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Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease, and patient susceptibility to its onset and progression is influenced by several factors. In this study, we investigated whether altered hepatic DNA methylation in liver tissue correlates with the degree of severity of NAFLD-like liver injury induced by a high-fat and high-sucrose (HF/HS) diet in Collaborative Cross (CC) mice. Using genome-wide targeted bisulphite DNA methylation next-generation sequencing, we found that mice with different non-alcoholic fatty liver (NAFL) phenotypes could be distinguished by changes in hepatic DNA methylation profiles. Specifically, NAFL-prone male CC042 mice exhibited more prominent DNA methylation changes compared with male CC011 mice and female CC011 and CC042 mice that developed only a mild NAFL phenotype. Moreover, these mouse strains demonstrated different patterns of DNA methylation. While the HF/HS diet induced both DNA hypomethylation and DNA hypermethylation changes in all the mouse strains, the NAFL-prone male CC042 mice demonstrated a global predominance of DNA hypermethylation, whereas a more pronounced DNA hypomethylation pattern developed in the mild-NAFL phenotypic mice. In a targeted analysis of selected genes that contain differentially methylated regions (DMRs), we identified NAFL phenotype-associated differences in DNA methylation and gene expression of the Apoa4, Gls2, and Apom genes in severe NAFL-prone mice but not in mice with mild NAFL phenotypes. These changes in the expression of Apoa4 and Gls2 coincided with similar findings in a human in vitro cell model of diet-induced steatosis and in patients with NAFL. These results suggest that changes in the expression and DNA methylation status of these three genes may serve as a set of predictive markers for the development of NAFLD.

As a common cause of liver injury, hepatic ischemia/reperfusion injury (HIRI) happens in various clinical conditions including trauma, hepatectomy and liver transplantation. Since transcription factor Yin Yang 1 (YY1) was reported to be downregulated after ischemia/reperfusion (I/R) injury, we focused on YY1 to explore its function in HIRI by functional assays like Cell Counting Kit-8 (CCK-8) assays and flow cytometry assays. The RT-qPCR assay revealed that YY1 was downregulated in hepatocytes after I/R injury. The function assays disclosed that YY1 facilitated cell viability and proliferation, but hindered cell apoptosis in hepatocytes after I/R injury. Through mechanism assays including luciferase reporter assay, RIP and RNA pulldown assay, miR-186-5p was found to bind with YY1 and promote hepatocyte apoptosis by targeting YY1. Subsequently, we verified that small nucleolar RNA host gene 1 (SNHG1) could sponge miR-186-5p to upregulate YY1. Importantly, we figured out that YY1 had a positive regulation on SNHG1. Along the way, YY1 was identified as the upstream transcription factor for SNHG1. In conclusion, our study unveiled a novel competing endogenous RNA (ceRNA) pattern of SNHG1/miR-186-5p/YY1 positive feedback loop in hepatic I/R injury, which might provide new insight into prevention of HIRI during liver transplantation or hepatic surgery.

Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.Abbreviations: Apob: apolipoprotein B; Atg1: autophagy-related 1; Atg7: autophagy related 7; Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; BL6: C57BL/6N mouse strain; BNIP3: BCL2/adenovirus E1B interacting protein 3; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mt-Atp8: mitochondrially encoded ATP synthase 8; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mt-Co3: mitochondrially encoded cytochrome c oxidase III; mt-Cytb: mitochondrially encoded cytochrome b; mtDNA: mitochondrial DNA; MUL1: mitochondrial ubiquitin ligase activator of NFKB 1; nDNA: nuclear DNA; Ndufa9: NADH:ubiquinone oxireductase subunit A9; NDUFB8: NADH:ubiquinone oxireductase subunit B8; Nnt: nicotinamide nucleotide transhydrogenase; NZB: NZB/BINJ mouse strain; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced putative kinase 1; Polg2: polymerase (DNA directed), gamma 2, accessory subunit; Ppara: peroxisome proliferator activated receptor alpha; Ppia: peptidylprolyl isomerase A; Prkn: parkin RBR E3 ubiquitin protein ligase; P10: post-natal day 10; P21: post-natal day 21; P100: post-natal day 100; qPCR: quantitative polymerase chain reaction; Rpl19: ribosomal protein L19; Rps18: ribosomal protein S18; SD: standard deviation; SEM: standard error of the mean; SDHB: succinate dehydrogenase complex, subunit B, iron sulfur (Ip); SQSTM1: sequestosome 1; Ssbp1: single-stranded DNA binding protein 1; TFAM: transcription factor A, mitochondrial; Tfb1m: transcription factor B1, mitochondrial; Tfb2m: transcription factor B2, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; UQCRC2: ubiquinol cytochrome c reductase core protein 2; WT: wild-type.

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.

Assessment and enhancement of liver clearance are promising strategies for protection of liver from various liver diseases. Iron-tannic nanoparticles (FTs) were previously considered as imageable autophagic enhancers with biodegradation potential. Herein, we present a new approach for utilizing Iron-tannic nanoparticles (FTs) as a tool for imaging and increasing liver clearance. Pharmacokinetic profiling suggested that FTs were initially found in blood circulation and thereafter were distributed to the liver. By using MR imaging (T1 weighted), maximum MRI signal enhancement was found to occur after 30 minutes post-injection (i.v.) and gradually decreased afterward. Decreasing MRI signal may be due to FTs metabolism by the liver. By assessing imaging-derived pharmacokinetics, we can simply determine the rate constant of liver degradation of FTs. Potentially, we might use this parameter to monitor liver function, where its clearance is of concern. Once functional implication of FTs in liver clearance was investigated, FTs were found to induce hepatocyte autophagy along with activation of lysosomes. Consequently, the hepatocytes were capable of efficiently clearing cellular debris. From these results, it is clear that FTs should be considered as a molecular tool for quantitative MRI-derived liver function assessment, and for enhancing clearance function in liver parenchyma. Hopefully, our findings will pave the way to develop new strategies for non-invasive assessment and enhancement of liver clearance.

