In vitro liver tissue models are valuable for studying liver function, understanding liver diseases, and screening candidate drugs for toxicity and efficacy. While three-dimensional (3D) bioprinting shows promise in creating various types of functional tissues, current efforts to engineer a functional liver tissue face challenges in replicating native high cell density (HCD) and maintaining long-term cell viability. HCD is crucial for establishing the cell-cell interactions necessary to mimic the liver's metabolic and detoxification functions. However, HCD bioinks exacerbate light scattering in light-based 3D bioprinting. In this study, we incorporated iodixanol into our bioink formulation to minimize light scattering, enabling the fabrication of hepatic tissue constructs with an HCD of 8 × 107 cells/mL while maintaining high cell viability (∼80 %). The printed dense hepatic tissue constructs showed enhanced cell-cell interactions, as evidenced by increased expression of E-cadherin and ZO-1. Furthermore, these constructs promoted albumin secretion, urea production, and P450 metabolic activity. Additionally, HCD hepatic tissue inactivated the YAP/TAZ pathway via cell-cell interactions, preserving primary hepatocyte functions. Further screening revealed that hepatocytes in the dense model were more sensitive to drug treatments than those in a lower-density hepatic model, highlighting the importance of HCD in recapitulating the physiological drug responses. Overall, our approach represents a significant advancement in liver tissue engineering, providing a promising platform for the development of physiologically relevant in vitro liver models for drug screening and toxicity testing.

Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child-Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications.

Sappanone A (SA), a kind of homoisoflavanone extracted from the dry heartwood of Caesalpinia sappan L., has been shown to possess diverse bioactivities involving anti-inflammatory, antioxidant, and anti-apoptotic properties. Sustained proinflammatory state is a major factor in the occurrence and development of various diseases. Given the characteristics of SA, many studies have explored the effect of SA on inflammation-related diseases, which uncovered the multifaceted therapeutic potential of SA in such diseases. In this mini-review, we summarized the current achievements of SA on inflammation-related diseases (such as myocardial ischemia-reperfusion injury, liver injury, respiratory diseases, and kidney injury, etc.), in order to provide useful insights into the role of SA in inflammation-related diseases and benefit future clinical applications.

Innate immune cells such as macrophages and dendritic cells play major roles in the progression of many cancerous, fibrotic, and autoimmune diseases, often due to environmental cues that skew these cells toward a phenotype that progresses or exacerbates the disease state. As such, a growing focus in treating such diseases is placed on exploiting the high plasticity of these cells to modify or reverse their pro-disease phenotypes using immunomodulatory materials. β-1,3 glucans are one such type of material that has exhibited diverse immunomodulatory effects on immune cells, including the mitigation or reversal of the adverse effects of dysregulated immune cells. In this review, we outline various fabrication techniques to produce β-1,3 glucan-derived microparticles and nanoparticles and discuss the diverse particle properties that can be obtained by tuning glucan chemistry, fabrication method, and formulation components. Furthermore, the immunomodulatory applications of β-1,3 glucan particles are highlighted with a focus on immune cell targeting, modulation, and the delivery of small molecule and macromolecular therapeutics.

The liver has a unique ability to regenerate to meet the body's metabolic needs, even following acute or chronic injuries. The cellular and molecular mechanisms underlying normal liver regeneration have been well investigated to improve organ transplantation outcomes. Once liver regeneration is impaired, pathological regeneration occurs, and the underlying cellular and molecular mechanisms require further investigations. Nevertheless, a plethora of cytokines and growth factor-mediated pathways have been reported to modulate physiological and pathological liver regeneration. Regenerative mitogens play an essential role in hepatocyte proliferation. Accelerator mitogens in synergism with regenerative ones promote liver regeneration following hepatectomy. Finally, terminator mitogens restore the proliferating status of hepatocytes to a differentiated and quiescent state upon completion of regeneration. Chronic loss of hepatocytes, which can manifest in chronic liver disorders of any etiology, often has undesired structural consequences, including fibrosis, cirrhosis, and liver neoplasia due to the unregulated proliferation of remaining hepatocytes. In fact, any impairment in the physiological function of the terminator mitogens results in the progression of pathological liver regeneration. In the current review, we intend to highlight the updated cellular and molecular mechanisms involved in liver regeneration and discuss the impairments in central regulating mechanisms responsible for pathological liver regeneration.

During chronic liver diseases, LSECs undergo a dedifferentiation process contributing to the development of hepatic microvascular dysfunction. Although microRNAs (miRNAs) have been associated with chronic liver disease, their role as modulators of liver endothelial phenotype is mostly unknown. Therefore, the aim of this study was to analyze miRNAs as regulators of hepatic sinusoidal endothelial dysfunction in chronic liver disease to suggest novel and translatable therapeutic options for cirrhosis.

Global expression of miRNAs was determined in primary LSECs from healthy and cirrhotic patients (alcohol abuse) and rats (CCl4 inhalation). LSECs were transfected with the mimetic or inhibitor of dysregulated miRNAs or with quantum dot nano-complexes containing miR-27b-3p or negative control, and endothelial phenotype was analyzed by RNA sequencing, quantitative PCR, and western blot. Endothelial or mesenchymal phenotypes were analyzed in LSEC by RNA sequencing, followed by pathway analyses and gene deconvolution.

In all, 30 and 69 dysregulated miRNAs were identified in human and rat cirrhosis, respectively, of which 6 miRNAs were commonly dysregulated. Specific exogenous downregulation of miR-27b-3p was associated with the upregulation of target genes, suggesting a correlation between loss of miR-27b-3p and LSEC dedifferentiation. Finally, the expression of miR-27b-3p was efficiently and physiologically re-established in cirrhotic LSECs using nano-miR-27b-3p, leading to modulation of 1055 genes compared with the negative control, ultimately leading to inhibition of the endothelial-to-mesenchymal transition process observed in cirrhosis.

