Hepatic Sinusoids Research Articles

Kupffer cells heterogeneity and replacement by monocyte-derived KCs contributes to visceral leishmaniasis resistance

Abstract Visceral leishmaniasis (VL) is a potentially fatal disease transmitted by sand fly bites and caused by Leishmania (L. donovani/L. infantum) protozoa. Kupffer cells (KCs) are the liver embryonic resident macrophages (emKCs), characterized by Clec4f and Tim4 expression and their sessile behavior within the liver sinusoids. KCs maintain their numbers via self-proliferation during homeostasis but can be replaced by monocyte-derived cells (moKCs) during inflammation. In the murine VL model, KCs are important for both initial parasite growth and granuloma formation, the latter being associated with the eventual protective response. The objective of our study is to investigate KC proliferation, migration, death, and their replacement by moKCs in VL. We found that KC proliferation was enhanced at 19 d.p.i., while at 42 d.p.i. the granulomas cores contained mixed KC clonal lineages and were located outside the liver sinusoids. At the same time point, Clec4f and Tim4 expression was reduced, and we found evidence of KC apoptosis and ferroptosis. Parabiotic mice demonstrated KC populations that bore either congenic marker, and CCR2 −/−infected mice showed enhanced frequencies of emKCs, reduced frequencies of moKCs, and higher parasite loads compared to WT mice. Reduction of ferroptosis in BACH1 −/−mice resulted in lower frequencies of moKCs. Collectively, our data indicates that KCs migrate to the liver parenchyma to form granulomas, facilitating their activation by other immune cells, and that KC death results in their partial replacement by moKCs, contributing to increased parasite killing. Thus, KC heterogeneity is an important hallmark of hepatic resistance in VL. Funded by the Division of Intramural Research, NIAID.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Don RockeyDon RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards. Reena SidhuReena SidhuProf. Reena Sidhu is a Consultant Gastroenterologist and an Honorary Professor with the University of Sheffield, UK. Her main area of interest is the small bowel and she completed a clinical MD with the University of Sheffield on modern modalities of investigation of the small bowel. She is currently the lead for the tertiary double balloon enteroscopy service at Sheffield Teaching Hospitals and co-runs one of the biggest Capsule Endoscopy services in Europe. Both of these services are established regional services which have won national awards. She runs an international capsule endoscopy course for doctors. She carries out clinical research related to the small bowel and continues to publish actively in this field with > 100 Medline publications to date. She has research fellows under her banner. She is regularly invited to speak at national and international meetings. She has led an ESGE curriculum for Capsule and Device Assisted Enteroscopy. She has also been involved in formalizing accreditation for capsule endoscopy and enteroscopy in the UK. She was awarded the Hopkins Endoscopy Prize by the BSG in 2012, the first female gastroenterologist to have ever won this. She is the first author of the British Society of Gastroenterology guidelines on capsule endoscopy and enteroscopy, published in 2008 and is also a co-author on the 2023 ESGE guidelines on small bowel endoscopy. She also led a UK wide Position Statement on the use of Propofol sedation for complex endoscopy in the UK and a co-author on the BSG Iron Deficiency Anaemia Guidelines 2021. She is the current BSG Education Chair and has curated an entirely new platform for e-learning for gastroenterology in the UK during her tenure as the BSG Web Editor.

Hepatocyte-specific knockout of HIF-2α cannot alleviate carbon tetrachloride-induced liver fibrosis in mice.

The effects of hypoxia inducible factor-2α (HIF-2α) deficiency on liver fibrosis have not been demonstrated in a fibrosis model induced by carbon tetrachloride (CCl4). We aimed to examine whether hepatocyte-specific HIF-2α deletion could ameliorate CCl4-induced liver fibrosis in mice. Hepatocyte-specific HIF-2α knockout mice were created using an albumin promoter-driven Cre recombinase. HIF-2α knockout (KO) mice and floxed control wild-type (WT) mice were fed a normal diet (ND) and received either twice weekly intraperitoneal injections of CCl4 solution (CCl4 dissolved in olive oil) or the corresponding amount of olive oil for 8 weeks. The indicators of liver function, glucose and lipid metabolism, and liver histology were compared among the different groups. Hepatocyte-specific HIF-2α knockout had no effect on the growth, liver function, glucose or lipid metabolism in mice. CCl4-treated KO and WT mice had a similar pattern of injury and inflammatory cell infiltration in the liver. Quantification of Masson staining, α-smooth muscle actin (α-SMA) immunohistochemistry, and the hydroxyproline (HYP) content revealed similar liver fibrosis levels between KO and WT mice injected intraperitoneally with CCl4. Immunohistochemistry analysis suggested that HIF-2α was mainly expressed in the portal area and hepatic sinusoids but not in hepatocytes. Bioinformatics analyses further indicated that HIF-2α expression was neither liver specific nor hepatocyte specific, and the effect of HIF-2α in hepatocytes on liver fibrosis may not be as important as that in liver sinuses. Hepatocyte HIF-2α expression may not be a key factor in the initiation of liver fibrogenesis, and hepatocyte-specific deletion of HIF-2α may not be the ideal therapeutic strategy for liver fibrosis.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti‐Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis (Adv. Mater. 17/2023)

