After partial hepatectomy (PHx), bleeding, infection, inflammation, and ROS overload blunt the regenerative drive of hepatocytes. We describe a dual strategy that remodels this hostile milieu while recharging hepatocyte regeneration. A rapidly crosslinking hydrogel (S@NV-Sr/GC), integrating dihydrocaffeic-acid-modified chitosan/GelMA, Sr2+, and Schisandrin B-loaded HUMSC nanovesicles, is applied intraoperatively to form a protective barrier. Its porous architecture supports material exchange and localized retention, minimizing off-target exposure. The CS-CA/Sr2+ network provides efficient hemostasis, antibacterial action, anti-inflammation, and ROS scavenging, as validated across assays. Concurrently, S@NV-Sr/GC operates through three parallel functions: (i) it augments hepatocyte bioenergetics-enhancing mitochondrial oxidative phosphorylation and ATP output, stabilizing Delta Psi m, and improving mitochondrial quality control-to reverse ROS-induced cell-cycle arrest and promote proliferation; (ii) via synergy among Sr2+/S@NV/CS-CA, it promotes angiogenesis and expedites microvascular recanalization; and (iii) by upregulating VEGF and bFGF, it activates quiescent CD63+ hepatic stem cells and drives transition to a proliferative CD63+CD56+ phenotype. Together these actions constitute a regenerative "charging station" that compensates for insufficient regenerative drive and accelerates liver mass recovery and function in a mouse PHx model. This concise, local, and biomimetic approach addresses key limitations of conventional care and offers a translatable perioperative adjunct for post-hepatectomy liver regeneration.

Bile acids were involved in vaccine response and modulating immune cells. Follicular helper T (Tfh) cells serve a critical immunoregulatory function in vaccine response. However, the precise role of bile acids in modulating Tfh cells and the underlying mechanisms remain unclear. Nano-adjuvant targeting and modulating Tfh cells may offer a promising strategy to improve vaccine response. In this study, we first discovered that 3-oxo-lithocholic acid (3-oxoLCA) impaired the differentiation and function of cultured Tfh vacells both in human and mice in vitro. In vivo, 3-oxoLCA gavage significantly reduced the proportion of Tfh cells in spleen and antibody responses in WT mice under NP-OVA immunization. Mechanistically, 3-oxoLCA promoted intracellular mitophagy of Tfh cells by RNA sequencing analysis and rescue experiment. Leveraging these insights, we engineered a mitophagy-inhibiting, Tfh cells-targeted nano-adjuvant (M-1@NP) decorated with anti-CXCR5 and anti-ICOS antibodies to precisely increased Tfh cells generation and function. This nanoplatform not only boosted cultured Tfh cells generation in vitro but also amplified germinal center (GC) responses and specific antibody production in immunized mice, with high targeting specificity and biocompatibility. In conclusion, 3-oxoLCA inhibited the differentiation and function of mouse and human Tfh cells by promoting intracellular mitophagy. Tfh cells-targeted nano-adjuvant effectively enhanced the ratio and functions of Tfh cells. M-1@NP represents a potentially valuable option for promoting vaccine response in clinical applications.

During organ transplantation, immune rejection is a primary cause of graft failure. In the underlying pathophysiology of rejection, T follicular helper (Tfh) cells and interleukin-21 (IL-21) play pivotal roles. Tfh cells exacerbate the humoral immune response by promoting B cell differentiation and antibody production, which leads to damage of the transplanted tissue. IL-21, a key pro-inflammatory cytokine, binds to its receptor (IL-21R) to enhance both the growth and function of Tfh cells, while also further driving B cell activation and differentiation into plasma cells. Building on this knowledge, we have developed a tacrolimus-based nano-inhibitor designed to target Tfh cells. This nano-inhibitor is constructed using a mPEG-PLGA-PLL (PEAL) scaffold, with IL-21R monoclonal antibodies conjugated to its surface, and tacrolimus encapsulated within the structure. In vitro experiments demonstrated that this nano-inhibitor effectively targets Tfh cells, inhibiting the differentiation of naive CD4+ T cells into Tfh cells. In co-culture systems of T and B cells, it significantly suppresses the activation of both cell types, leading to a reduction in IgG antibody production. In vivo, the nano-inhibitor selectively targets secondary lymphoid organs, reduces systemic inflammation, minimizes lymphocyte infiltration into the graft, and induces immune tolerance toward the transplanted tissue. In addition, no significant toxicity was observed in vitro or in vivo. As a therapeutic agent that simultaneously modulates both T and B cell responses, we believe it holds significant promise for broader applications in transplantation immunotherapy. STATEMENT OF SIGNIFICANCE: This study presents a groundbreaking nano-immunosuppressant designed to target both T and B cells, addressing the critical challenge of acute rejection in allogeneic transplantation. By combining tacrolimus nanoparticles with IL-21 receptor antibodies, this immunosuppressant effectively suppresses Tfh cell proliferation and B cell activation, significantly reducing IgG generation. The formulation enhances tacrolimus's bioavailability, minimizes off-target toxicity, and overcomes its narrow therapeutic window. In vitro and in vivo studies show reduced lymphocyte infiltration, lower inflammatory markers, and decreased nephrotoxicity compared to conventional tacrolimus.

