As the major driving factor of hepatic fibrosis, the activated hepatic stellate cells (aHSCs) rely on active glycolysis to support their aberrant proliferation and secretion of the extracellular matrix. Sorafenib (Sor) can combat liver fibrosis by suppressing HIF-1α and glycolysis, but its poor solubility, rapid metabolism, and low bioavailability restrict such a clinical application. Here, Sor was loaded onto polydopamine nanoparticles and then encapsulated by a retinoid-decorated red blood cell membrane, yielding HSC-targeted Sor nanovesicles (PDA/Sor@RMV-VA) with a high Sor-loading capacity and photothermally controlled drug release for antifibrotic treatment. These Sor RMVs not only exhibited a good particle size, dispersity and biocompatibility, prolonged circulation time, enhanced aHSC targetability, and hepatic accumulation both in vitro and in vivo, but also displayed a mild photothermal activity proper for promoting sorafenib release and accumulation in CCl4-induced fibrotic mouse livers without incurring phototoxicity. Compared with nontargeting Sor formulations, PDA/Sor@RMV-VA more effectively downregulated HIF-1α and glycolytic enzyme in both cultured aHSCs and fibrotic mice and reversed myofibroblast phenotype and amplification of aHSCs and thus more significantly improved liver damage, inflammation, and fibrosis, all of which could be even further advanced with NIR irradiation. These results fully demonstrate the antifibrotic power and therapeutic potential of PDA/Sor@RMV-VA as an antifibrotic nanomedicine, which would support a new clinical treatment for hepatic fibrosis.

Peritoneal fibrosis (PF) is a major, persistent complication of prolonged peritoneal dialysis that eventually leads to peritoneal ultrafiltration failure and termination of peritoneal dialysis. Prolonged exposure to high glucose concentrations, degradation products, uremic toxins, and episodes of peritonitis can cause some changes in the peritoneal membrane, resulting in intraperitoneal inflammation and PF, leading to failure of ultrafiltration and dialysis. CA-125 can be used as a biomarker of peritoneal mesothelial cell count in the peritoneal dialysate and for monitoring cell count in PD patients. Hypoxia-inducible factor 1-alpha (HIF-1α) has been reported to cause PF, but has not been reported to be associated with changes in peritoneal structure. We hypothesized that peritoneal adequacy can be followed using HIF-1α and CA-125 values. In the present study, therefore, we investigated the relationship between HIF-1α and CA-125 levels and parietal membrane permeability changes in PD patients.

Forty-five patients were included in the study. Peritoneal permeability was constant in 20 of these, while peritoneal permeability increased in 11 and decreased in 14. The HIF-1α value from the blood samples of the patients and the CA-125 measurement from the peritoneal fluids were measured. The relationship between peritoneal variability and CA-125 and HIF levels after follow-up was investigated.

We compared serum HIF-1α and peritoneal fluid CA-125 levels in the three groups receiving peritoneal dialysis treatment. HIF-1α levels increased with peritoneal permeability changes, while CA-125 levels decreased. In patients with high to low permeability changes, HIF-1α levels were higher compared to those with stable or low to high changes, which was statistically significant. Conversely, CA-125 levels significantly decreased in patients whose peritoneal permeability changed from high to low, compared to the other two groups.

Changes in peritoneal structure can be followed with biomarkers. It has been shown that CA-125 and HIF-1α levels can guide the changes in the peritoneal membrane. This can be useful in the monitoring of peritoneal dialysis.

Several parameters are used to assess future liver remnant (FLR) size before major hepatectomy. This study aimed to clarify which is the most appropriate method to use for the prediction of post-hepatectomy liver failure (PHLF).

The subjects of this study were 307 patients with Child-Pugh class A only, who underwent major hepatectomy, to focus on FLR size. The parameters we evaluated for their accuracy in predicting Grade B/C PHLF (PHLF B/C) using receiver operating characteristic curve analysis were FLR volume (FLRV), the FLRV to total liver volume ratio (FLRV/TLV), standard liver volume (FLRV/SLV), and body weight (FLRV/BW) according to body mass.

The predictive value accuracy of these four parameters for PHLF was similar for the entire cohort. However, in the subgroup analysis based on body mass index, FLRV/BW accuracy was highest in the obese group, whereas that of FLRV/TLV was highest in the lean group. Multivariate analysis identified that FLRV/BW (< 0.7%) and blood loss (≥ 1000 ml) were independent risk factors for PHLF B/C in the obese group. In the lean group, FLRV/TLV (< 40%) and biliary reconstruction were risk factors for PHLF B/C.

The FLR size evaluation method for predicting PHLF should be appropriately selected based on the patient's body mass.

Liver cirrhosis and portal hypertension (PHT) can lead to lymphatic abnormalities and coagulation dysfunction. Because lymphangiogenesis may relieve liver cirrhosis and PHT, the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT.

To investigate the role of lymphangiogenesis in preclinical PHT models.

Immunohistochemistry and transcriptome sequencing of bile duct ligation (BDL) and control lymphatic samples were conducted to reveal the indicated signaling pathways. Functional enrichment analyses were performed on the differentially expressed genes and hub genes. Adenoviral infection of vascular endothelial growth factor C (VEGF-C), platelet-rich plasma (PRP), and VEGF3 receptor (VEGFR) inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models. Histology, hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients.

