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Veterinary Pathology Nov 2022We performed a retrospective examination of spontaneous hepatocellular carcinomas (HCCs) (primary and metastatic tumors) in 14 captive prosimians brought to the...
We performed a retrospective examination of spontaneous hepatocellular carcinomas (HCCs) (primary and metastatic tumors) in 14 captive prosimians brought to the Veterinary Medical Diagnostic Laboratory in North Carolina State University over a period of 11 years (2003 to 2014) to characterize the tumors. These animals are endangered primates; a better understanding of the main fatal neoplasms is crucial. In addition to the histologic evaluation, an immunohistochemical study was also performed, using a hepatocyte marker (hepatocyte paraffin 1 [HepPar-1]) and 2 cholangiocyte markers (keratin 7 [K7] and keratin 19 [K19]), in an attempt to identify a specific profile for HCCs with metastatic behavior. Six of the 14 HCCs had pulmonary metastases. The most frequent histopathological findings were a trabecular pattern (14/14, 100%), presence of multinucleated cells (12/14, 85.7%), and foci of extramedullary hematopoiesis (9/14, 64.3%). The mitotic count was significantly higher in the metastatic HCCs ( < .05). HepPar-1 was detected in all primary and metastatic HCCs, with a strong intensity of staining. Labeling for K7 and K19 was positive in 12 HCCs (85.7%) and 1 HCC (7.1%), respectively. Contrary to the less aggressive HCCs, most of the metastatic HCCs (5/6) expressed K7 in more than 15% of cells. The percentage of K7-positive neoplastic hepatocytes was significantly higher in metastatic HCCs. This study suggests that K7 might be a prognostically relevant marker in HCCs of captive prosimians.
Topics: Animals; Biomarkers, Tumor; Carcinoma, Hepatocellular; Immunohistochemistry; Keratin-19; Keratin-7; Liver Neoplasms; Paraffin; Retrospective Studies; Strepsirhini
PubMed: 35876312
DOI: 10.1177/03009858221114471 -
World Journal of Hepatology Apr 2021Giant cell hepatitis (GCH) is characterized by large and multinucleated (syncytial) hepatocytes in the context of liver inflammation. Infantile GCH is typically... (Review)
Review
Giant cell hepatitis (GCH) is characterized by large and multinucleated (syncytial) hepatocytes in the context of liver inflammation. Infantile GCH is typically associated with autoimmune hemolytic anemia in the absence of any other systemic or organ-specific autoimmune comorbidity. The etiology is unknown; concomitant viral infections (as potential trigger factors) have been identified in a few patients. The pathogenesis reportedly relies upon immune-mediated/ autoimmune mechanisms. This condition should be considered in any infant developing Coombs-positive anemia; indeed, anemia usually precedes the development of hepatitis. The clinical course is usually aggressive without the appropriate immunosuppressive therapy, which may include steroids, conventional immunosuppressors (, azathioprine and cyclophosphamide as first-line treatments), intravenous immunoglobulin, and biologics (rituximab). Improvements in medical management (including the availability of rituximab) have significantly reduced the mortality of this condition in the last decade.
PubMed: 33959224
DOI: 10.4254/wjh.v13.i4.411 -
Autophagy Mar 2023Although it is admitted that secondary infection can complicate viral diseases, the consequences of viral infection on cell susceptibility to other infections remain...