Partial hepatectomy is an essential surgical technique used to treat advanced liver diseases such as liver tumors, as well as for performing liver transplants from living donors. However, postoperative complications such as bleeding, abdominal adhesions, wound infections, and inadequate liver regeneration pose significant challenges and increase morbidity and mortality rates. A self-repairing mixed hydrogel (O 5 H 2 /Cu 2+ /SCCK), containing stem cell derived cytokine (SCCK) derived from human umbilical cord mesenchymal stem cells (HUMSCs) treated with the traditional Chinese remedy Tanshinone IIA (TSA), is developed. This SCCK, in conjunction with O 5 H 2 , demonstrates remarkable effects on Kupffer cell activation and extracellular matrix (ECM) remodeling. This leads to the secretion of critical growth factors promoting enhanced proliferation of hepatocytes and endothelial cells, thereby facilitating liver regeneration and repair after partial hepatectomy. Furthermore, the hydrogel, featuring macrophage-regulating properties, effectively mitigates inflammation and oxidative stress damage in the incision area, creating an optimal environment for postoperative liver regeneration. The injectability and strong adhesion of the hydrogel enables rapid hemostasis at the incision site, while its physical barrier function prevents postoperative abdominal adhesions. Furthermore, the hydrogel's incorporation of Cu 2+ provides comprehensive antibacterial effects, protecting against a wide range of bacteria types and reducing the chances of infections after surgery.

Amidst the COVID-19 pandemic, uncertainty persists among caregivers regarding the vaccination of pediatric liver transplant recipients (PLTRs). This study evaluates the immunogenicity and safety of COVID-19 vaccination in this vulnerable population. A cohort of 30 PLTRs underwent sequential vaccinations with an inactivated SARS-CoV-2 vaccine followed by an Ad5-nCoV booster. We collected and analyzed blood samples pre-vaccination and four weeks post-vaccination to quantify antibody and IGRA (IFN-γ Release Assay) levels. We also documented any adverse reactions occurring within seven days post-vaccination and monitored participants for infections over six months post-vaccination, culminating in a comprehensive statistical analysis. The Ad5-nCoV booster substantially elevated IgG (T1: 18.01, 20%; T2: 66.61, 55%) and nAb (T1: 119.29, 8%; T2: 3799.75, 80%) levels, as well as T-cell responses, in comparison to the initial dose. The first dose was associated with some common adverse reactions, such as injection site pain (13.3%) and fever (16.6%), but a low rate of systemic reactions (16.0%). There was no significant difference in Omicron infection rates or RTPCR conversion times between vaccinated and unvaccinated groups. Notably, following Omicron infection, vaccinated individuals exhibited significantly higher SARS-CoV-2 IgG and nAb titers (average IgG: 231.21 vs. 62.09 S/CO, p = 0.0003; nAb: 5246.11 vs. 2592.07 IU/mL, p = 0.0002). The use of inactivated vaccines followed by an Ad5-nCoV booster in PLTRs is generally safe and elicits a robust humoral response, albeit with limited T-cell responses.

