Search Results (72)

Background: Gandouling (GDL) is a compound prepared in Chinese medicine and demonstrates favorable clinical efficacy. Studies have shown that sinusoid capillarization promoted hepatic fibrosis and was a potential target for preventing and treating liver fibrosis in Wilson’s disease (WD). This study aimed to explore whether GDL inhibited the sinusoid capillarization in WD by blocking the communication between hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). Methods: In this study, Atp7b-H1071Q (TX) mice were used as the WD model mice, and CuSO₄⋅5H₂O treated LX-2 cells were used as the HSC activation model. We used scanning electron microscopy, vascular tube formation assay, Western blot, cell transfection, and co-culture system to study how GDL blocked the communication between HSCs and LSECs, as well as its inhibitory effect on the sinusoid capillarization. Results: We found that GDL alleviated liver fibrosis in TX mice, inhibited HSC activation, and sinusoid capillarization in TX mice. Excessive secreted VEGFA by LX-2 cells promoted the sinusoid capillarization, played the role of a messenger molecule, and GDL blocked the VEGFA-mediated HSCs-LSECs communication. Furthermore, bioinformatics analysis, molecular docking, and molecular dynamics suggested that GDL may exert its effect by modulating the PDGFRβ/ERK/VEGFA signaling axis. We validated the above observation through experiments, that GDL reduced PDGFRβ/ERK signal pathway in LX-2 cells, inhibited the expression of messenger molecule VEGFA, blocked HSCs-LSECs communication, inhibited sinusoid capillarization, and improved WD. Conclusions: GDL blocked the communication between HSCs and LSECs and inhibited the sinusoid capillarization associated with liver fibrosis in WD by the PDGFRβ/ERK/VEGFA signaling axis. Full article

The endothelium, as the inner layer of the vascular wall, is in constant contact with blood components, so that leukocytes have the ability to adhere to endotheliocytes and penetrate to the subendothelial space. When studying heterogenic vascular samples containing endothelial cells or pathological processes related to inflammation within the endothelium, it may be necessary to distinguish DNA by endothelial and leukocyte origin, which is possible due to its specific epigenetic modifications. To identify CpG loci that could serve as markers for endothelial cells, we searched for their distinctive stable methylated or demethylated states by applying marginal filtering (selecting CpG loci with methylation Beta values closer to 0 and 1) to the microarray data and identified 47 CpG loci with relatively stable methylation/demethylation status that differentiate endothelial (HUVEC, HCMEC, HPAEC, HPMEC, and LSEC) DNA from leukocyte (granulocytes, monocytes, and lymphocytes) DNA. In addition, we compared CpG loci with high and low levels of DNA methylation between different types of endothelial cells and leukocytes. We believe that the obtained data will hopefully facilitate further studies on endothelial dysfunction. Full article

Liver sinusoidal endothelial cells (LSECs) are essential for preserving liver homeostasis. Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a category of hepatic disorders characterized by excessive fat accumulation in the liver, known as steatosis. Over time, accumulated hepatic fat can induce inflammation of the liver (hepatitis). MASLD is among the most prevalent types of chronic liver disease. Obesity and Type 2 diabetes mellitus (T2DM) are frequent etiological factors of MASLD. In the absence of therapy, MASLD can lead to more severe hepatic conditions, which can be life-threatening. MASLD is noteworthy due to its potential progression to MASH and further severe liver impairment, including cirrhosis and hepatocellular carcinoma (HCC), a neoplastic progression. This narrative review examines the distinctive functions of LSECs in regulating immunologic responses, collagenization, and drug-sensitive bioreactivity in healthy livers, MASLD, and metabolic dysfunction-associated steatohepatitis (MASH), as well as in a human primary 3D model. We found that LSECs serve as crucial regulators of immunological equilibrium in the liver by inhibiting disproportionate immunologic activation, concurrently filtering tissue antigens, and engaging with immunologic cells, such as Kupffer cells (KCs) and T lymphocytes. In chronic diseases of the liver, LSECs experience cellular dysfunction, resulting in capillarization (focal to diffuse), loss of fenestrations (fenestrae), and the activation of pro-fibrotic signaling pathways, including transforming growth factor-beta (TGF-β). Indeed, TGF-β is crucial in activating hepatic stellate cells (HSCs), a process that facilitates the progression of liver disease toward fibrosis. In addition to examining the dynamic interplay between LSECs, specifically HSCs, and other liver cells throughout the progression of fatty liver–MASH, we suggest that LSECs may become a potential therapeutic target for modifying immune responses and averting fibrosis in hepatic disorders. The limitations of animal models are also highlighted and discussed. Full article