Although it is admitted that secondary infection can complicate viral diseases, the consequences of viral infection on cell susceptibility to other infections remain underexplored at the cellular level. We though to examine whether the sustained macroautophagy/autophagy associated with measles virus (MeV) infection could help cells oppose invasion by Typhimurium, a bacterium sensitive to autophagic restriction. We report here the unexpected finding that markedly replicated in MeV-infected cultures due to selective growth within multinucleated cells. Hyper-replicating localized outside of LAMP1-positive compartments to an extent that equaled that of the predominantly cytosolic mutant . Bacteria were subjected to effective ubiquitination but failed to be targeted by LC3 despite an ongoing productive autophagy. Such a phenotype could not be further aggravated upon silencing of the selective autophagy regulator TBK1 or core autophagy factors ATG5 or ATG7. MeV infection also conditioned primary human epithelial cells for augmented replication. The analysis of selective autophagy receptors able to target revealed that a lowered expression level of SQSTM1/p62 and TAX1BP1/T6BP autophagy receptors prevented effective anti- autophagy in MeV-induced syncytia. Conversely, as SQSTM1/p62 is promoting the cytosolic growth of , MeV infection led to reduced replication. The results indicate that the rarefaction of dedicated autophagy receptors associated with MeV infection differentially affects the outcome of bacterial coinfection depending on the nature of the functional relationship between bacteria and such receptors. Thus, virus-imposed reconfiguration of the autophagy machinery can be instrumental in determining the fate of bacterial coinfection. ACTB/β-ACTIN: actin beta; ATG: autophagy related; BAFA1: bafilomycin A; CFU: colony-forming units; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; FIP: fusion inhibitory peptide; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MeV: measles virus; MOI: multiplicity of infection; OPTN: optineurin; PHH: primary human hepatocyte; SCV: Salmonella-containing vacuoles; SQSTM1/p62: sequestosome 1; . Typhimurium: serovar Typhimurium; TAX1BP1/T6BP: Tax1 binding protein 1; TBK1: TANK binding kinase 1.
Topics: Humans; Autophagy; Sequestosome-1 Protein; Coinfection; Measles virus; Salmonella typhimurium; Carrier Proteins
PubMed: 35900944
DOI: 10.1080/15548627.2022.2107309 -
International Journal of Molecular... Mar 2020The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed... (Review)
Review
The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.
Topics: Aneuploidy; Animals; Cell Fusion; Chromosomal Instability; Humans; Hybrid Cells; Polyploidy; Regeneration
PubMed: 32155721
DOI: 10.3390/ijms21051811 -
Toxicon : Official Journal of the... Oct 2020Some species of the genus Brachiaria are cultivated worldwide in tropical and subtropical climate regions as the main feed for ruminants. Several studies report...
Some species of the genus Brachiaria are cultivated worldwide in tropical and subtropical climate regions as the main feed for ruminants. Several studies report photosensitization by Brachiaria decumbens, Brachiaria brizantha, and Brachiaria humidicola, but the poisoning by Brachiaria ruziziensis have been reported only twice. Cutaneous and hepatic lesions may be caused by the steroidal saponins present in the leaves or by the mycotoxin sporidesmin produced by the saprophyte fungus Pithomyces chartarum. The present report describes the clinical and pathological changes observed in an outbreak of hepatogenic photosensitization in sheep kept in B. ruziziensis pastures. In addition, the present study will provide a better understanding of the etiology of this photosensitization through the evaluation of the saponin protodioscin and the spore count of P. chartarum. Santa Inês and Lacaune mixed-breed sheep showed signs of photosensitization after feeding B. ruziziensis. Clinical signs included jaundice, apathy, dehydration, and photosensitization characterized by facial edema and cutaneous scars, especially in the ears. Pathological examination of the liver revealed diffuse infiltrates of foamy cells, rare multinucleated cells, and mild enlargement of hepatocytes (megalocytosis). The skin showed acute epidermal and dermal necrosis with occlusive thrombi. B. ruziziensis showed low levels of protodioscin (0.020 ± 0.024% in mature leaves and 0.065 ± 0.084% in sprouts) but high P. chartarum spore counts (mean of 479,844 ± 443,951 spores/g plant). Thus, sheep grazing B. ruziziensis pastures must be closely monitored because of the risk of photosensitization.
Topics: Animals; Brachiaria; Diosgenin; Liver; Photosensitivity Disorders; Plant Poisoning; Saponins; Sheep; Sheep Diseases; Skin
PubMed: 32598988
DOI: 10.1016/j.toxicon.2020.06.022 -
Toxicology in Vitro : An International... Jun 2023Perfluorooctanoic acid (PFOA) is tumorigenic in rats and mice and potentially tumorigenic in humans. Here, we studied long-term PFOA exposure with an in vitro...