ObjectivesOur study aims to explore the clinical characteristics of Omicron infection in pediatric liver transplant recipients (PLTRs), after the national COVID-19 outbreak. Additionally, we will investigate changes in vaccine coverage and parental attitudes towards vaccinating their children after this current outbreak.MethodsWe conducted a web-based questionnaire survey to gather information on Omicron infection, vaccination status, and guardian attitude among PLTRs. Besides, utilized valid questionnaire and long-term follow-up information processing techniques, and performed statistical analysis of relevant parameters.Results528 valid questionnaires were collected, among which, 251 responses replied Omicron infection status. The Omicron infection rate in Chinese PLTRs was 56.2% (141/251), similar to the report in the normal population (around 60%). 99.3% of infected PLTRs presented mild symptoms, mostly with fever (78.0%), followed by Cough (76.6%), with a mean RTPCR conversion time of 7 days; the overall PLTRs' vaccination rate in this study was 13.3%, similar to that of our previous study (9.4%). Besides, we found no significant differences of either infection rate or clinical symptoms between the vaccinated and unvaccinated groups. Moreover, the study showed 61.6% of guardians supported COVID-19 inoculation despite the outbreak of Omicron status.ConclusionsThe symptoms of Omicron infection in Chinese PLTRs were relatively mild, vaccine immunization had a limited effect on PLTRs' defense against Omicron infection, besides, their guardians supported the inoculation policy with a caution.Clinical trial registrationhttp://www.chictr.org.cn, identifier ChiCTR2200055968.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-alpha-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1 beta and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most serious complications after transplantation. Epstein-Barr virus (EBV) is a key pathogenic driver of PTLD. About 80% of PTLD patients are EBV positive. However, the accuracy of preventing and diagnosing EBV-PTLD by monitoring EBV DNA load is limited. Therefore, new diagnostic molecular markers are urgently needed. EBV-encoded miRNAs can regulate a variety of EBV-associated tumors and are expected to be potential diagnostic markers and therapeutic targets. We found BHRF1-1 and BART2-5p were significantly elevated in EBV-PTLD patients, functionally promoting proliferation and inhibiting apoptosis in EBV-PTLD. Mechanistically, we first found that LZTS2 acts as a tumor suppressor gene in EBV-PTLD, and BHRF1-1 and BART2-5p can simultaneously inhibit LZTS2 and activate PI3K-AKT pathway. This study shows that BHRF1-1 and BART2-5p can simultaneously inhibit the expression of tumor suppressor LZTS2, and activate the PI3K-AKT pathway, leading to the occurrence and development of EBV-PTLD. Therefore, BHRF1-1 and BART2-5p are expected to be potential diagnostic markers and therapeutic targets for EBV-PTLD patients.

BACKGROUND:Hepatic steatosis commonly occurs in some chronic liver diseases and may affect disease progression.AIM:To investigate the performance of controlled attenuation parameter (CAP) for the diagnosis of hepatic steatosis in patients with autoimmune liver diseases (AILDs).METHODS:Patients who were suspected of having AILDs and underwent liver biopsy were consistently enrolled. Liver stiffness measurement (LSM) and CAP were performed by transient elastography. The area under the receiver operating characteristic (AUROC) curve was used to evaluate the performance of CAP for diagnosing hepatic steatosis compared with biopsy.RESULTS:Among 190 patients with biopsy-proven hepatic steatosis, 69 were diagnosed with autoimmune hepatitis (AIH), 18 with primary biliary cholangitis (PBC), and 27 with AIH-PBC overlap syndrome. The AUROCs of CAP for the diagnosis of steatosis in AILDS were 0.878 (0.791-0.965) for S1, 0.764 (0.676-0.853) for S2, and 0.821 (0.716-0.926) for S3. The CAP value was significantly related to hepatic steatosis grade (P < 0.001). Among 69 patients with AIH, the median CAP score was 205.63 ± 47.36 dB/m for S0, 258.41 ± 42.83 dB/m for S1, 293.00 ± 37.18 dB/m for S2, and 313.60 ± 27.89 dB/m for S3. Compared with patients with nonalcoholic fatty liver disease (NAFLD) presenting with autoimmune markers, patients with AIH concomitant with NAFLD were much older and had higher serum IgG levels and LSM values.CONCLUSION:CAP can be used as a noninvasive diagnostic method to evaluate hepatic steatosis in patients with AILDs. Determination of LSM combined with CAP may help to identify patients with AIH concomitant with NAFLD from those with NAFLD with autoimmune phenomena.

