liver transplantation remains a treatment option,existing clinical pharmacological interventionsface limitations,highlighting the urgent need for novel therapeutic approaches. The emergence of nanobiotechnology has introduced nanoparticle-based drug delivery systems as a promising avenue for the treatment of liver-related ailments. This reviewsystematically categorizes and synthesizesthe diverse nanomaterials currently employed in themanagement of LF. It analyzesexisting nanoplatforms used for LF treatment, focusing on various mechanismsfor targeting and regulating specific cell types, including hepatic stellate cells, liver sinusoidal endothelial cells, and Kupffer cells. Additionally, strategiesfor regulating the fibrotic microenvironment, such as modulating extracellular matrix (ECM) deposition and degradationand mitigating inflammatory and oxidative stress, are explored. Finally, potential future directions and challenges for nanoparticle-based LF therapiesare discussed.

Background Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition characterized by weight loss as a prominent feature. Non-alcoholic fatty liver disease (NAFLD), typically linked to obesity and metabolic dysregulation, is increasingly recognized as being influenced by the gut-liver axis. Notably, IBD patients exhibit a heightened susceptibility to NAFLD, although the underlying mechanisms remain poorly understood. Intestinal alkaline phosphatase (IAP), an endogenous enzyme, plays a critical role in preventing intestinal bacterial translocation. We hypothesized that IAP may serve as a potential therapeutic agent for mitigating IBD-associated NAFLD. Methods An IBD model was established using three cycles of 2 % dextran sulfate sodium (DSS) administration. Mice were subsequently treated with L-phenylalanine or IAP. The activity of stool IAP, gut microbiota composition, hepatic lipid accumulation, inflammatory markers, and gut microbiome diversity were assessed. Results DSS treatment markedly reduced IAP levels. Suppression of IAP significantly increased gut permeability and exacerbated hepatic inflammation and lipid deposition. Conversely, IAP supplementation restored these parameters, improved gut microbial diversity, and normalized microbiota composition. However, IAP failed to ameliorate hepatic inflammation and lipid accumulation in Toll-like receptor 4 (TLR4) knockout mice. Conclusion Deficiency in endogenous IAP contributes to the onset of NAFLD in the context of IBD. Oral IAP supplementation enhances gut barrier integrity, stabilizes gut microbiota, and prevents NAFLD development in IBD through a TLR4-dependent mechanism.

In this editorial, we discuss a recently published manuscript by Blüthner et al in the World Journal of Gastroenterology, with a specific focus on the delayed diagnosis of inflammatory bowel disease (IBD). IBD, which includes Crohn's disease and ulcerative colitis, is a chronic intestinal disorder. A time lag may exist between the onset of inflammation and the appearance of signs and symptoms, potentially leading to an incorrect or delayed diagnosis, a situation referred to as the delayed diagnosis of IBD. Early diagnosis is crucial for effective patient treatment and prognosis, yet delayed diagnosis remains common. The reasons for delayed diagnosis of IBD are numerous and not yet fully understood. One key factor is the nonspecific nature of IBD symptoms, which can easily be mistaken for other conditions. Additionally, the lack of specific diagnostic methods for IBD contributes to these delays. Delayed diagnosis of IBD can result in numerous adverse consequences, including increased intestinal damage, fibrosis, a higher risk of colorectal cancer, and a decrease in the quality of life of the patient. Therefore, it is essential to diagnose IBD promptly by raising physician awareness, enhancing patient education, and developing new diagnostic methods.

