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The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis.
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BACKGROUND AND OBJECTIVES: In Japan, cord blood transplantations exceed those done with adult-sourced unrelated stem cells. This study analyses cord blood (CB) storage criteria to maintain high-quality CB units. MATERIALS AND METHODS: The Kanto-Koshinetsu Cord Blood Bank received 29,795 units from 2014 to 2021, mostly >60 mL, and 5486 (18.4%) were stored as transplantable units. We investigated the mother's gestational period, CB volume, total nucleated cells (TNCs), CD34+ cells, total colony-forming units (CFUs), time from collection to reception and cryopreservation, cell viability, and the reasons for not storing a unit. RESULTS: The average time from collection to reception of 29,795 units was 18.0 h. The most common reason for not storing a CB unit was low cell numbers (pre-processing TNC count <1.2 billion), accounting for 67.9% of the units received. There was no correlation between the CB volume and the CD34+ cell count. The shorter the gestational period, the lower the TNC count, but the higher the CD34+ cell count. There was no correlation between the time from collection to cryopreservation, within a 36-h time limit, and the CD34+ cell recovery rate. CONCLUSION: We could accept units with a TNC count <1.2 billion and a CB volume <60 mL from a gestational period of 38 weeks or less if we did a pre-processing CD34+ cell count. This would secure more units rich in CD34+ cells.
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Bancos de Sangre , Conservación de la Sangre , Criopreservación , Sangre Fetal , Humanos , Sangre Fetal/citología , Japón , Bancos de Sangre/normas , Conservación de la Sangre/métodos , Femenino , Trasplante de Células Madre de Sangre del Cordón Umbilical , Antígenos CD34 , Embarazo , MasculinoRESUMEN
Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
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Ferroptosis , Hepatopatías , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Ratones , Animales , Humanos , Diclorhidrato de trans-1,4-Bis(2-clorobenzaminometil)ciclohexano , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismoRESUMEN
Originally, apomorphine was a broad-spectrum dopamine agonist with an affinity for all subtypes of the Dopamine D1 receptor to the D5 receptor. We previously identified apomorphine as a potential therapeutic agent for mitochondrial diseases by screening a chemical library of fibroblasts from patients with mitochondrial diseases. In this study, we showed that apomorphine prevented ferroptosis in fibroblasts from various types of mitochondrial diseases as well as in normal controls. Well-known biomarkers of ferroptosis include protein markers such as prostaglandin endoperoxide synthase 2 (PTGS2), a key gene for ferroptosis-related inflammation PTGS2, lipid peroxidation, and reactive oxygen species. Our findings that apomorphine induced significant downregulation of PTSG2 and suppressed lipid peroxide to the same extent as other inhibitors of ferroptosis also indicate that apomorphine suppresses ferroptosis. To our knowledge, this is the first study to report that the anti-ferroptosis effect of apomorphine is not related to dopamine receptor agonist action and that apomorphine is a potent inhibitor of ferroptotic cell death independent of dopaminergic receptors.
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Ferroptosis , Enfermedades Mitocondriales , Humanos , Apomorfina/farmacología , Ciclooxigenasa 2/genética , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologíaRESUMEN
Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.
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Ferroptosis , Ferroptosis/genética , NAD , Mutación , Mutagénesis , Sitios de Unión , ProtonesRESUMEN
Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1ß and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1ß, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1ß-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1ß-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1ß and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.