Lymphangiogenesis was increased in the BDL rat model. Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence, aggregation, and activation. The role of PHT in the rat model was investigated by activating (PRP) and inhibiting (MAZ-51) the lymphatic system. PRP promoted lymphangiogenesis, which increased lymphatic drainage, alleviated portal pressure, reduced liver fibrosis, inhibited inflammation, inhibited angiogenesis, and suppressed mesenteric artery remodeling. MAZ-51 reversed the above improvements.

Via VEGF-C/VEGFR-3, platelets impede fibrosis, angiogenesis, and mesenteric artery remodeling, ultimately alleviating PHT. Thus, platelet intervention is a therapeutic approach for cirrhosis and PHT.

To prospectively investigate dynamic 13N-ammonia PET-CT for evaluating early treatment response and predicting prognosis in advanced hepatocellular carcinoma (HCC) patients who have undergone antiangiogenic therapy.

Dynamic 13N-ammonia PET-CT was performed in 23 advanced HCC patients before antiangiogenic therapy (baseline) and in 18/23 patients after 8-10 weeks of treatment (post-therapy). At kinetic PET-CT analysis, mean, maximum, and peak values of K1 (mL/cm3/min) and k2 (min-1) were estimated in HCC lesions and non-neoplastic liver using cardiologic 13N-ammonia PET-CT in 15 patients without any liver diseases as normal controls. Outcome endpoints were treatment response after 8-10 weeks assessed by contrast-enhanced CT, progression-free survival (PFS), and overall survival (OS).

At both baseline and post-therapy PET-CT, all kinetic PET parameters were significantly higher (p < 0.05) in HCC lesions than in non-neoplastic and healthy liver of HCC patients and controls. According to mRECIST criteria, 13/18 patients (72.2%) were responders (1 CR, 1 PR, and 11 SD), and 5/18 patients (27.8%) were non-responders (PD), with no significant differences in baseline and post-therapy PET parameters between the two groups. At follow-up (median: 14.2 months), 15/18 patients (83.3%) experienced radiological progression, and 14/18 (77.8%) died (7/14 within 12 months from treatment). The nine earlier-progression patients (within 6 months from treatment) showed significantly lower baseline K1mean in HCC lesions than all nine patients with later or no-progression (p = 0.03). Patients still alive 12 months after treatment (n = 11) showed significantly lower post-therapy K1mean (p = 0.05), K1max (p = 0.05), and K1peak (p = 0.03) in non-neoplastic liver than patients with shorter OS (n = 7).

In advanced HCC patients treated with antiangiogenic agents, kinetic parameters from baseline and post-therapy 13N-ammonia PET-CT may predict early disease progression and survival. PET-CT seems not able to discriminate responders and non-responders after 8-10 weeks of treatment, suggesting the need for future and larger studies after a longer treatment period.

The vascular endothelial growth factor (VEGF) signaling pathway is closely related to pathological angiogenesis in liver disease. Anti-angiogenesis is an effective intervention in the clinical treatment of liver disease. Some antiangiogenic drugs are resistant and have limitations in clinical use.

This research uses bibliometric methods to assess the literature on the VEGF signaling pathway in liver disease from 2008 to 2023.

The number of publications has generally increased over the past 16 years, meaning that enormous researchers are interested in this field. China and the USA have published the most articles and cooperate closely with each other. Plos one has published the largest number of articles in this area, and Hepatology and Journal of Hepatology is the most authoritative journal. Llovet JM is an outstanding researcher in the field with the highest citations. Keywords and research hotspots analysis indicated that researchers are very concerned about the application and clinical research status of anti-angiogenic drugs in hepatocellular carcinoma (HCC). Continuing to deepen the research on the use of anti-angiogenic drugs alone and in combination is necessary. In addition, the resistance of anti-angiogenic therapeutic drugs leads to a complex mechanism of angiogenesis response caused by hypoxia, which requires further research.

This study analyzed the research situation related to the VEGF signaling pathway in liver disease from a bibliometric and visual perspective. Our analysis helps researchers better understand the research directions and hotspots in this area, enabling them to better carry out research in the future.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key to maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, especially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.

Hyperglycemia induces pathophysiological changes. Endoplasmic reticulum (ER) stress with Gα12 overexpression may promote hepatocyte death. This study investigated whether sustained hyperglycemia triggers ER stress-associated pyroptosis and fibrosis in the liver alongside an overexpression of Gα12, and examined the potential link with VEGF-A levels.

Mice were subjected to a high-fat diet (60 kcal% fat) with streptozotocin (50 mg/kg body weight, three consecutive times, between 12-13th weeks). AZ2 (a functional Gα12 inhibitor) was treated at 10 mg/kg body weight (5 times/week, 3 weeks). Immunoblotting and immunohistochemistry analyses were performed.