Background: Non-alcoholic fatty liver disease is a common chronic liver injury disease, and its incidence is rapidly increasing across the globe, thus becoming a serious threat to human health. So far, the clinical prevention and treatment of non-alcoholic fatty liver disease mainly include single-targeted drug therapy, surgical treatment and lifestyle changes. However, these treatments cannot completely address the complex pathogenesis of non-alcoholic fatty liver disease and have various side effects. Recent studies reveal that many herbal extracts are found to have potential anti-non-alcoholic fatty liver disease activities. Objective: This paper presents a review on herbal extracts used for the treatment of non-alcoholic fatty liver disease in experimental studies to provide a theoretical basis for their clinical application in the treatment of non-alcoholic fatty liver disease and for new drug development. Methods: Scientific papers were retrieved by searching the PubMed database up to Feb 2021 using the following keywords: ‘non-alcoholic fatty liver disease’, ‘herbal extracts’ (‘flavonoids’, ‘saponins’, ‘quinones’, ‘phenolic compounds’, ‘alkaloids’, ‘polysaccharides’, ‘ginkgolide B’, ‘schizandrin B’, ‘ursolic acid’) and ‘mechanism’. Results: The pharmacological effects and mechanisms of many herbal extracts can reverse the adverse health effects of non-alcoholic fatty liver disease. Conclusion: In vitro and in vivo experimental studies indicated that herbal extracts can improve the symptoms of non-alcoholic fatty liver disease by inhibiting inflammation, antioxidant stress, improvement of lipid metabolism and insulin sensitivity and regulating intestinal bacteria flora. However, there needs to be sufficient data from human clinical trials to prove their efficacy and safety.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), often associated with obesity and metabolic syndrome, manifests itself as steatosis, hepatic fibrosis, cirrhosis, or even end-stage liver disease. NAFLD causes inflammation, insulin resistance and cardiovascular complications. The current study aimed to evaluate the beneficial effects of bariatric surgery on biochemical parameters of hepatic functions in obese patients by comparing them before and one-year after the surgery. METHODS: A total of 72 morbidly obese patients underwent bariatric surgery between 2016 and 2018. The incidence of diabetes mellitus in this group was 29%, median body weight was 124.5 kg (109.0-140.0) and mean body mass index (BMI) was 44.38 ± 6.770 kg/m2. The used surgical procedures included gastric bypass, sleeve gastrectomy, laparoscopic gastric plication, and single anastomosis duodeno-ileal bypass-sleeve gastrectomy. Biochemical parameters including ALT/AST ratio (AAR), NAFLD fibrosis score (NFS), hepatic fibrosis index (FIB-4) and Fatty Liver Index (FLI) were evaluated in all patients at the time of surgery and one year after the intervention. RESULTS: Significant improvement after the intervention was observed in 64 patients. A significant reduction in body weight (P, University of Ostrava in The Czech Republic

Non-alcoholic fatty liver disease(NAFLD), as a metabolic stress liver injury disease, is one of the most common chronic liver diseases, which seriously threatens people's health. The pathogenesis of NAFLD is very complex. A large number of studies show that the hepatic mitochondrial dysfunction leads to the disorder of hepatic glucose and lipid metabolism, oxidative stress, and inflammation, thus inducing hepatocyte apoptosis, which plays an important role in the progression of NAFLD. In recent years, researchers have begun to focus on developing drugs that slowed the progression of NAFLD by regulating the hepatic mitochondrial function. Chinese medicine has a good curative effect on the treatment of NAFLD, with the advantages of high safety and few side effects. Various studies have shown that Chinese medicine prevented and treated NAFLD by regulating the mitochondrial function. Therefore, this paper summarized the relationship between NAFLD and mitochondria, and the mechanism of Chinese medicine(single Chinese medicine, Chinese medicine monomer, and Chinese medicine compound prescription) in the prevention and treatment of NAFLD by regulating mitochondrial function. This paper is expected to provide references for clinical application of traditional Chinese medicine in the treatment of NAFLD by regulating mitochondrial function.

Inflammation and thrombosis are complex processes that occur primarily in the microcirculation. Although standard histology may provide insight into the end pathway for both inflammation and thrombosis, it is not capable of showing the temporal changes that occur throughout the time course of these processes. Intravital microscopy (IVM) is the use of live-animal imaging to gain temporal insight into physiologic processes in vivo. This method is particularly powerful when assessing cellular and protein interactions within the circulation due to the rapid and sequential events that are often necessary for these interactions to occur. While IVM is an extremely powerful imaging methodology capable of viewing complex processes in vivo, there are a number of methodological factors that are important to consider when planning an IVM study. This paper outlines the process of conducting intravital imaging of the liver, identifying important considerations and potential pitfalls that may arise. Thus, this paper describes the use of IVM to study platelet-leukocyte-endothelial interactions in liver sinusoids to study the relative contributions of each in different models of acute liver injury.

The processing of Chinese medicine is a unique and dialectical treatment of traditional Chinese medicine in clinic.The processing theory ofquot;leading vinegar-processing Chinese medicine into liverquot; is one of the traditional processing theories of Chinese medicine.The vinegar-processing Chinese medicine under the guidance of the processing theory typically reflects the characteristics ofquot;reducing toxicity and enhancing efficacyquot; of the processing of Chinese medicine.This paper traced the origin and discussed the connotation of the traditional theory ofquot;leading vinegar-processing Chinese medicine into liverquot;.Combined with the research status ofquot;lea-ding vinegar-processing Chinese medicine into liverquot;, this paper explored the mechanism ofquot;leading vinegar-processing Chinese medicine into liverquot; from the aspects of material basis, medicine effect, and traditional Chinese medicine(TCM) meridian, and analyzed the existing problems in the current research.This paper reviewed the modern study on reducing toxicity and enhancing efficacy of vinegar-processing Chinese medicine, and deeply explored the scientific connotation of the traditional processing theory ofquot;leading vinegar-processing Chinese medicine into liverquot;.At the same time, the research trend and idea of the effect mechanism ofquot;leading vinegar-processing Chinese medicine into liverquot; based on the Quality markers(Q-Marker) of TCM, biological targets, and clinical prescriptions were put forward, providing references for the further study onquot;leading vinegar-processing Chinese medicine into liverquot;.This paper also provided a scientific basis for the rational selection of processed products in TCM clinical practice.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease globally. The first stage of NAFLD is steatosis, the accumulation of triacylglycerols within hepatocytes. Inflammation and oxidative stress both contribute to progression to more severe disease. In 2004 Clinical Science published two papers reporting on fatty acids and oxidative stress markers in the livers of patients with NAFLD; both these papers are highly cited. One paper reported an altered pattern of fatty acids within the livers of patients with NAFLD; there was a lower contribution of polyunsaturated fatty acids (PUFAs) including both n - 6 and n - 3 PUFAs and an altered balance between n - 6 and n - 3 PUFAs in favour of the former. Ratios of precursor PUFAs to their long chain more unsaturated derivatives were altered in NAFLD and were interpreted to indicate a reduced activity of the pathway of synthesis of long chain highly unsaturated PUFAs. The authors interpreted their findings to indicate that a low hepatic content of n - 3 PUFAs has a causal role in NAFLD. The second paper reported lower hepatic antioxidant defences and increased markers of oxidative stress in NAFLD, consistent with a role for oxidative stress in the disease. Many studies have now explored the effect of supplemental n - 3 PUFAs or antioxidants, including vitamin E, in patients with NAFLD with some benefits being reported. There remains much interest in n - 3 PUFAs and antioxidants as preventive and therapeutic strategies in NAFLD and therefore it seems likely that citation of the two papers from 2004 will be sustained.

