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1.
BMJ Case Rep ; 17(6)2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38839414

ABSTRACT

Tamoxifen is a non-steroidal selective oestrogen receptor modulator commonly used in the treatment of breast cancer. It is associated with the development of fatty liver and steatohepatitis however drug-induced liver injury is rare. We report a woman in her 50s who developed malaise with an acute moderate aminotransferase elevation without jaundice 6 months after starting tamoxifen. She was not commenced on any other recent drugs and extensive investigation including infective and autoimmune liver screen, cross-sectional imaging and FibroScan were unremarkable. Liver biopsy revealed moderate lobular hepatitis with hepatocyte drop-out. Tamoxifen was ceased and the liver enzymes showed resolution over the following 3 months and improvement of her symptoms.


Subject(s)
Antineoplastic Agents, Hormonal , Breast Neoplasms , Chemical and Drug Induced Liver Injury , Tamoxifen , Humans , Tamoxifen/adverse effects , Female , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/diagnosis , Middle Aged , Breast Neoplasms/drug therapy , Antineoplastic Agents, Hormonal/adverse effects , Liver/pathology , Liver/drug effects
2.
Sci Rep ; 14(1): 12613, 2024 06 01.
Article in English | MEDLINE | ID: mdl-38824206

ABSTRACT

The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [18F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [18F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1-3 was used to classify responders and DS 4-5, non-responders. [18F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1-2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS (p = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.


Subject(s)
Fluorodeoxyglucose F18 , Hodgkin Disease , Positron Emission Tomography Computed Tomography , Humans , Hodgkin Disease/drug therapy , Hodgkin Disease/diagnostic imaging , Hodgkin Disease/metabolism , Hodgkin Disease/pathology , Positron Emission Tomography Computed Tomography/methods , Male , Female , Adult , Middle Aged , Prognosis , Retrospective Studies , Young Adult , Bone Marrow/diagnostic imaging , Bone Marrow/metabolism , Bone Marrow/pathology , Bone Marrow/drug effects , Aged , Liver/diagnostic imaging , Liver/metabolism , Liver/pathology , Adolescent , Radiopharmaceuticals , Spleen/diagnostic imaging , Spleen/metabolism , Spleen/pathology
3.
Mol Med ; 30(1): 82, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38862918

ABSTRACT

BACKGROUND: Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death are involved in the pathological process of hepatic IR. ERRFI1 is involved in the regulation of cell apoptosis in myocardial IR. However, the function of ERRFI1 in hepatic IR injury and its modulation of programmed cell death remain largely unknown. METHODS: Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined. RESULTS: ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis. CONCLUSIONS: Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury.


Subject(s)
Apoptosis , Ferroptosis , GRB2 Adaptor Protein , Hepatocytes , Mice, Knockout , Reperfusion Injury , Animals , Hepatocytes/metabolism , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Reperfusion Injury/genetics , Ferroptosis/genetics , Mice , Apoptosis/genetics , GRB2 Adaptor Protein/metabolism , GRB2 Adaptor Protein/genetics , Male , Liver/metabolism , Liver/pathology , Disease Models, Animal , Humans
4.
Ulus Travma Acil Cerrahi Derg ; 30(6): 390-396, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38863289

