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Schistosomiasis, a widespread neglected tropical disease, presents a complex and multifaceted clinical-pathological profile. Using hamsters as final hosts, we dissected molecular events following Schistosoma mansoni infection in the liver-the organ most severely affected in schistosomiasis patients. Employing tandem mass tag-based proteomics, we studied alterations in the liver proteins in response to various infection modes and genders. We examined livers from female and male hamsters that were: noninfected (control), infected with either unisexual S. mansoni cercariae (single-sex) or both sexes (bisex). The infection induced up-regulation of proteins associated with immune response, cytoskeletal reorganization, and apoptotic signaling. Notably, S. mansoni egg deposition led to the down-regulation of liver factors linked to energy supply and metabolic processes. Gender-specific responses were observed, with male hamsters showing higher susceptibility, supported by more differentially expressed proteins than found in females. Of note, metallothionein-2 and S100a6 proteins exhibited substantial up-regulation in livers of both genders, suggesting their pivotal roles in the liver's injury response. Immunohistochemistry and real-time-qPCR confirmed strong up-regulation of metallothionein-2 expression in the cytoplasm and nucleus upon the infection. Similar findings were seen for S100a6, which localized around granulomas and portal tracts. We also observed perturbations in metabolic pathways, including down-regulation of enzymes involved in xenobiotic biotransformation, cellular energy metabolism, and lipid modulation. Furthermore, lipidomic analyses through liquid chromatography-tandem mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry imaging identified extensive alterations, notably in cardiolipin and triacylglycerols, suggesting specific roles of lipids during pathogenesis. These findings provide unprecedented insights into the hepatic response to S. mansoni infection, shedding light on the complexity of liver pathology in this disease.
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Schistosomiasis is a neglected tropical disease caused by worm parasites of the genus Schistosoma. Upon infection, parasite eggs can lodge inside of host organs like the liver. This leads to granuloma formation, which is the main cause of the pathology of schistosomiasis. To better understand the different levels of host-pathogen interaction and pathology, our study focused on the characterization of glycosphingolipids (GSLs). For this purpose, GSLs in livers of infected and noninfected hamsters were studied by combining high-spatial-resolution atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) with nanoscale hydrophilic interaction liquid chromatography tandem mass spectrometry (nano-HILIC MS/MS). Nano-HILIC MS/MS revealed 60 GSL species with a distinct saccharide and ceramide composition. AP-SMALDI MSI measurements were conducted in positive- and negative-ion mode for the visualization of neutral and acidic GSLs. Based on nano-HILIC MS/MS results, we discovered no downregulated but 50 significantly upregulated GSLs in liver samples of infected hamsters. AP-SMALDI MSI showed that 44 of these GSL species were associated with the granulomas in the liver tissue. Our findings suggest an important role of GSLs during granuloma formation.
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Glicoesfingolípidos , Hígado , Schistosoma mansoni , Esquistosomiasis mansoni , Animales , Glicoesfingolípidos/metabolismo , Glicoesfingolípidos/química , Hígado/metabolismo , Hígado/parasitología , Cricetinae , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Mesocricetus , Cromatografía Liquida , MasculinoRESUMEN
BACKGROUND & AIMS: Schistosomiasis is one of the most prominent parasite-induced infectious diseases, affecting more than 250 million people. Schistosoma mansoni causes metabolic exhaustion and a strong redox imbalance in the liver, causing parenchymal damage, and may predispose for cancer. We investigated whether oxidative stress provokes hepatocellular proliferation upon S. mansoni infection. METHODS: The cell cycle, replication stress response, and proliferation were analyzed on transcriptional and protein levels in the livers of S. mansoni-infected hamsters and by mechanistic gain- and loss-of-function experiments in human hepatoma cells. Major results were validated in human biopsy specimens of S. mansoni-infected patients. RESULTS: S. mansoni infection induced licensing factors of DNA replication and cell-cycle checkpoint cyclins in parallel with a DNA damage response in hamster hepatocytes. Moreover, even unisexual infection without egg effects, as a reflection of a chronic inflammatory process, resulted in a moderate activation of several cell-cycle markers. S. mansoni soluble egg antigens induced proliferation of human hepatoma cells that could be abolished by reduced glutathione. CONCLUSIONS: Our data suggest that hepatocellular proliferation is triggered by S. mansoni egg-induced oxidative stress.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Esquistosomiasis mansoni , Cricetinae , Animales , Humanos , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/metabolismo , Estrés Oxidativo , Proliferación CelularRESUMEN
Schistosomiasis is a parasitic disease affecting more than 250 million people worldwide. The transcription factor c-Jun, which is induced in S. mansoni infection-associated liver disease, can promote hepatocyte survival but can also trigger hepatocellular carcinogenesis. We aimed to analyze the hepatic role of c-Jun following S. mansoni infection. We adopted a hepatocyte-specific c-Jun knockout mouse model (Alb-Cre/c-Jun loxP) and analyzed liver tissue and serum samples by quantitative real-time PCR array, western blotting, immunohistochemistry, hydroxyproline quantification, and functional analyses. Hepatocyte-specific c-Jun knockout (c-JunΔli) was confirmed by immunohistochemistry and western blotting. Infection with S. mansoni induced elevated aminotransferase-serum levels in c-JunΔli mice. Of note, hepatic Cyclin D1 expression was induced in infected c-Junf/f control mice but to a lower extent in c-JunΔli mice. S. mansoni soluble egg antigen-induced proliferation in a human hepatoma cell line was diminished by inhibition of c-Jun signaling. Markers for apoptosis, oxidative stress, ER stress, inflammation, autophagy, DNA-damage, and fibrosis were not altered in S. mansoni infected c-JunΔli mice compared to infected c-Junf/f controls. Enhanced liver damage in c-JunΔli mice suggested a protective role of c-Jun. A reduced Cyclin D1 expression and reduced hepatic regeneration could be the reason. In addition, it seems likely that the trends in pathological changes in c-JunΔli mice cumulatively led to a loss of the protective potential being responsible for the increased hepatocyte damage and loss of regenerative ability.