A pressing health problem, both in clinical and socio-economic terms, is the increase in the number of patients with liver damage caused by viral diseases (hepatitis), cancer, toxicological damage, or metabolic disorders. Liver function assessment is a complex task, for which various existing diagnostic methods are used. Unfortunately, they all have several limitations which frequently make prompt and accurate diagnosis impossible. The high level of disability and mortality caused by liver diseases makes the development of new liver diagnostic methods very urgent. In this paper, we describe a new joint methodology for studying liver function based on optical densitometry and dynamic light scattering. This will help to diagnose and predict the dynamics of liver function during treatment with greater efficiency, due to including in consideration the individual characteristics of the cardiovascular system and tissue metabolism. In this paper, we present a laboratory model of a combined sensor for optical densitometry and dynamic light scattering. We also developed special software for controlling the sensor and processing the recorded data. Modeling experiments and physical medical studies were carried out to adjust and calibrate the sensor and software. We also assessed the sensor resolution when registering the concentration of dye in the human body and the minimum measured flow rate.

This paper by Alfred G. Hildebrandt and Ronald W. Estabrook at the University of Texas (Southwestern) Medical School, led to the concept of cytochrome b(5) (b(5)) as an auxiliary protein facilitating some cytochrome P450 (P450) reactions in the liver and other tissues. The gist of the paper is that DPNH (now known as NADH) enhanced rates of TPNH (now NADPH)-supported N-demethylation of O-ethylmorphine in rat liver microsomes. The conclusion was that b(5) was providing an electron to the ferrous-oxy form of P450 (Fe(2+)O(2)), which was supported by some spectral observations on the oxidation state of b(5) in the microsomes in the steady state. This observation led to a flurry of activity, which is still in progress. This paper has been cited 678 times in Google (558 in Clarivate), and I have often cited it myself. A PubMed search for the terms P450 and b(5) yielded 2,244 results.

Detection of early-stage liver fibrosis has direct clinical implications on patient management and treatment. The aim of this paper is to develop a non-invasive, cost-effective method for classifying liver disease between "non-fibrosis" (F0) and "fibrosis" (F1-F4), and to evaluate the classification performance quantitatively.Image data from 75 patients who underwent a simultaneous liver biopsy and non-contrast CT examination were used for this study. Non-contrast CT image texture features such as wavelet-based features, standard deviation of variance filter, and mean CT number were calculated in volumes of interest (VOIs) positioned within the liver parenchyma. In addition, a combined feature was calculated using logistic regression with L2-norm regularization to further improve fibrosis detection. Based on the final pathology from the liver biopsy, the patients were labelled either as "non-fibrosis" or "fibrosis". Receiver-operating characteristic (ROC) curve, area under the ROC curve (AUROC), specificity, sensitivity, and accuracy were determined for the algorithm to differentiate between "non-fibrosis" and "fibrosis".The combined feature showed the highest classification performance with an AUROC of 0.86, compared to the wavelet-based feature (AUROC, 0.76), the standard deviation of variance filter (AUROC, 0.65), and mean CT number (AUROC, 0.84). The combined feature's specificity, sensitivity, and accuracy were 0.66, 0.88, and 0.76, respectively, showing the most promising results.A new non-invasive and cost-effective method was developed to classify liver diseases between "non-fibrosis" (F0) and "fibrosis" (F1-F4). The proposed method makes it possible to detect liver fibrosis in asymptomatic patients using non-contrast CT images for better patient management and treatment.

Despite the substantial progress made by deep networks in the field of medical image segmentation, they generally require sufficient pixel-level annotated data for training. The scale of training data remains to be the main bottleneck to obtain a better deep segmentation model. Semi-supervised learning is an effective approach that alleviates the dependence on labeled data. However, most existing semi-supervised image segmentation methods usually do not generate high-quality pseudo labels to expand training dataset. In this paper, we propose a deep semi-supervised approach for liver CT image segmentation by expanding pseudo-labeling algorithm under the very low annotated-data paradigm. Specifically, the output features of labeled images from the pretrained network combine with corresponding pixel-level annotations to produce class representations according to the mean operation. Then pseudo labels of unlabeled images are generated by calculating the distances between unlabeled feature vectors and each class representation. To further improve the quality of pseudo labels, we adopt a series of operations to optimize pseudo labels. A more accurate segmentation network is obtained by expanding the training dataset and adjusting the contributions between supervised and unsupervised loss. Besides, the novel random patch based on prior locations is introduced for unlabeled images in the training procedure. Extensive experiments show our method has achieved more competitive results compared with other semi-supervised methods when fewer labeled slices of LiTS dataset are available.

Anabolic androgenic steroids (AASs) are a group of molecules including endogenous testosterone and synthetic derivatives that have both androgenic and anabolic effects. These properties make them therapeutically beneficial in medical conditions such as hypogonadism. However, they are commonly bought illegally and misused for their anabolic, skeletal muscle building, and performance- enhancing effects. Supraphysiologic and long-term use of AASs affects all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders. Hepatotoxicity is one of the major concerns regarding AASs treatment and abuse. Testosterone and its derivatives have been most often shown to induce a specific form of cholestasis, peliosis hepatis, and hepatic benign and malignant tumors. It is currently believed that mechanisms of pathogenesis of these disorders include disturbance of antioxidative factors, upregulation of bile acid synthesis, and induction of hepatocyte hyperplasia. Most toxicity cases are treated with supportive measures and liver function normalizes with discontinuation of AAS. However, some long-term consequences are irreversible. AAS-induced liver injury should be taken in consideration in patients with liver disorders, especially with the increasing unintentional ingestion of supplements containing AAS. In this paper, we review the most current knowledge about AAS-associated adverse effects on the liver, and their clinical presentations, prevalence, and pathophysiological mechanisms.

Bisphenol S (BPS), an analog of bisphenol A (BPA), has been frequently detected in consumer products, food wrappers, plastics, and thermal papers. Since the liver is a hub of metabolic and detoxification pathways, thus intimately related to BPS presence in the environment and body. The current study was designed to investigate the effects of BPS administration in an animal model. Twenty-five male Wistar rats weighing 175 ± 25 g were randomly divided into control and treated groups. The control group was further divided into group I (no treatment) and group II (corn oil), whereas the treatment group was divided into D-I (40 mg/kg/day), D-II (200 mg/kg/day), and D-III (400 mg/kg/day) groups, getting oral doses of BPS for 15 days. Data analysis showed a significant statistical increase in hepatic enzymes ALT (33.4%), AST (25.4%), and ALP (529.6%) in the D-III group along with the development of hypercholesterolemia and hypertriglyceridemia in all BPS groups. Aberrant mRNA expressions of some key hepatic iron regulatory genes and inflammatory mediators were evident through qRT-PCR. Bisphenol S caused congestion of central vein from mild to moderate in hepatic sections. In conclusion, our investigation insinuates BPS intoxication potential and therefore may not be a safe alternative to BPA.