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Cardiomiopatías , Inflamasomas , Interleucina-18 , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Cardiomiopatías/genética , Caspasa 1/genética , Caspasa 1/metabolismo , Citocinas , Inflamasomas/metabolismo , Inflamación , Interleucina-18/genética , Interleucina-1beta/metabolismo , Lipopolisacáridos/efectos adversos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
Rhabdomyolysis is a severe condition that commonly leads to acute kidney injury (AKI). While double-stranded DNA (dsDNA) released from injured muscle can be involved in its pathogenesis, the exact mechanism of how dsDNA contributes to rhabdomyolysis-induced AKI (RIAKI) remains obscure. A dsDNA sensor, absent in melanoma 2 (AIM2), forms an inflammasome and induces gasdermin D (GSDMD) cleavage resulting in inflammatory cell death known as pyroptosis. In this study using a mouse model of RIAKI, we found that Aim2-deficiency led to massive macrophage accumulation resulting in delayed functional recovery and perpetuating fibrosis in the kidney. While Aim2-deficiency compromised RIAKI-induced kidney macrophage pyroptosis, it unexpectedly accelerated aberrant inflammation as demonstrated by CXCR3+CD206+ macrophage accumulation and activation of TBK1-IRF3/NF-κB. Kidney macrophages with intact AIM2 underwent swift pyroptosis without IL-1ß release in response to dsDNA. On the other hand, dsDNA-induced Aim2-deficient macrophages escaped from swift pyroptotic elimination and instead engaged STING-TBK1-IRF3/NF-κB signalling, leading to aggravated inflammatory phenotypes. Collectively, these findings shed light on a hitherto unknown immunoregulatory function of macrophage pyroptosis. dsDNA-induced rapid macrophage cell death potentially serves as an anti-inflammatory program and determines the healing process of RIAKI.
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Lesión Renal Aguda , Proteínas de Unión al ADN , Rabdomiólisis , Humanos , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , ADN , Proteínas de Unión al ADN/metabolismo , Inflamasomas/metabolismo , Inflamación , FN-kappa B , Piroptosis/genética , Rabdomiólisis/complicacionesRESUMEN
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome, the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1ß. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1ß release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.
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Síndromes Periódicos Asociados a Criopirina , Proteínas Portadoras/genética , Caspasa 1/genética , Síndromes Periódicos Asociados a Criopirina/genética , Humanos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
BACKGROUND There is no consensus about the long-term prognosis of pediatric patients with a variety of rare liver diseases but with inherited metabolic diseases (IMDs). We retrospectively reviewed the developmental outcomes of patients with IMDs undergoing living donor liver transplantation (LDLT). MATERIAL AND METHODS Between May 2001 and December 2020, of 314 pediatric patients who underwent LDLT, 44 (14%) had IMDs. The median age at LDLT was 3.0 years old (range 0-15.0 years). Associations between the post-transplant complications and graft survival rate in patients with IMDs and biliary atresia (BA) were calculated. We evaluated the safety of LDLT from heterozygous carrier donors, the prognosis of patients with IMDs who have metabolic defects expressed in other organs, and developmental outcomes of patients with IMDs. RESULTS The 10-year graft survival rates in patients with IMDs and BA were 87% and 94%, respectively (P=0.041), and the causes of graft failure included pneumocystis pneumonia, acute lung failure, hemophagocytic syndrome, hepatic vein thrombosis, portal vein thrombosis, and sepsis. The rate of post-transplant cytomegalovirus viremia in patients with IMDs was higher than that of patients with BA (P=0.039). Of 39 patients with IMDs, 15 patients (38%) had severe motor and intellectual disabilities in 4 patients, intellectual developmental disorders including epilepsy in 2, and attention-deficit hyperactivity disorder in 2. Of 28 patients with IMDs, 13 (46%) needed special education. CONCLUSIONS The long-term outcomes of LDLT in patients with IMDs are good. However, further long-term social and educational follow-up regarding intellectual developmental disorders is needed.