Drug Delivery In article number 2212206, Ying Zhao, Xiaolong Qi, Guangjun Nie, and co-workers propose a liver sinusoid capillarization and hepatic stellate cells activation combined regulation strategy for liver fibrosis treatment. Liver sinusoid fenestrae restoration enhances the transport efficiency of nanomedicine through the liver sinusoid wall, which represents a promising approach for liver fibrosis treatment.

Liver manifestations of tick-borne diseases.

Liver manifestations of tick-borne diseases.

Clinical Encounters with Kupffer Cells While Managing Patients with Liver Diseases

Reticuloendothelial cells such as tissue-resident macrophages have an important function of clearing unwanted material from our bloodstream. Kupffer cells residing in liver sinusoids comprise the largest contingent of tissue-resident macrophages in our body. Different radiological techniques used to diagnose and treat patients with liver diseases employ the scavenging function of Kupffer cells to clear the contrast agents administered into peripheral vein or hepatic artery. It is useful for the clinician to understand the utility of these “unsung heroes” in liver microcirculation: The Kupffer cells act as scavengers removing waste material from bloodstream and work silently to maintain homeostasis.

ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic cancer liver metastasis

Invariant natural killer T (iNKT) cells are innate-like T cells that are abundant in liver sinusoids and play a critical role in tumor immunity. However, the role of iNKT cells in pancreatic cancer liver metastasis (PCLM) has not been fully explored. In this study, we employed a hemi-spleen pancreatic tumor cell injection mouse model of PCLM, a model that closely mimics clinical conditions in humans, to explore the role of iNKT cells in PCLM. Activation of iNKT cells with α-galactosylceramide (αGC) markedly increased immune cell infiltration and suppressed PCLM progression. Via single cell RNA sequencing (scRNA-seq) we profiled over 30,000 immune cells from normal liver and PCLM with or without αGC treatment and were able to characterize the global changes of the immune cells in the tumor microenvironment upon αGC treatment, identifying a total of 12 subpopulations. Upon treatment with αGC, scRNA-Seq and flow cytometry analyses revealed increased cytotoxic activity of iNKT/NK cells and skewing CD4 T cells towards a cytotoxic Th1 profile and CD8 T cells towards a cytotoxic profile, characterized by higher proliferation and reduced exhaustion marker PD1 expression. Moreover, αGC treatment excluded tumor associated macrophages. Lastly, imaging mass cytometry analysis uncovered the reduced epithelial to mesenchymal transition related markers and increased active CD4 and CD8 T cells in PCLM with αGC treatment. Overall, our findings uncover the protective function of activated iNKT cells in pancreatic cancer liver metastasis through increased NK and T cell immunity and decreased tumor associated macrophages.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis.

During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs-targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor-mediated targeted delivery of the anti-fibrosis agent, JQ1, via peptide-nanoparticles (IGNP-JQ1). The riociguat reversed the liver sinusoid capillarization to maintain a relatively normal LSECs porosity, thus facilitating the transport of IGNP-JQ1 through the liver sinusoid endothelium wall and enhancing the accumulation of IGNP-JQ1 in the Disse space. IGNP-JQ1 is then selectively taken up by activated HSCs, inhibiting their proliferation and decreasing collagen deposition in the liver. The combined strategy results in significant fibrosis resolution in carbon tetrachloride-induced fibrotic mice as well as methionine-choline-deficient-diet-induced nonalcoholic steatohepatitis (NASH) mice. The work highlights the key role of LSECs in therapeutics transport through the liver sinusoid. The strategy of restoring LSECs fenestrae by riociguat represents a promising approach for liver fibrosis treatment.

Glutathione-Activated Emission of Ultrasmall Gold Nanoparticles in the Second Near-Infrared Window for Imaging of Early Kidney Injury.

