Hepatic Sinusoids Research Articles

Mitochondrial Transplantation: A Novel Therapy for Liver Ischemia/Reperfusion Injury.

To investigate the hepatoprotective effects of mitochondrial transplantation in a murine liver ischemia/reperfusion (I/R) model. Sequential liver ischemia followed by reperfusion (I/R) is a pathophysiological process underlying hepatocellular injury in a number of clinical contexts, such as hemorrhagic shock/resuscitation, major elective liver surgery and organ transplantation. A unifying pathogenic consequence of I/R is mitochondrial dysfunction. Restoration of mitochondria via transplantation (MTx) has emerged as potential therapeutic in I/R. However, its role in liver I/R and its mechanisms of action remain poorly defined. We investigated the hepatoprotective effects of MTx in an in vivo mouse model of liver I/R and used in vivo imaging and various knockout and transgenic mouse models to determine the mechanism of protection. We found that I/R-induced hepatocellular injury was prevented by MTx, as measured by plasma ALT, AST and liver histology. Additionally, I/R-induced pro-inflammatory cytokine release (IL-6, TNFα) was dampened by MTx, and anti-inflammatory IL-10 was enhanced. Moreover, MTx lowered neutrophil infiltration into both the liver sinusoids and lung BALF, suggesting a local and distant reduction in inflammation. Using in vivo intravital imaging, we found that I/R-subjected Kupffer cells (KCs), rapidly sequestered transplanted mitochondria, and acidified mitochondria within lysosomal compartments. To specifically interrogate the role of KCs, we depleted KCs using the diphtheria toxin-inducible Clec4f/iDTR transgenic mouse, then induced I/R, and discovered that KCs are necessary for the beneficial effects of MTx. Finally, we induced I/R in complement receptor of the immunoglobulin superfamily (CRIg) knockout mice and found that CRIg was required for mitochondria capture by KCs and mitochondrial-mediated hepatoprotection. In this study, we demonstrated that CRIg-dependent capture of mitochondria by I/R-subjected Kupffer cells is a hepatoprotective mechanism in vivo. These data progress knowledge on the mechanisms of MTx and opens new avenues for clinical translation.

Effects of nano-selenium and/or vitamin E supplementation on growth performance, antioxidant status, histopathology and resistance to Aspergillus flavus in Nile tilapia (Oreochromis niloticus)

Abstract Background This study aimed to evaluate the effects of selenium nanoparticles (SeNPs) and/or vitamin E (VE) on the growth, body composition, metabolic parameters, histopathology, and resistance of Nile tilapia to Aspergillus flavus. Results Monosex Nile tilapia fingerlings were sourced from the Bazina farm and hatchery in Ismailia Governorate, Egypt, where the experiment was also conducted. The fish were acclimatized for 15 days before the trial. A total of 240 fingerlings (average weight 46 ± 3.0 g/fish) were divided equally across 12 concrete tanks (1 × 1 × 1.2 m, 1 m³ capacity), with 20 fish per tank. The fish were fed a control diet (T0), which was a basal diet with no supplementation, or one of three experimental diets for 60 days: T1 (1 mg SeNPs/kg), T2 (100 mg VE/kg), and T3 (1 mg SeNPs + 100 mg VE/kg). The experiment followed a completely randomized design (CRD) with three replicates per treatment. The combination of SeNPs and VE (T3) resulted in the best feed conversion ratio. A slight but significant increase (P < 0.05) in whole-body composition was observed in all treatment groups compared to the control. Biochemical parameters, serum digestive enzyme activity, and antioxidant levels improved significantly with dietary supplementation. Histopathological analysis revealed somewhat lacerated gill arches in fish fed SeNPs, VE, or their combination, but the overall gill structure remained normal. The SeNPs + VE group exhibited improved villi length and normal morphology of portal veins and hepatic sinusoids, though some vacuolated hepatocytes were noted. Fish in the SeNPs + VE group had the lowest mortality rates and the highest resistance to A. flavus. Conclusion Supplementing diets with SeNPs and/or VE enhances growth, body composition, biochemical parameters, and histopathology in Nile tilapia. The combination of 1 mg SeNPs + 100 mg VE/kg improves immune response and growth, offering a promising strategy to enhance Tilapia health and productivity.