Loss of miR-27b-3p expression contributes to LSECs dedifferentiation in cirrhosis. The use of nano-miR-27b-3p represents a new therapeutic option for hepatic diseases coursing with endothelial dysfunction.

Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.

Liver fibrosis is a pathological process characterized by the activation of hepatic stellate cells (HSCs) and the excessive accumulation of extracellular matrix (ECM) proteins. Cellular communication network 5 (CCN5) has been recently recognized for its ability to counteract the profibrotic effects of CCN2 in fibrotic diseases. Herein, we report the discovery of a CCN5-derived peptide CDP199 that effectively suppresses HSC activation and reduces ECM protein deposition. Notably, CDP199 exhibits strong inhibitory effects on HSC proliferation and migration. The subsequent in vivo study demonstrated that peptide CDP199 significantly alleviates liver injury, enhances liver function, and mitigates liver fibrosis in a carbon tetrachloride-induced mouse model. Mechanistically, CDP199 inhibits the phosphorylation of ERK1/2 and PI3K both in vitro and in vivo. These findings highlight the therapeutic potential of CCN5-derived peptides, specifically CDP199, as a promising antifibrotic candidate for treating liver diseases through inhibition of ERK1/2 and PI3K signaling pathways.

The development of portal hypertension (PH) is a key prognostic factor in patients with compensated advanced chronic liver disease (cACLD). The gold standard for assessing PH is the hepatic venous pressure gradient measurement. However, noninvasive tools have gained significant importance in recent years, mainly liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE). Spleen stiffness measurement (SSM) by VCTE using a dedicated 100-Hz module has emerged as a promising non-invasive diagnostic tool, although data on its prognostic value remain limited. This study aimed to evaluate the accuracy of SSM, as measured by transient elastography, in predicting the risk of liver decompensation.

A prospective study was conducted including patients with cACLD followed at a tertiary center from January 2020 to April 2024. All patients underwent liver and spleen VCTE (utilizing the 100-Hz module) performed by the same blinded operator. Patients were subsequently monitored at the same institution for the development of PH complications.

The study included 242 patients with cACLD, with a mean age of 63.0 ± 10.5 years and who were 78.5% male. The most common etiology was alcoholic liver disease (62.0%). The median LSM value was 21.9 kPa (interquartile range [IQR], 15.0-34.0 kPa), and the median SSM value was 38.9 kPa (IQR, 28.0-58.0 kPa). The median follow-up period was 501.5 days (IQR, 343.0-725.3 days). During this time, 28 patients (11.6%) developed liver decompensations, with 20 requiring hospital admission. SSM demonstrated good predictive capacity for the risk of liver decompensation (area under the curve, 0.823; 95% confidence interval, 0.742-0.904). Alongside LSM, SSM was an effective predictor of liver decompensation, with a cutoff of 50.0 kPa indicating a significantly increased risk of hepatic decompensation.

Noninvasive assessment using SSM may serve as an excellent tool for predicting the risk of liver-related complications and risk-stratifying patients with cACLD, thereby improving their management.

Eugenol possesses anti-inflammatory and antioxidant properties, and may serve as a potential therapeutic agent for hepatic fibrosis. However, the development of solid eugenol formulations is challenging due to its volatility. To address this issue, this study employed porous silica to adsorb solidified eugenol. The solidified powder was characterized using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In addition, the differences in in vitro release and oral bioavailability between eugenol and solidified eugenol powder were investigated. The effectiveness of eugenol and eugenol powder in treating liver fibrosis was investigated using enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and histopathological observations. Our results indicate that porous silica can effectively solidify eugenol into powder at a lower dosage. Furthermore, we observed that porous silica accelerates eugenol release in vitro and in vivo. The pharmacodynamic results indicated that eugenol has a positive therapeutic effect against hepatic fibrosis and that porous silica does not affect its efficacy. In conclusion, porous silica was able to solidify eugenol, which may facilitate the preparation and storage of solid formulations.

Wilson's disease (WD) is a rare autosomal recessive inherited disorder characterized by dysregulated copper metabolism, amenable to treatment with chelating agents. It manifests with hepatic and neurological symptoms, often precipitating the development of liver cirrhosis as a prominent complication. This study aims to elucidate the factors, biomarker alterations, and therapeutic modalities influencing the progression of cirrhosis in WD patients.

This retrospective cohort study utilized WD patient data from West China Fourth Hospital (May 2018-September 2023). The primary outcome was the development of cirrhosis in initially cirrhosis-free WD patients. LASSO-COX regression identified predictive factors. The 1:1 propensity score matching generated a matched subgroup for robust Cox regression validation.

Among 133 initially cirrhosis-free WD patients, 47 developed cirrhosis during 35.98 (22.04-49.21) months. Significant differences were observed between the cirrhosis and non-cirrhosis groups in age at enrollment, age at WD diagnosis, clinical symptoms, educational levels, and administration of dimercaptosuccinic acid, compound glycyrrhizin polyene, and phosphatidylcholine. Multivariate Cox regression identified age at enrollment (hazard ratio [HR]: 1.038, 95% CI: 1.002-1.075), the use of glycyrrhizin (HR: 0.421, 95% CI: 0.192-0.926), erythrocyte (HR: 0.748, 95% CI: 0.626-0.895), and platelet counts (HR: 0.993, 95% CI: 0.988-0.998) associated with cirrhosis. Robust Cox analysis on the matched subgroup confirmed these findings.

Glycyrrhizic acid emerges as a potential hepatoprotective agent for WD patients. Furthermore, the progression of cirrhosis in WD patients is characterized by advanced age and decreased baseline levels of erythrocytes and platelets, suggesting their potential utility as prognostic indicators.

MicroRNAs (miRNAs) represent a class of noncoding small RNAs and are implicated in many diseases. However, the role of miRNA in obstructive sleep apnea (OSA)-induced white adipose tissue (WAT) dysfunction remains to be fully elucidated. Using miRNA sequencing (miRNA-seq), we uncovered the miRNA expression profiles in chronic intermittent hypoxia (CIH)-induced WAT dysfunction mice.