Biomarker-activatable luminescent probes with high sensitivity and specificity show great promise in advanced bioimaging applications. However, the lack of stable biomarkers at an early stage is currently a major obstacle for sensitive early disease imaging. Herein, we develop a facile in vivo ligand exchange strategy to achieve renal-clearable activatable luminescent gold nanoparticles (AuNPs), which are independent of biomarkers for sensitive and long-time imaging of early kidney injury. Significantly activated emission in the second near-infrared region (∼1026 nm) is realized from the ligand exchange of triphenylphosphine-3,3',3″-trisulfonic acid (TPPTS)-coated AuNPs (∼1.4 nm, TPPTS-AuNPs) with quantitative amounts of glutathione (GSH). The abundant GSH in cells, particularly in liver sinusoids, is then demonstrated successfully to activate the emission of TPPTS-AuNPs with an extremely low background for both cell imaging and in vivo visualization of visceral organs (e.g., liver and kidneys). In addition, the in vivo GSH-exchanged TPPTS-AuNPs show enhanced interactions with acidic renal tubular epithelial cells, resulting in sensitive (contrast index, ∼3.9) and long-time (>6.5 h) noninvasive monitoring of acidosis-induced early kidney injury. This facile ligand exchange strategy opens new possibilities for designing activatable luminescent probes independent of biomarkers for earlier disease diagnosis and treatment.

Noninvasive diagnosis of liver fibrosis in schistosomiasis japonica: Opportunities and challenges

Noninvasive diagnosis of liver fibrosis in schistosomiasis japonica: Opportunities and challenges

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Chantal HoussetChantal HoussetChantal Housset is Professor of Cell Biology at Sorbone Université, Paris, France, since 2000. She is Course Director of molecular and cellular biology at Sorbonne Université Medical School & Life Science Department. She is Hepatologist in the Reference Center for Inflammatory Biliary Diseases and Auto-immune Hepatitis, in Saint-Antoine Hospital, and of the Rare Liver Disease National Network (FILFOIE). She is the Head of an INSERM-Sorbonne Université Laboratory of translational research on metabolic and biliary diseases of the liver in Centre de Recherche Saint-Antoine (CRSA), Paris. Dr Housset is member of the University National Council (CNU) in Cell Biology. She published 193 articles. Her main scientific contributions relate to the pathophysiology of bile secretion and biliary diseases, the progression of metabolic and biliary diseases towards fibrosis, the origins and functions of myofibroblasts in the liver. Don C. RockeyDon C. RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards.

Inhibition of γδ-TcR or IL17a Reduces T-Cell and Neutrophil Infiltration after Ischemia/Reperfusion Injury in Mouse Liver.

Neutrophil and T-cell recruitment contribute to hepatic ischemia/reperfusion injury. The initial inflammatory response is orchestrated by Kupffer cells and liver sinusoid endothelial cells. However, other cell types, including γδ-Τ cells, seem to be key mediators in further inflammatory cell recruitment and proinflammatory cytokine release, including IL17a. In this study, we used an in vivo model of partial hepatic ischemia/reperfusion injury (IRI) to investigate the role of the γδ-Τ-cell receptor (γδTcR) and the role of IL17a in the pathogenesis of liver injury. Forty C57BL6 mice were subjected to 60 min of ischemia followed by 6 h of reperfusion (RN 6339/2/2016). Pretreatment with either anti-γδΤcR antibodies or anti-IL17a antibodies resulted in a reduction in histological and biochemical markers of liver injury as well as neutrophil and T-cell infiltration, inflammatory cytokine production and the downregulation of c-Jun and NF-κΒ. Overall, neutralizing either γδTcR or IL17a seems to have a protective role in liver IRI.

Morphological and Histological Changes in Liver and Lung of mice and Their Embryos Administred with Parkizol Drug