BACKGROUND:Intrahepatic infiltration of neutrophils is a character of alcoholic hepatitis (AH) and neutrophil extracellular traps (NETs) are an important strategy for neutrophils to fix and kill invading microorganisms. The gut-liver axis has been thought to play a critical role in many liver diseases also including AH. However, whether NETs appear in AH and play role in AH is still unsure.METHODS:Serum samples from AH patients were collected and LPS and MPO-DNA were detected. WT, NE KO, and TLR4 KO mice were used to build the AH model, and the intestinal bacteria were eliminated at the same time and LPS was given. Then the formation of NETs and AH-related markers were detected.RESULTS:The serum MPO-DNA and LPS concentration was increased in AH patients and a correlation was revealed between these two indexes. More intrahepatic NETs formed in AH mice. NETs formation decreased with antibiotic intervention and restored with antibiotic intervention plus LPS supplement. While NETs formation failed to change with gut microbiome or combine LPS supplement in TLR4 KO mice. As we tested AH-related characters, liver injury, intrahepatic fat deposition, inflammation, and fibrosis alleviated with depletion of NE. These related marks were also attenuated with gut sterilization by antibiotics and recovered with a combined treatment with antibiotics plus LPS. But the AH-related markers did show a difference in TLR4 KO mice when they received the same treatment.CONCLUSION:Intestinal-derived LPS promotes NETs formation in AH through the TLR4 pathway and further accelerates the AH process by NETs.

Background: Endoscopic transaxillary approaches to thyroidectomy have been well described and gasless transaxillary endoscopic thyroidectomy (GTET) is the most popular method. However, this require a single long axillary incision which is longer than most remote access thyroidectomy procedures. We improved the GTET and provided a novel way to access the thyroid. The purpose of this study was to test the feasibility of our novel transaxillary thyroidectomy procedure and to attempt to reduce the size of the scar and reduce the flap creation area. Methods: 116 patients who underwent our novel transaxillary thyroidectomy procedure were compared with the patients who underwent open and GTET procedures. The patients’ demographics, outcomes, and complications were analyzed. Results: Although the operation time (121.48±23.91mins) was longer in the novel endoscopic group compare to the open group, it was shorter than GTET group. Intraoperative blood loss was similar between the groups. However, the novel procedure group had more drainage volume within 48 postoperative hours compare to other two groups. Despite the VAS pain score didn’t reveal a difference between the open and novel endoscopic procedure, it was lower in the novel procedure than GTET. The hospital stay days didn’t show a difference between the two groups. The number of resected central lymph nodes was similar between the groups. Differences didn’t reveal between the groups regarding to the complications rate. Conclusion: Our results showed that our novel transaxillary thyroidectomy procedure is feasible and safe. This procedure can be an alternative endoscopic transaxillary method for thyroidectomy.

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.

Endoscopic transaxillary thyroidectomy is a common method for remote-access thyroidectomy. The approach typically uses a gasless method, and a long incision to insert a special retractor. In addition, it is considered only suitable for unilateral lobectomy because of problems accessing contralateral parts of the thyroid gland. We describe here, a case of a young woman who had a total thyroidectomy performed using an endoscopic approach. We reduced the non-inflated 4–6 cm incision that is usually required, into three holes, and performed unilateral transaxillary thyroidectomy; this was verified by radioactive iodine uptake and thyroglobulin levels during follow-up. The approach was clinically successful and resulted in minimal scarring. More studies are required to optimize this promising technique.

Background: In the original axillary approach described by Ikeda et al. with three points incisions, they began by accessing the central neck region by dissecting the sternocleidomastoid muscle (SCM) off from the sternohyoid muscle. Later this approach was modified by utilizing a gasless approach that is popularized worldwide. The central neck region was accessed directly by dissociation of the sternal and clavicular heads of the SCM. However, this procedure required a 5–6 cm incision and also place a special static retractor. We modified the conventional gasless transaxillary thyroidectomy procedure to a transaxillary gas insufflation approach with shorter incisions, and a smaller flap creation area. This video is aimed to describe the step-by-step procedure of a case of modified endoscopic transaxillary gas insufflation thyroidectomy (ETGT).