Efficacy of Lycopene Extracted from Tomato on Liver Enzymes and Tissues of Animal Model Infected with Acrylamide

Lycopene is a carotenoid derivative, which is a natural pigment synthesized by plants and microorganisms during the photosynthesis process. The study aimed to extract lycopene from tomatoes using organic solvents in a ratio of 2:1:1 of hexane, acetone, and ethanol. The amount of lycopene extracted was (4.87 mg/100 g). We notice a decrease in the values of the liver enzymes ALT, ALK, and AST upon oral administration of lycopene to male infected rats compared to with their values when acrylamide is given alone. A change was also noted in the liver tissue after treatment with lycopene compared to the infected group, as there was an improvement in the central vein, lobules, hepatic sinusoids, and Coover cells after they were congested, expanded, and contained bloody bleeding. In conclusion, lycopene as an antioxidant phyto-component, can protect liver against damages caused by acrylamide (or acrylic amide). Tomatoes can be considering as functional vegetable for protecting liver from damages of chemicals such as acrylamide. Keywords: Acrylamide, lycopene extraction, physiological properties, phytocomponent.

Histopathological Effect of Aqua Fix Supplementation on the Skeletal Muscle and Liver of Labeo rohita (Hamilton,1822) during Immunomodulation and Aeromoniasis

The impact of oral feeding diet (supplement) Aqua Fix was studied on the histopathological changes in skeletal muscles and liver of L.rohita during immunomodulation and aeromoniasis. Three groups (D,E,F) of six months old fish were employed; groups D and E were treated with Aqua Fix for 4 days, on day 5 fish of group E and F were infected with Aeromonas hydrophila @ 10-6CFU/fish(fish of group F were fed with normal diet for 4 days).Controls (group G) were untreated and uninfected. Histological examination of the skeletal muscle and liver tissues were carried out on selected days of experimentation (day 1 and day 4 of experiment). The stained sections were observed under microscope and histological changes were noted. Immunostimulated fish (group D) showed normal arrangement of muscle fibers and muscle bundles compared to other groups (E and F) of fish. Both the muscle fibers and muscle bundles were healthy as in controls (Group G). In infected group (untreated with Aqua Fix, group F), fragmentation of muscle fibers was noticed along with sarcoplasmic debris. Dermal lesions and moderate edema is noticed in necrotic muscle fibers. Liver in immunostimulated fish showed large, polygonal hepatocytes with distinct, round nuclei. Hepatic central vein and sinusoids were clearly visible. By day 1 of infection, liver exhibited necrosis of hepatocytes, pycnosis of hepatocyte nuclei, granulation and vacuolisation (group F). Dilation of hepatic vein and sinusoids were observed. Necrotic foci and haemorrhages were evident in the capillaries of liver and occurred more severely in group F compared to group E (treated with Aqua Fix and infected). The fish (group E) which received immunostimulant and infection showed moderate effect on liver suggesting that Aqua Fix supplementation ameliorate the ill effects of A. hydrophila, showing the positive influence of herbal immunostiomulant i.e, Aqua Fix in fresh water fish.

The Role of Key Molecules of Pyroptosis in Liver Damage of Rats With Exertional Heat Stroke.