Hepatic Gα12/Gα13 were overexpressed in the diabetic mice. The following proteins downstream from the Gα12 axis were upregulated: PGC1α, PPARα, and SIRT1. Sustained hyperglycemia promoted ER stress marker levels. Histopathological and biochemical assays showed large-sized lipid droplet accumulation, hepatocyte degeneration, and damage as blood transaminase activities increased. Moreover, the diabetic condition increased IL-1β, caspase-1, and NLRP3 levels, which were supportive of pyroptosis. Consistently, the intensities of Masson's trichrome, collagen-1A1, α-SMA, vimentin, and fibronectin all increased. VEGF-A and VEGFR2 levels also increased in the liver and/or sera. The levels of hepatic pigment epithelial-derived factor (PEDF), a physiological antagonist of VEGF-A, decreased with its reciprocal increase in serum. These events were reversed by AZ2 treatment, supporting the role of Gα12 in hyperglycemic stress in the liver.

Chronic hyperglycemia causes hepatic pyroptosis and fibrosis related to ER stress with Gα12/Gα13 and VEGF overexpression, which may be overcome by AZ2 treatments.

China is a major consumer of alcohol and tobacco. Tobacco and alcohol use are closely linked, with up to 90% of alcoholics having a history of tobacco use, and heavy smokers also tending to be alcoholics. Alcohol-related liver disease (ALD), one of the most common and serious complications of chronic alcohol intake, involving hepatic steatosis, hepatitis, hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC), has become one of the globally prevalent chronic diseases. An increasing number of studies have focused on the association between smoking and ALD and explored the mechanisms involved. Clinical evidence suggests that smoking has a negative impact on the incidence and severity of fatty liver disease, progression of liver fibrosis, development of HCC, prognosis of patients with advanced liver disease, and alcohol-related liver transplant recipients. The underlying mechanisms are complex and involve different pathophysiological pathways, including free radical exposure, endoplasmic reticulum stress, insulin resistance, and oncogenic signaling. This review discusses the deleterious effects of smoking on ALD patients and the possible underlying mechanisms at several levels. It emphasizes the importance of discouraging smoking among ALD patients. Finally, the pathogenic role of electronic cigarettes, which have emerged in recent years, is discussed, calling for an emphasis on social missions for young people.

The Fontan operation, which directly connects the superior and inferior vena cava to the pulmonary artery, is a palliative surgery for children with a functional or anatomic single ventricle. This procedure leads to hemodynamic changes (Fontan circulation) in patients, who tend to develop congestive hepatic fibrosis characterized by sinusoidal fibrosis and dilatation beginning approximately 10 years after the procedure. In addition, in the context of severe fibrosis and cirrhosis, hepato-gastrointestinal complications including hepatocellular carcinoma, focal nodular hyperplasia, and portal hypertension can arise. Fontan-associated liver disease (FALD) encompasses the broad spectrum of liver alterations secondary to postoperative hemodynamic changes, and the effective management of FALD requires contributions from specialists in hepatology, gastroenterology, surgery, radiology, histopathology, and pediatric and adult cardiology. In this article, we outline the pathogenesis of FALD and discuss the importance of a multidisciplinary collaborative approach to its management.

Liver fibrosis is a chronic pathological condition lacking specific clinical treatments. Stem cells, with notable potential in regenerative medicine, offer promise in treating liver fibrosis. However, stem cell therapy is hindered by potential immunological rejection, carcinogenesis risk, efficacy variation, and high cost. Stem cell secretome-based cell-free therapy offers potential solutions to address these challenges, but it is limited by low delivery efficiency and rapid clearance. Herein, an innovative approach for in situ implantation of smart microneedle (MN) arrays enabling precisely controlled delivery of multiple therapeutic agents directly into fibrotic liver tissues is developed. By integrating cell-free and platinum-based nanocatalytic combination therapy, the MN arrays can deactivate hepatic stellate cells. Moreover, they promote excessive extracellular matrix degradation by more than 75%, approaching normal levels. Additionally, the smart MN arrays can provide hepatocyte protection while reducing inflammation levels by ≈70-90%. They can also exhibit remarkable capability in scavenging almost 100% of reactive oxygen species and alleviating hypoxia. Ultimately, this treatment strategy can effectively restrain fibrosis progression. The comprehensive in vitro and in vivo experiments, supplemented by proteome and transcriptome analyses, substantiate the effectiveness of the approach in treating liver fibrosis, holding immense promise for clinical applications.

The mechanobiological response mechanism of the fenestrae of liver sinusoidal endothelial cells (LSECs) to the physical stiffness of the extracellular matrix (ECM) remains unclear. We investigated how the mechanical properties of their substrates affect the LSECs' fenestrae by the nitric oxide (NO)-dependent pathway and how they relate to the progression of hepatic sinus capillarization during liver fibrosis. We detected different stiffnesses of ECM in the progress of liver fibrosis (LF) and developed polyacrylamide hydrogel (PAM) substrates to simulate them. Softer stiffness substrates contributed to LSECs maintaining fenestrae phenotype in vitro. The stiffness of liver fibrosis tissue could be reversed in vivo via treatment with anti-ECM deposition drugs. Similarly, the capillarization of LSECs could be reversed by decreasing the ECM stiffness. Our results also indicate that the NO-dependent pathway plays a key regulatory role in the capillarization of ECM-LSECs. Our study reveals ECM-induced mechanotransduction of capillarized LSECs through a NO-dependent pathway via a previously unrevealed mechanotransduction mechanism. The elucidation of this mechanism may offer precise biomechanics-specific intervention strategies targeting liver fibrosis progression.

Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD).

Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups.

We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH.

We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.

The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.

Inflammatory bowel disease (IBD) is a chronic and debilitating disorder characterized by inflammation of the gastrointestinal tract. Despite extensive research, the exact cause of IBD remains unknown, hampering the development of effective therapies. However, emerging evidence suggests that hypoxia, a condition resulting from inadequate oxygen supply, plays a crucial role in intestinal inflammation and tissue damage in IBD. Hypoxia-inducible factors (HIFs), transcription factors that regulate the cellular response to low oxygen levels, have gained attention for their involvement in modulating inflammatory processes and maintaining tissue homeostasis. The two most studied HIFs, HIF-1α and HIF-2α, have been implicated in the development and progression of IBD. Toxicological factors encompass a wide range of environmental and endogenous agents, including dietary components, microbial metabolites, and pollutants. These factors can profoundly influence the hypoxic microenvironment within the gut, thereby exacerbating the course of IBD and fostering the progression of colitis-associated colorectal cancer. This review explores the regulation of hypoxia signaling at the molecular, microenvironmental, and environmental levels, investigating the intricate interplay between toxicological factors and hypoxic signaling in the context of IBD, focusing on its most concerning outcomes: intestinal fibrosis and colorectal cancer.

Hypoxia is a common feature of solid tumours affecting their biology and response to therapy. One of the main transcription factors activated by hypoxia is hypoxia-inducible factor (HIF), which regulates the expression of genes involved in various aspects of tumourigenesis including proliferative capacity, angiogenesis, immune evasion, metabolic reprogramming, extracellular matrix (ECM) remodelling, and cell migration. This can negatively impact patient outcomes by inducing therapeutic resistance. The importance of hypoxia is clearly demonstrated by continued research into finding clinically relevant hypoxia biomarkers, and hypoxia-targeting therapies. One of the problems is the lack of clinically applicable methods of hypoxia detection, and lack of standardisation. Additionally, a lot of the methods of detecting hypoxia do not take into consideration the complexity of the hypoxic tumour microenvironment (TME). Therefore, this needs further elucidation as approximately 50% of solid tumours are hypoxic. The ECM is important component of the hypoxic TME, and is developed by both cancer associated fibroblasts (CAFs) and tumour cells. However, it is important to distinguish the different roles to develop both biomarkers and novel compounds. Fibronectin (FN), collagen (COL) and hyaluronic acid (HA) are important components of the ECM that create ECM fibres. These fibres are crosslinked by specific enzymes including lysyl oxidase (LOX) which regulates the stiffness of tumours and induces fibrosis. This is partially regulated by HIFs. The review highlights the importance of understanding the role of matrix stiffness in different solid tumours as current data shows contradictory results on the impact on therapeutic resistance. The review also indicates that further research is needed into identifying different CAF subtypes and their exact roles; with some showing pro-tumorigenic capacity and others having anti-tumorigenic roles. This has made it difficult to fully elucidate the role of CAFs within the TME. However, it is clear that this is an important area of research that requires unravelling as current strategies to target CAFs have resulted in worsened prognosis. The role of immune cells within the tumour microenvironment is also discussed as hypoxia has been associated with modulating immune cells to create an anti-tumorigenic environment. Which has led to the development of immunotherapies including PD-L1. These hypoxia-induced changes can confer resistance to conventional therapies, such as chemotherapy, radiotherapy, and immunotherapy. This review summarizes the current knowledge on the impact of hypoxia on the TME and its implications for therapy resistance. It also discusses the potential of hypoxia biomarkers as prognostic and predictive indictors of treatment response, as well as the challenges and opportunities of targeting hypoxia in clinical trials.

Obesity is a global health crisis, with its prevalence steadily rising over the past few decades. One concerning consequence of obesity is its association with metabolic associated steatohepatitis [MASH], portal hypertension and liver cirrhosis. Cirrhosis is irreversible, but stages of liver disease before the development of cirrhosis are reversible with appropriate interventions. Studies have brought into light new entities that influences the pathophysiology of portal hypertension. This review provides evidence supporting that, Paneth cells[PCs] in the intestinal epithelium, which remained enigmatic for a century, are the maneuverer of pathophysiology of portal hypertension and obesity. PC dysfunction can cause perturbation of the intestinal microbiota and changes in intestinal permeability, which are the potential triggers of systemic inflammation. Thus, it can offer unique opportunities to understand the pathophysiology of portal hypertension for intervention strategies.