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Schistosoma mansoni , Esquistosomiasis mansoni , Humanos , Ratones , Animales , Ciclina D1/metabolismo , Esquistosomiasis mansoni/parasitología , Hígado/metabolismo , Hepatocitos/metabolismo , Proliferación CelularRESUMEN
The liver, as a central metabolic organ, is systemically linked to metabolic-inflammatory diseases. In the pathogenesis of the metabolic syndrome, inflammatory and metabolic interactions between the intestine, liver, and adipose tissue lead to the progression of hepatic steatosis to metabolic-dysfunction-associated steatohepatitis (MASH) and consecutive MASH-induced fibrosis. Clinical and animal studies revealed that IL-13 might be protective in the development of MASH through both the preservation of metabolic functions and Th2-polarized inflammation in the liver and the adipose tissue. In contrast, IL-13-associated loss of mucosal gut barrier function and IL-13-associated enhanced hepatic fibrosis may contribute to the progression of MASH. However, there are only a few publications on the effect of IL-13 on metabolic diseases and possible therapies to influence them. In this review article, different aspects of IL-13-associated effects on the liver and metabolic liver diseases, which are partly contradictory, are summarized and discussed on the basis of the recent literature.
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Hígado Graso , Interleucina-13 , Animales , Citocinas , Cirrosis Hepática , Cicatrización de Heridas , HumanosRESUMEN
Gastrointestinal (GI) bleeding is one of the most common complications associated with the use of direct oral anticoagulants (DOAC). Clear algorithms exist for the emergency measures in (suspected) GI bleeding, including assessing the medication history regarding anti-platelet drugs and anticoagulants as well as simple coagulation tests during pre-endoscopic management. Platelet transfusions, fresh frozen plasma (FFP), or prothrombin complex concentrate (4F-PCC) are commonly used for optimizing the coagulation status. For severe bleeding under the thrombin inhibitor dabigatran, idarucizumab is available, and for bleeding under the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa is available as specific antidotes for DOAC antagonization. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures including emergency endoscopy. Antagonization of oral anticoagulants should be considered for severe gastrointestinal bleeding in the following situations: (1) refractory hemorrhagic shock, (2) endoscopically unstoppable bleeding, or (3) nonavoidable delays until emergency endoscopy for life-threatening bleeding. After successful (endoscopic) hemostasis, anticoagulation (DOACs, vitamin K antagonist, heparin) should be resumed timely (i.e. usually within a week), taking into account individual bleeding and thromboembolic risk.
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Drug-induced toxic hepatopathies and drug-induced liver injury, DILI, are characterized by a variety of clinical manifestations and therefore represent a significant diagnostic challenge. This article shows how DILI is diagnosed and what therapy options exist. Current special cases of DILI genesis are also discussed (DOACs, IBD drugs, tyrosine kinase inhibitors). These newer substances and corresponding hepatotoxic effects are not yet fully understood. The internationally recognized and online available RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the probability of drug-related toxic liver damage.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Factores de RiesgoRESUMEN
Chronic hepatitis B virus (HBV) infection is a global health threat. Mutations in the surface antigen of HBV (HBsAg) may alter its antigenicity, infectivity, and transmissibility. A patient positive for HBV DNA and detectable but low-level HBsAg in parallel with anti-HBs suggested the presence of immune and/or diagnostic escape variants. To support this hypothesis, serum-derived HBs gene sequences were amplified and cloned for sequencing, which revealed infection with exclusively non-wildtype HBV subgenotype (sgt) D3. Three distinct mutations in the antigenic loop of HBsAg that caused additional N-glycosylation were found in the variant sequences, including a previously undescribed six-nucleotide insertion. Cellular and secreted HBsAg was analyzed for N-glycosylation in Western blot after expression in human hepatoma cells. Secreted HBsAg was also subjected to four widely used, state-of-the-art diagnostic assays, which all failed to detect the hyperglycosylated insertion variant. Additionally, the recognition of mutant HBsAg by vaccine- and natural infection-induced anti-HBs antibodies was severely impaired. Taken together, these data suggest that the novel six-nucleotide insertion as well as two other previously described mutations causing hyperglycosylation in combination with immune escape mutations have a critical impact on in vitro diagnostics and likely increase the risk of breakthrough infection by evasion of vaccine-induced immunity.