Purpose: This study is aimed at investigating the role of key molecular elements involved in pyroptosis in liver injury caused by exertional heat stroke (EHS). Methods: We established a model of EHS-induced liver injury in Sprague-Dawley rats, with a control group (receiving no treatment) for comparison and 12 rats in each group. Alanine transaminase (ALT) and aspartate transaminase (AST) levels in the blood were detected. Interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) levels were assessed using enzyme-linked immunosorbent assays (ELISA). Pathological changes in liver tissue were examined by hematoxylin and eosin (H&E) staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect mRNA and protein expression levels of Caspase-1 and Gasdermin D. Results: Compared to the control group, the liver tissue of the EHS group showed congestion in hepatic sinusoids, hepatocyte edema, eosinophilic changes, necrosis, and infiltration of inflammatory cells. ALT and AST levels in the EHS group were significantly higher than those in the control group (p < 0.05). The mRNA expressions of Caspase-1, Gasdermin D, IL-1β, and IL-18 were significantly increased in the EHS group compared to the control group (p < 0.001). The protein expressions of Caspase-1, cleaved Caspase-1, Gasdermin D, and cleaved Gasdermin D were significantly increased in the EHS group. Conclusion: These findings indicated that hepatic pyroptosis plays an important role in EHS-induced liver injury.

Quantification of Vascular Remodeling and Sinusoidal Capillarization to Assess Liver Fibrosis with Photoacoustic Imaging.

Background Photoacoustic microscopy (PAM) can be used to detect strong absorption from endogenous and exogenous contrast material, making it promising for detailed structural and functional imaging of hepatic sinusoids, including dynamic visualization of permeability. Purpose To evaluate whether PAM-based quantitative parameters of liver function and integrity (lacunarity, blood oxygen saturation [Sao2], and Evans blue [EB] permeability) are associated with histopathologic indexes of fibrosis in a mouse model. Materials and Methods Between October 2022 and July 2023, a total of 35 male C57BL/6 mice were included in this study and received intraperitoneal injection of carbon tetrachloride to establish mouse models of progressive liver fibrosis, with seven mice in each group. PAM was performed to visualize vascular structure, Sao2 distribution, and EB penetration within the hepatic lobule. Histologic findings were used as the reference standard. Associations between the PAM parameters and the pathologic results were evaluated with Spearman rank correlation. Results Mean lacunarity, a PAM parameter, gradually increased with liver fibrosis stage (control: 0.018 arbitrary units [au] ± 0.004 [SD]; fibrosis: 1 week, 0.024 au ± 0.002; 2 weeks, 0.028 au ± 0.003; 4 weeks, 0.034 au ± 0.002; 10 weeks, 0.040 au ± 0.005; P < .001) and was positively correlated with collagen-positive area (Spearman r = 0.88-0.90; P < .001). PAM revealed that Sao2 decreased with disease progression (control, 0.921 au ± 0.017; 1 week, 0.875 au ± 0.019; 2 weeks, 0.846 au ± 0.020; 4 weeks, 0.802 au ± 0.025; 10 weeks, 0.732 au ± 0.036; P < .001) and was inversely related to hypoxia-inducible factor 1α expression (Spearman r = -0.83; P < .001). EB permeability, indicative of hepatic sinusoid capillarization, was reduced at advanced stages of fibrosis (control: 11.6% [IQR, 11.2%-11.8%]; fibrosis: 1 week, 24.8% [IQR, 23.3%-25.8%]; 2 weeks, 18.4% [IQR, 18.4%-20.0%]; 4 weeks, 5.1% [IQR, 4.9%-6.2%]; 10 weeks, 3.7% [IQR, 3.4%-4.5%]; P < .001). Conclusion PAM-based structural and functional parameters were associated with liver fibrosis severity, and PAM imaging of EB dynamics helped detect sinusoidal capillarization. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Li and Yao in this issue.

Tissue Determinants of Antiviral Immunity in the Liver.

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.

Hepatic Damage Induced By Fructose And Aspartame In Carbonated Drinks: Morphological And Histological Analysis In Adult Male Albino Rats