ABSTRACT

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a significant clinical condition that can arise during liver resections, trauma, and shock. Geraniol, an isoterpene molecule commonly found in nature, possesses antioxidant and hepatoprotective properties. This study investigates the impact of geraniol on hepatic damage by inducing experimental liver I/R injury in rats. METHODS: Twenty-eight male Wistar Albino rats weighing 350-400 g were utilized for this study. The rats were divided into four groups: control group, I/R group, 50 mg/kg geraniol+I/R group, and 100 mg/kg geraniol+I/R group. Ischemia times were set at 15 minutes with reperfusion times at 20 minutes. Ischemia commenced 15 minutes after geraniol administration. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactic acid were measured, along with superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity levels in liver tissues. Liver tissues were also examined histopathologically. RESULTS: It was observed that intraperitoneal administration of 50 mg/kg and 100 mg/kg geraniol significantly reduced AST, lactic acid, and tumor necrosis factor-alpha (TNF-α) levels. The serum ALT level decreased significantly in the 50 mg/kg group, whereas no significant decrease was found in the 100 mg/kg group. SOD and GPx enzyme activities were shown to increase significantly in the 100 mg/kg group. Although there was an increase in these enzyme levels in the 50 mg/kg group, it was not statistically significant. Similarly, CAT enzyme activity increased in both the 50 mg/kg and 100 mg/kg groups, but the increase was not significant. The Suzuki score significantly decreased in both the 50 mg/kg and 100 mg/kg groups. CONCLUSION: The study demonstrates that geraniol reduced hepatic damage both biochemically and histopathologically and increased antioxidant defense enzymes. These findings suggest that geraniol could be used to prevent hepatic I/R injury, provided it is corroborated by large-scale and comprehensive studies.


Subject(s)
Acyclic Monoterpenes , Disease Models, Animal , Liver , Rats, Wistar , Reperfusion Injury , Terpenes , Animals , Acyclic Monoterpenes/pharmacology , Reperfusion Injury/drug therapy , Reperfusion Injury/prevention & control , Male , Rats , Terpenes/pharmacology , Terpenes/therapeutic use , Liver/drug effects , Liver/pathology , Liver/blood supply , Antioxidants/pharmacology , Oxidative Stress/drug effects , Aspartate Aminotransferases/blood
5.
Arch Virol ; 169(7): 146, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38864914

ABSTRACT

Adenoviruses are a diverse group of viruses that can cause a variety of diseases in poultry, including respiratory and gastrointestinal infections. In turkeys (Meleagris gallopavo), adenoviruses commonly cause hemorrhagic enteritis and, rarely, inclusion body hepatitis. In this study, we investigated fowl adenoviruses (FAdVs) circulating in turkeys in Egypt. Following clinical examination of 500 birds, a portion of the hexon gene was amplified from four out of 50 samples from diseased birds (8%), and one amplicon that produced a strong band was selected for sequencing. Molecular and phylogenetic analysis revealed that the virus in that sample belonged to serotype FAdV-8b. Histopathological and immunohistochemical examinations of prepared tissue sections were performed to confirm the pathological findings. Diseased birds exhibited ruffled feathers, low body weight, a crouching posture, and diarrhea. Gross examination revealed petechial hemorrhage on the spleen, swollen pale liver, and congested intestine. Microscopic examination revealed the presence of eosinophilic and basophilic intranuclear inclusion bodies, nuclear pyknosis, and apoptotic bodies in the liver, congestion, hemorrhage, and fibrosis in the lungs, and desquamation of enterocytes. The presence of viral antigens in the liver, lungs, and intestine was confirmed by immunohistochemistry. To our knowledge, this is the first report of the characterization of an outbreak of inclusion body hepatitis in turkeys (hybrid converter breeds) due to FAdV-8b in Egypt. This finding raises an epidemiological alarm, necessitating further studies, including full-genome sequencing, to trace the virus's origin and genetic diversity.


Subject(s)
Adenoviridae Infections , Aviadenovirus , Phylogeny , Poultry Diseases , Turkeys , Animals , Adenoviridae Infections/veterinary , Adenoviridae Infections/virology , Adenoviridae Infections/pathology , Poultry Diseases/virology , Poultry Diseases/pathology , Turkeys/virology , Aviadenovirus/genetics , Aviadenovirus/classification , Aviadenovirus/isolation & purification , Hepatitis, Viral, Animal/virology , Hepatitis, Viral, Animal/pathology , Egypt , Liver/virology , Liver/pathology , Inclusion Bodies, Viral/virology , Capsid Proteins/genetics
6.
Mol Biol Rep ; 51(1): 740, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38874802