For the first time, based on the expression analysis of a wide range of pro- and anti-fibrotic, pro- and anti-inflammatory, and pro- and anti-apoptotic genes, key markers of endoplasmic reticulum stress (ER-stress), molecular mechanisms for the regulation of fibrosis, and accompanying negative processes caused by thioacetamide (TAA) injections and subsequent injections of selenium-containing nanoparticles and sorafenib have been proposed. We found that selenium nanoparticles of two types (doped with and without sorafenib) led to a significant decrease in almost all pro-fibrotic and pro-inflammatory genes. Sorafenib injections also reduced mRNA expression of pro-fibrotic and pro-inflammatory genes but less effectively than both types of nanoparticles. In addition, it was shown for the first time that TAA can be an inducer of ER-stress, most likely activating the IRE1α and PERK signaling pathways of the UPR, an inducer of apoptosis and pyroptosis. Sorafenib, despite a pronounced anti-apoptotic effect, still did not reduce the expression of caspase-3 and 12 or mitogen-activated kinase JNK1 to control values, which increases the risk of persistent apoptosis in liver cells. After injections of selenium-containing nanoparticles, the negative effects caused by TAA were leveled, causing an adaptive UPR signaling response through activation of the PERK signaling pathway. The advantages of selenium-containing nanoparticles over sorafenib, established in this work, once again emphasize the unique properties of this microelement and serve as an important factor for the further introduction of drugs based on it into clinical practice.

The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.

Alterations in liver perfusion and venous hypertension have been implicated in the pathophysiology of Fontan-associated liver disease (FALD). However, the correlation between exercise hemodynamics and markers of FALD have not been studied.

We performed a retrospective review of 32 consecutive adults undergoing exercise catheterisation at the Mayo Clinic, Minnesota. Invasive hemodynamics were correlated with aspartate transaminase to platelet ratio index (APRI) and the Fibrosis-4 (Fib-4) score, well validated surrogates of liver fibrosis.

The mean age was 30.9 ± 7 years. The mean APRI was 0.5 ± 0.2 and the mean Fib-4 score 1.3 ± 0.8. Fib-4 scores correlated with spleen size on abdominal imaging (r = 0.40; P = 0.03). Resting Fontan pressure was 13.9 ± 3.9 mm Hg and pulmonary artery wedge pressure (PAWP) 10.0 ± 3.5 mm Hg. At peak exercise (69.4 ± 23.2 W), Fontan pressures increased to 26.5 ± 6.2 mm Hg and PAWP to 22.4 ± 7.1 mm Hg. APRI and Fib-4 score were directly related to Fontan pressure and PAWP at rest and during exercise, and inversely related to exercise arterial O2 saturation. Fib-4 inversely correlated with O2 delivery indices. Similarly, when categorising patients according to high APRI (> 0.5 vs ≤ 0.5) or Fib-4 score (≥ 1.45 vs < 1.45) according to previously proposed cutoffs for diagnosis of liver fibrosis, those with elevated scores had higher resting and exercise Fontan and PAWP pressure with lower O2 arterial saturation.

APRI and Fib-4 score correlated with resting and exercise Fontan pressure and PAWP. In addition, Fib-4 scores were inversely related to O2 delivery indices. These findings support a role played by hepatic venous hypertension and reduced O2 supply in patients with FALD.

In recent years, the study of lymphangiogenesis and fibrotic diseases has made considerable achievements, and accumulating evidence indicates that lymphangiogenesis plays a key role in the process of fibrosis in various organs. Although the effects of lymphangiogenesis on fibrosis disease have not been conclusively determined due to different disease models and pathological stages of organ fibrosis, its importance in the development of fibrosis is unquestionable. Therefore, we expounded on the characteristics of lymphangiogenesis in fibrotic diseases from the effects of lymphangiogenesis on fibrosis, the source of lymphatic endothelial cells (LECs), the mechanism of fibrosis-related lymphangiogenesis, and the therapeutic effect of intervening lymphangiogenesis on fibrosis. We found that expansion of LECs or lymphatic networks occurs through original endothelial cell budding or macrophage differentiation into LECs, and the vascular endothelial growth factor C (VEGFC)/vascular endothelial growth factor receptor (VEGFR3) pathway is central in fibrosis-related lymphangiogenesis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), as a receptor of LECs, is also involved in the regulation of lymphangiogenesis. Intervention with lymphangiogenesis improves fibrosis to some extent. In the complex organ fibrosis microenvironment, a variety of functional cells, inflammatory factors and chemokines synergistically or antagonistically form the complex network involved in fibrosis-related lymphangiogenesis and regulate the progression of fibrosis disease. Further clarifying the formation of a new fibrosis-related lymphangiogenesis network may potentially provide new strategies for the treatment of fibrosis disease.

It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.

Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.

Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway.

Wild-type and multidrug resistance 2 knockout (Mdr2-/-) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used.

Mdr2-/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2-/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2-/- mice. Mdr2-/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro, ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro, human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment.

ET-A inhibition reduced biliary and liver damage in Mdr2-/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.

Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor-designed galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactose-PEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

Hepatic stellate cells (HSCs) upregulate hypoxia inducible factor 1 alpha (HIF-1α) expression in response to fibrosis-induced hypoxia. The mechanism by which HIF-1α promotes liver fibrosis in HSCs is not fully understood. In this study, we found that increased expression of α-SMA, HIF-1α and IL-6, as well as colocalization of α-SMA and HIF-1α, and HIF-1α and IL-6, were observed in liver fibrotic tissues of patients and a mouse model. HIF-1α expression induced IL-6 secretion in activated HSCs and the increase could be abolished by HIF-1α suppression or HIF1A gene knockdown. HIF-1α directly bound to the hypoxia response element (HRE) region in HSC IL6/Il6 promoters. Additionally, culturing naïve CD4 T cells with supernatant from HSCs in which HIF-1α is highly expressed increased IL-17A expression, and the expression could be abolished by HIF1A knockdown in LX2. In turn, the IL-17A-enriched supernatant induced IL-6 secretion in HSCs. Together, these results show that HIF-1α upregulates IL-6 expression in HSCs and induces IL-17A secretion through directly binding to the HRE of IL6 promoter.

Background Liver microcirculation dysfunction plays a vital role in the occurrence and development of liver diseases, and thus, there is a clinical need for in vivo, noninvasive, and quantitative evaluation of liver microcirculation. Purpose To evaluate the feasibility of ultrasensitive US microvessel imaging (UMI) in the visualization and quantification of hepatic microvessels in healthy and cirrhotic rats. Materials and Methods In vivo studies were performed to image hepatic microvasculature by means of laparotomy in Sprague-Dawley rats (five cirrhotic and five control rats). In vivo conventional power Doppler US and ex vivo micro-CT were performed for comparison. UMI-based quantifications of perfusion, tortuosity, and integrity of microvessels were compared between the control and cirrhotic groups by using the Wilcoxon test. Spearman correlations between quantification parameters and pathologic fibrosis, perfusion function, and hepatic hypoxia were evaluated. Results UMI helped detect minute vessels below the liver capsule, as compared with conventional power Doppler US and micro-CT. With use of UMI, lower perfusion indicated by vessel density (median, 22% [IQR, 20%-28%] vs 41% [IQR, 37%-46%]; P = .008) and fractional moving blood volume (FMBV) (median, 6.4% [IQR, 4.8%-8.6%] vs 13% [IQR, 12%-14%]; P = .008) and higher tortuosity indicated by the sum of angles metric (SOAM) (median, 3.0 [IQR, 2.9-3.0] vs 2.7 [IQR, 2.6-2.9]; P = .008) were demonstrated in the cirrhotic rat group compared with the control group. Vessel density (r = 0.85, P = .003), FMBV (r = 0.86, P = .002), and median SOAM (r = -0.83, P = .003) showed strong correlations with pathologically derived vessel density labeled with dextran. Vessel density (r = -0.81, P = .005) and median SOAM (r = 0.87, P = .001) also showed strong correlations with hepatic tissue hypoxia. Conclusion Contrast-free ultrasensitive US microvessel imaging provided noninvasive in vivo imaging and quantification of hepatic microvessels in cirrhotic rat liver. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Fetzer in this issue.

Biliary atresia is a neonatal disease characterized by choledochal obstruction and progressive cholangiopathy requiring liver transplantation in most patients. Hypoxia-ischemia affecting the biliary epithelium may lead to biliary obstruction. We hypothesized that ischemic cholangiopathy involving disruption of the peribiliary vascular plexus could act as a triggering event in biliary atresia pathogenesis.

Liver and porta hepatis paraffin-embedded samples of patients with biliary atresia or intrahepatic neonatal cholestasis (controls) were immunohistochemically evaluated for HIF-1alpha-nuclear signals. Frozen histological samples were analyzed for gene expression in molecular profiles associated with hypoxia-ischemia. Prospective clinical-laboratory and histopathological data of biliary atresia patients and controls were reviewed.

Immunohistochemical HIF-1alpha signals localized to cholangiocytes were detected exclusively in liver specimens from biliary atresia patients. In 37.5% of liver specimens, HIF-1alpha signals were observed in biliary structures involving progenitor cell niches and peribiliary vascular plexus. HIF-1alpha signals were also detected in biliary remnants of 81.8% of porta hepatis specimens. Increased gene expression of molecules linked to REDOX status, biliary proliferation, and angiogenesis was identified in biliary atresia liver specimens. In addition, there was a trend towards decreased GSR expression levels in the HIF-1alpha-positive group compared to the HIF-1alpha-negative group.

Activation of the HIF-1alpha pathway may be associated with the pathogenesis of biliary atresia, and additional studies are necessary to confirm the significance of this finding. Ischemic cholangiopathy and REDOX status disturbance are putative explanations for HIF-1alpha activation. These findings may give rise to novel lines of clinical and therapeutic investigation in the BA field.

The aim of this study was to explore the effect and mechanism of pirfenidone (PFD) combined with 2-methoxyestradiol (2-ME2) perfusion through portal vein on hepatic artery hypoxia-induced hepatic fibrosis.

Sprague-Dawley rats were divided into 5 groups (n ​= ​3/group): control group, hepatic artery ligation (HAL) group, HAL ​+ ​PFD (portal vein perfusion of PFD) group, HAL+2-ME2 (portal vein perfusion of 2-ME2) group and HAL ​+ ​PFD+2-ME2 group depending on whether they received HAL and/or portal vein perfusion (PFD and/or 2-ME2). Livers were harvested for pathology, western blotting (WB), and quantitative real-time PCR (qRT-PCR).