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Hepatitis B Crónica , Hepatitis B , Humanos , Virus de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/genética , Anticuerpos contra la Hepatitis B , Vacunas contra Hepatitis B , Mutación , Factores Inmunológicos , Nucleótidos , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects more than 18 million individuals in Germany. Real-world data help to better characterize the natural history of disease and standard of care. METHODS: The German NAFLD-Registry is a prospective non-interventional study initiated by the German Liver Foundation and aims to describe clinical characteristics and observe outcomes in patients with NAFLD recruited in secondary and tertiary care. RESULTS: From this ongoing study, baseline data of the first 501 patients (mean age 54 years, 48% women) were analysed. 13 % of the study population had a high risk for advanced fibrosis (FIB-4 ≥2.67), approximately one-third had a liver stiffness value ≥9.6kPa measured by transient elastography, and the clinical diagnosis of liver cirrhosis was present in 10%. Typical comorbidities were more prevalent in high risk as compared to low risk patients (FIB-4 <1.3) including arterial hypertension (85 vs. 42%), hypercholesterolemia (39 vs. 16%), and type 2 diabetes mellitus (T2DM) (69 vs. 26%). Patients with T2DM (192/501) had a higher NAFLD disease burden as shown by liver stiffness values ≥9.6 kPa (51%) and clinical diagnosis of cirrhosis (20%). Statins were used in 22% of the main population, while in diabetic patients, metformin, GLP-1 agonists, and SGLT2 inhibitors were used in 65, 17, and 17%, respectively. Uptake of life-style interventions such as physical exercise or nutritional counselling was generally low. CONCLUSION: First data of the German NAFLD registry show that approximately every 10th patient has advanced NAFLD, highlights T2DM patients as a high-risk group and gives insights in the use of comedication and life-style interventions in secondary and tertiary care.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Persona de Mediana Edad , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/terapia , Diabetes Mellitus Tipo 2/epidemiología , Factores de Riesgo , Estudios Prospectivos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/complicaciones , Alemania/epidemiología , Sistema de RegistrosRESUMEN
Background & Aims: Schistosomiasis is a parasitic infection which affects more than 200 million people globally. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma. Methods: Metabolic reprogramming was analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging, liquid chromatography with high-resolution mass spectrometry, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies. Results: The infection with S. mansoni provokes hepatic exhaustion of neutral lipids and glycogen. Furthermore, the distribution of distinct lipid species and the regulation of rate-limiting metabolic enzymes is disrupted in the liver of S. mansoni infected animals. Notably, eggs mobilize, incorporate, and store host lipids, while the associated metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of reactive oxygen species scavengers ameliorates these deleterious effects. Conclusions: Our findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism via soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma. Impact and implications: The authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming, causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host's immune response. S. mansoni eggs take advantage of the host environment through metabolic reprogramming of hepatocytes and enterocytes. By inducing DNA damage, this neglected tropical disease might promote hepatocellular damage and thus influence international health efforts.
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Nonalcoholic fatty liver disease (NAFLD) is nowadays the leading cause of chronic liver disease worldwide and shows a strong association with the metabolic syndrome. The NAFLD is a systemic disease associated with a plethora of extrahepatic manifestations and comorbidities, such as type 2 diabetes, obesity and dyslipidemia. These extrahepatic disorders are related either to secondary effects of the associated obesity or to pathophysiological effects of insulin resistance in NAFLD. The three most common causes of the observed increased morbidity and mortality associated with NAFLD are cardiovascular diseases, liver diseases, such as cirrhosis, and cancer. In this overview, cardiovascular diseases, type 2 diabetes mellitus and chronic kidney diseases in connection with NAFLD are discussed as examples, as well as tumor entities, in particular colon cancer, lung diseases (obstructive sleep apnea), endocrine diseases (hypothyroidism) and systemic phenomena associated with NAFLD (e.g. iron overload and thrombophilia). In addition to focusing on the pathogenesis of these extrahepatic manifestations, the clinical implications are highlighted. So far there are no drugs approved for the indication NAFLD in Germany. The new NAFLD S2k guidelines offer a way out of the current "therapeutic nihilism". Diagnostic and therapeutic algorithms based on the metabolic comorbidities and the stage of fibrosis are designed with practical relevance and can be used in everyday medical practice. Therefore, clear basic measures and drug recommendations can be given for NAFLD depending on the comorbidities and stage of fibrosis.