ABSTRACT

BACKGROUND: Sonic Hedgehog (SHH) is a fundamental signaling pathway that controls tissue reconstruction, stem cell biology, and differentiation and has a role in gut tissue homeostasis and development. Dysregulation of SHH leads to the development of HCC. METHODS, AND RESULTS: The present study was conducted to compare the effects of mesenchymal stem cells (MSCs) and curcumin on SHH molecular targets in an experimental model of HCC in rats. One hundred rats were divided equally into the following groups: control group, HCC group, HCC group received MSCs, HCC group received curcumin, and HCC group received MSCs and curcumin. Histopathological examinations were performed, and gene expression of SHH signaling target genes (SHH, PTCH1, SMOH, and GLI1) was assessed by real-time PCR in rat liver tissue. Results showed that SHH target genes were significantly upregulated in HCC-untreated rat groups and in MSC-treated groups, with no significant difference between them. Administration of curcumin with or without combined administration of MSCs led to a significant down-regulation of SHH target genes, with no significant differences between both groups. As regards the histopathological examination of liver tissues, both curcumin and MSCs, either through separate use or their combined use, led to a significant restoration of normal liver pathology. CONCLUSIONS: In conclusion, SHH signaling is upregulated in the HCC experimental model. MSCs do not inhibit the upregulated SHH target genes in HCC. Curcumin use with or without MSCs administration led to a significant down-regulation of SHH signaling in HCC and a significant restoration of normal liver pathology.


Subject(s)
Carcinoma, Hepatocellular , Curcumin , Hedgehog Proteins , Liver Neoplasms , Mesenchymal Stem Cells , Signal Transduction , Hedgehog Proteins/metabolism , Hedgehog Proteins/genetics , Animals , Curcumin/pharmacology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Signal Transduction/drug effects , Rats , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/drug effects , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mesenchymal Stem Cell Transplantation/methods , Male , Disease Models, Animal , Patched-1 Receptor/genetics , Patched-1 Receptor/metabolism , Zinc Finger Protein GLI1/metabolism , Zinc Finger Protein GLI1/genetics , Gene Expression Regulation, Neoplastic/drug effects , Liver/metabolism , Liver/pathology , Liver/drug effects
7.
Int J Biol Macromol ; 272(Pt 1): 132744, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38834122

ABSTRACT

Dictyophora indusiata is a common edible mushroom with great potential in the field of medicine against metabolic disorders, inflammation, and immunodeficiency. Our previous studies have shown that different fractions of the polysaccharide from Dictyophora indusiata (DIP) have various structural characteristics and morphology. However, the impact of the structural features on the protective effects of DIP against metabolic syndrome remains unclear. In this study, three distinct polysaccharide fractions have been extracted from Dictyophora indusiata and a high-fat diet-induced metabolic syndrome (MetS) was constructed in mice. The effects of these fractions on a range of MetS-associated endpoints, including abnormal blood glucose, lipid profiles, body fat content, liver function, intestinal microbiota and their metabolites were investigated. Through correlation analysis, the potential link between the monosaccharide composition of the polysaccharides and their biological activities was determined. The study aimed to explore the potential mechanisms and ameliorative effects of these polysaccharide fractions on MetS, thereby providing statistical evidence for understanding the relationship between monosaccharides composition of Dictyophora indusiata polysaccharides and their potential utility in treating metabolic disorders.


Subject(s)
Diet, High-Fat , Metabolic Syndrome , Animals , Metabolic Syndrome/drug therapy , Mice , Diet, High-Fat/adverse effects , Fungal Polysaccharides/pharmacology , Fungal Polysaccharides/chemistry , Male , Monosaccharides/analysis , Polysaccharides/pharmacology , Polysaccharides/chemistry , Gastrointestinal Microbiome/drug effects , Basidiomycota/chemistry , Liver/drug effects , Liver/metabolism , Liver/pathology , Blood Glucose/drug effects , Blood Glucose/metabolism , Disease Models, Animal , Agaricales/chemistry
8.
Life Sci ; 350: 122782, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38848941

ABSTRACT

Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.