Results expressed the pathological effects through visual microscopical and Histological examination of parkizol in liver and Lung of pregnant mice and their embryos were administered on the7th day of pregnancy as till the18th day of pregnancy. The administration of parkizol doses induced behavioral changes in the form of drowsiness, sluggish movement, mice become isolated, and were consumed less food and water. Abortions recorded 8%,10%and55% following the doses 250,350and450mg/kg b.w., respectively. Death of some pregnant mice occurred at the 16th and 17th day of pregnancy following the dose450 mg/kg b.w., Lesions seen on organs of pregnant mice and included hepatotoxic changes (congestion, vacuolar degeneration and coagulative necrosis of hepatocytes, dilatation of sinusoids .Also inflammation that covered pulmonary changes (emphysema, edema, hyperplasia of bronchial associated lymphoid tissue. Inflammation and hypertrophy of smooth muscles in the walls of blood vessels);The abortion percentages were48%,63% and89% caused by the doses 250,350 and 450mg/kg b.w., respectively. Malformations were noted on encephalocele, encephalomyelocele, anencephalia, displacements of the ears and eyes, cleft palate, aberrations of the vertebral column, shortening and thickening of the limbs, and defects of the tail. The lesions were observed on organs of the fetus included haphazard arrangement of the hepatocytes, vacuolar degeneration and coagulative necrosis of hepatocytes, dilation of the hepatic sinusoids; congestion, hemorrhage, edema and inflammation of the lungs. These results supported the putative pathological effect of parkizol in liver and lung of pregnant mice and their embryos.

Platelets mediate acute hepatic microcirculatory injury in a protease-activated-receptor-4-dependent manner after extended liver resection

BackgroundSmall-for-size syndrome (SFSS) is a major complication following extended liver resection. The role of platelets in the early development of SFSS remains to be cleared. We aimed to investigate the impact of platelets and PAR-4, a receptor for platelet activation, on the acute phase microcirculatory injury after liver resection by in vivo microscopy analyzing the changes in leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis-induced perfusion failure. MethodsSixty-percent partial hepatectomy (PH) models using C57BL/6 mice receiving platelet depletion with anti-GPIbα, PAR-4 blockade with tcY-NH2, or vehicle treatment with saline were used. Sham-operated animals served as controls. Epifluorescence microscopic analysis was performed 2 h after PH to quantify the leukocyte recruitment and microcirculatory changes. Sinusoidal neutrophil recruitment, platelet-neutrophil interaction, and microthrombosis were evaluated using two-photon microscopy. ICAM-1 expression and liver liver injury were assessed in tissue/blood samples. ResultsThe increments of leukocyte recruitment in post-sinusoidal venules and sinusoidal perfusion failure, the upregulation of ICAM-1 expression, and the deterioration of liver function 2 h after 60% PH were alleviated in the absence of platelets or by PAR-4 blockade. Intensified platelet-neutrophil interaction and microthrombosis in sinusoids were observed 2 h after 60% PH, which significantly attenuated after PAR-4 blockade. ConclusionPlatelets play a critical role in acute liver injury after extended liver resection within 2 h. The deactivation of platelets via PAR-4 blockade ameliorated liver function deterioration by suppressing early leukocyte recruitment, platelet-neutrophil interaction, and microthrombosis in hepatic sinusoids.

Zonated quantification of immunohistochemistry in normal and steatotic livers.

Immunohistochemical stains (IHC) reveal differences between liver lobule zones in health and disease, including nonalcoholic fatty liver disease (NAFLD). However, such differences are difficult to accurately quantify. In NAFLD, the presence of lipid vacuoles from macrovesicular steatosis further hampers interpretation by pathologists. To resolve this, we applied a zonal image analysis method to measure the distribution of hypoxia markers in the liver lobule of steatotic livers.The hypoxia marker pimonidazole was assessed with IHC in the livers of male C57BL/6J mice on standard diet or choline-deficient L-amino acid-defined high-fat diet mimicking NAFLD. Another hypoxia marker, carbonic anhydrase IX, was evaluated by IHC in human liver tissue. Liver lobules were reconstructed in whole slide images, and staining positivity was quantified in different zones in hundreds of liver lobules. This method was able to quantify the physiological oxygen gradient along hepatic sinusoids in normal livers and panlobular spread of the hypoxia in NAFLD and to overcome the pronounced impact of macrovesicular steatosis on IHC. In a proof-of-concept study with an assessment of the parenchyma between centrilobular veins in human liver biopsies, carbonic anhydrase IX could be quantified correctly as well.The method of zonated quantification of IHC objectively quantifies the difference in zonal distribution of hypoxia markers (used as an example) between normal and NAFLD livers both in whole liver as well as in liver biopsy specimens. It constitutes a tool for liver pathologists to support visual interpretation and estimate the impact of steatosis on IHC results.

Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks

Background. For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues but whether such control (and lack of thereof) is achieved by utilizing different movement strategies remains poorly understood. Liver-localized CD8 T cells perform correlated random walks (CRWs)— a type of a Brownian walk – in liver sinusoids but in some conditions, these T cells may also perform Levy flights – rapid and large displacements by floating with the blood flow. CD8 T cells in lymph nodes or skin also undergo Brownian walks. A recent study suggested that brain-localized CD8 T cells, specific to Toxoplasma gondii, perform generalized Levy walks (LWs) – a walk type in which T cells alternate pausing and displacing long distances — which may indicate that brain is a unique organ where T cells exhibit movement strategies different from other tissues. Methods. We quantified movement patterns of brain-localized Plasmodium berghei-specific CD4 and CD8 T cells by using well-established statistical and computational methods. Results. We found that T cells change their movement pattern with time since infection and that CD4 T cells move faster and turn less than CD8 T cells. Importantly, both CD4 and CD8 T cells move in the brain by CRWs without long displacements challenging previous observations. We have also re-analyzed movement data of brain-localized CD8 T cells in T. gondii-infected mice from a previous study and found no evidence of LWs. We hypothesize that the previous conclusion of LWs of T. gondii-specific CD8 T cells in the brain was reached due to missing timeframes in the data that create an impression of large displacements between assumed-to-be sequential movements. Conclusion. Our results suggest that movement strategies of CD8 T cells are largely similar between LNs, liver, and the brain and consistent with CRWs and not LWs.

CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC50 of 0.75 ± 0.07 μM, has been proven to directly enhance insulin sensitivity. The present study aimed to investigate the effects of CX08005 on hepatic lipid accumulation and microcirculation dysfunction in both KKAy mice and diet-induced obesity (DIO) mice. Hepatic lipid accumulation was evaluated by hepatic triglyceride determination and B-ultrasound analysis in KKAy mice. Insulin sensitivity and blood lipids were assessed by insulin tolerance test (ITT) and triglyceride (TG)/total cholesterol (TC) contents, respectively. In addition, the hepatic microcirculation was examined in DIO mice by in vivo microscopy. The results showed that CX08005 intervention significantly reduced the TG and echo-intensity attenuation coefficient in the livers of KKAy mice. Furthermore, we found that CX08005 treatment significantly enhanced insulin sensitivity, and decreased plasma TG and/or TC contents in KKAy and DIO mice, respectively. In addition, CX08005 treatment ameliorated hepatic microcirculation dysfunction in DIO mice, as evidenced by increased RBCs velocity and shear rate of the blood flow in central veins and in the interlobular veins, as well as enhanced rate of perfused hepatic sinusoids in central vein area. Additionally, CX08005 administration decreased the adhered leukocytes both in the center veins and in the hepatic sinusoids area. Taken together, CX08005 exhibited beneficial effects on hepatic lipid accumulation and microcirculation dysfunction associated with NAFLD, which was involved with modulating insulin sensitivity and leukocyte recruitment, as well as restoration of normal microcirculatory blood flow.

Polysaccharide of Atractylodes macrocephala Koidz alleviate lipopolysaccharide-induced liver injury in goslings via the p53 and FOXO pathways