Induced pluripotent stem cells (iPSCs) have been the focus of cellular therapy studies. The use of iPSCs in regenerative medicine is limited by their tumorigenic potential. This study sought to determine whether iPSCs-derived podocytes attenuate acute kidney injury (AKI) and the molecular mechanism. Inoculation of iPSCs-podocytes significantly promoted the repair of kidney injury in AKI mice, reduced the levels of kidney injury factors Scr, BUN, and urinary NAG, and alleviated the inflammatory response. Histological analysis revealed a significant increase in the number of M2 macrophages and a significant decrease in M1 macrophages in the kidney tissues. Subsequently, the genes and signaling pathways that may be associated with kidney injury repair in mice were analyzed by RNA-seq and bioinformatics prediction. The polarization of M2 macrophages was promoted by MAF bZIP transcription factor B (Mafb)-mediated activation of C-C motif chemokine receptor 5 (Ccr5) and nicotinamide phosphoribosyltransferase (Nampt) signaling pathway. Taken together, these results show that iPSCs-podocytes depend on Mafb to activate the Nampt signaling pathway through transcriptional activation of Ccr5, thereby promoting the repair of AKI caused by ischemia-reperfusion.

Backgrounds: Intrahepatic infiltration of neutrophils is a character of alcoholic acute-on-chronic liver failure (AACLF) and neutrophil extracellular traps (NETs) are an important strategy for neutrophils to fix and kill invading microorganisms. Intestinal bacteria and the gut-liver axis have been thought to play a key role in many liver diseases also including AACLF. However, whether NETs appear in AACLF and play a role in AACLF is still unsure. Methods: WT, NE KO, and TLR4 KO mice were used to build the AACLF model, and the intestinal bacteria were eliminated at the same time and LPS was given. Then the formation of NETs and AACLF related markers were detected. Results: The serum MPO-DNA and LPS concentration was increased in AACLF patients and a correlation was revealed between these two indexes. More intrahepatic NETs formed in AACLF mice by testing MPO-DNA, Cit H3, and NE. These markers decreased with gut detergent and restored markers with gut detergent plus LPS supplement. While NETs formation failed to change with gut microbiome or combine LPS supplement in TLR4 KO mice. As we tested AACLF related characters, liver injury, intrahepatic fat deposition, inflammation, and fibrosis alleviated with depletion of NE. These related marks were also attenuated with gut sterilization by antibiotics and recovered with combined treatment with antibiotics plus LPS. But the liver injury, intrahepatic fat, fibro deposition, and liver inflammation-related markers did show a significant difference in TLR4 KO mice when they received the same treatment. Conclusion: Intestinal-derived LPS promotes NETs formation in AACLF through the TLR4 pathway and further accelerates the AACLF process by NETs.

Background/Aims Binge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and the activation of neutrophil extracellular traps (NETs). Methods Serum samples from both binge drinking and alcohol-avoiding patients were analyzed. Mouse models of chronic plus binge alcohol-induced hepatosteatosis and HCC models were used. Results A marker of NETs formation, lipopolysaccharide (LPS), was significantly higher in alcoholic hepatosteatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE knockout mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and development of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product LPS. When mice lacking toll-like receptor 4 (TLR4) received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. Conclusions Formation of NETs following LPS stimulation of TLR4 upon chronic alcohol use leads to increased alcoholic steatosis and subsequent HCC.

目的 探讨单向倒刺线连续一期缝合胆总管方式在双镜联合治疗胆总管结石术中的应用效果及安全性.方法 回顾性分析2018年2月至2021年2月于本院行双镜联合治疗胆总管结石术的30例患者的临床资料,依据不同一期缝合方式将患者分为对照组和观察组,各15例.对照组采用薇荞线行间断缝合,观察组采用单向倒刺线行连续缝合.比较两组的应用效果.结果 观察组的手术时间、胆总管缝合时间短于对照组,术中出血量少于对照组,术中疼痛评分低于对照组(P<0.05).术后12 h,两组的ACTH、Cor、NE水平均高于术前,但观察组低于对照组,差异具有统计学意义(P<0.05).两组的并发症总发生率、术后进食时间、术后引流管拔除时间、住院时间、术后3 d的IL-6、hs-CRP水平及术后胆管结石残留、复发发生率比较,差异均无统计学意义(P>0.05).结论 单向倒刺线连续一期缝合胆总管方式应用于双镜联合治疗胆总管结石术中,可缩短手术和缝合用时,减少术中出血量,减轻手术应激反应,且不会增加并发症发生风险.