Background and Aim Chronic inflammation links closely to insulin resistance and lipid metabolism in nonalcoholic fatty liver disease (NAFLD). Macrophage M1 activation plays an important role in the initiation and continuing of pro-inflammatory response of NAFLD. Our study was to investigate whether macrophage M1/M2 polarization switching would affect hepatic inflammation and lipid metabolism through modulation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activity in vivo and in vitro. Methods RAW264.7 macrophages were treated with different fatty acids, and cell culture supernatants were collected to prepare conditioned media (CM). Different co-culture systems between primary hepatocytes and CM from macrophages were established. A PPAR-gamma agonist or antagonist was administered to regulate PPAR-gamma activity and macrophage polarization. M1/M2 phenotype markers, inflammatory signaling pathway, and lipid-related genes expression were determined. Wild-type C57BL/6 mice were fed a high-fat diet to induce NAFLD and given rosiglitazone to regulate PPAR-gamma activity in vivo. Results Saturated fatty acids induced M1-polarized macrophages while polyunsaturated fatty acids induced M2-polarized macrophages. M1-polarized macrophages significantly promoted lipid synthesis and accumulation in primary hepatocytes through upregulation of a toll-like receptor 4 (TLR4)/NF-kappa B signaling pathway. The PPAR-gamma agonist made lipid-induced M1-polarized macrophages switch to an M2-predominant phenotype, while PPAR-gamma antagonist had the opposite effect. Macrophage polarization shifting subsequently affected lipid metabolism in primary hepatocytes. Administration of rosiglitazone improved high-fat diet induced hepatic steatosis and lipid metabolism through reducing hepatic TLR4/NF-kappa B expression and M1-polarized Kupffer cells. Conclusions Lipid-induced macrophage M1 polarization promoted hepatic lipid metabolism. Modulation of PPAR-gamma activity could shift macrophage polarization and subsequently affect lipid metabolism. Upregulation of the TLR4/NF-kappa B signaling pathway is closely linked to dysregulated lipid metabolism in NAFLD.

肝纤维化是各种慢性肝脏疾病向肝硬化发展的重要病理过程,影响患者的治疗和预后,准确及时的评估肝纤维化是慢性肝病患者诊治过程中的重要环节.近年来瞬时弹性成像作为一种无创性肝纤维化检测手段在评估肝纤维化、肝硬化方面展示出良好的准确性和可靠性.随着该项技术在临床应用的逐步广泛,瞬时弹性成像在慢性肝病治疗效果的评估和长期随访监测中的应用亦得到了诸多研究的验证,本文就其进展作一综述.

AIM:To investigate the performance of transient elastography (TE) for diagnosis of fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome.METHODS:A total of 70 patients with biopsy-proven AIH-PBC overlap syndrome were included. Spearman correlation test was used to analyze the correlation of liver stiffness measurement (LSM) and fibrosis stage. Independent samples Student's t-test or one-way analysis of variance was used to compare quantitative variables. Receiver operating characteristics (ROC) curve was used to calculate the optimal cut-off values of LSM for predicting individual fibrosis stages. A comparison on the diagnostic accuracy for severe fibrosis was made between LSM and other serological scores.RESULTS:Patients with AIH-PBC overlap syndrome had higher median LSM than healthy controls (11.3 ± 6.4 kPa vs 4.3 ± 1.4 kPa, P < 0.01). LSM was significantly correlated with fibrosis stage (r = 0.756, P < 0.01). LSM values increased gradually with an increased fibrosis stage. The areas under the ROC curves of LSM for stages F ≥ 2, F ≥ 3, and F4 were 0.837 (95%CI: 0.729-0.914), 0.910 (0.817-0.965), and 0.966 (0.893-0.995), respectively. The optimal cut-off values of LSM for fibrosis stages F ≥ 2, F ≥ 3, and F4 were 6.55, 10.50, and 14.45 kPa, respectively. LSM was significantly superior to fibrosis-4, glutaglumyl-transferase/platelet ratio, and aspartate aminotransferase-to-platelet ratio index scores in detecting severe fibrosis (F ≥ 3) (0.910 vs 0.715, P < 0.01; 0.910 vs 0.649, P < 0.01; 0.910 vs 0.616, P < 0.01, respectively).CONCLUSION:TE can accurately detect hepatic fibrosis as a non-invasive method in patients with AIH-PBC overlap syndrome.