Objective: The study aims to analyze the changes produced by fructose and aspartame in regular and zero-calorie carbonated drinks respectively on the morphology and histology of the liver of adult male albino rats. Methods: Regular and zero-calorie carbonated drinks in a dosage of 10 ml/kg body weight were administered by oral gavage daily to experimental groups B and C (10 rats in each group) respectively for 21 consecutive days. The weight of animals was noted at the start and end of the experiment. The liver was excised in each animal, weighed, fixed in formalin, and stained with Hematoxylin and Eosin and histological changes such as detachment of capsule, congestion and inflammation of portal triad were observed for comparison between the experimental groups. Results: Results were recorded and analyzed in the form of photomicrographs. Observations showed a rise in the weight of animals and liver of experimental groups B and C compared to control group A. The shape of the liver was normal. Histological changes including detachment of capsule, inflammation of portal triad, congestion of hepatic sinusoids and portal triad, were observed in both the experimental groups indicating damage to hepatic tissue. Conclusion: Therefore, it is concluded that consumption of regular and zero-calorie carbonated drinks should be restricted to avoid their harmful effects on the liver leading to hepatotoxicity. Keywords: Fructose, Aspartame, regular and zero calorie carbonated drinks, liver

Natural antibodies to polysaccharide capsules enable Kupffer cells to capture invading bacteria in the liver sinusoids

The interception of blood-borne bacteria in the liver defines the outcomes of invasive bacterial infections, but the mechanisms of this antibacterial immunity are not fully understood. This study shows that natural antibodies (nAbs) to capsules enable liver macrophage Kupffer cells (KCs) to rapidly capture and kill blood-borne encapsulated bacteria in mice. Affinity pulldown with serotype-10A capsular polysaccharides (CPS10A) of Streptococcus pneumoniae (Spn10A) led to the identification of CPS10A-binding nAbs in serum. The CPS10A–antibody interaction enabled KCs to capture Spn10A bacteria from the bloodstream, in part through complement receptors on KCs. The nAbs were found to recognize the β1-6-linked galactose branch of CPS10A and similar moieties of serotype-39 S. pneumoniae and serotype-K50 Klebsiella pneumoniae capsules. More importantly, the nAbs empowered KCs to capture serotype-39 S. pneumoniae and serotype-K50 K. pneumoniae in the liver. Collectively, our data have revealed a highly effective immune function of nAb against encapsulated bacteria and emphasize the concept of treating septic encapsulated bacterial diseases with monoclonal antibodies.

Combination of spatial transcriptomics analysis and retrospective study reveals liver infection of SARS-COV-2 is associated with clinical outcomes of COVID-19.

Liver involvement is a common complication of coronavirus disease 2019 (COVID-19), especially in hospitalized patients. However, the underlying mechanisms involved are not fully understood. Immunohistochemistry (IHC) staining of SARS-CoV-2 spike (S) and nucleocapsid (N) proteins was conducted on liver tissues from six patients with COVID-19. The 10x Genomics Visium CytAssist Spatial Gene Assay was designed to analyze liver transcriptomics. TCR CDR3 sequences were analyzed in DNA from liver tissues. Liver function indicators were retrospectively studied in 650 hospitalized patients with COVID-19. SARS-CoV-2 proteins were initially detected in the livers of naturally infected golden (Syrian) hamsters, prompting us to investigate the situation in clinical cases. Thus, we collected liver tissues from patients with abnormal liver biochemical values. Viral S and N proteins were detected in the livers of severe and deceased patients but not in those of moderate patients. We further demonstrated that hepatocytes and erythroid cells in hepatic sinusoids are major cells targeted by SARS-CoV-2. Immune cells, especially T cells, were enriched in surviving severe patients, characterized by enhanced CDR3α clonality and novel CDR3β recombination of the T-cell receptor. In contrast, hepatocyte apoptosis was triggered, and the transcription of albumin (ALB) was obviously impaired in the deceased patients. We then performed a retrospective study including patients with COVID-19. Serum aspartate aminotransferase (AST) and ALB levels at baseline significantly differed in the deceased cohort. However, AST regression did not decrease the risk of death. ALB recovery indicated clinical improvement, and declining or low serum ALB concentrations were associated with death. This study provides clinical evidence for liver infection with SARS-CoV-2, insight into the impact of SARS-CoV-2 on the liver, and a potential way to evaluate the risk of death via assessing serum ALB concentration fluctuations in patients with COVID-19. National Key R&D Program of China (2021YFC2300602), National Natural Science Foundation of China (92369110), National Natural Science Foundation of China (U23A20474), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), Shanghai Jinshan District Medical and Health Technology Innovation Fund Project (2023-WS-31).