Subject(s)
AMP-Activated Protein Kinases , Acetaminophen , Cell Adhesion Molecules, Neuronal , Chemical and Drug Induced Liver Injury , Mice, Inbred C57BL , Mice, Knockout , NF-E2-Related Factor 2 , Animals , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/genetics , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Mice , AMP-Activated Protein Kinases/metabolism , Humans , Male , Cell Adhesion Molecules, Neuronal/metabolism , Cell Adhesion Molecules, Neuronal/genetics , Signal Transduction/drug effects , Oxidative Stress/drug effects , Hepatocytes/metabolism , Hepatocytes/drug effects , Liver/metabolism , Liver/drug effects , Liver/pathology , Female , Nerve Growth Factors
9.
Life Sci ; 350: 122776, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38852794

ABSTRACT

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-ß-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC.


Subject(s)
Disease Models, Animal , Liver , Niemann-Pick Disease, Type C , gamma-Cyclodextrins , Animals , Niemann-Pick Disease, Type C/drug therapy , Niemann-Pick Disease, Type C/pathology , Mice , Liver/drug effects , Liver/metabolism , Liver/pathology , gamma-Cyclodextrins/pharmacology , Tissue Distribution , Cholesterol/metabolism , Male , Mice, Inbred BALB C
10.
Sci Rep ; 14(1): 13473, 2024 06 12.
Article in English | MEDLINE | ID: mdl-38866800

ABSTRACT

Aging enhances numerous processes that compromise homeostasis and pathophysiological processes. Among these, activated HSCs play a pivotal role in advancing liver fibrosis. This research delved into how aging impacts liver fibrosis mechanisms. The study involved 32 albino rats categorized into four groups: Group I (young controls), Group II (young with liver fibrosis), Group III (old controls), and Group IV (old with liver fibrosis). Various parameters including serum ALT, adiponectin, leptin, and cholesterol levels were evaluated. Histopathological analysis was performed, alongside assessments of TGF-ß, FOXP3, and CD133 gene expressions. Markers of fibrosis and apoptosis were the highest in group IV. Adiponectin levels significantly decreased in Group IV compared to all other groups except Group II, while cholesterol levels were significantly higher in liver fibrosis groups than their respective control groups. Group III displayed high hepatic expression of desmin, α-SMA, GFAP and TGF- ß and in contrast to Group I. Increased TGF-ß and FOXP3 gene expressions were observed in Group IV relative to Group II, while CD133 gene expression decreased in Group IV compared to Group II. In conclusion, aging modulates immune responses, impairs regenerative capacities via HSC activation, and influences adipokine and cholesterol levels, elevating the susceptibility to liver fibrosis.


Subject(s)
Aging , Hepatic Stellate Cells , Liver Cirrhosis , Animals , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/pathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/genetics , Rats , Male , Transforming Growth Factor beta/metabolism , Cholesterol/metabolism , Cholesterol/blood , Apoptosis , Liver/metabolism , Liver/pathology
11.
BMC Vet Res ; 20(1): 256, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867202