Perfluorooctanoic acid (PFOA) is tumorigenic in rats and mice and potentially tumorigenic in humans. Here, we studied long-term PFOA exposure with an in vitro transformation model using the rat liver epithelial cell, TRL 1215. Cells were cultured in 10 μM (T10), 50 μM (T50) and 100 μM (T100) PFOA for 38 weeks and compared to passage-matched control cells. T100 cells showed morphological changes, loss of cell contact inhibition, formation of multinucleated giant and spindle-shaped cells. T10, T50, and T100 cells showed increased LC values 20%, 29% to 35% above control with acute PFOA treatment, indicating a resistance to PFOA toxicity. PFOA-treated cells showed increases in Matrix metalloproteinase-9 secretion, cell migration, and developed more and larger colonies in soft agar. Microarray data showed Myc pathway activation at T50 and T100, associating Myc upregulation with PFOA-induced morphological transformation. Western blot confirmed that PFOA produced significant increases in c-MYC protein expression in a time- and concentration-related manner. Tumor invasion indicators MMP-2 and MMP-9, cell cycle regulator cyclin D1, and oxidative stress protein GST were all significantly overexpressed in T100 cells. Taken together, chronic in vitro PFOA exposure produced multiple cell characteristics of malignant progression and differential gene expression changes suggestive of rat liver cell transformation.
Topics: Humans; Rats; Mice; Animals; Hepatocytes; Caprylates; Fluorocarbons; Cell Transformation, Neoplastic; Liver
PubMed: 36849026
DOI: 10.1016/j.tiv.2023.105577 -
Veterinary Pathology Nov 2014Multinucleated hepatocytes (MNHs) have been occasionally reported in macaques, as well as chimpanzees and gorillas, as an incidental finding. However, information is...
Multinucleated hepatocytes (MNHs) have been occasionally reported in macaques, as well as chimpanzees and gorillas, as an incidental finding. However, information is sparse on variations in incidence in the cynomolgus macaque (Macaca fascicularis). A survey was conducted to assess the occurrence of MNHs in the liver of stock (nonstudy) animals from SNBL SRC (Alice, TX) and SNBL USA (Everett, WA) submitted for diagnostic purposes. A total of 215 cynomolgus monkeys originally from Cambodia (61), China (5), Indonesia (125), and Mauritius (24) were used for this investigation. From each animal, usually 2 liver samples were processed for histopathology with 2 sections in each slide. An MNH was defined as a hepatocyte with 3 or more nuclei. A threshold of 3 MNHs was selected for the Multinucleated Hepatocyte Grading System: 0 = not remarkable (≤3 MNHs counted from 2-4 liver sections), minimal = 4 to 15 MNHs, mild = 16 to 30 MNHs, moderate = 31 to 59 MNHs, and severe ≥60 MNHs. The incidence of MNHs was 60 of 86 (70%) in males and 72 of 129 (56%) in females for a total overall incidence of 132 of 215 animals (61%). Affected hepatocytes were frequently observed close to the capsule and generally had 3 to 8 nuclei per hepatocyte but as many as 15 occurred in a single cell. Awareness of the incidence of MNHs in cynomolgus monkeys is important for potential use as background data in preclinical safety and toxicity evaluation studies.
Topics: Animals; Cell Nucleus; Female; Hepatocytes; Liver; Macaca fascicularis; Male
PubMed: 24395914
DOI: 10.1177/0300985813516641 -
Scientific Reports Jun 2021Previous reports have demonstrated that Reversine can reverse differentiation of lineage-committed cells to mesenchymal stem cells and suppress tumors growth. However,...
Previous reports have demonstrated that Reversine can reverse differentiation of lineage-committed cells to mesenchymal stem cells and suppress tumors growth. However, the molecular mechanisms of antitumor activity and promoting cellular dedifferentiation for reversine have not yet been clearly elucidated. In the present study, it was demonstrated that reversine of 5 μM could induce multinucleated cells through cytokinesis failure rather than just arrested in G2 or M phase. Moreover, reversine reversed the differentiation of sheep fibroblasts into MSC-like style, and notably increased the expression of pluripotent marker genes Oct4 and MSCs-related surface antigens. The fibroblasts treated with reversine could transdifferentiate into all three germ layers cells in vitro. Most importantly, the induced β-like cells and hepatocytes had similar metabolic functions with normal cells in vivo. In addition, reversine promoted fibroblasts autophagy, ROS accumulation, mitochondrial dysfunction and cell apoptosis via the mitochondria mediated intrinsic pathway. The results of high-throughput RNA sequencing showed that most differentially expressed genes (DEGs) involved in Mismatch repair, Nucleotide excision repair and Base excision repair were significantly up-regulated in reversine treated fibroblasts, which means that high concentration of reversine will cause DNA damage and activate the DNA repair mechanism. In summary, reversine can increase the plasticity of sheep fibroblasts and suppress cell growth via the mitochondria mediated intrinsic pathway.