Hepatic Sinusoidal Obstruction Syndrome (SOS) Associated with Checkpoint Inhibitor Therapy.

Understand less common side effects of immunotherapy, now used in daily clinical practice.Consider sinusoidal obstruction syndrome (SOS) in patients who develop liver dysfunction and/or portal hypertension during or after immunotherapy for neoplastic disease.Early identification and severity assessment is crucial in facilitating prompt diagnosis and timely treatment, improving the prognosis of patients.

Spontaneous natural killer cell lymphoproliferative disorder in a rhesus macaque.

Lymphoproliferative disorders of natural killer (NK)-cell lineage are well documented in humans but have yet to be documented in non-human primates (NHPs). Here we describe a case of NK-cell lymphoproliferative disorder/leukemia in a 20-y-old captive female rhesus macaque (Macaca mulatta). The animal clinically had mild splenomegaly and marked lymphocytosis with small-to-medium lymphocytes in blood smears. By flow cytometry and cluster differentiation, the lymphocytes were CD3-negative, CD8-positive, CD4-negative, and CD20-negative for cell surface markers; immunohistochemistry revealed the presence of intracellular CD3 and granzyme B. This immunoprofile is consistent with a NK-cell phenotype. Histologically, these cells were predominantly intravascular within the splenic red pulp, liver sinusoids, and to a lesser degree bone marrow. Oncogenic viruses, such as Mason-Pfizer monkey viruses (MPMV; formerly, and commonly known as, simian retroviruses or SRV; Retroviridae, Betaretrovirus maspfimon); simian immunodeficiency virus (SIV; Retroviridae, Lentivirus simimdef), and primate T-lymphotropic virus 1 (PTLV1; commonly known as simian T-lymphotropic virus type 1, STLV1; Retroviridae, Deltaretrovirus priTlym1), were not detected in this animal by serology. Immunohistochemistry using EBNA2 antibody to detect rhesus and cynomolgus monkey lymphocryptovirus (McGHV4/RLV and McGHV10 respectively; Orthoherpesviridae, Lymphocryptovirus macacinegamma4 and Lymphocryptovirus macacinegamma13, respectively) was negative. Together these findings are consistent with a diagnosis of naturally occurring NK-cell lymphoproliferative disorder. NK-cell lymphoproliferative disorder has not been reported previously in rhesus macaques, to our knowledge.

The Role of Fibrinogen and platelets in mouse Liver Ischemia-Reperfusion Injury: Distribution and Pathophysiological Insights

Liver ischemia-reperfusion (I/R) injury is a critical issue in clinical settings, particularly in liver transplantation and resection, leading to severe hepatocellular dysfunction and organ failure. This study investigates the role of fibrinogen and platelets in liver I/R injury, focusing on their distribution and pathophysiological impact within liver lobules. Using a mouse model, we examined the expression and localization of fibrinogen and platelets at various time points post-reperfusion. In normal liver, fibrinogen is predominantly expressed in hepatic sinusoids near the portal vein, with sparse platelet distribution. Following I/R injury, fibrinogen expression significantly increases in hepatic sinusoids and hepatocytes, accompanied by substantial platelet aggregation and embolization, particularly in Zone 1 of the liver lobules. These findings highlight the zonal heterogeneity of fibrinogen distribution and its regulatory function in platelet adhesion and microthrombi formation. This study provides crucial insights for developing therapeutic strategies targeting fibrinogen and platelet interactions to mitigate liver I/R injury.