We established an apolipoprotein-deficient (ApoE-/-) CIH mouse model and identified differentially expressed miRNAs (DEmiRs) using miRNA-seq technology. With the help of Gene Ontology (GO) functional enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, we determined the biological functions of these DEmiRs. In addition, RT-qPCR was performed for further evaluation of the sequencing data. Finally, we constructed a conserved negative correlation (CNC) network to expound the relationship between miRNA and target genes.

Overall, 13 miRNAs were found to be upregulated and 18 miRNAs downregulated in the CIH-induced mouse model of WAT dysfunction. KEGG pathway analysis results indicated that the lysosome pathway participated in CIH-induced WAT dysfunction. Then, eight miRNAs were shortlisted for RT-qPCR validation. Based on the data, we chose these DEmiRs to construct a miRNA-mRNA regulatory network.

Overall, we identified 31 DEmiRs in the ApoE-/- CIH mouse model. Our findings may play a major role in explaining the pathophysiological mechanisms of WAT dysfunction induced by obstructive sleep apnea.

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis.

Tissue damage by viral hepatitis is a major cause of morbidity and mortality worldwide. Oxidation reactions and reactive oxygen species (ROS) transform proteins and lipids in plasma low-density lipoproteins (LDL) into the abnormal oxidized LDL (ox-LDL). Hepatitis C virus (HCV) infection induces oxidative/nitrosative stress from multiple sources, including the inducible nitric oxide synthase (iNOS), the mitochondrial electron transport chain, hepatocyte NAD(P)H oxidases (NOX enzymes), and inflammation. Further, HCV decreases reduced glutathione (GSH) synthesis and regeneration.

Cross-section.

to quantify ox-LDL in serum of chronic non-cirrhotic HCV patients, and to assess ox-LDL association with HCV-induced extra hepatic manifestations.

Twenty chronic, non-cirrhotic HCV female patients with extra hepatic manifestations, twenty chronic, non-cirrhotic female HCV patients without extra hepatic manifestations and twenty healthy age, sex matched controls.

Serum was used for determination of liver function tests, ox-LDL and the extracellular antioxidant enzyme Superoxide Dismutase EC CuZn-SOD.

Patients with extra hepatic manifestations had statistically higher ox-LDL (76.63 ± 6.86 μg/L) than patients without extra hepatic manifestations (63.05 ± 6.6 μg/L) p < 0.001, and both patient groups had higher ox-LDL levels than the control group (44.1 ± 4.1 μg/L) p < 0.001. EC CuZn-SOD correlated negatively with ox-LDL in HCV patients with extra hepatic manifestation only.

Extra hepatic manifestations were not risk for anthropometric changes seen with HCV infection. Extra hepatic manifestations were associated with high serum ox-LDL. High serum levels of ox-LDL associated with- or were due to deregulated expression of serum EC CuZn-SOD in chronic HCV patients.

Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.

Liver fibrosis, caused by chronic hepatic injury, is a major threat to human health worldwide, as there are no specific drugs available for its treatment. Natural compounds, such as berberine (BBR) and quercetin (QR), have shown the ability to regulate energy metabolism and protect the liver without significant adverse effects. Additionally, combination therapy (the cocktail therapy approach), using multiple drugs, has shown promise in treating complicated conditions, including liver injury. In this study, we prepared a salt formulation of BBR and QR (BQS) to enhance their combined effect on liver fibrosis. The formation of BQS was confirmed using various analytical techniques, including nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD), and scanning electron microscopy (SEM). The results demonstrated that the dissolution efficiency and bioavailability of QR significantly increased in the BQS form, aligning with that of BBR, compared to the physically mixed (BQP) form. Moreover, BQS exhibited a superior inhibitory effect on fibrosis compared to BQP in the human hepatic stellate cell line LX-2 by modulating lipid accumulation, inflammation, apoptosis, and the cell cycle. Furthermore, in a mouse model of hepatic fibrosis induced by methionine and choline-deficient (MCD) diets, BQS demonstrated enhanced anti-fibrotic activities compared to BQP. These findings suggest that BQS holds promise as a potential alternative treatment for liver fibrosis. Importantly, this study provides novel insights into achieving a cocktail effect through the salt formation of two or more drugs. The results highlight the potential of salt formulations in enhancing the therapeutic efficacy and consistent biological processes of drug combinations.

This study evaluates the predictive value of the lactate/albumin ratio (LAR) for all-cause mortality in cirrhosis patients.

Retrospective observational study.

Intensive care unit (ICU).

626 first-time ICU-admitted cirrhosis patients in the USA (MIMIC-IV v2.2).

None.

LAR index, 28-day, and 90-day all-cause mortality.

Of 626 patients (60.86% male), 27.80% and 39.14% died within 28 and 90 days, respectively. Multivariate Cox analysis showed a significant association between higher LAR and mortality. Adjusted for confounders, elevated LAR increased the 28-day mortality risk [HR: 1.31 (1.21-1.42), P < 0.001]. A restricted cubic spline analysis revealed non-linear relationships between LAR and mortality. For 28-day mortality, the inflection point was 1.583: below this, HR was 2.29 (95% CI: 1.61-3.27, P < 0.001); above, HR was 1.16 (95% CI: 1.02-1.31, P = 0.021; P = 0.002). For 90-day mortality, the inflection point was 1.423: below, HR was 1.60 (95% CI: 1.04-2.47, P = 0.033); above, HR was 0.94 (95% CI: 0.75-1.16, P = 0.542; P = 0.012).

LAR predicts 28-day and 90-day mortality with a segmented effect. An LAR ≥1.583 signals high 28-day mortality risk, necessitating intensified monitoring and potential ICU admission. For 90-day mortality, LAR near 1.423 serves as an early warning for high-risk patients and guides interventions. Continuous LAR monitoring aids management, but prospective studies are needed to confirm clinical utility.