Sepsis is capable of causing systemic infections resulting in multiple organ damage. Dexpanthenol (DXP) has been reported to protect against kidney and liver injury. Therefore, this paper attempts to explore the role of DXP in sepsis-induced kidney and liver injury. A mice model of sepsis was established using the cecal ligation and puncture (CLP) method. The expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and monocyte chemoattractant protein (MCP)-1 in the serum of mice were measured utilizing enzyme linked immunosorbent assay (ELISA). Additionally, the damage of kidney and liver tissues in CLP-induced mice was determined by their respective commercial kits, western blot, and hematoxylin-eosin (HE) staining kits. The apoptosis of kidney and liver tissues in CLP-induced mice was assessed by means of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and western blot. It was observed that DXP decreased the expressions of TNF-α, IL-1β, IL-6, and MCP-1 in the serum of CLP-induced mice, attenuated the functional impairment, pathological damage, inflammation, and cell apoptosis of kidney tissue. Meanwhile, DXP decreased the functional impairment of liver in CLP-induced mice, reduced the levels of inflammatory factors and antioxidant enzymes, attenuated liver pathological damage, and decreased cell apoptosis in liver tissues. In conclusion, DXP attenuates inflammatory damage and apoptosis in kidney and liver organs in a sepsis model.

Automatic segmentation of medical lesions is a prerequisite for efficient clinic analysis. Segmentation algorithms for multimodal medical images have received much attention in recent years. Different strategies for multimodal combination (or fusion), such as probability theory, fuzzy models, belief functions, and deep neural networks, have also been developed. In this paper, we propose the modality weighted UNet (MW-UNet) and attention-based fusion method to combine multimodal images for medical lesion segmentation.MW-UNet is a multimodal fusion method which is based on UNet, but we use a shallower layer and fewer feature map channels to reduce the amount of network parameters, and our method uses the new multimodal fusion method called fusion attention. It uses weighted sum rule and fusion attention to combine feature maps in intermediate layers. During training, all the weight parameters are updated through backpropagation like other parameters in the network. We also incorporate residual blocks into MW-UNet to further improve segmentation performance. The comparison between the automatic multimodal lesion segmentations and the manual contours was quantified by (1) five metrics including Dice, 95% Hausdorff Distance (HD95), volumetric overlap error (VOE), relative volume difference (RVD), and mean-Intersection-over-Union (mIoU); (2) Number of parameters and flops to calculate the complexity of the network.The proposed method is verified on ZJCHD, which is the data set of contrast-enhanced computed tomography (CECT) for Liver Lesion Segmentation taken from Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China. For accuracy evaluation, we use 120 patients with liver lesions from ZJCHD, of which 100 are used for fourfold cross-validation (CV) and 20 are used for hold-out (HO) test. The mean Dice wasThe results show that our method performs well on multimodal liver lesion segmentation. It can be easily extended to other multimodal data sets and other networks for multimodal fusion. Our method is the potential to provide doctors with multimodal annotations and assist them with clinical diagnosis.

Recognizing and organizing different series in an MRI examination is important both for clinical review and research, but it is poorly addressed by the current generation of picture archiving and communication systems (PACSs) and post-processing workstations. In this paper, we study the problem of using deep convolutional neural networks for automatic classification of abdominal MRI series to one of many series types. Our contributions are three-fold. First, we created a large abdominal MRI dataset containing 3717 MRI series including 188,665 individual images, derived from liver examinations. 30 different series types are represented in this dataset. The dataset was annotated by consensus readings from two radiologists. Both the MRIs and the annotations were made publicly available. Second, we proposed a 3D pyramid pooling network, which can elegantly handle abdominal MRI series with varied sizes of each dimension, and achieved state-of-the-art classification performance. Third, we performed the first ever comparison between the algorithm and the radiologists on an additional dataset and had several meaningful findings.

Drug-induced liver injury (DILI) is an important but rare adverse event which can range from mild liver enzyme elevations to liver failure, transplantation or death. A large proportion of commonly used medications, in addition to herbal and dietary supplements, can cause liver injury. DILI has been categorized as direct or idiosyncratic but indirect liver injury has emerged as a third type of drug-induced liver injury. These types of liver injury may warrant different clinical approach and treatment. Associations of HLA genotypes and risk of DILI have highlighted the importance of the immune system in the pathogenesis of DILI. Furthermore, novel agents affecting the immune response can lead to liver injury, often associated with autoimmune features in serologic tests and liver biopsies. Overall, the diagnosis of DILI remains a challenge as it is requires detailed case evaluation in addition to reviewing the hepatotoxic potentials and clinical signatures of the implicated agents. Biochemical profiles vary between agents and although individual drugs tend to portray a consistent clinicopathologic signature, many drugs have multiple signatures. Thanks to multicenter prospective studies on DILI and websites in the public domain such as LiverTox, physicians are provided with tools to investigate suspected DILI cases to increase the likelihood of establishing adiagnosis. The pathogenesis of DILI, epidemiology and current challenges in the diagnosis and management of the disease are reviewed in the paper.

Polydatin, one of the natural active small molecules, was commonly applied in protecting and treating liver disorders in preclinical studies. Oxidative stress plays vital roles in liver injury caused by various factors, such as alcohol, viral infections, dietary components, drugs, and other chemical reagents. It is reported that oxidative stress might be one of the main reasons in the progressive development of alcohol liver diseases (ALDs), nonalcoholic liver diseases (NAFLDs), liver injury, fibrosis, hepatic failure (HF), and hepatocellular carcinoma (HCC). In this paper, we comprehensively summarized the pharmacological effects and potential molecular mechanisms of polydatin for protecting and treating liver disorders via regulation of oxidative stress. According to the previous studies, polydatin is a versatile natural compound and exerts significantly protective and curative effects on oxidative stress-associated liver diseases via various molecular mechanisms, including amelioration of liver function and insulin resistance, inhibition of proinflammatory cytokines, lipid accumulation, endoplasmic reticulum stress and autophagy, regulation of PI3K/Akt/mTOR, and activation of hepatic stellate cells (HSCs), as well as increase of antioxidant enzymes (such as catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), glutathione reductase (GR), and heme oxygenase-1 (HO-1)). In addition, polydatin acts as a free radical scavenger against reactive oxygen species (ROS) by its phenolic and ethylenic bond structure. However, further clinical investigations are still needed to explore the comprehensive molecular mechanisms and confirm the clinical treatment effect of polydatin in liver diseases related to regulation of oxidative stress.