Histopathological effects of titanium dioxide nanoparticles on the liver in rats by light and transmission electron microscopy

Background: As one of the most influential and in-demand nanoparticles for commercial applications, titanium dioxide nanoparticles are commonly used in industry as a white pigment, in cosmetic and health products, and as a disinfection agent. In food and drugs, this additive is known as E171 and helps define colors clearly and can prevent UV degradation. This study used light and transmission electron microscopy to examine the effects of titanium dioxide nanoparticles on the liver in rats. Methods: Titanium dioxide nanoparticles were administered to 40 rats at 0, 10, 20, and 50 mg per kilogram of rat body weight suspended in one millilitre of distilled water over 60 days (every second day) by oral gavage.The rats were euthanized and tissue samples were dissected from the liver for light (thick section)and transmission electron (thin section) microscopy study. Results: Histopathological examinations in treated groups revealed dilation of hepatic sinusoids, hepatocytes degeneration and necrosis, observed as cellular swelling, cytoplasmic vacuolation, and loss of nuclei, nuclear pyknosis, karyorrhexis, and karyolysis. Some pathologic changes were also observed in mitochondria; the enlargement of the mitochondrial membrane and cristae, the disintegration of the mitochondria, and the destruction of the cristae were evident in response to all doses utilized in the study. Conclusions: Our studydemonstrated that the continuous use of titanium dioxide nanoparticles(E171) can cause histopathological damages in the liver and disrupt the function of this organ. Consequently, it is recommended to limit the use of this ingredient in industrial, sanitary, foods, and cosmetic products.

Effects of molecular interaction and liver sinusoidal mechanical properties on leukocyte adhesions

It is interesting to find pathologically that leukocytes, especially neutrophils, tend to adhere in the liver sinusoids dominantly but not in the post-sinusoidal venules. While both views of receptor-ligand interactions and physical trapping are proposed for mediating leukocyte adhesion in liver sinusoids, integrated investigations for classifying their respective contributions are poorly presented. With a combination of Monte Carlo simulation and immersed boundary method (IBM), this study explored numerically the effects of molecular interaction kinetics and sinusoidal mechanical properties on leukocyte adhesion in liver sinusoid jointly. Results showed that, within the range of biological limitations, the lumen stenosis ratio, leukocyte stiffness, Disse space stiffness and endothelium permeability regulate the comprehensive adhesion process in a descending order of significance in the presence of receptor-ligand interactions. While leukocyte adhesions could be mutually promoted with proper combinations of leukocyte stiffness, lumen stenosis, and molecular interaction, the binding affinity is insensitive under the conditions with low leukocyte stiffness in normal lumen stenosis and high leukocyte stiffness in high lumen stenosis. This work deepened the understanding of recruitment mechanism of leukocyte in liver sinusoids.

Role of CD34, SMA &amp; Ki-67 Immunohistochemistry– An Important Diagnostic Tool in Differentiating Early Well Differentiated Hepatocellular Carcinoma from Benign Hepatic Mimickers: A Retrospective Study from North East India

North East India has higher incidence of cancers than rest of the country&amp; with advent of early screening, Hepatocellular carcinoma is getting detected at an early stage. Core needle biopsies have become indispensible tool for diagnosis of HCC and it is difficult to identify cell thickness in early well-differentiated HCC from benign mimickers on histomorphology. To overcome this difficulty, present study was designed to see the utility of CD 34, SMA &amp; Ki-67 in this regard and also to see role of these markers in differentiating Early well differentiated hepatocellular carcinoma from benign hepatic mimickers. 48 FFPE blocks of various lesions of liver were retrieved from Oncopathology Department, BBCI Guwahati in last one year. Cases were divided into Group A (n=28-HCC) Group B (n=20-benign mimickers). IHC CD34, SMA &amp; Ki-67 were done on all cases. Demographic &amp;clinical details with histomorphological findings were correlated. In Group A- 26 out of 28 HCC cases (92.8%), CD34 was strongly, completely &amp; diffusely expressed by sinusoidal vessels with more than 3 cell plate thickness. Group B- In normal liver (10 out of 20), hepatic sinusoids are negative to weak positive for CD34.In 7 out of 20 (35.1%) benign conditions, it is sparsely expressed in capillarized sinusoids at periportal &amp; perinodular area&amp; high-grade dysplastic nodules showed peripheral and focal staining for CD34. Stromal cells are strongly Positive for SMA in 85.7% (group A 24 out of 28). Ki-67 was slightly increased in Group A (6-10%) than in Group B (1-2 %). Our data demonstrates that CD34, SMA &amp; Ki-67 has significant increased expression in early WD HCC as compared to benign mimickers. Hence, CD34, SMA &amp; ki-67 are significant helpful IHC tool for reaching to a definite diagnosis of Early WD HCC when disease is yet at early stage &amp; and ideal for setup where specific markers of malignant hepatic tumors are not available. Thus, immunohistochemical markers essentially expressed in HCC in a specific ...