Ascites is a common condition seen by clinicians in secondary care. Data on the epidemiology of ascites in Asians is lacking.

A retrospective case record review was performed in this large, referral institution between January 2016 and December 2019. Clinical and epidemiological data of adult (age > 18 years) patients with ascites, identified from the Radiology database, were obtained from this institutions' electronic medical records.

A total of 838 patients (median age 59.77 ± 14.46 years, 56% males, ethnicity: Chinese 41.9%, Malay 34.8%, Indian 22.7%) were included in the study. Malignancy (28.9%) and liver cirrhosis (27.9%) were the most common etiology of ascites. Most of the malignant etiology of ascites were due to female-related (breast and ovarian) and gastrointestinal (colon, liver, pancreatic, bile duct) cancer. Liver cirrhosis-related ascites was mostly due to metabolic-associated fatty liver disease (MASLD, 35.5%) and hepatitis B infection (20.5%). An increased age (> 40 years) was associated with all causes of ascites. The etiology of ascites varied with ethnicity as follows: the most common cause of ascites was malignancy (37.6%) among ethnic Chinese, heart failure (20.5%) in ethnic Malays and chronic liver disease (43.7%) in ethnic Indians.

Malignancy and liver cirrhosis are the leading cause of ascites in a multi-ethnic Asian population. Demographic factors, particularly ethnicity, have a strong influence on the etiology of ascites.

The liver is a vital organ responsible for numerous metabolic processes in the human body, including the metabolism of drugs and nutrients. After liver damage, the organ can rapidly return to its original size if the causative factor is promptly eliminated. However, when the harmful stimulus persists, the liver's regenerative capacity becomes compromised. Substantial theoretical feasibility has been demonstrated at the levels of gene expression, molecular interactions, and intercellular dynamics, complemented by numerous successful animal studies. However, a robust model and carrier that closely resemble human physiology are still lacking for translating these theories into practice. The potential for liver regeneration has been a central focus of ongoing research. Over the past decade, the advent of organoid technology has provided improved models and materials for advancing research efforts. Liver organoid technology represents a novel in vitro culture system. After several years of refinement, human liver organoids can now accurately replicate the liver's morphological structure, nutrient and drug metabolism, gene expression, and secretory functions, providing a robust model for liver disease research. Regenerative medicine aims to replicate human organ or tissue functions to repair or replace damaged tissues, restore their structure or function, or stimulate the regeneration of tissues or organs within the body. Liver organoids possess the same structure and function as liver tissue, offering the potential to serve as a viable replacement for the liver, aligning with the goals of regenerative medicine. This review examines the role of liver organoids in regenerative medicine.

Liver cirrhosis is the terminal stage of various acute and chronic liver diseases and ranks 11th among the most common causes of death worldwide. In recent years, with the progress of clinical research, there has been increasing support from evidence-based medicine for the treatment of liver cirrhosis with integrated traditional Chinese and Western medicine. In 2023, the Chinese Association of Integrative Medicine, the China Association of Chinese Medicine, and the Chinese Medical Association jointly released the first evidence-based guideline in this field, the Guidelines for Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Liver Cirrhosis. By combining the latest research at home and abroad, this article provides a detailed interpretation of the highlights in the guideline, including traditional Chinese medicine etiology and pathogenesis, diagnostic progress, disease and syndrome combination, stage-based diagnostic mode, and treatment strategies of integrated traditional Chinese and Western medicine. The aim is to enhance understanding of this guideline among health workers and promote the improvement of the diagnosis and treatment of liver cirrhosis with integrated traditional Chinese and Western medicine.

Infusion of mesenchymal stem cells (MSCs) via portal vein is one of the main ways for MSCs transplantation to treat liver cirrhosis (LC). As the tissue of LC showed diffuse fibrosis and thickened Glission sheath, the soft pig-tail catheter, or central venous catheter can not successfully insert the portal vein. Thus, our study used an improved method and performed a relatively comprehensive system to evaluate the effect for human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) transplantation.

Fifteen patients with hepatitis B-related cirrhosis were enrolled in the study, and we performed hUC-MSCs transplantation via portal vein by using an 16-G needle and 0.035-inch guide wire combined with 7FR "retentional metal stiffner trocar" of pig-tail catheter under the guidance of contrast-enhanced ultrasound. Serum liver function, fibrotic indicators, tissue stiffness, coagulation function, and hemodynamics were measured at weeks 4, 12, and 24 after MSCs transplantation. Liver biopsy was performed before and 24 weeks after hUC-MSCs transplantation.

After hUC-MSCs transplantation, the prothrombin time was lower than before. The levels of hyaluronic acid and IV-C(Type IV collagen) in fibrotic indicators were significantly reduced, and the Young's modulus was also decreased. Moreover, liver biopsy showed that the lytic necrosis of hepatocyte was decreased. In liver hemodynamics, the portal vein diameter was decreased after hUC-MSCs transplantation.

hUC-MSCs transplantation can alleviate liver damage caused by LC. The improved "retentional metal stiffner trocar" of pig-tail catheter was safe and effective in the infusion of hUC-MSCs transplantation, which is worth promoting in clinical practice.

Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.

This work presents the development of an amperometric biosensor for detecting aspartate aminotransferase (AST) activity in biological fluids using a platinum disk electrode as the working transducer. Optimal concentrations of substrates (aspartate, α-ketoglutarate) and the coenzyme (pyridoxal phosphate) were determined to ensure efficient biosensor operation. A semi-permeable poly-m-phenylenediamine membrane was applied to enhance selectivity against electroactive interferents. The biosensor demonstrated good stability (storage, continuous operation, and production reproducibility) and analytical performance (sensitivity 8.56 nA/min for 50 U/L AST, LOD 1 U/L, linear range 1-110 U/L). Testing with real samples showed a high correlation (R = 0.989) with spectrophotometric analysis, supporting its potential for further applications.