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Trasplante de Hígado , Donadores Vivos , Enfermedades Metabólicas , Adolescente , Niño , Preescolar , Femenino , Supervivencia de Injerto , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/genética , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Calciprotein particles (CPPs) are nanoparticles composed of calcium phosphate crystals and fetuin-A and have been implicated in diseases associated with inflammation. In the current study, we investigated the molecular mechanisms underlying CPP-induced inflammation in mice. CPPs predominantly upregulated IL-1ß and IL-1α and provided priming and activation signals for the NLRP3 inflammasome in murine macrophages. Pharmacological and genetic inhibition of the NLRP3 inflammasome revealed that CPPs induced the release of IL-1ß and IL-1α via NLRP3 inflammasome-dependent and -independent mechanisms, respectively. CPPs also induced necrotic cell death, but gasdermin D was dispensable for CPP-induced IL-1ß release and necrotic cell death. Although phagocytosis of CPPs was required for CPP-induced IL-1ß/α release and necrotic cell death, lysosomal dysfunction and K+ efflux were mainly involved in CPP-induced NLRP3 inflammasome activation and subsequent IL-1ß release but not in CPP-induced IL-1α release and necrotic cell death. In vivo experiments showed that CPP administration evoked acute inflammatory responses characterized by neutrophil accumulation via both IL-1ß and IL-1α. In particular, CPP-induced neutrophil inflammation was mediated predominantly through an IL-1α-induced CXCL1/CXCR2 signaling pathway. These results provide new insights into the mechanism underlying CPP-induced inflammation and suggest that targeting both IL-1ß and IL-1α is necessary to regulate the CPP-induced inflammatory response and to treat CPP-associated inflammatory disorders.
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Fosfatos de Calcio/inmunología , Inflamación/inmunología , alfa-2-Glicoproteína-HS/inmunología , Animales , Fosfatos de Calcio/química , Línea Celular , Modelos Animales de Enfermedad , Humanos , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fagocitosis/inmunología , Transducción de Señal/inmunología , alfa-2-Glicoproteína-HS/químicaRESUMEN
BACKGROUND: Complications associated with ultrasonographically guided percutaneous transhepatic liver biopsy (PTLB) after liver transplantation (LT) have been rarely reported, and there is no consensus about its safety. We retrospectively reviewed the safety and outcomes of PTLB after pediatric LT. METHODS: Between January 2008 and December 2019, 8/1122 (0.71%) pediatric patients who underwent ultrasonographically guided PTLB after LT developed complications. The median age at PTLB was 7.8 years (range 0.1-17.9). Grafts included left lobe/left lateral segment in 1050 patients and others in 72. PTLB was performed using local anesthesia±sedation in 1028 patients and general anesthesia in 94. RESULTS: Complications after PTLB included acute cholangitis in 3 patients, sepsis in 2, respiratory failure due to over-sedation in 1, subcapsular hematoma in 1, and intrahepatic arterioportal fistula in 1. The incidence of complications of PTLB in patients with biopsy alone and those with simultaneous interventions was 0.49% and 3.19%, respectively (p = .023). Patients who developed acute cholangitis, respiratory failure, subcapsular hematoma, and arterioportal fistula improved with non-operative management. Of two patients with sepsis, one underwent PTLB and percutaneous transhepatic portal vein balloon dilatation and developed fever and seizures the following day. Sepsis was treated with antibiotic therapy. Another patient who underwent PTLB and exchange of percutaneous transhepatic biliary drainage catheter developed fever and impaired consciousness immediately. Sepsis was treated with antibiotic therapy, mechanical ventilation, and continuous hemofiltration. CONCLUSIONS: Percutaneous transhepatic liver biopsy after pediatric LT is safe. However, combining liver biopsy with simultaneous procedures for vascular and biliary complications is associated with an increased risk of complications.