Topics: Animals; Apoptosis; Autophagy; Cell Cycle; Cell Differentiation; DNA; DNA Damage; DNA Repair; Fibroblasts; Mesenchymal Stem Cells; Mitochondria; Morpholines; Purines; Sequence Analysis, RNA; Sheep
PubMed: 34117304
DOI: 10.1038/s41598-021-91468-w -
Biological Trace Element Research Dec 2023A growing body of evidence suggests that long-term arsenic exposure can induce liver injury. Our previous studies have demonstrated that liver injury occurs in...
A growing body of evidence suggests that long-term arsenic exposure can induce liver injury. Our previous studies have demonstrated that liver injury occurs in arsenic-poisoning patients and arsenic-exposed rats. However, therapeutic targets are still unclear, and there is a lack of effective drugs. This study aimed to investigate the effects of sodium arsenite (arsenite) exposure on hepatocyte senescence and the intervention effect of ginkgo biloba extract in rats. In this study, 24 male Sprague-Dawley rats (weighing 180-200 g) were randomized into three groups. The control group received a normal diet, and the arsenic-exposed group was given 10 mg/L arsenite for 3 months by free drinking along with a normal diet. The ginkgo biloba extract treatment group was consecutively administered EGb761 (10 mg/kg, by gavage) for 1 month following 2 months of arsenite exposure. Our results showed that exposure to 10 mg/L arsenite induced narrowing of the hepatic sinus space, enlargement of hepatocytes, and increased multinucleated hepatocytes and inflammatory cell infiltration in rat liver tissue compared with the normal control group. Moreover, 10 mg/L arsenite also caused abnormal expression of inflammation-related indices (IL1-β, IL-6, TNF-α), oxidative damage-related indices (SOD, MDA, GPx), and senescence-related proteins (p16, p-p53, E2F1). EGb761 could effectively reduce the pathological damage of liver tissue and antagonize the abnormal expression of liver tissue inflammation and oxidative damage-related indices as well as cellular senescence-related proteins caused by arsenite exposure. Notably, EGb761 reduced the accumulation of arsenic in rat liver tissues. These results suggested that EGb761 could effectively alleviate subchronic arsenic exposure-induced senescence of hepatocytes, which may be achieved partially through inhibiting inflammation and oxidative damage in rats. This study may provide a new therapeutic target for arsenic-induced liver injury.
PubMed: 38110608
DOI: 10.1007/s12011-023-04021-3 -
Developmental Dynamics : An Official... Jun 2021Axolotls have remarkable organ-level regeneration capability. They can regenerate their limbs, tail, brain, gills, and heart. The liver had been considered to be a...
BACKGROUND
Axolotls have remarkable organ-level regeneration capability. They can regenerate their limbs, tail, brain, gills, and heart. The liver had been considered to be a regenerative organ in these highly regeneration-competent animals. Therefore, no research had been performed on liver regeneration in urodele amphibians. In the present study, we focused on axolotl liver regeneration and found a unique regeneration mechanism compared with other vertebrates.
RESULTS
Partial hepatectomy (PH) was performed to assess axolotl liver regeneration. Regeneration was assessed using block-face imaging (CoMBi), histology, cell proliferation, weight gain, and Albumin (Alb) + area. Axolotl liver histology was compared with other vertebrates. Axolotl liver consists of Glisson's capsule, sinusoids, and hepatic cord with no apparent lobule structures. Hepatocytes were mononucleated or multinucleated. PH increased the multinucleated hepatocytes and the Alb + area, but there was no apparent liver shape recovery even 40 days after PH. Gene expression pattern suggests that no epimorphic regeneration takes place. We also found that the increase in the number of proliferating hepatocytes was regulated by ERK-signaling.
CONCLUSION
Our findings suggest that axolotls, which have epimorphic regeneration ability, regenerate their liver via unique mechanisms, compensatory congestion.
Topics: Ambystoma mexicanum; Animals; Cell Proliferation; Hepatectomy; Liver; Liver Regeneration; MAP Kinase Signaling System; Weight Gain
PubMed: 33064366
DOI: 10.1002/dvdy.262