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BACKGROUND: Interventional therapy, in conjunction with tyrosine kinase inhibitors (TKIs), has shown promising outcomes for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). With the advent of immunotherapy, the combined use of immune checkpoint inhibitors (ICIs) has attracted great attention due to their potential effectiveness in advanced HCC. This study aims to compare the efficacy and safety of a triple therapy regimen (Interventional therapy, TKIs and ICIs, IT-TKI-ICI) with a dual therapy regimen (Interventional therapy and TKIs, IT-TKI) in the treatment of HCC and PVTT (HCC-PVTT). METHODS: A comprehensive search was carried out in PubMed, Web of Science, Embase, Scopus, and the Cochrane Library databases. Primary outcome measures were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response rate, adverse event incidence as well as downstaging surgery rate. Statistical analysis was conducted using Revman 5.4 software. RESULTS: The meta-analysis finally included 6 cohort studies. The triple therapy group demonstrated significantly prolonged OS and PFS compared to the dual therapy group. Meanwhile, the former exhibited significantly higher rates of objective response rate (ORR), disease control rate (DCR) and better downstaging effects with a higher salvage surgery rate without significantly increasing adverse events. CONCLUSION: In comparison to dual therapy, the triple therapy with interventional therapy, TKIs, and ICIs demonstrates superior efficacy and equivalent safety for HCC-PVTT.
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Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet ß-cells. Several factors contribute to ß-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated ß-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated ß-cell loss.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Ratones , Animales , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Polipéptido Amiloide de los Islotes Pancreáticos/química , Amiloide/química , Péptidos beta-AmiloidesRESUMEN
Background: Recent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links. Methods: Summary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations. Results: Our analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales (P =0.04), Enterobacteriaceae (P =0.04), Lachnospiraceae UCG-004 (P =0.02), and Prevotella9 (P =0.04) and increased risk of NAFLD. Dorea (P =0.03) and Veillonella (P =0.04) could increase the risks of NASH while Oscillospira (P =0.04) and Ruminococcaceae UCG-013 (P=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in Holdemania (P =0.007) and Ruminococcus2 (P =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH. Conclusion: This study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.
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Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Microbioma Gastrointestinal/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Clostridiaceae , ClostridialesRESUMEN
Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.
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Liver abscesses caused by Clostridium perfringens are rare but rapidly fatal. In only a few days, patients progress from liver abscess to sepsis, intravascular hemolysis, multiple organ failure, and even death. These abscesses often occur in patients after trauma or surgery or in those with immunodeficiency. Because patients only show non-specific symptoms such as fever and abdominal pain in the early stage, they can easily be misdiagnosed and miss the therapeutic window, resulting in a poor prognosis. The diagnosis of Clostridium perfringens liver abscess mainly depends on computed tomography (CT), needle aspiration, and/or blood culture. After diagnosis, treatments such as antibiotic therapy, surgical abscess drainage, blood transfusion as needed, and correction of metabolic disturbances must be immediately administered to prevent severe complications. Here, we present two cases of liver abscess due to Clostridium perfringens infection. Both patients initially presented only with fever, abdominal pain, and jaundice, symptoms that were easily confused with cholangitis caused by cholelithiasis. The patients then progressed rapidly and, despite receiving antimicrobial and multimodal sepsis treatment, both eventually died of multiple organ dysfunction syndrome. Clinicians should be on high alert for Clostridium perfringens liver abscesses disguised as biliary disease. Early diagnosis and treatment with the appropriate antibiotics and surgery are fundamental for the survival of the affected patients.
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Uropathogenic Escherichia coli account for the largest proportion of nosocomial infections in the United States. Nosocomial infections are a major source of increased costs and treatment complications. Many infections are biofilm associated, rendering antibiotic treatments ineffective or cause additional complications (e.g., microbiome depletion). This work presents a potentially complementary non-antibiotic strategy to fight nosocomial infections by inhibiting the formation of amyloid fibrils, a proteinaceous structural reinforcement known as curli in E. coli biofilms. Despite extensive characterization of the fibrils themselves and their associated secretion system, mechanistic details of curli assembly in vivo remain unclear. We hypothesized that, like other amyloid fibrils, curli polymerization involves a unique secondary structure termed "α-sheet". Biophysical studies herein confirmed the presence of α-sheet structure in prefibrillar species of CsgA, the major component of curli, as it aggregated. Binding of synthetic α-sheet peptides to the soluble α-sheet prefibrillar species inhibited CsgA aggregation in vitro and suppressed amyloid fibril formation in biofilms. Application of synthetic α-sheet peptides also enhanced antibiotic susceptibility and dispersed biofilm-resident bacteria for improved uptake by phagocytic cells. The ability of synthetic α-sheet peptides to reduce biofilm formation, improve antibiotic susceptibility, and enhance clearance by macrophages has broad implications for combating biofilm-associated infections.