Human Herpes Virus 8 (HHV-8) is involved in autoimmunity. However, its association with advanced liver disease has not been fully explained. Herein, the prevalence of HHV-8 viremia was assessed in Iranian liver transplant candidates with a confirmed diagnosis of cirrhosis.

This cross-sectional study was conducted on 230 patients with cryptogenic cirrhosis, virus-related cirrhosis, and autoimmune hepatitis, as well as 140 healthy blood donors from April 2022 to September 2023. The HHV-8 IgG antibody concentration and viral load were evaluated via ELISA and RT‒PCR, respectively.

Anti-HHV-8 IgG antibodies were detected in 25 cirrhotic patients (10.8 %) and four healthy individuals (2.6 %) (p = 0.022). The majority of the seropositive patients had cryptogenic cirrhosis (20.4 %), followed by autoimmune hepatitis (13.1 %) and virus-related cirrhosis (4.7 %). The seropositivity of HHV-8 IgG antibody was significantly different among the etiologies of liver cirrhosis (p = 0.011). However, HHV-8 genomic DNA was not detected in the sera of the patients or healthy blood donors.

The role of HHV-8 infection in the development of posttransplant diseases, together with the higher seroprevalence of HHV-8 antibodies in cirrhotic patients than in healthy individuals, highlights the importance of both primary and latent infections in liver transplantation. Therefore, serological and molecular screening of HHV-8 is highly suggested for liver transplant candidates and organ donors. The possibility of antibody-mediated epitope mimicry in cryptogenic and autoimmune groups with moderate HHV-8 antibody positivity and negative viral loads may account for the development of advanced liver diseases.

Lactate, once viewed as a byproduct of glycolysis and a metabolic "waste", is now recognized as an energy-providing substrate and a signaling molecule that modulates cellular functions under pathological conditions. The discovery of histone lactylation in 2019 marked a paradigm shift, with subsequent studies revealing that lactate can undergo lactylation with both histone and non-histone proteins, implicating it in the pathogenesis of various diseases, including cancer, liver fibrosis, sepsis, ischemic stroke, and acute kidney injury. Aberrant lactate metabolism is associated with disease onset, and its levels can predict disease outcomes. Targeting lactate production, transport, and lactylation may offer therapeutic potential for multiple diseases, yet a systematic summary of the small molecules modulating lactate and its metabolism in various diseases is lacking. This review outlines the sources and clearance of lactate, as well as its roles in cancer, liver fibrosis, sepsis, ischemic stroke, myocardial infarction, and acute kidney injury, and summarizes the effects of small molecules on lactate regulation. It aims to provide a reference and direction for future research.

Treatment options for hepatic fibrosis, a prevalent liver condition closely linked to cirrhosis, are currently limited. While Guizhi Fuling Wan (GFW), a pill derived from traditional Chinese herbs, has been reported to possess hepatoprotective properties, its therapeutic effect and mechanism in hepatic fibrosis remain elusive.

This study aimed to evaluate the anti-fibrotic impact of GFW and its underlying mechanisms in both in vivo and in vitro settings.

Tetrachloromethane (CCl4) was used to induce hepatic fibrosis in male rats. In vitro, activation of hepatic stellate cells (HSCs) was triggered by platelet-derived growth factor-BB (PDGF-BB). In vivo, liver function, pathological alterations, and HSC activation were evaluated. Additionally, the impact of GFW on the activated phenotypes of Lieming Xu-2 (LX-2) cells was examined in vitro. Network pharmacology was employed to identify the potential targets of GFW in hepatic fibrosis. Lastly, the impact of GFW on the PTEN/AKT/mTOR pathway and PTEN ubiquitination in HSCs was investigated.

GFW alleviated CCl4-induced liver damage and scarring in rats in a dose-dependent manner and suppressed HSC activation in vivo. Moreover, GFW inhibited the proliferation, migration, differentiation, and extracellular matrix (ECM) production of activated HSCs in vitro. GFW also promoted autophagy and apoptosis of HSCs. Meanwhile, network pharmacology and in vitro studies suggested that GFW inhibits the AKT/mTOR pathway by preventing PTEN degradation by suppressing ubiquitination.

GFW attenuates Ccl4-induced hepatic fibrosis in male rats by regulating the PTEN/AKT/mTOR signaling pathway, positioning it as a potential candidate for the treatment of hepatic fibrosis.

Background and objectives: Liver cirrhosis is a chronic, progressive condition characterized by fibrosis and architectural distortion of the liver, leading to impaired liver function and severe complications. Accurately predicting these complications is crucial to the improvement of patient outcomes. Therefore, this study aimed to evaluate the accuracy of various non-invasive biomarkers and clinical scores in assessing the risk of complications among cirrhotic patients. Materials and methods: We conducted an observational retrospective study involving 236 cirrhotic patients from two tertiary care hospitals in Italy and Romania, in a timespan ranging from January 2021 to March 2024. Data on clinical characteristics, liver function tests, hematological indices, various non-invasive biomarkers, and clinical scores were collected and analyzed. Receiver operating characteristic analysis was performed to assess the accuracy of these biomarkers and clinical scores in predicting complications, including the presence of varices and hepato-renal syndrome. Results: The Child-Pugh score showed the highest accuracy for cirrhosis-related complications, with an area under curve (AUC) = 0.667. The red cell distribution width coefficient of variation followed closely with an AUC = 0.646. While the Child-Pugh score had a high specificity (85.42%), its sensitivity was low (37.97%). In patients with varices, non-invasive scores such as platelet distribution width (PDW) and the RDW-to-platelet ratio (RPR) showed modest predictive ability, with an AUC = 0.594. For hepato-renal syndrome, the Model for End-Stage Liver Disease (MELD) score showed the highest diagnostic accuracy with an AUC = 0.758. Conclusions: The most reliable biomarkers for detecting complications, varices, and hepato-renal syndrome, are, respectively, the Child-Pugh Score, PDW along with RPR, and the MELD score. However, while these scores remain valuable, the moderate diagnostic accuracy of other indices suggests the need for a more integrated approach to risk stratification. Future research should focus on validating these tools across different populations and incorporating emerging biomarkers to enhance predictive accuracy and inform more effective clinical decision-making.