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Trasplante de Hígado , Hígado/patología , Complicaciones Posoperatorias/patología , Ultrasonografía Intervencional , Adolescente , Niño , Preescolar , Femenino , Humanos , Biopsia Guiada por Imagen/efectos adversos , Biopsia Guiada por Imagen/instrumentación , Biopsia Guiada por Imagen/métodos , Lactante , Hígado/diagnóstico por imagen , Masculino , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Ultrasonografía Intervencional/efectos adversos , Ultrasonografía Intervencional/instrumentación , Ultrasonografía Intervencional/métodosRESUMEN
OBJECTIVES: Predicting the risk of posthepatectomy liver failure is important when performing extended hepatectomy. However, there is no established method to evaluate liver function and improve preoperative liver function in pediatric patients. MATERIALS AND METHODS: We show the clinical features of pediatric patients who underwent living donor liver transplant for posthepatectomy liver failure in hepatoblastoma. The subjects were 4 patients with hepatoblastoma who were classified as Pretreatment Extent of Disease III, 2 of whom had distal metastasis (chest wall and lung). RESULTS: Hepatic right trisegmentectomy was performed in 3 patients and extended left hepatectomy in 1 patient. The median alpha-fetoprotein level at the diagnosis of hepatoblastoma was 986300 ng/mL (range, 22500-2726350 ng/mL), and the median alpha-fetoprotein level before hepatectomy was 8489 ng/mL (range, 23-22500 ng/mL). The remnant liver volume after hepatectomy was 33.3% (range, 20% to 34.9%). Four patients had cholangitis after hepatectomy and progressed to posthepatectomy liver failure. The peak serum total bilirubin after hepatectomy was 11.4 mg/dL (range, 8.7-14.6 mg/dL). Living donor liver transplant was performed for these 4 patients with posthepatectomy liver failure, and they did not have a recurrence. CONCLUSIONS: When the predictive remnant liver volume by computed tomography-volumetry before extended hepatectomy for patients with hepatoblastoma is less than 40%, the possibility of posthepatectomy liver failure should be recognized.
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Hepatectomía/efectos adversos , Hepatoblastoma/cirugía , Fallo Hepático/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Factores de Edad , Niño , Preescolar , Femenino , Hepatoblastoma/diagnóstico por imagen , Hepatoblastoma/secundario , Humanos , Lactante , Japón , Fallo Hepático/diagnóstico , Fallo Hepático/etiología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Masculino , Reoperación , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Platelets are critical mediators of vascular homeostasis and thrombosis, and also contribute to the development of inflammation. NLRP3 inflammasome is a cytosolic multi-protein complex that consists of NLRP3, ASC and caspase-1, and regulates IL-1ß-mediated inflammation. METHOD AND RESULTS: Using two mouse models of thrombosis (i.e., occlusion of the middle cerebral artery and inferior vena cava), we found that thrombus formation was significantly enhanced in ASC-deficient (ASC-/-) mice, compared to that in wild-type (WT) and IL-1ß-/- mice. ASC deficiency had no effects on blood coagulation parameters (i.e., prothrombin time [PT] and activated partial thromboplastin time [APTT]). Platelets from WT mice express ASC, but neither NLRP3 nor caspase-1. ASC deficiency significantly enhanced the expression of P-selectin and GPIIb/IIIa in response to a GPVI agonist (collagen-related peptide [CRP]), but not to thrombin, in platelets. CRP induced ASC speck formation in WT platelets. ASC deficiency also enhanced cytosolic Ca2+ elevation and phosphorylation of ERK1/2 and Akt in platelets. CONCLUSION: Our results demonstrate that ASC negatively regulates GPVI signaling in platelets and enhances thrombus formation, independent of NLRP3 inflammasome and IL-1ß, and provide novel insights into the link between inflammation and thrombosis.
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Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Activación Plaquetaria , Trombosis/metabolismo , Trombosis/patología , Animales , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/metabolismo , Calcio/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1ß, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1ß prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1ß is a novel potential target for treating and preventing this disorder.