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Proteínas de Escherichia coli , Escherichia coli Uropatógena , Escherichia coli Uropatógena/metabolismo , Proteínas de Escherichia coli/metabolismo , Amiloide/metabolismo , Biopelículas , Péptidos/química , Proteínas Bacterianas/metabolismoRESUMEN
Borderline resectable pancreatic cancer (BRPC) is a complex clinical entity with specific biological features. Criteria for resectability need to be assessed in combination with tumor anatomy and oncology. Neoadjuvant therapy (NAT) for BRPC patients is associated with additional survival benefits. Research is currently focused on exploring the optimal NAT regimen and more reliable ways of assessing response to NAT. More attention to management standards during NAT, including biliary drainage and nutritional support, is needed. Surgery remains the cornerstone of BRPC treatment and multidisciplinary teams can help to evaluate whether patients are suitable for surgery and provide individualized management during the perioperative period, including NAT responsiveness and the selection of surgical timing.
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Neoadjuvant therapy (NAT) for pancreatic cancer (PC) has achieved certain results. This article was aimed to analyze the trends in NAT in PC over the past 20 years using bibliometric analysis and visualization tools to guide researchers in exploring future research hotspots. Articles related to NAT for PC were retrieved from the Web of Science Core Collection for the period 2002-2021. The information was analyzed and visualized using VOSviewer, Citespace, Microsoft Excel and R software. The number of articles per year has continued to increase over the past 20 years. Of the 1,598 eligible articles, the highest number was from the United States (760), and an analysis of institutions indicated that the University of Texas System (150) had the highest number of articles. Matthew H. G. Katz had the highest number of citations and the highest H-index. "Pancreatic cancer" (981), "Resection" (623), "Cancer" (553), "Neoadjuvant therapy" (509) and "Survival" (484) were the top five ranked keywords. Combined with the keywords-cluster analysis and citation burst analysis, current research hotspots were the optimal NAT regimen, NAT response assessment, NAT for resectable PC and management of complications. NAT has received increasing attention in the field of PC over the past 20 years, but greater collaboration between countries and additional multicenter randomized clinical trials are needed. Overall, we have revealed current research hotspots and provided valuable information for the choice of future research directions.
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Terapia Neoadyuvante , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Bibliometría , Neoplasias PancreáticasRESUMEN
Purpose: The impact of surgery on non-functional pancreatic neuroendocrine tumors (NF-PNETs) ≤2â cm is controversial. This study sought to demonstrate the impact of surgery on the prognosis of NF-PNETs ≤2â cm with different biological behaviors. Methods: Patients with NF-PNETs ≤2â cm from 2004 to 2015 in the Surveillance, Epidemiology, and End Results database were included in this study. An inverse probability of treatment weighting (IPTW) method was used to reduce the selection bias. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to evaluate the effect of surgery on the prognosis. Results: In the IPTW-adjusted Cox proportional hazards regression analysis, surgery improved the cancer-specific survival (CSS) in the overall cohort (hazard ratio [HR], 0.187; 95% confidence interval [CI], 0.102-0.343; p < 0.001), patients with poorly differentiated or undifferentiated tumor grades (HR, 0.238; 95% CI, 0.105-0.64; p < 0.001), patients with distant metastasis (HR, 0.102; 95% CI, 0.021-0.496; p = 0.005), and patients with local invasion (HR, 0.059; 95% CI, 0.005-0.683; p = 0.002). Surgery did not improve the CSS in patients with lymph node metastasis only (HR, 0.26; 95% CI, 0.0462-1.461; p = 0.126) or patients with well or moderate differentiation while without distant and lymph node metastasis (HR, 0.387; 95% CI, 0.146-1.028; p = 0.057). Conclusions: Among patients with NF-PNETs ≤2â cm, different biological behaviors correlate with different prognostic impacts of surgery. As long as distant metastasis does not occur and the grade is well-moderately differentiated, these patients will not benefit from surgery no matter whether lymph node metastasis occurs or not. However, when local invasion appears in this group of patients, surgery should be performed. Moreover, patients with a tumor grade of poorly differentiated or undifferentiated or those with distant metastases may benefit from surgery.