Diabetic retinopathy (DR), a prevalent complication in patients with type 2 diabetes, has attracted increasing attention. Recent studies have explored a plausible association between retinopathy and significant liver fibrosis. The aim of this investigation was to develop a sophisticated machine learning (ML) model, leveraging comprehensive clinical datasets, to forecast the likelihood of significant liver fibrosis in patients with retinopathy and to interpret the ML model by applying the SHapley Additive exPlanations (SHAP) method.

This inquiry was based on data from the National Health and Nutrition Examination Survey 2005-2008 cohort. Utilizing the Fibrosis-4 index (FIB-4), liver fibrosis was stratified across a spectrum of grades (F0-F4). The severity of retinopathy was determined using retinal imaging and segmented into four discrete gradations. A ten-fold cross-validation approach was used to gauge the propensity towards liver fibrosis. Eight ML methodologies were used: Extreme Gradient Boosting, Random Forest, multilayer perceptron, Support Vector Machines, Logistic Regression (LR), Plain Bayes, Decision Tree, and k-nearest neighbors. The efficacy of these models was gauged using metrics, such as the area under the curve (AUC). The SHAP method was deployed to unravel the intricacies of feature importance and explicate the inner workings of the ML model.

The analysis included 5,364 participants, of whom 2,116 (39.45%) exhibited notable liver fibrosis. Following random allocation, 3,754 individuals were assigned to the training set and 1,610 were allocated to the validation cohort. Nine variables were curated for integration into the ML model. Among the eight ML models scrutinized, the LR model attained zenith in both AUC (0.867, 95% CI: 0.855-0.878) and F1 score (0.749, 95% CI: 0.732-0.767). In internal validation, this model sustained its superiority, with an AUC of 0.850 and an F1 score of 0.736, surpassing all other ML models. The SHAP methodology unveils the foremost factors through importance ranking.

Sophisticated ML models were crafted using clinical data to discern the propensity for significant liver fibrosis in patients with retinopathy and to intervene early.

Improved early detection of liver fibrosis risk in retinopathy patients enhances clinical intervention outcomes.

Silibinin, a bioactive component found in milk thistle extract (Silybum marianum), is known to have significant therapeutic potential in the treatment of various liver diseases. It is considered a key element of silymarin, which is traditionally used to support liver function. The main mechanisms of action of silibinin are attributed to its antioxidant properties protecting liver cells from damage caused by free radicals. Experimental studies conducted in vitro and in vivo have confirmed its ability to inhibit inflammatory and fibrotic processes, as well as promote the regeneration of damaged liver tissue. Therefore, silibinin represents a promising tool for the treatment of liver diseases. Since the silibinin molecule is insoluble in water and has poor bioavailability in vivo, new perspectives on solving this problem are being sought. The two most promising approaches are the water-soluble derivative silibinin-C-2',3-dihydrogen succinate, disodium salt, and the silibinin-phosphatidylcholine complex. Both drugs are currently under evaluation in liver disease clinical trials. Nevertheless, the mechanism underlying silibinin biological activity is still elusive and its more detailed understanding would undoubtedly increase its potential in the development of effective therapeutic strategies against liver diseases. This review is focused on the therapeutic potential of silibinin and its derivates, approaches to increase the bioavailability and the benefits in the treatment of liver diseases that have been achieved so far. The review discusses the relevant in vitro and in vivo studies that investigated the protective effects of silibinin in various forms of liver damage.

Hepatocellular carcinoma with cirrhosis promotes the advancement of malignancy and the development of fibrosis in normal liver tissues. Understanding the pathological mechanisms underlying the development of HCC with cirrhosis is important for developing effective therapeutic strategies. Herein, the RNA-sequencing (RNA-seq) data and corresponding clinical features of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) database using the University of California Santa Cruz (UCSC) Xena platform. The enrichment degree of hallmarkers for each TCGA-LIHC cohort was quantified by ssGSEA algorithm. Weighted gene co-expression network analysis (WGCNA) revealed two gene module eigengenes (MEs) associated with cirrhosis, namely, MEbrown and MEgreen. Analysis of these modules using AUCell showed that MEbrown had higher enrichment scores in all immune cells, whereas MEgreen had higher enrichment scores in malignant cells. The CellChat package revealed that both immune and malignant cells contributed to the fibrotic activity of myofibroblasts through diverse signaling pathways. Additionally, spatial transcriptomic data showed that hepatocytes, proliferating hepatocytes, macrophages, and myofibroblasts were located in closer proximity in HCC tissues. These cells may potentially participate in the process of stimulating myofibroblast fibrotic activity, which may be related to the development of liver fibrosis. In summary, we made full use of multi-omics data to explore gene networks and cell types that may be involved in the development and progression of cirrhosis in HCC.

The impact of primary biliary cholangitis (PBC) on sleep disturbance is relevant to treatment decision-making processes. Studies on sleep disturbance in Chinese patients with PBC are still lacking.

We analyzed and compared the health-related quality of life (HRQoL) of 107 PBC patients by using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire 9 (PHQ-9), Short Form (36) Health Survey Questionnaire (SF-36), Fatigue Visual Analog Scale (F-VAS). Patients' biochemical markers were also collected for correlation analysis with HRQoL. Receiver operating characteristic (ROC) curves and area under the curve (AUCs) were used to determine the diagnostic performance of PSQI, GAD-7, and biochemical markers for assessing the impaired liver function (Child-Pugh B-C) of PBC diagnosis.