Audio-driven emotional talking face generation aims to generate talking face videos with rich facial expressions and temporal coherence. Current diffusion model-based approaches predominantly depend on either single-label emotion annotations or external video references, which often struggle to capture the complex relationships between modalities, resulting in less natural emotional expressions. To address these issues, we propose MF-ETalk, a multimodal feature-guided method for emotional talking face generation. Specifically, we design an emotion-aware multimodal feature disentanglement and fusion framework that leverages Action Units (AUs) to disentangle facial expressions and models the nonlinear relationships among AU features using a residual encoder. Furthermore, we introduce a hierarchical multimodal feature fusion module that enables dynamic interactions among audio, visual cues, AUs, and motion dynamics. This module is optimized through global motion modeling, lip synchronization, and expression subspace learning, enabling full-face dynamic generation. Finally, an emotion-consistency constraint module is employed to refine the generated results and ensure the naturalness of expressions. Extensive experiments on the MEAD and HDTF datasets demonstrate that MF-ETalk outperforms state-of-the-art methods in both expression naturalness and lip-sync accuracy. For example, it achieves an FID of 43.052 and E-FID of 2.403 on MEAD, along with strong synchronization performance (LSE-C of 6.781, LSE-D of 7.962), confirming the effectiveness of our approach in producing realistic and emotionally expressive talking face videos. Full article

Liver diseases encompass a wide range of etiologies and involve highly heterogeneous cellular environments, yet the specific cellular states through which genetic risk contributes to disease remain incompletely understood. In this study, we integrated genome-wide association study (GWAS) data from six liver diseases and two metabolic traits with transcriptomic profiles of approximately 168,000 human liver cells at single-cell resolution, using the single-cell disease relevance score (scDRS) approach. Our results revealed that disease-associated genetic signals are predominantly localized to non-parenchymal cells—particularly liver sinusoidal endothelial cells (LSECs), cholangiocytes, and specific subsets of lymphocytes. Notably, we identified marked intra-cell-type heterogeneity, with disease associations confined to specific subpopulations exhibiting immune activation or stress-responsive transcriptional programs. For example, autoimmune and viral liver diseases were linked to immunologically active LSECs and cholangiocytes, whereas their metabolically active counterparts showed no enrichment. These findings highlight the necessity of resolving liver cell complexity to uncover the functional basis of genetic risk and suggest that susceptibility to liver disease is driven by specialized cell states within broader cellular categories. Our study provides a refined cellular map of liver disease susceptibility, offering new perspectives for understanding pathogenic mechanisms and informing targeted therapeutic strategies. Full article

Liver fibrosis is a common pathological manifestation of various chronic liver diseases, distinguished by the excessive accumulation of the extracellular matrix. If unresolved, liver fibrosis can progress to cirrhosis or hepatocellular carcinoma. Fenestrae are important structures of liver sinusoidal endothelial cells (LSECs) regulating hepatic substance exchange, immune response and hemodynamics. The loss of this structure is usually accompanied by dysfunction of LSECs, which disrupts normal liver physiology by impairing hepatic substance exchange, compromising liver microcirculation, and activating hepatic stellate cells (HSCs). This cascade of events ultimately contributes to the onset and development of liver fibrosis. Oxidative stress, impairment of the NO signaling pathway, actin–myosin complex remodeling and pathological angiogenesis are considered to be the main mechanisms underlying LSEC defenestration. Recently, research on the treatment of LSEC defenestration has made notable progress, and findings suggest a potential value in the application of anti-fibrotic therapies. This article expounds the important correlation between defenestration of LSECs and liver fibrosis, while also reviews therapeutic agents and approaches targeting this pathological process. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is closely associated with type 2 diabetes mellitus (T2DM), where T2DM serves as a crucial driving factor for MAFLD progression. While vitamin D (VD) demonstrates protective effects against MAFLD, the underlying mechanisms through which it influences MAFLD-related liver sinusoidal endothelial cell (LSEC) capillarization remain to be elucidated. This study aimed to explore how vitamin D ameliorates LSEC capillarization in T2DM-associated MAFLD. Methods: Culture human liver sinusoidal endothelial cells (HLSECs) according to the established protocol. After 1,25(OH)₂D₃ intervention in high glucose (HG)-induced HLSECs, determine the changes in liver sinusoidal capillarization-related proteins (LN, PLVAP), autophagy and pyroptosis levels. Observe the changes in cell lipid accumulation and fenestration structures. After adding Bafilomycin A1, MCC950, compound C and rapamycin to HLSECs, explore the therapeutic mechanism of 1,25(OH)₂D₃. After supplementing VD to MAFLD model mice, further verify the therapeutic mechanism of VD on MAFLD. Results: HG can induce the capillarization and lipid accumulation of HLSEC, increase the level of pyroptosis, and simultaneously reduce the autophagy level. Vitamin D alleviated high-glucose-induced pyroptosis (by suppressing GSDMD/NLRP3) and autophagic inhibition by activating the AMPK-mTOR axis (upregulating p-AMPK and downregulating mTOR), and improved lipid accumulation and hepatic sinusoidal capillarization. In the mouse model of MAFLD, VD supplementation can induce autophagy, inhibit pyroptosis and capillarization, and improve MAFLD. Conclusions: These results demonstrate, for the first time, that VD mitigates LSEC dysfunction through dual mechanisms: activating AMPK-dependent autophagy and inhibiting pyroptosis, providing a therapeutic rationale for VD in treating MAFLD-related sinusoidal pathology. Full article