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Radio-frequency-assisted Liver Partition with Portal Vein Ligation (RALPP) induces comparable hypertrophy of the liver remnant compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) in humans. However, whether it is significantly improved compared to ALPPS is unclear, and the underlying mechanisms of liver regeneration after RALPP need to further investigate. The present study was to develop an animal model mimicking RALPP and explore mechanisms of liver regeneration. The mice in RALPP group received liver radiofrequency ablation and 90% portal vein ligation (PVL), followed by resection of the targeted liver within two days after the first surgery. The mice in ALPPS group underwent 90% PVL combined with parenchyma transection. Controls received liver radiofrequency ablation (RAF group) or PVL (PVL group) or small left lateral lobe (LLL group) resection alone. Liver regeneration was assessed by liver weight and proliferation-associated molecules. The role of Kupffer cells (KCs) in liver regeneration was investigated after RALPP. The results showed that RALPP induced comparable liver regeneration compared to ALPPS, but with less liver injury and mortality in mice. RALPP led to over-expression of TNF-α and IL-6 in the circulating plasma compared with PVL. KCs infiltrating in liver tissues was a characteristic of mice in the RALPP group. KCs depletion markedly depressed cytokine expression and delayed liver regeneration after RALPP. These results suggested that RALPP in mice induced accelerated liver regeneration similar to ALPPS, but safer than ALPPS. KCs depletion altered cytokine expression and delayed liver regeneration after RALPP.
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Neoplasias Hepáticas , Regeneración Hepática , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hepatectomía/métodos , Macrófagos del Hígado , Ligadura/métodos , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Ratones , Vena Porta/cirugíaRESUMEN
OBJECTIVES: This study aimed to investigate the protective effect of SCARF1 on acute rejection (AR), phagocytic clearance of Kupffer cells (KCs), M2 polarization and the exact mechanism underlying these processes. METHODS: AAV was transfected into the portal vein of rats, and AR and immune tolerance (IT) models of liver transplantation were established. Liver tissue and blood samples were collected. The level of SCARF1 was detected via WB and immunohistochemical staining. Pathological changes in liver tissue were detected using HE staining. Apoptotic cells were detected using TUNEL staining. KC polarization was assessed via immunohistochemical staining. Primary KCs were isolated and co-cultured with apoptotic T lymphocytes. Phagocytosis of apoptotic cells and polarization of KCs were both detected using immunofluorescence. Calcium concentration was determined using immunofluorescence and a fluorescence microplate reader. The levels of PI3K, p-AKT and P-STAT3 were assessed via WB and immunofluorescence. RESULTS: Compared to the IT group, the level of SCARF1 was significantly decreased in the AR group. Overexpression of SCARF1 in KCs improved AR and liver function markers. Enhanced phagocytosis mediated by SCARF1 is beneficial for improving the apoptotic clearance of AR and promoting M2 polarization of KCs. SCARF1-mediated enhancement of phagocytosis promotes increased calcium concentration in KCs, thus further activating the PI3K-AKT-STAT3 signalling pathway. CONCLUSIONS: SCARF1 promotes the M2 polarization of KCs by promoting phagocytosis through the calcium-dependent PI3K-AKT-STAT3 signalling pathway.