ABSTRACT

Acetamiprid (ACDP) is a widely used neonicotinoid insecticide that is popular for its efficacy in controlling fleas in domestic settings and for pets. Our study aims to offer a comprehensive examination of the toxicological impacts of ACDP and the prophylactic effects of cinnamon nanoemulsions (CMNEs) on the pathological, immunohistochemical, and hematological analyses induced by taking ACDP twice a week for 28 days. Forty healthy rats were divided into four groups (n = 10) at random; the first group served as control rats; the second received CMNEs (2 mg/Kg body weight); the third group received acetamiprid (ACDP group; 21.7 mg/Kg body weight), and the fourth group was given both ACDP and CMNEs by oral gavage. Following the study period, tissue and blood samples were extracted and prepared for analysis. According to a GC-MS analysis, CMNEs had several bioactive ingredients that protected the liver from oxidative stress by upregulating antioxidant and anti-inflammatory agents. Our findings demonstrated that whereas ACDP treatment considerably boosted white blood cells (WBCs) and lymphocytes, it significantly lowered body weight gain (BWG), red blood cells (RBCs), hemoglobin (Hb), hematocrit (HCT), and platelets (PLT). ACDP notably reduced antioxidant enzyme activities: superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) and elevated hydrogen peroxide and malondialdehyde levels compared with other groups. ACDP remarkably raised alanine aminotransferase (ALT), aspartate amino transaminase (AST), and alkaline phosphatase (ALP) levels.Moreover, the histopathological and immunohistochemistry assays discovered a severe toxic effect on the liver and kidney following ACDP delivery. Furthermore, cyclooxygenase 2 (COX-2) + immunoexpression was enhanced after treatment with CMNEs. All of the parameters above were returned to nearly normal levels by the coadministration of CMNEs. The molecular docking of cinnamaldehyde with COX-2 also confirmed the protective potential of CMNEs against ACDP toxicity. Our findings highlighted that the coadministration of CMNEs along with ACDP diminished its toxicity by cutting down oxidative stress and enhancing antioxidant capacity, demonstrating the effectiveness of CMNEs in lessening ACDP toxicity.


Subject(s)
Cinnamomum zeylanicum , Emulsions , Insecticides , Liver , Molecular Docking Simulation , Neonicotinoids , Animals , Neonicotinoids/pharmacology , Cinnamomum zeylanicum/chemistry , Insecticides/toxicity , Rats , Emulsions/chemistry , Emulsions/pharmacology , Male , Liver/drug effects , Liver/pathology , Kidney/drug effects , Kidney/pathology , Oxidative Stress/drug effects , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/prevention & control , Antioxidants/pharmacology , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Kidney Diseases/pathology , Rats, Sprague-Dawley
12.
Nat Commun ; 15(1): 4755, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834568

ABSTRACT

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Macrophages , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Sphingosine , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Male , Macrophages/metabolism , Macrophages/drug effects , Humans , Mice , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Liver/metabolism , Liver/pathology , Liver/drug effects , Mice, Inbred C57BL , Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism , Aryl Hydrocarbon Receptor Nuclear Translocator/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Liver Cirrhosis/genetics , Disease Models, Animal
13.
Cancer Immunol Immunother ; 73(8): 158, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834790

ABSTRACT

BACKGROUND: The liver function reserve has a significant impact on the therapeutic effects of anti-programmed cell death-1 (PD-1) for hepatocellular carcinoma (HCC). This study aimed to comprehensively evaluate the ability of liver-function-based indicators to predict prognosis and construct a novel prognostic score for HCC patients with anti-PD-1 immunotherapy. METHODS: Between July 2018 and January 2020, patients diagnosed with HCC who received anti-PD-1 treatment were screened for inclusion in the study. The valuable prognostic liver-function-based indicators were selected using Cox proportional hazards regression analysis to build a novel liver-function-indicators-based signature (LFIS). Concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and Kaplan-Meier survival curves were utilized to access the predictive performance of LFIS. RESULTS: A total of 434 HCC patients who received anti-PD-1 treatment were included in the study. The LFIS, based on alkaline phosphatase-to-albumin ratio index, Child-Pugh score, platelet-albumin score, aspartate aminotransferase-to-lymphocyte ratio index, and gamma-glutamyl transpeptidase-to-lymphocyte ratio index, was constructed and identified as an independent risk factor for patient survival. The C-index of LFIS for overall survival (OS) was 0.692, which was higher than the other single liver-function-based indicator. The AUC of LFIS at 6-, 12-, 18-, and 24-month were 0.74, 0.714, 0.747, and 0.865 for OS, respectively. Patients in the higher-risk LFIS group were associated with both worse OS and PFS. An online and easy-to-use calculator was further constructed for better application of the LFIS signature. CONCLUSION: The LFIS score had an excellent prognosis prediction ability superior to every single liver-function-based indicator for anti-PD-1 treatment in HCC patients. It is a reliable, easy-to-use tool to stratify risk for OS and PFS in HCC patients who received anti-PD-1 treatment.