Multiscale X-ray phase-contrast CT uncovers adaptive changes and compensatory mechanisms of circulatory pathways during acute liver injury

Intrahepatic circulation is essential for the repair of acute liver injury (ALI); however, very limited information is available concerning changes in the circulatory pathways during ALI. Therefore, multi-scale X-ray phase-contrast CT combined with three-dimensional (3D) visualization is used to quantitatively analyze the intrahepatic circulation pathway (including the hepatic vein, portal vein and hepatic sinusoid) in the mouse model via the intraperitoneal injection of carbon tetrachloride (CCl4) from acute injury to recovery. The results demonstrate that the liver still preserves some vessel-like channels accessed to the central vein when the injury causes the severe collapse of the hepatic sinusoids that cannot be observed in two-dimensional pathologic slices. Moreover, angiogenesis is observed in the terminal branches of the hepatic vein and portal vein. Additionally, we extend the two-dimensional primary lobule to a 3D model and find that the sinusoids in zone III have the most severe injury. The sinusoids in different zones also show changes in parameters such as density and mean diameter during the ALI. In conclusion, phase-contrast CT can reveal the intact vascular system within the liver lobes, thus providing critical information for studying the mechanisms involved in the evolution of circulatory structures from damage to repair.

Metastatic Melanoma of Unknown Primary with Plasmacytoid Morphology Presenting as Acute Liver Failure

Abstract Introduction/Objective Viral hepatitis, drug toxicity, and autoimmune disorders are common etiologies of acute liver failure (ALF). Very rarely, a cause like metastatic melanoma may present as a primary driver of ALF. Malignant melanoma is histologically diverse and plasmacytoid melanoma is an unusual variant that may present as a solitary tumor or metastatic disease. Methods/Case Report A 48-year-old female presented with 2 weeks of right upper quadrant pain, nausea, coffee ground emesis and bleeding per rectum. She had no history of liver disease or alcohol use. On presentation, AST was 83 U/L, ALT was 29U/L, ALP was 159U/L and total bilirubin was 12.7g/dl. Viral hepatitis panel, HIV and chronic liver disease workup was negative. Esophagogastroduodenoscopy and colonoscopy showed no sources of bleeding. She was diagnosed with decompensated cirrhosis, ALF, and acute kidney injury from hepatorenal syndrome. Cirrhosis and multifocal indeterminate T1 hyper/T2 hypo intense lesions (dysplastic or regenerative nodules) were seen on MRI. Liver biopsy revealed metastatic melanoma. Almost entire liver parenchyma on biopsy was replaced by a population of neoplastic cells with plasmacytoid features. Immunostaining was positive for MART-1, HMB45 and SOX-10. Staining for Pan Cytokeratin and CK-7 highlighted the bile ducts and negative staining was seen for CK20, CD3, CD20, PAX-8, GATA-3, CDX-2 and P63. No primary lesion was found. It was deemed unlikely that she would benefit from therapy before complications occur. She passed away in 16 days. Results (if a Case Study enter NA) NA Conclusion In most cases of ALF associated with malignant melanoma, the liver may have a seemingly normal appearance on imaging studies due to the distinctive histology of leukemoid tumor infiltration within the liver sinusoids, resulting in sinusoidal obstruction and subsequent hepatocellular dysfunction. The rapidity of liver failure in these cases is related to the replacement of liver parenchyma by malignant cells. The plasmacytoid morphology is seen in a variety of malignancies and to avoid a potential misdiagnosis of an aggressive malignant melanoma, it is imperative to perform a thorough histopathological evaluation aided with immunohistochemistry. It is important to keep in mind that the potential involvement of malignant tumor cell infiltration may cause ALF and early histological assessment with a liver biopsy may be of paramount significance and may possibly change the course of the disease.