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Lesión Pulmonar Aguda/metabolismo , Células Endoteliales/metabolismo , Inflamasomas/metabolismo , Pulmón/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/metabolismo , Animales , Caspasa 1/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: There have been no reports on the effectiveness of the administration of antithrombin III (AT III) for post-transplant portal vein thrombosis (PVT). We herein report a case of post-transplant PVT that was resolved by AT III treatment after living donor liver transplantation (LDLT). CASE PRESENTATION: The patient was a 57-year-old man who had been diagnosed with decompensate liver cirrhosis by hepatitis C virus infection. He presented with repeated hepatic coma and refractory ascites. Computed tomography (CT) revealed PVT of Yerdel classification grade II before LDLT. He underwent ABO-identical LDLT using a right lobe graft. A liver function test revealed elevated liver enzyme levels on post-operative day (POD) 14. The CT examination on POD 15 revealed PVT in the left side of the main portal vein at the side of left gastric vein ligation. AT III treatment from POD 15 to POD 24 was performed. Magnetic resonance imaging revealed that the PVT had decreased 10% on POD 27. Furthermore, AT III treatment from POD 28 to POD 32 was performed. The CT examination demonstrated the disappearance of PVT on POD 69 and thereafter, he had no recurrence of PVT on 10 post-operative month (POM). CONCLUSIONS: The present case suggests that the administration of AT III is safe and suitable for the treatment of post-transplant PVT.
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BACKGROUND The number of pregnancies after liver transplantation (LT) is increasing; however, the safety and incidence of complications associated with these pregnancies are still unclear. In this report, we retrospectively assessed the influences and problems associated with post-transplant pregnancy on allografts, recipients, and fetuses. MATERIAL AND METHODS A total of 14 pregnancies were identified in 8 female recipients between 2005 and 2018. The original disease was biliary atresia in all recipients. We provide a basic guide for the management of planned pregnancies in female recipients. RESULTS Of the 7 planned pregnancies, no recipients took mycophenolate mofetil (MMF) or had allograft liver dysfunction. Among the 7 unplanned conceptions, we judged that the pregnancy was inadequate to continue in 4 recipients due to taking MMF and 2 recipients due to allograft liver dysfunction at conception. However, 4 recipients who immediately stopped taking MMF continued with their pregnancies. Ten pregnancies resulted in live 11 births. Among obstetric complications or fetal and neonatal complications, gestational diabetes mellitus in 3 recipients was the most common. There were 3 miscarriages and 1 planned termination because of MMF medication and liver dysfunction. CONCLUSIONS Planned pregnancies in LT recipients can lead to the birth of a healthy baby and no influence on either the allograft or the recipient. However, unplanned pregnancies in LT recipients, such as recipients who take MMF or have allograft liver dysfunction, may have an adverse influence on the fetus.
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Atresia Biliar/cirugía , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Prednisolona/uso terapéutico , Tacrolimus/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Japón , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Adulto JovenRESUMEN
Pyroptosis is a form of regulated cell death that is characterized by gasdermin processing and increased membrane permeability. Caspase-1 and caspase-11 have been considered to be essential for gasdermin D processing associated with inflammasome activation. In the present study, we found that NLRP3 inflammasome activation induces delayed necrotic cell death via ASC in caspase-1/11-deficient macrophages. Furthermore, ASC-mediated caspase-8 activation and subsequent gasdermin E processing are necessary for caspase-1-independent necrotic cell death. We define this necrotic cell death as incomplete pyroptosis because IL-1ß release, a key feature of pyroptosis, is absent, whereas IL-1α release is induced. Notably, unprocessed pro-IL-1ß forms a molecular complex to be retained inside pyroptotic cells. Moreover, incomplete pyroptosis accompanied by IL-1α release is observed under the pharmacological inhibition of caspase-1 with VX765. These findings suggest that caspase-1 inhibition during NLRP3 inflammasome activation modulates forms of cell death and permits the release of IL-1α from dying cells.
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Acetaminofén/toxicidad , Analgésicos no Narcóticos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ferroptosis/efectos de los fármacos , Hígado/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Dilatación Mitocondrial/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/ultraestructura , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/ultraestructura , Factores de TiempoRESUMEN
Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.