Computed tomography (CT) is a common modality for liver diagnosis, treatment, and follow-up process. Providing accurate liver segmentation using CT images is a crucial step towards those tasks. In this paper, we propose a stacked 2-U-Nets model with three different types of skip connections. The proposed connections work to recover the loss of high-level features on the convolutional path of the first U-Net due to the pooling and the loss of low-level features during the upsampling path of the first U-Net. The skip connections concatenate all the features that are generated at the same level from the previous paths to the inputs of the convolutional layers in both paths of the second U-Net in a densely connected manner. We implement two versions of the model with different number of filters at each level of each U-Net by maximising the Dice similarity between the predicted liver region and that of the ground truth. The proposed models were trained with 3Dircadb public dataset that were released for Sliver and 3D liver and tumour segmentation challenges during MICCAI 2007-2008 challenge. The experimental results show that the proposed model outperformed the original U-Net and 2-U-Nets variants, and is comparable to the state-of-the-art mU-Net, DC U-Net, and Cascaded UNET.

Due to the low accuracy of traditional three-dimensional fusion technology in radiofrequency ablation of hepatocellular carcinoma, this paper studies the advantages of three-dimensional CT fusion technology over traditional two-dimensional imaging technology in preoperative visualization and radiofrequency ablation path selection of hepatocellular carcinoma. To study the prognostic differences of hepatocellular carcinoma patients with different ablation margins (AM) in the three groups, so as to explore the best AM value, so as to minimize the liver injury caused by radiofrequency ablation. The selected patients underwent CT plain scan and three-phase enhancement at 1, 3, 6, and 12 months after operation and were rechecked every 6 months. For recurrent patients, CT was rechecked every three months. The images were obtained by GE 64-slice spiral CT. The thickness of the reconstruction layer is 1 mm, and the interval is 1 mm. The reconstructed image is imported into 3D fusion software. The three-dimensional images of tumor focus, hepatic artery, portal vein, and hepatic vein were reconstructed by two experienced doctors by superimposing the saved tumor images, merging the vascular images into the display, and measuring the ablation boundary (AM value). The results showed that the recurrence rate in group A was higher than that in group B ( P = 0.041 ), and there was no significant difference between group B and group C ( P = 1.000 ). Compared with traditional two-dimensional imaging, three-dimensional CT fusion technology can display the anatomical structure and three-dimensional spatial relationship of tumors and blood vessels and select the best radiofrequency ablation path, so as to achieve accurate radiofrequency ablation.

The aim: The aim of the paper was the experimental study of the morphological features of albino rat hepatocytes after the consumption of the complex of food additives (monosodium glutamate, sodium nitrite, Ponceau 4R) supplemented into the ration and consumed for four weeks. Materials and methods: The study was performed on 30 outbred albino rats of both genders, weighing 204±0.67 g. The ration of the experimental animals, supplemented with a combination of food additives, namely, monosodium glutamate, Ponceau 4R, sodium nitrate, was consumed for 1 and 4 weeks. The study of the structure of hepathocytes was carried out on traditional histological preparations and preparations stained with Best’s carmine. Results: Supplementation of ration with the complex of food additives for one week showed the phenomena of fatty degeneration that dominated in hepatocytes, and in a longer consumption of food additives in the ration (for four weeks), the number of liver cells with the phenomena of hydropic degeneration significantly increased, while individual hepatocytes had signs of irreversible destructive changes. Conclusions: Consumption of the complex of food additives supplemented into the standard ration of laboratory animals for 4 weeks leads to a significant change in the dimensions of the liver cells, a decrease in their glycogen content, and a progressive increase in the number of hepatocytes with alterations.

This paper proposes a semi-automatic Fontan surgery planning method for designing and manufacturing hemodynamically optimized patient-specific grafts. Fontan surgery is a palliative procedure for patients with a single ventricle heart defect by creating a new path using a vascular graft for the deoxygenated blood to be directed to the lungs, bypassing the heart. However, designing patient-specific grafts with optimized hemodynamic performance is a complex task due to the variety of patient-specific anatomies, confined surgical planning space, and the requirement of simultaneously considering multiple design criteria for vascular graft optimization. To address these challenges, we used parameterized Fontan pathways to explore patient-specific vascular graft design spaces and search for optimal solutions by formulating a nonlinear constrained optimization problem, which minimizes indexed power loss (iPL) of the Fontan model by constraining hepatic flow distribution (HFD), percentage of abnormal wall shear stress (%WSS) and geometric interference between Fontan pathways and the heart models (InDep) within clinically acceptable thresholds. Gaussian process regression was employed to build surrogate models of the hemodynamic parameters as well as InDep and [Formula: see text] (conduit model smoothness indicator) for optimization by pattern search. We tested the proposed method on two patient-specific models (n=2). The results showed the automatically optimized (AutoOpt) Fontan models hemodynamically outperformed or at least are comparable to manually optimized Fontan models with significantly reduced surgical planning time (15 hours versus over 2 weeks). We also demonstrated feasibility of manufacturing the AutoOpt Fontan conduits by using electrospun nanofibers.

Taking the hepatic sinusoid (HS) as the main delivery area of liver nutrients and metabolic waste, recognizing its structure is important for a deep understanding of liver function. In this paper, based on lycopersicon esculentum lectin (LEL), with targeting ability for endothelial cells, and carbon quantum dots (CQDs), with high biosafety, an LEL-coupled CQD immunofluorescence probe (CQD@LEL) that can label microvessels is designed and used for the fluorescence labeling and imaging of HS in liver tissue sections. The CQD size is approximately 2 nm. Blue fluorescence is emitted under excitation; its optimal excitation wavelength is 400 nm while the emission is at about 450 nm. Gel electrophoresis and capillary electrophoresis confirm that glutaraldehyde can couple LEL to CQD, and the obtained CQD@LEL retains the fluorescence property and has good stability. Optimization experiments show that its labeling effect is positively correlated with time and probe concentration for dyeing the blood vessels of mouse liver slices. In order to improve the effect further, a probe concentration of 0.17 mg mL

Partial hepatectomy has been widely used to investigate liver regeneration in mice, but the isolation of high yields of viable hepatocytes for downstream single-cell applications is challenging. A marked accumulation of lipids within regenerating hepatocytes is observed during the first 2 days of normal liver regeneration in mice. This so-called transient regeneration-associated steatosis (TRAS) is temporary but partially overlaps the major proliferative phase. Density-gradient purification is the backbone of most existing protocols for the isolation of primary hepatocytes. As gradient purification relies on the density and size of cells, it separates non-steatotic from steatotic hepatocyte populations. Therefore, fatty hepatocytes often are lost, yielding non-representative hepatocyte fractions. The presented protocol describes an easy and reliable method for the in vivo isolation of regenerating hepatocytes regardless of their lipid content. Hepatocytes from male C57BL/6 mice are isolated 24-48 h after hepatectomy by a classic two-step collagenase perfusion approach. A standard peristaltic pump drives the warmed solutions via the catheterized inferior vena cava into the remnant, using a retrograde perfusion technique with outflow through the portal vein. Hepatocytes are dissociated by collagenase for their release from the Glisson's capsule. After washing and careful centrifugation, the hepatocytes can be used for any downstream analyses. In conclusion, this paper describes a straightforward and reproducible technique for the isolation of a representative population of regenerating hepatocytes after partial hepatectomy in mice. The method may also aid the study of fatty liver disease.