Sirius red staining showed that portal vein perfusion of drugs resulted in degradation of liver fibrosis. Immunohistochemistry showed decreased hypoxia-inducible factor-1 α (HIF-1α) and α-smooth muscle actin (α-SMA) after portal intravenous drugs infusion compared with HAL group (P ​< ​0.05). WB analysis showed increased Smad7 in HAL ​+ ​PFD group compared with HAL group (P ​< ​0.05). qRT-PCR analysis showed decreased matrix metallo-proteinase 2 (MMP2), transforming growth factor β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and Collagen I mRNA in HAL ​+ ​PFD group except for tissue inhibitor of metalloproteinase-1 (TIMP-1) compared with HAL group (P ​< ​0.05). Compared with HAL ​+ ​PFD group, the addition of 2-ME2 did not lead to better results in qRT-PCR analysis.

The portal vein perfusion of PFD significantly reduced the hepatic artery hypoxia-induced fibrosis degree in treated rats by down-regulating the expression of HIF-1α, α-SMA, MMP2, TGF-β1, MCP-1, and Collagen I, as well as up-regulating the TIMP-1 expression and Smad7 protein level. Combined 2-ME2 infusion was not better than PFD alone.

The role and underlying mechanism of liver macrophages and their derived miR-155-5p in hepatic lymphangiogenesis in liver fibrosis remain unclear. Here, we investigated the mechanism by which macrophages and miR-155-5p were involved in lymphangiogenesis during liver fibrosis and cirrhosis.

In vivo, hepatic lymphatic vessel expansion was evaluated; the liver macrophage subsets, proportion of peripherally-derived macrophages and expressions of CCL25, MCP-1, VAP-1 and MAdCAM-1 were documented; and miR-155-5p in the peripheral blood and liver was detected. In vitro, macrophages with miR-155-5p overexpression and inhibition were used to clarify the effect of miR-155-5p on regulation of macrophage polarization and the possible signalling pathway.

Hepatic lymphangiogenesis was observed in mice with liver fibrosis and cirrhosis challenged with carbon tetrachloride (CCl4). In the liver, the number of M1 macrophages was associated with lymphangiogenesis and the degree of fibrosis. The liver recruitment of peripherally-derived macrophages occurred during liver fibrosis. The levels of miR-155-5p in the liver and peripheral blood gradually increased with aggravation of liver fibrosis. In vitro, SOCS1, a target of miR-155-5p, regulated macrophage polarization into the M1 phenotype through the JAK1/STAT1 pathway.

MiR-155-5p-SOCS1/JAK1/STAT1 pathway participates in hepatic lymphangiogenesis in mice with liver fibrosis and cirrhosis induced by CCl4 by regulating the polarization of macrophages into the M1 phenotype.

Liver fibrosis develops as a result of severe liver damage and is considered a major clinical concern throughout the world. Many factors are crucial for liver fibrosis progression. While advancements have been made to understand this disease, no effective pharmacological drug and treatment strategies have been established that can effectively prevent liver fibrosis or even could halt the fibrotic process. Most of those advances in curing liver fibrosis have been aimed towards mitigating the causes of fibrosis, including the development of potent antivirals to inhibit the hepatitis virus. It is not practicable for many individuals; however, a liver transplant becomes the only suitable alternative. A liver transplant is an expensive procedure. Thus, there is a significant need to identify potential targets of liver fibrosis and the development of such agents that can effectively treat or reverse liver fibrosis by targeting them. Researchers have identified hypoxia-inducible factors (HIFs) in the last 16 years as important transcription factors driving several facets of liver fibrosis, making them possible therapeutic targets. The latest knowledge on HIFs and their possible role in liver fibrosis, along with the cell-specific activities of such transcription factors that how they play role in liver fibrosis progression, is discussed in this review.

Cholestasis is a main clinical feature of biliary atresia (BA), which leads to liver fibrosis (LF). The focus of BA treatment is preventing and slowing the progress of LF. This study reports the improvement effect of anlotinib on common bile duct ligature (BDL)-induced LF in young rats. The BDL young rats were treated with anlotinib and the serum levels of aspartate aminotransferase, alanine aminotransferase, albumin, and total bilirubin were determined. Histological staining was performed and pathological changes in liver tissue were observed. The expression levels of α-SMA, collagen I, CD31, TGF-β1, phospho-VEGFR2, phospho-4E/BP1, and phospho-S6K1 were determined. The results showed that anlotinib significantly improved the liver function and histopathological injury of BDL rats, inhibited the deposition of collagen and hepatocyte apoptosis, and downregulated the protein expression of α-SMA and collagen I. Furthermore, anlotinib treatment significantly inhibited microvascular formation in the liver and downregulated the expression level of phospho-VEGFR2, thereby suggesting that the antifibrosis effect of anlotinib may be achieved by antiangiogenesis. In addition, anlotinib downregulated the expression of phospho-S6K1 and upregulated the expression of phospho-4E/BP1, two downstream proteins of the mammalian target of rapamycin (mTOR) pathway. MHY1485, an agonist of mTOR, significantly reversed the inhibitory effect of anlotinib on angiogenesis and LF but did not influence the effect of anlotinib on the downregulation of phospho-VEGFR2 expression. Together, the above-mentioned results suggest that the effect of anlotinib on BDL-induced LF involves at least antiangiogenesis regulated by the VEGFR2/mTOR signaling pathway.