Sixty-two (57.9%) PBC patients suffered from poor sleep quality (PSQI >5). The global PSQI score was positively correlated with GAD-7 (r = 0.561, p < 0.001), and PHQ-9 scores (r = 0.652, p < 0.001). There was a negative correlation (r = -0.216, p = 0.025) between sleep quality and red blood cell (RBC) count. PBC patients with poor sleep quality had significantly higher GAD-7 scores (5 vs. 0, p < 0.001), PHQ-9 scores (5.5 vs. 0, p < 0.001), and lower albumin levels (39.6 vs. 37.6 g/L, p = 0.040) than those with good sleep quality. Based on the SF-36 scores, PBC patients with poor sleep quality had lower physical functioning scores (85 vs. 80, p = 0.022), role physical scores (100 vs. 75, p = 0.007), and worse mental health (60 vs. 56, p = 0.002) than those with good sleep quality. ROC analyses showed that the AUC and optimal cut-off values of the combination of PSQI, GAD-7, and RBC for assessing the impaired liver function in PBC diagnosis were 0.771 and 0.193, respectively.

The sleep disturbance was strongly correlated with the severity of anxiety, depression, and RBC count in PBC patients. Meanwhile, PBC patients with poor sleep had poor HRQoL and lower albumin levels. It is feasible to use the combination of PSQI, GAD-7, and RBC for initial screening of the impaired liver function in PBC. Besides routine blood biochemical and imaging indicators, evaluating mental health-related indicators in PBC patients is imperative.

Even with advancement of medical technologies, liver transplantation still faces several major challenges. Hence, other treatment modalities are urgently needed for patients with end-stage liver disease. Stem cells from human exfoliated deciduous teeth (SHED) was discovered to have highly proliferative and pluripotent properties; including differentiation into hepatocyte-like cells. This study aims to investigate the capability of intrasplenic transplanted SHED and SHED-Hep cells in inducing proliferation of stem cells and native hepatocytes in order to accelerate liver regeneration in liver fibrosis mice models.

Three carbon tetrachloride (CCl4)-injured male mice groups were used in this study. Two of those groups were transplanted with either SHED or SHED-Hep, while the other did not undergo transplantation. One age- and sex- matched healthy mice group was used as control. All specimens were immunohistochemically stained with anti-Ki-67 antibodies and anti-proliferating cell nuclear antigen (PCNA) antibodies before counter stained with hematoxylin-eosin.

Anti-Ki-67 antibodies staining: at both 8 and 12 weeks, proliferating activity was predominantly seen on both SHED- and SHED-Hep-transplanted CCl4-injured mice groups, while control and non-transplanted CCl4-injured mice group showed little to no sign of proliferation activity. Anti-PCNA staining: at both 8 and 12 weeks, significant proliferating activity was detected by PCNA staining, mainly on stem cells population area on SHED- and SHED-Hep-treated group.

In conclusion, this study has provided the evidence that transplantation of SHED or SHED-Hep on liver-injured mice induced proliferation of both transplanted stem cells and native liver cells in order to accelerate liver regeneration.

Liver Cirrhosis, defined as the final stage of chronic liver disease, may become more prevalent in the lower level of body defense against oxidation and inflammation. Therefore, we assessed the association of dietary total antioxidant capacity (DTAC) with the severity and mortality of cirrhosis in a cohort study. 120 newly diagnosed cirrhosis patients from Tehran, Iran, participated in this study. The patients' habitual diet was assessed using a 168-item validated food frequency questionnaire. Both ferric-reducing antioxidant potential (FRAP) and oxygen radical scavenging capacity (ORAC) methods were computed to achieve DTAC scores. The association between DTAC with disease severity and mortality was estimated by multivariate linear regression and cox proportional hazards regression models. Dietary total antioxidant capacity-ORAC had a significant inverse association with disease severity in both crude and adjusted models (P for trend: <0.001 and 0.016 respectively). The risk of mortality in the first and second tertiles of ORAC was 5.56 (95 % CI: 2.25-13.75; P = 0.002) and 3.20 (95 % CI: 1.25-8.19; P = 0.015) higher than those in the third category, respectively. In conclusion, a higher antioxidant capacity of diet is associated with less disease severity and mortality risk in cirrhosis.

Hepatic fibrosis and its associated consequences continue to pose a substantial global health challenge. Developing novel approaches to hepatic fibrosis management and prevention is critically necessary. Radix Paeoniae Alba (RPA) is widely used in Traditional Chinese Medicine (TCM) to treat various diseases. Our earlier research found that a bioactive component of RPA had a dose-dependent effect on anti-allergic asthma. RPA reduces allergic asthma by slowing the hepatic wind, according to "Treatise on Febrile Diseases". However, this bioactive fraction's pharmacological effects and mechanisms on the liver are unknown.

This study examined the bioactive fraction MP-40, the methanol extract of RPA (MRPA), on bile duct ligation (BDL) for its anti-hepatic fibrosis activity and potential mechanisms.

First, the effectiveness of MP-40 in treating BDL-induced hepatic fibrosis in mice and rats was evaluated through survival rates, ALT, AST HYP, and pathological changes. Molecular assays were performed using in vitro cultures of HSC-T6 activation. The expression of α-SMA and Collagen I evaluated fibro-tropic factors with HSC activation. Furthermore, the levels of pyroptosis were assessed by examining the expression of the pyroptosis-related proteins, including NLRP3, Cleaved Caspase-1, GSDMD-N, and 1L-1β. Additionally, the effective constituents of MP-40 were identified by extraction, separation, and identification. Finally, PF and TGG, as the delegate compounds of MP-40, were tested to confirm their inhibition effects on HSC-T6 activation.