Subject(s)
Carcinoma, Hepatocellular , Immune Checkpoint Inhibitors , Liver Neoplasms , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Male , Female , Prognosis , Middle Aged , Immune Checkpoint Inhibitors/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Aged , Liver Function Tests/methods , Retrospective Studies , Survival Rate , Liver/pathology , Immunotherapy/methods , Biomarkers, Tumor , Adult
14.
Nat Commun ; 15(1): 4760, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38834654

ABSTRACT

Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuates older HIRI phenotypes. Mass spectrometry reveals that fat mass and obesity-associated gene (FTO) expression is downregulated in older livers, especially during HIRI. Overexpressing FTO improves older HIRI phenotypes by inhibiting ferroptosis. Mechanistically, acyl-CoA synthetase long chain family 4 (ACSL4) and transferrin receptor protein 1 (TFRC), two key positive contributors to ferroptosis, are FTO targets. For ameliorative effect, FTO requires the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrate nicotinamide mononucleotide can upregulate FTO demethylase activity, suppressing ferroptosis and decreasing older HIRI. Collectively, these findings reveal an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO to improve graft function after older donor liver transplantation.


Subject(s)
Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Coenzyme A Ligases , Ferroptosis , Liver , Receptors, Transferrin , Reperfusion Injury , Up-Regulation , Reperfusion Injury/metabolism , Reperfusion Injury/genetics , Reperfusion Injury/pathology , Animals , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Ferroptosis/genetics , Liver/metabolism , Liver/pathology , Mice , Receptors, Transferrin/metabolism , Receptors, Transferrin/genetics , Male , Coenzyme A Ligases/metabolism , Coenzyme A Ligases/genetics , Mice, Inbred C57BL , Humans , Liver Transplantation , RNA Stability/genetics , Antigens, CD
15.
Hepatol Commun ; 8(6)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38840336

ABSTRACT

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery. APPROACH AND RESULT: A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. "Loss-of-function" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-ß1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro. CONCLUSIONS: These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.


Subject(s)
Hepatic Stellate Cells , Liver , Receptors, Immunologic , Reperfusion Injury , Animals , Reperfusion Injury/metabolism , Reperfusion Injury/prevention & control , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , Receptors, Immunologic/deficiency , Mice , Hepatic Stellate Cells/metabolism , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Male , Mice, Knockout , Humans
16.
Sci Rep ; 14(1): 13315, 2024 06 10.
Article in English | MEDLINE | ID: mdl-38858439

ABSTRACT

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.


Subject(s)
Dietary Supplements , Radiation-Protective Agents , Animals , Radiation-Protective Agents/pharmacology , Vitamin E/pharmacology , Vitamin E/analogs & derivatives , Acute Radiation Syndrome/prevention & control , Acute Radiation Syndrome/drug therapy , Acute Radiation Syndrome/pathology , Chromans/pharmacology , Male , Radiation Injuries, Experimental/prevention & control , Radiation Injuries, Experimental/pathology , Macaca mulatta , Liver/drug effects , Liver/radiation effects , Liver/pathology
17.
BMJ Open Gastroenterol ; 11(1)2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844374