Lipopolysaccharide (LPS) can affect the immune system of geese by inducing liver injury. The polysaccharide of Atractylodes macrocephala Koidz (PAMK) have obvious immune-enhancing effects. Accordingly, this experiment investigated the effect of PAMK on LPS-induced liver injury in goslings. Two hundred 1-day-old goslings were randomly divided into the control group, LPS group, PAMK group, and PAMK+ LPS group, and the PAMK and PAMK+ LPS groups were fed the basal diet with 400 mg/kg PAMK, while the control and LPS groups were fed the basal diet. On D 21, 23, and 25 of the formal trial, the goslings in the LPS and PAMK+LPS groups were injected intraperitoneally with 2 mg/kg LPS, and goslings in the control and PAMK groups were injected intraperitoneally with the same amount of saline. Livers were collected on D 25. HE-stained sections showed that PAMK could effectively alleviate the LPS-induced indistinct hepatic cord structure, loss of cytoplasmic contents of hepatocytes, and dilatation of hepatic sinusoids. The biochemical parameters of liver tissues showed that PAMK could alleviate the LPS-induced upregulation of alanine aminotransferase and aspartate aminotransferase. To further investigate the mechanism of the mitigating effect of PAMK on LPS-induced injury, livers from the LPS and PAMK+LPS groups were selected for transcriptome sequencing. The sequencing results showed that there were 406 differentially expressed genes (DEGs) in the livers of LPS and PAMK+LPS goslings, of which 242 upregulated and 164 downregulated. The Kyoto Encyclopedia of Genes and Genome (KEGG) analysis showed that DEGs were significantly enriched in immune signal transduction, cell cycle, and cell metabolism. Besides, protein‒protein interaction analysis showed that 129 DEGs were associated with each other, including 7 DEGs enriched in the p53 and FOXO signaling pathway. In conclusion, PAMK may alleviate LPS-induced liver injury in gosling through the p53 and FOXO signaling pathway. These results provide a basis for further development of PAMK as an immunomodulator.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR Don RockeyDon RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards. SECTION EDITOR Anthony BuckleyAnthony BuckleyDr Anthony Buckley, PhD, is a Lecturer in Microbiology at the University of Leeds, UK, and leads the Microbiome & Nutritional Sciences group. He also holds an honorary position at the Leeds Teaching Hospital Trust, NHS, UK. Dr Buckley obtained his PhD in Molecular Microbiology at the University of Birmingham, UK, where he investigated the role of efflux pumps towards Salmonella Typhimurium in vivo pathogenicity under the supervision of Professor Laura J. V. Piddock. Dr Buckley is passionate about student education and supporting early career researchers, and he sits on the steering committees for the Leeds Biofilm Network and [email protected] Network. The research interests of his group centers on influencing disease outcome by manipulating the human microbiota through probiotics and prebiotics. His group develops novel models of the human digestive tract to study the interactions between xenobiotics, microbe, and host, and determine the efficacy of novel drugs and biotherapeutics. He is an author on over 40 primary research articles, review articles, and book chapters. Russell D. CohenRussell D. CohenRussell D. Cohen, MD. FACG, AGAF is a Professor of Medicine at the Pritzker School of Medicine, in the Department of Medicine, Section of Gastroenterology at the University of Chicago, USA. Currently he is Director of the IBD Center and the Co-Director of the Advanced IBD Fellowship Program, and serves as Illinois Governor for the American College of Gastroenterology, USA. Dr Cohen earned his BS at Cornell University, USA, his MD with honors at Mount Sinai School of Medicine, USA, and his residency in internal medicine at Beth Israel Hospital/Harvard Medical School, USA, and his fellowship in gastroenterology and senior fellowship in IBD at the University of Chicago. He has been Principal or Co-Investigator for more than 185 research projects. He is an editor of three medical textbooks, and has authored more than 200 articles, abstracts, reviews, books, book chapters, and audiotapes. He is published in prestigious journals such as Gastroenterology, American Journal of Gastroenterology, and Inflammatory Bowel Diseases. He also is a reviewer for multiple journals, including New England Journal of Medicine, Gastroenterology, Gut, and American Journal of Gastroenterology, and is a member of multiple prestigious medical societies. Dr Cohen is named in Best Doctors in America, America's Top Gastroenterologists, Top Doctors in the Chicago Metro Area, and Chicago Magazine's Top Doctor in Gastroenterology.

Mechanobiology in the development and progression of non-alcoholic fatty liver disease: an updated review

Mechanobiology is a rapidly emerging field focused on the biological impact of physical forces at the molecular, cellular, and tissue level. Living cells perceive mechanical cues and transform them into biochemical signals through mechanotransduction. Mechanotransduction is a complex process that involves mechanosensors (which are located in the plasma membrane or within the cell) and mechanotransmission to the nucleus (which occurs either by physical connection between the mechanosensor and the nucleus or by mechanosignaling through biochemical pathways). Essential biological functions, including development, growth, motility, and metabolism, depend on the mechanoresponses generated by these events. Multiple lines of evidence indicate that disruption of mechanical homeostasis may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a highly prevalent metabolic disorder characterized by abnormal accumulation of lipid droplets in hepatocytes (steatosis) and often associated with inflammation and liver cell injury (steatohepatitis). While predicting individual predisposition to adverse outcomes in NAFLD remains a challenge, there is increasing evidence that steatosis and steatohepatitis trigger mechanoresponses that contribute to the early stages of pathogenesis in NAFLD and critically impact disease progression. Lipid accumulation and lipotoxicity modify liver viscoelasticity, alter the biomechanics of liver sinusoids, and initiate aberrant pathways of mechanotransduction in hepatocytes and non-parenchymal liver cells, such as sinusoidal endothelial cells and hepatic stellate cells. Interactions of these cells at mechanical interfaces with each other, with extracellular matrix, and with sinusoidal blood flow are profoundly altered by steatosis and steatohepatitis; such changes may promote a pro-angiogenic and pro-fibrotic milieu. A better understanding of liver mechanobiology may facilitate the identification of novel molecular and cellular targets in the management of NAFLD.