Background: Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, with liver metastasis representing the leading cause of CRC-related mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently gained attention due to its overexpression in colorectal tumor tissues and its potential role in driving metastatic progression. This aims to investigate the involvement of PCSK9 in the liver metastatic niche, focusing on its effects on liver sinusoidal endothelial cells (LSECs), key components of the liver microenvironment. Methods: LSECs were stimulated with conditioned media derived from differentiated colorectal cancer cells and cancer stem cells (CSCs), the latter generated by reprogramming SW620 and CT26 cell lines. RNA sequencing was used to profile gene expression in LSECs. PCSK9 mRNA and protein levels were quantified by qPCR and Western blotting, respectively. PCSK9 expression in CRC liver metastases was evaluated by immunofluorescent staining. Results: PCSK9 was detected in both human and murine LSECs and significantly upregulated following exposure to CSC-conditioned media. Immunofluorescent staining confirmed PCSK9 expression in LSECs within CRC liver metastases. Total RNA sequencing revealed that a pre-treatment of LSECs with the PCSK9 inhibitor PF-06446864 prior to CSC stimulation seems to reduce the expression of microRNAs linked to cell migration and proliferation. Functional assays demonstrated that CSC-conditioned media enhanced LSEC proliferation and migration, effects reversed by PCSK9 inhibition. Conclusions: PCSK9 promotes the activation of LSECs in response to colorectal CSCs, contributing to a pro-metastatic phenotype. These findings highlight PCSK9 as a potential therapeutic target in colorectal liver metastasis. Full article

Background/Objectives: Recent studies show that the gut microbiome plays a pivotal role in the (patho)physiology of metabolic dysfunction-associated steatotic liver disease (MASLD), likely via metabolites they produce that are transported via the portal vein towards the liver where they first encounter liver sinusoidal endothelial cells (LSECs). LSECs may modulate the effects the gut microbes have on the liver, e.g., on the progression of MASLD. Methods: This review aims to describe the current knowledge on the role of LSECs in mediating the effect of gut microbial products in MASLD. Results: Various studies show that LSECS have a contributing role in MASLD pathogenesis, suggesting that proper LSEC functionality is required to protect the liver from gut-driven attacks. Conclusions: Dedicated studies on the role and effects of gut-derived molecules on LSEC functionality are lacking, likely because such studies depend on labor-intensive techniques such as scanning electron microscopy (SEM). Full article

Liver Sinusoidal Endothelial Cells (LSECs) play a crucial role in maintaining liver homeostasis, regulating immune responses, and fibrosis in liver diseases. This review explores the unique functions of LSECs in liver pathology, particularly their roles in immune tolerance, antigen presentation, and the modulation of hepatic stellate cells (HSCs) during fibrosis. LSECs act as key regulators of immune balance in the liver by preventing excessive immune activation while also filtering antigens and interacting with immune cells, including Kupffer cells and T cells. Metabolic Dysfunction-Associated Fatty Liver Disease(MAFLD) is significant because it can lead to advanced liver dysfunction, such as cirrhosis and liver cancer. The prevalence of Metabolic Associated Steatohepatitis (MASH) is increasing globally, particularly in the United States, and is closely linked to rising rates of obesity and type 2 diabetes. Early diagnosis and intervention are vital to prevent severe outcomes, highlighting the importance of studying LSECs in liver disease. However, during chronic liver diseases, LSECs undergo dysfunction, leading to their capillarization, loss of fenestrations, and promotion of pro-fibrotic signaling pathways such as Transforming growth factor-beta (TGF-β), which subsequently activates HSCs and contributes to the progression of liver fibrosis. The review also discusses the dynamic interaction between LSECs, HSCs, and other hepatic cells during the progression of liver diseases, emphasizing how changes in LSEC phenotype contribute to liver scarring and fibrosis. Furthermore, it highlights the potential of LSECs as therapeutic targets for modulating immune responses and preventing fibrosis in liver diseases. By restoring LSECs’ function and targeting pathways associated with their dysfunction, novel therapies could be developed to halt or reverse liver disease progression. The findings of this review reinforce the importance of LSECs in liver pathology and suggest that they hold significant promises as targets for future treatment strategies aimed at addressing chronic liver diseases. Full article

Liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic homeostasis, clearance, and microcirculatory regulation. Their fenestrations—patent transcellular pores—are essential for proper liver function, yet disappear in pathological conditions such as liver fibrosis and inflammation through a process known as defenestration. Defenestrated sinusoids are often linked to the liver stiffening that occurs through mechanotransduction-regulated processes. We performed a detailed characterization of polyacrylamide (PAA) hydrogels using atomic force microscopy (AFM), rheometry, scanning electron microscopy, and fluorescence microscopy to assess their potential as biomimetic substrates for LSECs. We additionally implemented AFM; quantitative fluorescence microscopy, including high-resolution structured illumination microscopy (HR-SIM); and an endocytosis assay to characterize the morphology and function of LSECs. Our results revealed significant local variations in hydrogel stiffness and differences in pore sizes. The primary LSECs cultured on these substrates had a range of stiffnesses and were analyzed with regard to their number of fenestrations, cytoskeletal organization, and endocytic function. To explore mechanotransduction in inflammatory liver disease, we investigated LSECs from a genetic model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes and examined their ability to restore their fenestrations on soft substrates. Our study demonstrates the beneficial effect of soft hydrogels on LSECs. Control cells exhibited a similar fenestrated morphology and function compared to cells cultured on plastic substrates. However, the pathological LSECs from the genetic model of systemic inflammation regained their fenestrations when cultured on soft hydrogels. This observation supports previous findings on the beneficial effects of soft substrates on LSEC fenestration status. Full article

Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence. Full article

Sepsis is a complex clinical syndrome closely associated with the occurrence of acute organ dysfunction and is often characterized by high mortality. Due to the rapid progression of sepsis, early diagnosis and intervention are crucial. Recent research has focused on exploring the pathological response involved in the process of sepsis. Liver sinusoidal endothelial cells (LSECs) are a special type of endothelial cell and an important component of liver non-parenchymal cells. Unlike general endothelial cells, which mainly provide a barrier function within the body, LSECs also have important functions in the clearance and regulation of the immune response. LSECs are not only vital antigen-presenting cells (APCs) in the immune system but also play a significant role in the development of infectious diseases and tumors through their specific immune regulatory pathways. However, in certain disease states, the functions of LSECs may be impaired, leading to immune imbalance and the development of organ failure. Investigating the immune pathways of LSECs in sepsis may provide new solutions for the prevention and treatment of sepsis and is crucial for maintaining microcirculation and improving patient outcomes. Full article

Endothelial dysfunction (ED) is the in the background of multiple metabolic diseases and a key process in liver disease progression and cirrhosis decompensation. ED affects liver sinusoidal endothelial cells (LSECs) in response to different damaging agents, causing their progressive dedifferentiation, unavoidably associated with an increase in intrahepatic resistance that leads to portal hypertension and hyperdynamic circulation with increased cardiac output and low peripheral artery resistance. These changes are driven by a continuous interplay between different hepatic cell types, invariably leading to increased reactive oxygen species (ROS) formation, increased release of pro-inflammatory cytokines and chemokines, and reduced nitric oxide (NO) bioavailability, with a subsequent loss of proper vascular tone regulation and fibrosis development. ED evaluation is often accomplished by serum markers and the flow-mediated dilation (FMD) measurement of the brachial artery to assess its NO-dependent response to shear stress, which usually decreases in ED. In the context of liver cirrhosis, the ED assessment could help understand the complex hemodynamic changes occurring in the early and late stages of the disease. However, the instauration of a hyperdynamic state and the different NO bioavailability in intrahepatic and systemic circulation—often defined as the NO paradox—must be considered confounding factors during FMD analysis. The primary purpose of this review is to describe the main features of ED and highlight the key findings of the dynamic and intriguing relationship between ED and liver disease. We will also focus on the significance of FMD evaluation in this setting, pointing out its key role as a therapeutic target in the never-ending battle against liver cirrhosis progression. Full article

Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body’s natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis. Full article