ABSTRACT

INTRODUCTION: The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been reported to decrease proinflammatory cytokine production and may have a potential role in treating NASH. We aimed to evaluate the efficacy and safety of misoprostol in treating patients with NASH. METHODS: In this phase 2, double-blind, randomised, placebo-controlled trial, patients with NASH were randomly assigned in a 1:1 ratio to receive 200 µg of misoprostol or placebo thrice daily for 2 months. The primary endpoint was an improvement in liver function tests (LFTs), interleukin-6 (IL-6) and endotoxin levels. The secondary endpoint was improvement in insulin resistance, dyslipidaemia, hepatic fibrosis and hepatic steatosis. RESULTS: A total of 50 patients underwent randomisation, of whom 44 (88%) were males. The age range was 25-64 years (mean±SE of mean (SEM) 38.1±1.4). 19 (38%) patients had concomitant type 2 diabetes mellitus. 32 (64%) patients were either overweight or obese. At the end of 2 months' treatment, a reduction in total leucocyte count (TLC) (p=0.005), alanine aminotransferase (ALT) (p<0.001), aspartate aminotransferase (AST) (p=0.002) and controlled attenuation parameter (CAP) (p=0.003) was observed in the misoprostol group, whereas placebo ensued a decline in ALT (p<0.001), AST (p=0.018), gamma-glutamyl transferase (GGT) (p=0.003), CAP (p=0.010) and triglycerides (p=0.048). There was no diminution in insulin resistance, hepatic fibrosis (elastography) and dyslipidaemia in both groups. However, misoprostol resulted in a significant reduction in CAP as compared with the placebo group (p=0.039). Moreover, in the misoprostol group, pretreatment and post-treatment IL-6 and endotoxin levels remained stable, while in the placebo group, an increase in the IL-6 levels was noted (p=0.049). Six (12%) patients had at least one adverse event in the misoprostol group, as did five (10%) in the placebo group. The most common adverse event in the misoprostol group was diarrhoea. No life-threatening events or treatment-related deaths occurred in each group. CONCLUSION: Improvement in the biochemical profile was seen in both misoprostol and placebo groups without any statistically significant difference. However, there was more improvement in steatosis, as depicted by CAP, in the misoprostol group and worsening of IL-6 levels in the placebo group. TRIAL REGISTRATION NUMBER: NCT05804305.


Subject(s)
Insulin Resistance , Interleukin-6 , Misoprostol , Non-alcoholic Fatty Liver Disease , Humans , Male , Female , Non-alcoholic Fatty Liver Disease/drug therapy , Middle Aged , Double-Blind Method , Adult , Misoprostol/administration & dosage , Misoprostol/therapeutic use , Misoprostol/adverse effects , Interleukin-6/blood , Treatment Outcome , Insulin Resistance/physiology , Liver Cirrhosis/drug therapy , Liver Function Tests/methods , Liver/drug effects , Liver/pathology , Liver/metabolism
18.
Sci Rep ; 14(1): 12922, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38839921

ABSTRACT

The incidence of non-alcoholic fatty liver disease (NAFLD) tends to be younger. And the role of theobromine in fatty liver disease remains unclear. The purpose of this study was to investigate the relationship between dietary theobromine intake and degree of hepatic steatosis in individuals aged 45 and below, using data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) and liver ultrasonography transient elastography. A total of 1796 participants aged below 45 years were included from NHANES 2017-2020 data after applying exclusion criteria. Multivariate regression and subgroup analyses were conducted to examine the associations between theobromine intake and controlled attenuation parameter (CAP), adjusting for potential confounders. Generalized additive models and two-piecewise linear regression were used to analyze nonlinear relationships. In the unadjusted Model 1 and preliminarily adjusted Model 2, there was no significant correlation between theobromine intake and CAP values. However, in Models 3 and 4, which accounted for confounding factors, a higher intake of theobromine was significantly associated with lower CAP values. Subgroup analyses in the fully adjusted Model 4 revealed a significant negative correlation among individuals aged 18-45, women, and white populations. Nonlinear analysis revealed a U-shaped relationship in black Americans, with the lowest CAP values at 44.5 mg/day theobromine. This study provides evidence that higher theobromine intake is correlated with lower degree of hepatic steatosis in young people, especially those aged 18-45 years, women, and whites. For black Americans, maintaining theobromine intake around 44.5 mg/day may help minimize liver steatosis. These findings may help personalize clinical nutritional guidance, prevent the degree of hepatic steatosis, and provide pharmacological approaches to reverse fatty liver disease in young people.