The findings demonstrated that MP-40 and MRPA could lower ALT, AST, and HYP levels, boost survival rates, and reduce liver damage in BDL mice and rats. Furthermore, MP-40 outperforms MRPA. MP-40 was proven to drastically diminish fibrotic α-SMA and Collagen I. The expression of pyroptosis-related proteins NLRP3, Cleaved Caspase-1, TGF-β1, GSDMD-N, and 1L-1β decreased. MP-40 inhibited the synthesis of pyroptosis-related proteins more effectively than MCC950 (an NLRP3-specific inhibitor). Monoterpene glycosides and tannins were shown to be the most potent MP-40 components. Finally, the delegate compounds MP-40, PF, and TGG were shown to have substantial inhibitory effects on HSC-T6 activation.

The results proved that MP-40 alleviates BDL-induced cholestatic hepatic fibrosis by inhibiting NLRP3-mediated pyroptosis. PF and TGG play a role in treating BDL-induced cholestatic hepatic fibrosis in MP-40.

Gut dysbiosis and liver cirrhosis are two corelated complications that highly disturbs the metabolism of a normal human body. Liver cirrhosis is scarring of the hepatic tissue and gut dysbiosis is the imbalance in the microbiome of the gut. Gut dysbiosis in cirrhosis occurs due to increased permeability of the intestinal membrane which might induce immune responses and damage the normal functioning of the body. Dysbiosis can cause liver damage from cirrhosis and can further lead to liver failure by hepatocellular carcinoma. In this review we discuss if eubiosis can revert the poorly functioning cirrhotic liver to normal functioning state? A normal microbiome converts various liver products into usable forms that regulates the overgrowth of microbiome in the gut. The imbalance caused by dysbiosis retards the normal functioning of liver and increases the complications. To correct this dysbiosis, measures like use of antibiotics with probiotics and prebiotics are used. This correction of the gut microbiome serves as a ray of hope to recover from this chronic illness. In case of alcohol induced liver cirrhosis, intervention of microbes can possibly be helpful in modulating the addiction as well as associated complications like depression as microbes are known to produce and consume neurotransmitters that are involved in alcohol addiction. Hence a correction of gut liver brain axis using microbiome can be a milestone achieved not only for treatment of liver cirrhosis but also for helping alcohol addicts quit and live a healthy or at least a near healthy life.

Infection with Schistosoma japonicum (S. japonicum) is an important zoonotic parasitic disease that causes liver fibrosis in both human and domestic animals. The activation of hepatic stellate cells (HSCs) is a crucial phase in the development of liver fibrosis, and inhibiting their activation can alleviate this progression. Total flavonoids of litchi seed (TFL) is a naturally extracted drug, and modern pharmacological studies have shown its anti-fibrotic and liver-protective effects. However, the role of TFL in schistosomiasis liver fibrosis is still unclear. This study investigated the therapeutic effects of TFL on liver fibrosis in S. japonicum infected mice and explored its potential mechanisms. Animal study results showed that TFL significantly reduced the levels of Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α), Interleukin-4 (IL-4), and Interleukin-6 (IL-6) in the serum of S. japonicum infected mice. TFL reduced the spleen index of mice and markedly improved the pathological changes in liver tissues induced by S. japonicum infection, decreasing the expression of alpha-smooth muscle actin (α-SMA), Collagen I and Collagen III protein in liver tissues. In vitro studies indicated that TFL also inhibited the activation of HCSs induced by Transforming Growth Factor-β1 (TGF-β1) and reduced the levels of α-SMA. Gut microbes metagenomics study revealed that the composition, abundance, and functions of the mice gut microbiomes changed significantly after S. japonicum infection, and TLF treatment reversed these changes. Therefore, our study indicated that TFL alleviated granulomatous lesions and improved S. japonicum induced liver fibrosis in mice by inhibiting the activation of HSCs and by improving the gut microbiomes.

Increasing attention to liver-bone crosstalk has spurred interest in targeted interventions for various forms of osteoporosis. Liver injury induced by different liver diseases can cause an imbalance in bone metabolism, indicating a novel regulatory paradigm between the liver and bone. However, the role of the liver-bone axis in both primary and secondary osteoporosis remains inadequately elucidated. Therefore, exploring the exact regulatory mechanisms of the liver-bone axis may offer innovative clinical approaches for treating diseases associated with the liver and bone.

Here, we summarize the latest research on the liver-bone axis by searching the PubMed and Web of Science databases and discuss the possible mechanism of the liver-bone axis in different types of osteoporosis. The literature directly reporting the regulatory role of the liver-bone axis in different types of osteoporosis from the PubMed and Web of Science databases has been included in the discussion of this review (including but not limited to the definition of the liver-bone axis, clinical studies, and basic research). In addition, articles discussing changes in bone metabolism caused by different etiologies of liver injury have also been included in the discussion of this review (including but not limited to clinical studies and basic research).

Several endocrine factors (IGF-1, FGF21, hepcidin, vitamin D, osteocalcin, OPN, LCAT, Fetuin-A, PGs, BMP2/9, IL-1/6/17, and TNF-α) and key genes (SIRT2, ABCB4, ALDH2, TFR2, SPTBN1, ZNF687 and SREBP2) might be involved in the regulation of the liver-bone axis. In addition to the classic metabolic pathways involved in inflammation and oxidative stress, iron metabolism, cholesterol metabolism, lipid metabolism and immunometabolism mediated by the liver-bone axis require more research to elucidate the regulatory mechanisms involved in osteoporosis.

During primary and secondary osteoporosis, the liver-bone axis is responsible for liver and bone homeostasis via several hepatokines and osteokines as well as biochemical signaling. Combining multiomics technology and data mining technology could further advance our understanding of the liver-bone axis, providing new clinical strategies for managing liver and bone-related diseases.The translational potential of this article is as follows: Abnormal metabolism in the liver could seriously affect the metabolic imbalance of bone. This review summarizes the indispensable role of several endocrine factors and biochemical signaling pathways involved in the liver-bone axis and emphasizes the important role of liver metabolic homeostasis in the pathogenesis of osteoporosis, which provides novel potential directions for the prevention, diagnosis, and treatment of liver and bone-related diseases.