Cholestasis is associated with disease severity and worse outcome in COVID-19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described.

Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced CLD (non-ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non-COVID-19 pneumonia were matched to patients with CLD and COVID-19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% (n = 65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID-19-related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS-CoV-2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma-glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD (n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID-19, and 15.4% of patients (n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID-19 than in patients with CLD and non-COVID-19 pneumonia (p = 0.040). COVID-19-associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% (n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS-CoV-2 infection.

About 20% of patients with CLD develop progressive cholestasis after SARS-CoV-2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

Non-alcoholic fatty liver disease (NAFLD) is emerging as an epidemic risk factor for hepatocellular carcinoma (HCC). The progression of NAFLD to HCC is closely associated with paracrine communication among hepatic cells. Vascular endothelial growth factor A (VEGFA) plays a key role in NAFLD and HCC; however, the cellular communication of VEGFA in the pathological transition from NAFLD to HCC remains unclear. Here, we found that VEGFA elevation was considerably distributed in hepatocytes of clinical and murine NAFLD-HCC specimens. Notably, progression from NAFLD to HCC was attenuated in hepatocyte-specific deletion of Vegfa (VegfaΔhep) mice. Mechanistically, VEGFA activated human hepatic stellate cell (HSC) LX2 into a fibrogenic phenotype via VEGF-VEGFR signaling in fatty acid medium, and HSC activation was largely attenuated in VegfaΔhep mice during NAFLD-HCC progression. Additionally, a positive correlation between VEGFA and hepatic fibrosis was observed in the NAFLD-HCC cohort, but not in the HBV-HCC cohort. Moreover, LX2 cells could be activated by conditioned medium from NAFLD-derived organoids, but not from HBV livers, whereas this activation was blocked by a VEGFA antibody. In summary, our findings reveal that hepatocyte-derived VEGFA contributes to NAFLD-HCC development by activating HSCs and highlight the potential of precisely targeting hepatocytic VEGFA as a promising therapeutic strategy for NAFLD-HCC.

No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling.

The CCl₄ -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects.

Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.

Pregnant women are more susceptible to malaria due to a combination of physiological and immunological changes. The infection may even affect the growth and survival of the foetus, which mainly occur when parasite enters the placenta. The sequestration of infected erythrocytes may trigger the host response, leading to placental inflammation and altered development, affecting the structure and nutrient transport of placenta. These factors collectively impair placental functions and affect foetal growth.

Pregnant women with peripheral parasitaemia for P. falciparum and P. vivax (20 each) were included in the present study, along with 15 age-matched uninfected healthy pregnant women. Placentae were analysed for the presence of local parasitaemia along with pathological lesions caused due to the parasite. Immunohistochemical staining for CD20, CD45 and CD68 cells was performed for examining the specific leucocytes in the intervillous space of the placenta.

Of the 20 individuals with P. falciparum, only seven placentae showed parasitaemia, whereas individuals with P. vivax showed no placental infection. The pathological changes observed in the P. falciparum-infected placenta include syncytial knotting, excess fibrinoid deposition, syncytiotrophoblast necrosis, syncytial rupture, thickening of trophoblast basement membrane and increased collagen deposition. Immunohistochemical staining showed a significant increase in B cells (CD20), leucocytes (CD45) and monocytes and macrophages (CD68) in the P. falciparum-infected placenta (p < 0.0001).

The result implies that P. falciparum is responsible for pathological alterations in placenta, affecting the nutrient transport across placenta and foetal growth. The immune cells also migrate to the placenta and accumulate in the intervillous space to show humoral and cell-mediated immunity against the parasite.

We speculated impacts of BM-MSCs and UC-EPCs on reversal of hepatic injury induced by carbon tetrachloride (CCl4). Fifty adult rats were divided into five groups: control group, CCl4A group, CCl4B group, CCl4/BM-MSCs group and CCl4/UC-EPCs group. Blood samples were driven to measure concentration of albumin and ALT. Quantitative expression of HGF, TGF-β, MMP-2, and VEGF were assessed by PCR. Histological and immunohistochemistry examination of the liver tissue were performed.

There was elevating albumin (p < .05) and reducing ALT (p < .05) concentrations in groups treated with BM-MSCs and UC-EPCs compared to untreated CCL4A&B groups. UC-EPCs treated group have significantly higher MMP-2 and VEGF (p < .01) genes expression than BM-MSCs treated group. Furthermore, UC-EPCs were more valuable than BMMSCs in increasing gene expression of HGF (p < .05) and immunohistochemistry of α-SMA and Ki-67 (p < .01). BM-MSCs have significantly lower TGF-β (p < .00) compared to UC-EPCs.

This study highlighted on liver regeneration role of both UC-EPCs and BM-MSCs in liver fibrosis.