Subject(s)
Non-alcoholic Fatty Liver Disease , Nutrition Surveys , Theobromine , Humans , Theobromine/administration & dosage , Female , Male , Adult , Non-alcoholic Fatty Liver Disease/epidemiology , Adolescent , Young Adult , Middle Aged , Liver/diagnostic imaging , Liver/pathology , Elasticity Imaging Techniques , Fatty Liver/epidemiology , Fatty Liver/diagnostic imaging
19.
Transpl Int ; 37: 12787, 2024.
Article in English | MEDLINE | ID: mdl-38845758

ABSTRACT

Organ quality can be assessed prior to transplantation, during normothermic machine perfusion (NMP) of the liver. Evaluation of mitochondrial function by high-resolution respirometry (HRR) may serve as a viability assessment concept in this setting. Freshly collected tissue is considered as optimal sample for HRR, but due to technical and personnel requirements, more flexible and schedulable measurements are needed. However, the impact of cold storage following NMP before processing biopsy samples for mitochondrial analysis remains unknown. We aimed at establishing an appropriate storage protocol of liver biopsies for HRR. Wedge biopsies of 5 human livers during NMP were obtained and assessed by HRR. Analysis was performed after 0, 4, 8, and 12 h of hypothermic storage (HTS) in HTK organ preservation solution at 4°C. With HTS up to 4 h, mitochondrial performance did not decrease in HTS samples compared with 0 h (OXPHOS, 44.62 [34.75-60.15] pmol·s-1·mg wet mass-1 vs. 43.73 [40.69-57.71], median [IQR], p > 0.999). However, at HTS beyond 4 h, mitochondrial respiration decreased. We conclude that HTS can be safely applied for extending the biopsy measurement window for up to 4 h to determine organ quality, but also that human liver respiration degrades beyond 4 h HTS following NMP.


Subject(s)
Liver Transplantation , Liver , Organ Preservation , Perfusion , Humans , Organ Preservation/methods , Liver/pathology , Biopsy , Male , Middle Aged , Female , Mitochondria, Liver/metabolism , Organ Preservation Solutions , Aged , Cell Respiration , Adult
20.
J Obes ; 2024: 7204607, 2024.
Article in English | MEDLINE | ID: mdl-38831961

ABSTRACT

Obesity is a complex chronic disease characterized by excess body fat (adipose) that is harmful to health and has been a major global health problem. It may be associated with several diseases, such as nonalcoholic fatty liver disease (NAFLD). Polyunsaturated fatty acids (PUFA) are lipid mediators that have anti-inflammatory characteristics and can be found in animals and plants, with capybara oil (CO) being a promising source. So, we intend to evaluate the hepatic pathophysiological alterations in C57Bl/6 mice with NAFLD, caused by obesity, and the possible beneficial effects of OC in the treatment of this disease. Eighteen 3-month-old male C57Bl/6 mice received a control or high-fat diet for 18 weeks. From the 15th to the 18th week, the animals received treatment-through orogastric gavage-with placebo or free capybara oil (5 g/kg). Parameters inherent to body mass, glucose tolerance, evaluation of liver enzymes, percentage of hepatic steatosis, oxidative stress, the process of cell death with the apoptotic biomarkers (Bax, Bcl2, and Cytochrome C), and the ultrastructure of hepatocytes were analyzed. Even though the treatment with CO was not able to disassemble the effects on the physiological parameters, it proved to be beneficial in reversing the morphological and ultrastructural damage present in the hepatocytes. Thus, demonstrating that CO has beneficial effects in reducing steatosis and the apoptotic pathway, it is a promising treatment for NAFLD.


Subject(s)
Apoptosis , Liver , Non-alcoholic Fatty Liver Disease , Oils , Rodentia , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/therapy , Male , Animals , Mice , Hepatocytes/drug effects , Hepatocytes/pathology , Hepatocytes/ultrastructure , Oils/pharmacology , Oils/therapeutic use , Obesity/complications , Apoptosis/drug effects , Liver/drug effects , Liver/pathology , Liver/ultrastructure , Oxidoreductases/metabolism , Enzyme Activation/drug effects , Oxidative Stress/drug effects
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