Overcoming Hepatic Biotransformation Barrier of Gold Nanoparticles via Au-Se Bond for Enhanced In Vivo Active Targeting.

As a key metabolic function of the liver, the hepatic biotransformation process can alter the predesigned surface chemistry of nanoparticles in vivo, leading to hampered functionality and targeting ability. However, strategies to modulate the hepatic biotransformation of nanoparticles have been rarely explored. Herein, using indocyanine green (ICG)-conjugated gold nanoparticles that target liver hepatocytes as a model, we showed that merely changing the metal-ligand bond from gold-sulfur (Au-S) to gold-selenium (Au-Se) completely reshaped the hepatic biotransformation profiles of the nanoparticle as well as its targeting and transport behaviors in vivo. Compared with those of Au-S bond, Au-Se bond markedly slowed down nanoparticle biotransformation in liver sinusoids, enhanced ICG-mediated nanoparticle targeting to hepatocytes by 15-fold, and also altered nanoparticle intrahepatic transport, distribution, and clearance pathways. Moreover, we demonstrated that Au-Se bond could improve the active targeting of gold nanoparticles to hepatic tumors by reducing liver biotransformation-induced dissociation of targeting ligands. These discoveries not only deepen our understanding of nanoparticle biotransformation in the liver but also offer a strategy to overcome the biochemical barrier of hepatic biotransformation, providing guidance for the design and engineering of related nanomedicines by tuning their in vivo biotransformation profiles.

Mouse liver sinusoidal endothelial cell responses to the glucocorticoid receptor agonist dexamethasone.

Liver sinusoidal endothelial cells (LSECs) which make up the fenestrated wall of the hepatic sinusoids, are active scavenger cells involved in blood waste clearance and liver immune functions. Dexamethasone is a synthetic glucocorticoid commonly used in the clinic and as cell culture supplement. However, the response is dependent on tissue, cell type, and cell state. The aim of this study was to investigate the effect of dexamethasone on primary mouse LSECs (C57BL/6J); their viability (live-dead, LDH release, caspase 3/7 assays), morphology (scanning electron microscopy), release of inflammatory markers (ELISA), and scavenging functions (endocytosis assays), and associated biological processes and pathways. We have characterized and catalogued the proteome of LSECs cultured for 1, 10, or 48h to elucidate time-dependent and dexamethasone-specific cell responses. More than 6,000 protein IDs were quantified using tandem mass tag technology and advanced mass spectrometry (synchronous precursor selection multi-notch MS3). Enrichment analysis showed a culture-induced upregulation of stress and inflammatory markers, and a significant shift in cell metabolism already at 10h, with enhancement of glycolysis and concomitant repression of oxidative phosphorylation. At 48h, changes in metabolic pathways were more pronounced with dexamethasone compared to time-matched controls. Dexamethasone repressed the activation of inflammatory pathways (IFN-gamma response, TNF-alpha signaling via NF-kB, Cell adhesion molecules), and culture-induced release of interleukin-6, VCAM-1, and ICAM-1, and improved cell viability partly through inhibition of apoptosis. The mouse LSECs did not proliferate in culture. Dexamethasone treated cells showed upregulation of xanthine dehydrogenase/oxidase (Xdh), and the transcription regulator Foxo1. The drug further delayed but did not block the culture-induced loss of LSEC fenestration. The LSEC capacity for endocytosis was significantly reduced at 48h, independent of dexamethasone, which correlated with diminished expression of several scavenger receptors and C-type lectins and altered expression of proteins in the endocytic machinery. The glucocorticoid receptor (NR3C1) was suppressed by dexamethasone at 48h, suggesting limited effect of the drug in prolonged LSEC culture. Conclusion: The study presents a detailed overview of biological processes and pathways affected by dexamethasone in mouse LSECs in vitro.