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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 -
International Journal of Surgical... May 2024Garcinia cambogia, a weight control herbal, can cause mild liver toxicity with nonspecific histologic changes. Herein, we reported a case of herbal-induced fulminant...
Garcinia cambogia, a weight control herbal, can cause mild liver toxicity with nonspecific histologic changes. Herein, we reported a case of herbal-induced fulminant cholestatic giant cell hepatitis due to garcinia cambogia use. A 65-year-old woman with breast cancer treated 18 years earlier was admitted for obstructive jaundice for 2 weeks. She started using garcinia cambogia 3 months ago for weight loss. Physical exam showed scleral icterus. Serum studies excluded Wilson's disease, systemic infection including COVID-19 (coronavirus disease 2019), autoimmune hepatitis, and metabolic or toxicologic causes. An urgent liver biopsy showed severe giant cell hepatitis in absence of HSV-1/2, cytomegalovirus, HBsAg and HBcAg (immunostain), and EBV (in situ hybridization). Despite supportive therapy, the patient developed grade 2-3 hepatic encephalopathy and necessitated liver transplant. The explanted liver was markedly atrophy, in which the most striking histologic finding was diffuse distribution of multinucleated giant hepatocytes with syncytial pattern in a background of extensive zone-1 accentuated, geographic, hemorrhagic, confluent hepatocytic necrosis, along with remarkable hepatocytic and canalicular cholestasis. Marked hepatocellular and sinusoidal iron orverload present. The patient recovered uneventfully.
Topics: Female; Humans; Aged; Garcinia cambogia; Hepatitis; Hemochromatosis; Liver; Liver Failure, Acute
PubMed: 37461217
DOI: 10.1177/10668969231186926 -
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 -
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 -
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 -
Food Science and Biotechnology Jun 2022Sub-chronic toxicity studies using rats have been conducted for (Maxim.) Hemsley (CW) and Royle ex Wight (CA). CW water extract didn't show any adverse effects whereas...
Sub-chronic toxicity studies using rats have been conducted for (Maxim.) Hemsley (CW) and Royle ex Wight (CA). CW water extract didn't show any adverse effects whereas administering CW powder decreased body weights in complication with decreased food consumptions. In the case of CA water extract, triglyceride and absolute/relative liver weights were elevated and vacuolation was observed in liver. Treated CA powder in male rats increased alanine aminotransferase and aspartate aminotransferase and induced single cell necrosis and multinucleated hepatocyte in liver. As for female rats, increased absolute/relative weights and hypertrophy/vacuolation in adrenal glands and vacuolation in ovaries were observed when administered CA powder. In conclusion, no observed adverse effect level (NOAEL) of CW water extract was over 5000 mg/kg/day, while NOAEL of CW powder was 700 mg/kg/day for female and 150 mg/kg/day for male. In case of CA, NOAEL of water extract was 1500 mg/kg/day for male and 2000 mg/kg/day for female, while NOAEL of powder was 150 mg/kg/day for both gender. To the best of our knowledge, this is the first sub-chronic toxicity study on the adverse effects, target organs and its dose levels of (Maxim.) Hemsley and Royle ex Wight following GLP protocols.
PubMed: 35646417
DOI: 10.1007/s10068-022-01072-5 -
World Journal of Clinical Cases Sep 2021The immune-mediated invasion of IgG4-positive plasma cells in the liver is found in some autoimmune hepatitis. Giant-cell hepatitis (GCH) is a very rare pathological...
BACKGROUND
The immune-mediated invasion of IgG4-positive plasma cells in the liver is found in some autoimmune hepatitis. Giant-cell hepatitis (GCH) is a very rare pathological feature in adults, and the clinical characteristics of the simultaneous appearance of the two pathological phenomena are not clear.
CASE SUMMARY
A 68-year-old woman was hospitalized with fatigue, poor appetite, and yellow urine for 20 d. Liver function tests and immunological indexes were significantly abnormal and accompanied by elevated serum IgG4 levels. Liver pathology revealed severe inflammation of the interface between the portal tract and hepatocytes, portal area inflammation, plasma cell infiltration, formation of rosette cells, IgG4-positive plasma cells > 10/high-power field, IgG4/IgG > 40%, and multinucleated liver cell swelling. IgG4-related autoimmune hepatitis (AIH) combined with GCH was diagnosed, and methylprednisolone was administered at 40 mg/day. Two weeks later, the clinical symptoms disappeared, and the liver function and immunological indicators were significantly improved. Methylprednisolone was reduced at a rate of 4-8 mg per week to 8 mg/day for maintenance. A second liver biopsy 48 wk later indicated that liver inflammation and fibrosis were significantly improved. IgG4-positive plasma cells and GCH were not detected. A literature search was conducted to analyze articles reporting similar pathological phenomena.
CONCLUSION
AIH with simultaneous IgG4-positive plasma cell infiltration and GCH, liver inflammation, and fibrosis is possibly more severe than typical AIH but sensitive to corticosteroids.
PubMed: 34616822
DOI: 10.12998/wjcc.v9.i25.7527 -
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 -
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 -
Canadian Liver Journal 2021Giant cell hepatitis (GCH) is a rare entity in adults that is characterized by large multinucleated hepatocyte formation and parenchymal inflammation. We present a case...
Giant cell hepatitis (GCH) is a rare entity in adults that is characterized by large multinucleated hepatocyte formation and parenchymal inflammation. We present a case of acute liver failure in a 33-year-old woman secondary to autoimmune hepatitis (AIH). A liver biopsy revealed submassive hepatocyte necrosis consistent with GCH. We conducted a literature review of 187 reported cases of post-infantile GCH in adults. AIH was the most commonly reported cause of GCH, but GCH was associated with a wide spectrum of etiologies, including infections, rheumatological diseases, hematological diseases, malignancies, and medications. The severity of disease can range from mild hepatitis to fulminant hepatic failure. The mortality rate among the cases in the literature was 18.82%. GCH is managed by treating the underlying cause, and ribavirin has been proposed as a treatment option for idiopathic GCH. A small number of patients progress to requiring orthotopic liver transplant, but recurrence is possible post-transplant.
PubMed: 35991767
DOI: 10.3138/canlivj-2020-0024