The liver is a complex and heterogenous tissue responsible for carrying out many critical physiological functions, such as the maintenance of energy homeostasis and the metabolism of xenobiotics, among others. These tasks are performed through tight coordination between hepatic parenchymal and non-parenchymal cells. Additionally, various metabolic activities are confined to specific areas of the hepatic lobule-a phenomenon called liver zonation. Recent advances in single-cell sequencing technologies have empowered researchers to investigate tissue heterogeneity at a single-cell resolution. In many complex tissues, including the liver, harsh enzymatic and/or mechanical dissociation protocols can negatively affect the viability or the quality of the single-cell suspensions needed to comprehensively characterize this organ in health and disease. This paper describes a robust and reproducible protocol for isolating nuclei from frozen, archived liver tissues. This method yields high-quality nuclei that are compatible with downstream, single-cell omics approaches, including single-nucleus RNA-seq, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), as well as multimodal omics (joint RNA-seq and ATAC-seq). This method has been successfully used for the isolation of nuclei from healthy and diseased human, mouse, and non-human primate frozen liver samples. This approach allows the unbiased isolation of all the major cell types in the liver and, therefore, offers a robust methodology for studying the liver at the single-cell resolution.

Excess acetaminophen(APAP) can be converted by the cytochrome P450 system to the toxic metabolite N-acetyl-p-benzoquinoneimine(NAPQI), which consumes glutathione(GSH). When GSH is depleted, NAPQI covalently binds with proteins, inducing mitochondrial dysfunction and oxidative stress and thereby leading to hepatotoxicity. Schisandrin C(SinC) is a dibenzocyclooctadiene derivative isolated from Schisandra chinensis. Although there is some evidence showing that SinC has hepatoprotective activity, its protective effect and mechanism on APAP-induced liver injury remain unclear. In this paper, an acute liver injury mouse model was established by intraperitoneal injection of APAP at a dose of 400 mg·kg~(-1) to evaluate the effect of SinC administration on the APAP-induced liver injury and its mechanism through an animal experiment. At the same time, a potential candidate drug was provi-ded for traditional Chinese medicine(TCM) prevention and treatment of overdose APAP-induced liver injury. In the APAP-induced liver injury mouse model, we found that SinC can relieve hepatic histopathological lesions and significantly reduce the activities of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and alkaline phosphatase(ALP). It was also capable of increasing the content of GSH and superoxide dismutase(SOD) and decreasing the levels of total bilirubin(TBIL), direct bilirubin(DBIL), malondialdehyde(MDA), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α). Further analysis showed that SinC decreased the content of CYP2 E1 in liver tissues at protein and mRNA levels and increased nuclear factor erythroid 2-related factor 2(Nrf2) and the expression of its downstream targets(including HO-1, NQO1 and GCLC). Taken together, the above results indicate that SinC can alleviate APAP-induced liver injury by reducing the expression of CYP2 E1, suppressing apoptosis, improving inflammatory response and activating the Nrf2 signaling pathway to inhibit oxidative stress.

Although the liver may present a range of congenital anomalies, often involving shape irregularities or the number of lobules, less common variations include the presence of accessory liver lobes (ALL), consisting of a supernumerary lobe of normal hepatic parenchyma in continuity with the liver. This paper reviews the embryology, frequency, anatomy, and types of ALL. Furthermore, we describe computed tomography and magnetic resonance imaging findings in a range of such cases, including those simulating disease or presenting with complications. Knowledge about ALL may facilitate imaging interpretation of such alterations, avoiding inappropriate additional work-up and unnecessary interventions.

Nonalcoholic fatty liver disease (NAFLD) is a clinical syndrome, and pathologically characterized by diffuse macro-vesicular fatty change in the hepatocytes. NAFLD includes simple nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH) and hepatic cirrhosis. NASH is a disease evolving under the influence of various stimuli still poorly understood, but where insulin resistance is prominently. In this paper, we present a new diagnosis model to predict NASH.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. A range of natural products have been reported as regulators of NAFLD in vivo and in vitro. This paper reviews the pathogenesis of NAFLD and some natural products that have been shown to have therapeutic effects on NAFLD. Our work shows that natural products can be a potential therapeutic option for NAFLD.

Fish bile poisoning may damage human liver and kidney, causing degeneration and necrosis. Can also damage brain cells and heart muscle, resulting in nervous system and cardiovascular system lesions. This paper reports a case of a patient who developed multiple organ dysfunction syndrome (MODS) after oral administration of fish bile with Xiexin folk prescription for eye disease. In January 2020, he went to the poisoning and occupational diseases department of the emergency department of Qilu hospital. After receiving hemoperfusion, continuous renal replacement therapy (CRRT) and symptomatic support treatment, the patient was improved and discharged. CRRT combined with HP is one of the rapid and effective methods for the treatment of acute fish bile poisoning.鱼胆中毒可能损害人体肝脏和肾脏，使其变性坏死；也可损伤脑细胞和心肌，造成神经系统和心血管系统的病变。本文报道一例患者听信偏方口服鱼胆一枚治疗眼疾，后出现多器官功能障碍综合征（MODS），于2020年1月到齐鲁医院急诊科中毒与职业病科就诊，经给予血液灌流、连续性肾脏替代治疗（CRRT）及对症支持治疗后好转出院。对于急性鱼胆中毒，CRRT联合HP可能是快速、有效治疗鱼胆中毒的方法之一。.

Mercury (Hg) is harmful to the environment and human health. The gut plays important roles as the biological, chemical, mechanical, and immune barriers in animals and human beings. It has been known that Hg can be absorbed and methylated/demethylated in the gut, on the other hand, the impacts of Hg to the gut (especially the gut microbiota) is less studied. This review paper summarizes the impacts of inorganic Hg (IHg) and methyl Hg (MeHg) on gut barriers and the extraintestinal effects (damage to other organs such as the liver and brain). Both IHg and MeHg were found to cause intestinal microbial disorders, abnormal metabolites production, tight junction damage, and immune responses in the gut. The damage to the gut also contributed to the extraintestinal effects like the hepatotoxicity by IHg and the neurotoxicity by MeHg. In all, it is proposed that the gut should be considered as an important target tissue of Hg exposure, and the regulation of gut microbiota may have the potential for the prevention and control of the toxicity of Hg.