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Calcio/metabolismo , Trasplante de Hígado , Receptores Depuradores de Clase F/metabolismo , Transducción de Señal , Animales , Apoptosis , Polaridad Celular , Células Cultivadas , Técnicas de Cocultivo , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Fagocitosis , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas Lew , Factor de Transcripción STAT3/metabolismo , Receptores Depuradores de Clase F/genética , Linfocitos T/citología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Left-sided portal hypertension (LSPH) is an extremely rare clinical syndrome, and it is the only form of curable portal hypertension. It is primarily caused by pancreatic disease, and is associated with complications that cause spleen vein compression. Specific symptoms are often lacking, rendering it difficult to diagnose. Splenectomy is the main treatment for cases complicated by variceal bleeding, and the effects of treatment primarily depend on the condition of the primary disease. CASE PRESENTATION: The patient was a 29-year-old woman who was admitted to the hospital for repeated hematemesis and black stool. She had been misdiagnosed with pancreatic cancer 7 years prior. Combined imaging and endoscopic examination indicated varicose gastric fundus veins, a pancreatic mass, and enlarged peripancreatic lymph nodes. Laboratory investigations revealed reduced erythrocyte, platelet, and leukocyte counts, the interferon gamma release assay was positive, and liver function was normal. Abdominal exploration, splenectomy, varicose vein dissection, and lesion resection were performed via laparotomy. Postoperative biopsy analysis confirmed the diagnosis of lymph node tuberculosis. Based on the above-described factors, LSPH caused by peripancreatic lymph node tuberculosis was a diagnosed. CONCLUSIONS: Herein we describe the first reported case of LSPH caused by peripancreatic lymph node tuberculosis. When left portal hypertension occurs simultaneously, peripancreatic lymph node tuberculosis is often misdiagnosed as pancreatic cancer. Further studies are necessary to develop a more favorable diagnostic method for pancreas masses and more advantageous therapy for LSPH, especially in cases caused by mechanical compression.
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Várices Esofágicas y Gástricas , Hipertensión Portal , Neoplasias Pancreáticas , Tuberculosis Ganglionar , Adulto , Errores Diagnósticos , Várices Esofágicas y Gástricas/etiología , Femenino , Hemorragia Gastrointestinal , Humanos , Hipertensión Portal/diagnóstico , Hipertensión Portal/etiología , Ganglios Linfáticos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/diagnósticoRESUMEN
BACKGROUND: Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. METHODS: Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. RESULTS: IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. CONCLUSIONS: IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.
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Interleucina-4/inmunología , Histona Demetilasas con Dominio de Jumonji/inmunología , Macrófagos del Hígado/inmunología , Trasplante de Hígado , Hígado/inmunología , Daño por Reperfusión/inmunología , Factor de Transcripción STAT6/inmunología , Animales , Macrófagos del Hígado/patología , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/patologíaRESUMEN
In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1ß, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.
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Ácidos Aminosalicílicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Trasplante de Hígado/efectos adversos , Disfunción Primaria del Injerto/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Aloinjertos/irrigación sanguínea , Aloinjertos/inmunología , Ácidos Aminosalicílicos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Supervivencia de Injerto , Proteína HMGB1/inmunología , Proteína HMGB1/metabolismo , Humanos , Hígado/irrigación sanguínea , Hígado/inmunología , Masculino , Ratones , Ratones Noqueados , Disfunción Primaria del Injerto/etiología , Transducción de Señal/inmunología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Isquemia Tibia/efectos adversosRESUMEN
OBJECTIVE: The α-ketoglutarate (αKG), a metabolite of glutaminolysis, is reported to orchestrate macrophages activation. This study aims to clarify whether the αKG / glutaminolysis metabolism can suppress Kupffer cells (KCs) activation during liver transplantation and attenuate hepatic ischemia-reperfusion injury (IRI). METHODS: Donor livers were perfused with DM-αKG (a cell-permeable analog of αKG) or BPTES (an inhibitor of glutaminase 1) via portal vein during cold preservation, and controls were perfused with UW solution. Then, a rat model of liver transplantation was performed. Serum levels of alanine transaminase (ALT), total bilirubin (TBIL) and inflammatory cytokines, as well as histology, were analyzed after 24 h. KCs were isolated from grafts. RT-PCR and immunofluorescence were used to evaluate polarization-specific marker genes. Western bolt was employed to assess the expression of phosphorylation of glycogen synthase kinase 3ß (p-GSK3ß) and suppressor of cytokine signaling 1 (SOCS1). EMSA was utilized to quantify the NF-κB transcriptional activity. RESULTS: Compared with controls, DM-αKG perfusion decreased ALT and TBIL levels, alleviated liver damage, and reduced apoptosis, while BPTES group showed higher ALT and TBIL levels, severe damage and more apoptosis. Furthermore, DM-αKG perfusion suppressed NF-κB activity, up-regulated the expression of p-GSK3ß and SOCS1 in KCs, and shifted the M1/M2 balance toward an anti-inflammatory profile. Besides, DM-αKG suppressed serum pro-inflammatory cytokines secretion and increased IL-10. CONCLUSIONS: αKG produced by glutaminolysis protects liver graft from IRI by regulating the inflammatory response and modifying the polarization of KCs.