肝脏脂肪变性可表现在多种慢性肝脏疾病中并影响其治疗效果和预后.近年来,受控衰减参数(CAP)已广泛应用于肝脏脂肪变性的评估中,具有良好的诊断价值.该文就CAP在临床上的诊断应用、影响因素及随访应用等方面作一综述.

Background:Kupffer cells and hepatic stellate cells(HSC)play important roles in the initiation and progression of hepatic inflammation and fibrosis in chronic liver injury. Aims:To investigate the roles of Kupffer cell polarization and HSC activation in the development of hepatic inflammation and fibrosis in progression of non-alcoholic fatty liver disease (NAFLD). Methods:C57BL/6 mice were fed with high fat(HF)diet and methionine-choline-deficient(MCD)diet to induce experimental non-alcoholic fatty liver(NAFL)and non-alcoholic steatohepatitis(NASH),respectively. Liver steatosis,inflammation and fibrosis were determined by histopathological examination through HE staining and Masson staining. Kupffer cell phenotypes and HSC activation were assessed by immunohistochemistry. Expressions of PPAR-γ as well as inflammation-and fibrosis-related genes were measured by real-time PCR. Results:F4/80-positive Kupffer cells, CD11c-positive M1 polarized macrophages and α-SMA-positive HSC were significantly increased in liver tissue of mice with HF diet-induced NAFL and MCD diet-induced NASH(P<0.05),and was more apparent in MCD diet-induced NASH (P<0.05). Expressions of TNF-α and TGF-β1 mRNA in liver tissue were significantly increased in both groups(P<0.05),whereas expressions of α-SMA and Col1 mRNA were significantly increased only in NASH(P<0.05). Hepatic PPAR-γ mRNA expression was significantly increased in NAFL(P<0.05)but significantly decreased in NASH(P<0.05). Conclusions:Hepatic Kupffer cells exists a sustained M1 polarization in the development of NAFLD. Activation of HSC appears in the early stage of NAFLD,and accelerates in the progression of NAFL to NASH. Polarization of Kupffer cells and activation of HSC initiate and promote hepatic inflammation and fibrosis in NAFLD.

原发性硬化性胆管炎(PSC)是由多发性、弥漫性肝内外胆管纤维性狭窄而引起的慢性胆汁淤积性肝病.关于PSC的研究大多源于西方国家,而日本的许多现状与国外不同,故较难直接采纳用于临床实践.本指南采用德尔菲法将发表证据与专家意见相结合,由筹备委员会、专家小组和作为评价委员会的日本胆道协会科学委员会共同制订.指南共由16条问题列表组成,主要针对PSC的流行病学/病理生理学、诊断、治疗和预后,每条指南的证据质量和推荐强度由等级制确定.这些指南将有助于临床医生管理PSC,改善和发展PSC有关的医疗策略.

Abnormal lipid-mediated hepatic inflammatory-immune dysfunction and chronic low grade inflammation play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophage polarization is an important mechanism for the regulation of inflammatory response. Since PPAR-γ has emerged as a master regulator of macrophage polarization, we aimed to investigate the lipid-induced macrophage/Kupffer cell polarization in vivo and in vitro, and explore the association between PPAR-γ activity and macrophages M1/M2 polarization shifting. Here we showed that long-term high-fat diet increased Kupffer cells content with M1-predominant phenotype and increasing production of pro-inflammatory cytokines. Saturated fatty acids polarized Kupffer cells/macrophages to an M1-predominant phenotype while n-3 PUFA polarized Kupffer cells/macrophages to an M2 phenotype, which was associated with activation of NF-κB signal pathway and PPAR-γ respectively. Furthermore, up-regulation of PPAR-γ shifted lipid-induced macrophages polarization from M1-predominant phenotype to M2 phenotype. Macrophages polarization switch was associated with the interaction between PPAR-γ and NF-κBp65 signal pathway. Rosiglitazone restored high-fat diet-induced imblance of Kupffer cells M1/M2 polarization and alleviated hepatic steatosis as well as local pro-inflammatory response. These findings suggest that manipulation of PPAR-γ activity has the potential to balance lipid-induced M1/M2 macrophage/Kupffer cell polarization, and leading to prevent the development of NAFLD.