Ultrasound exam output of large organs like liver has traditionally been limited to still images or 2D cine loops of key structures, without 3D context. Having 3D context for follow up studies makes ultrasound scanning much easier and for interventional applications such as biopsy. 3D context will reduce wrong sample selection thereby increasing patient comfort. As of today, there is no existing solution which provides 3D anatomical context to users during scanning for large organs like liver. Even for routine measurements like liver volume, patients have to undergo CT or MR scan. In this paper, we propose a novel approach to build-patient specific 3D anatomical surface models from B-mode ultrasound images and tracking information from position sensors. The complexity of the problem stems from the fact that liver boundaries are often not very clear in ultrasound images, in addition to large variability in liver size and shape across patients. Our work uses state-of-the-art deep learning algorithms to detect surface landmarks of liver followed by registering a geometric model to surface point cloud to build patient specific 3D liver model. Further, the developed models will be used to guide users to right lesion locations during the interventional procedure. Our proposed semi -automated workflow ensures the accuracy of the developed models are within acceptable limits for the targeted problem.

Multiphase computed tomography (CT) images are widely used for the diagnosis of liver disease. Since each phase has different contrast enhancement (i.e., different domain), the multiphase CT images should be annotated for all phases to perform liver or tumor segmentation, which is a time-consuming and labor-expensive task. In this paper, we propose a dual discriminator-based unsupervised domain adaptation (DD-UDA) for liver segmentation on multiphase CT images without annotations. Our framework consists of three modules: a task-specific generator and two discriminators. We have performed domain adaptation at two levels: one is at the feature level, and the other is at the output level, to improve accuracy by reducing the difference in distributions between the source and target domains. Experimental results using public data (PV phase only) as the source domain and private multiphase CT data as the target domain show the effectiveness of our proposed DD-UDA method. Clinical relevance- This study helps to efficiently and accurately segment the liver on multiphase CT images, which is an important preprocessing step for diagnosis and surgical support. By using the proposed DD-UDA method, the segmentation accuracy has improved from 5%, 8%, and 6% respectively, for all phases of CT images with comparison to those without UDA.

Insulin resistance (IR) is a pathological reaction of hyperinsulinemia and impaired glucose tolerance caused by decreased sensitivity of target tissues such as liver to insulin.The pathogenesis of IR as a typical pathological feature of type 2 diabetes is the focus of anti-diabetes research.In this paper,we reviewed the molecular mechanisms of glucose and lipid metabolism,oxidative stress,mitochondrial dysfunction,endoplasmic reticulum stress,inflammation,and hepatic IR in the case of type 2 diabetes mellitus,which might provide new ideas and theoretical guidance for the treatment of diabetes mellitus.

With the recent availability and upgrading of many emerging intestinal microbes sequencing technologies, our research on intestinal microbes is changing rapidly. A variety of investigations have found that intestinal microbes are essential for immune system regulation and energy metabolism homeostasis, which impacts many critical organs. The liver is the first organ to be traversed by the intestinal portal vein, and there is a strong bidirectional link between the liver and intestine. Many intestinal factors, such as intestinal microbes, bacterial composition, and intestinal bacterial metabolites, are deeply involved in liver homeostasis. Intestinal microbial dysbiosis and increased intestinal permeability are associated with the pathogenesis of many chronic liver diseases, such as alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic hepatitis B (CHB), chronic hepatitis C (CHC), autoimmune liver disease (AIH) and the development of hepatocellular carcinoma (HCC). Intestinal permeability and dysbacteriosis often lead to Lipopolysaccharide (LPS) and metabolites entering in serum. Then, Toll-like receptors activation in the liver induces the exposure of the intestine and liver to many small molecules with pro-inflammatory properties. And all of these eventually result in various liver diseases. In this paper, we have discussed the current evidence on the role of various intestinal microbes in different chronic liver diseases. As well as potential new therapeutic approaches are proposed in this review, such as antibiotics, probiotics, and prebiotics, which may have an improvement in liver diseases.

The homodyned-K distribution is an important ultrasound backscatter envelope statistics model of physical meaning, and the parametric imaging of the model parameters has been explored for quantitative ultrasound tissue characterization. In this paper, we proposed a new method for liver fibrosis characterization by using radiomics of ultrasound backscatter homodyned-K imaging based on an improved artificial neural network (iANN) estimator. The iANN estimator was used to estimate the ultrasound homodyned-K distribution parameters k and α from the backscattered radiofrequency (RF) signals of clinical liver fibrosis ( n = 237), collected with a 3-MHz convex array transducer. The RF data were divided into two groups: Group I corresponded to liver fibrosis with no hepatic steatosis ( n = 94), and Group II corresponded to liver fibrosis with mild to severe hepatic steatosis ( n = 143). The estimated homodyned-K parameter values were then used to construct k and α parametric images using the sliding window technique. Radiomics features of k and α parametric images were extracted, and feature selection was conducted. Logistic regression classification models based on the selected radiomics features were built for staging liver fibrosis. Experimental results showed that the proposed method is overall superior to the radiomics method of uncompressed envelope images when assessing liver fibrosis. Regardless of hepatic steatosis, the proposed method achieved the best performance in staging liver fibrosis ≥ F1, ≥ F4, and the area under the receiver operating characteristic curve was 0.88, 0.85 (Group I), and 0.85, 0.86 (Group II), respectively. Radiomics has improved the ability of ultrasound backscatter statistical parametric imaging to assess liver fibrosis, and is expected to become a new quantitative ultrasound method for liver fibrosis characterization.

Xanthohumol (XN) improves cognition of wild-type rodents on a high-fat diet (HFD). Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farnesoid X receptor (FXR; also known as NR1H4), the primary receptor for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR ablation (FXRIntestine−/− and FXRLiver−/−, respectively) on an HFD or an HFD containing XN were cognitively tested. XN improved cognitive performance in a genotype- and sex-dependent manner, with improved task learning in females (specifically wild-type), reversal learning in males (specifically wild-type and FXRIntestine−/− mutant) and spatial learning (both sexes). XN increased hippocampal diacylglycerol and sphingomyelin levels in females but decreased them in males. XN increased the ratio of shorter-chain to longer-chain ceramides and hexaceramides. Higher diacylglycerol and lower longer-chain ceramide and hexaceramide levels were linked to improved cognitive performance. Thus, the beneficial sex-dependent cognitive effects of XN are linked to changes in hippocampal diacylglycerol and ceramide levels. This article has an associated First Person interview with the first author of the paper.

Cholestasis is a key causative factor in alcohol-related liver disease (ALD) and variable degrees of cholestasis occur in all stages of ALD. However, the pathogenetic mechanisms and biomarkers associated with cholestasis are not well characterized. Cholestatic disease is marked by the disruption of bile acids (BA) transport and homeostasis. Consequently, in both human and experimental ALD, the disease shows a direct correlation with an imbalance in BA equilibrium, which in turn may also affect the severity of the disease. Modulation of BA metabolism or signaling pathways is increasingly considered as a potential therapeutic strategy for ALD in humans. In this paper, we highlight the key advances made in the past two decades in characterizing the molecular regulatory mechanisms of BA synthesis, enterohepatic circulation, and BA homeostasis. We summarize recent insights into the nature of the linkage between BA dysregulation and ALD, including the abnormal expression of genes involved in BA metabolism, abnormal changes in receptors that regulate BA metabolism, and disturbance in the gut flora engaged in BA metabolism caused by alcohol consumption. Additionally, we provide novel perspectives on the changes in BAs in various stages of ALD. Finally, we propose potential pharmacological therapies for ALD targeting BA metabolism and signaling.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) continues to rise, yet effective treatments are lacking due to the complex pathogenesis of this disease. Although recent research has provided evidence for the “multiple strikes” theory, the classic “two strikes” theory has not been overturned. Therefore, there is a crucial need to identify multiple targets in NAFLD pathogenesis for the development of diagnostic markers and targeted therapeutics. Since its discovery, the mechanistic target of rapamycin (mTOR) has been recognized as the central node of a network that regulates cell growth and development and is closely related to liver lipid metabolism and other processes. This paper will explore the mechanisms by which mTOR regulates lipid metabolism (SREBPs), insulin resistance (Foxo1, Lipin1), oxidative stress (PIG3, p53, JNK), intestinal microbiota (TLRs), autophagy, inflammation, genetic polymorphisms, and epigenetics in NAFLD. The specific influence of mTOR on NAFLD was hypothesized to be divided into micro regulation (the mechanism of mTOR’s influence on NAFLD factors) and macro mediation (the relationship between various influencing factors) to summarize the influence of mTOR on the developmental process of NAFLD, and prove the importance of mTOR as an influencing factor of NAFLD regarding multiple aspects. The effects of crosstalk between mTOR and its upstream regulators, Notch, Hedgehog, and Hippo, on the occurrence and development of NAFLD-associated hepatocellular carcinoma are also summarized. This analysis will hopefully support the development of diagnostic markers and new therapeutic targets in NAFLD.

The charring tissue formation in the ablated lesion during the microwave ablation (MWA) of tumors would induce various unwanted inflammatory responses. This paper aimed to deliver appropriate thermal dose for effective ablations while preventing tissue carbonization by optimizing the treatment protocol during MWA with the set combinations of temperature control and pulsed microwave energy delivery.The thermal phase transition ofThe DSC scans demonstrated that theThis study developed a straight-forward anti-carbonization strategy in MWA by modulating the pulsing mode and intermittent time. The programmed protocols of intermittent pulsing MWA have demonstrated its potentials toward future expansion of MWA technology in clinical application.

Matrix stiffening has been recognized as one of the key drivers of the progression of liver fibrosis. It has profound effects on various aspects of cell behavior such as cell function, differentiation, and motility. However, as these processes are not homogeneous throughout the whole organ, it has become increasingly important to understand changes in the mechanical properties of tissues on the cellular level. To be able to monitor the stiffening of collagen-rich areas within the liver lobes, this paper presents a protocol for measuring liver tissue elastic moduli with high spatial precision by atomic force microscopy (AFM). AFM is a sensitive method with the potential to characterize local mechanical properties, calculated as Young's (also referred to as elastic) modulus. AFM coupled with polarization microscopy can be used to specifically locate the areas of fibrosis development based on the birefringence of collagen fibers in tissues. Using the presented protocol, we characterized the stiffness of collagen-rich areas from fibrotic mouse livers and corresponding areas in the livers of control mice. A prominent increase in the stiffness of collagen-positive areas was observed with fibrosis development. The presented protocol allows for a highly reproducible method of AFM measurement, due to the use of mildly fixed liver tissue, that can be used to further the understanding of disease-initiated changes in local tissue mechanical properties and their effect on the fate of neighboring cells.

This paper presents a novel, low cost, organ perfusion machine designed for use in research. The modular and versatile nature of the system allows for additional sensing equipment to be added or adapted for specific use. Here we introduce the system and present its preliminary evaluation by assessing its ability to maintain a predetermined input pressure. A proportional-integral-derivative (PID) controller was implemented and tested on a porcine liver to maintain input pressure to the hepatic artery and compared to bench tests. The results confirmed the effectiveness of the controller for maintaining input through the hepatic artery (HA) in a timely manner. Clinical Relevance-Machine Perfusion (MP) is proving to be an invaluable adjunct in clinical practice. With its ongoing success in the transplant arena, we propose MP for use in research. A cost-effective, versatile system that can be modified for specific research use to test new pharmacological therapies, imaging techniques or develop simulation training would be beneficial.

We sought to characterise the syndrome of isolated paracetamol-induced acute kidney injury (AKI), whose incidence and mechanisms are poorly understood.Using systematic review methodology, fifty-six papers relating to paracetamol-induced AKI were identified.24 cases of isolated paracetamol-induced AKI were identified and compared to 87 identified cases of concurrent renal and hepatic injury. Paracetamol-induced AKI became detectable 3-4 days after exposure; liver injury, where it occurred, preceded AKI detection by 1 day. Risk factors affecting hepatotoxicity risk do not appear to influence isolated AKI, with no clear associated factors except younger age (mean 18.8 versus 33.1 years).Isolated paracetamol-induced AKI appears commoner in younger patients. Paracetamol-induced AKI occurs late and may go undetected by current treatment guidelines.

In our previous paper, we demonstrated the ex vivo studies of non-toxic liposome-nanogel systems by which the long-term drug release could be provided from hybrid systems for the 5-fluorouracil (5-FU) drug molecule. The aim of this study was the in vivo magnetic targeting of 5-FU-loaded Fe

Obesity can lead to chronic inflammation in different tissues, generating insulin and leptin resistance and alterations in glucose and lipid metabolism, favoring the development of degenerative diseases, including type II diabetes. Congruently, the inflammatory signaling inhibition prevents the development of obesity and restores insulin sensitivity. Via the enhancement of central nervous system activity, an enriched environment (EE) has beneficial effects on learning and memory as well as on immune cell functions and inflammation in different disease models. Here, we explored whether an EE can restore energy balance in obese mice that previously presented metabolic alterations. We discovered that an EE improved glucose metabolism, increased insulin signaling in liver, and reduced hepatic steatosis and inflammation, and increased lipolysis and browning in the white adipose tissue of high-fat diet (HFD)-fed mice. Finally, we found reduced inflammatory signaling and increased anorexigenic signaling in the hypothalamus of HFD-fed mice exposed to an EE. These data indicate that an EE is able to restore the metabolic imbalance caused by HFD feeding. Thus, we propose EE as a novel therapeutic approach for treating obesity-related metabolic alterations. This article has an associated First Person interview with the first author of the paper.