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Ácidos Cetoglutáricos/farmacología , Hepatopatías/tratamiento farmacológico , Hígado/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Alanina Transaminasa/metabolismo , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/metabolismo , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-10/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hepatopatías/metabolismo , Trasplante de Hígado/métodos , Masculino , FN-kappa B/metabolismo , Sustancias Protectoras/farmacología , Ratas , Ratas Endogámicas Lew , Daño por Reperfusión/metabolismoRESUMEN
BACKGROUND: Vascular endothelial growth factor receptor-3 (VEGFR-3) / vascular endothelial growth factor -c (VEGF-C) signaling is reported to negatively regulate TLR4-triggered inflammation of macrophages. This study aims to clarify whether the VEGFR-3/VEGF-C signaling can suppress Kupffer cells (KCs) activation and attenuate hepatic ischemia-reperfusion injury (IRI) after liver transplantation. METHODS: A rat model of liver transplantation was performed. Donor livers were perfused with VEGF-C injection via portal vein during cold preservation, and controls were perfused with UW solution. Serum levels of alanine transaminase (ALT), total bilirubin (TBIL) and inflammatory cytokines, as well as histology were analyzed after 24â¯h. KCs were isolated from grafts, RT-PCR and immunofluorescence were used to evaluate polarization-specific marker genes, western bolt was employed to assess the expression of suppressor of cytokine signaling 1(SOCS1) and phosphorylated glycogen synthase kinase 3ß (p-GSK3ß), and EMSA was utilized to quantify the NF-κB transcriptional activity. RESULTS: Compared with controls, VEGF-C perfusion reduced ALT and TBIL levels and alleviated liver damage. Furthermore, VEGF-C perfusion suppressed serum proinflammatory cytokines secretion and increased IL-10.In addition, the VEGFR-3 mRNA of KCs was increased after reperfusion. VEGF-C perfusion suppressed NF-κB activity and up-regulated the expression of SOCS1 and p-GSK3ß in KCs, and shifted the M1/M2 balance toward an anti-inflammatory profile. CONCLUSION: Exogenous VEGF-C protects liver graft from IRI by regulating the inflammatory response and modifying polarization of KCs.
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Macrófagos del Hígado/metabolismo , Trasplante de Hígado , Hígado/patología , Daño por Reperfusión/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Alanina Transaminasa/sangre , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Macrófagos del Hígado/patología , Masculino , Ratas , Ratas Endogámicas Lew , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Regulación hacia Arriba , Factor C de Crecimiento Endotelial Vascular/administración & dosificación , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Purpose: Suppression of the Toll like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signaling was critical in protection against liver IRI. Previous studies revealed that Liver X receptors (LXRs) activation could antagonize TLR4-NF-κB signaling. The purpose of this study is to determine whether LXRs agonist GW3965 can suppress the TLR4-NF-κB signaling during liver transplantation and protect ischemia-reperfusion injury (IRI). Materials and Methods: Sprague Dawley (SD) rats were used to perform orthotropic liver transplantation. Donors were pretreatment with GW3965 (0.3 mg/kg) through caudal vein injection 30 min before the surgery. The followings were analyzed after transplantation: alanine aminotransferase (ALT), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) level in serum, ATP binding cassette transporter A1 (Abca1) expression, NF-κB transcriptional activity, apoptosis and histological injury. Results: GW3965 pretreatment significantly ameliorated the degree of IRI associated with the effects of upregulating Abca1 expression, inhibiting NF-κB transcriptional activity, and downregulating TNF-α and IL-6 level. Conclusion: LXRs activation attenuated hepatic IRI by preventing TLR4-NF-κB signaling.
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Benzoatos/administración & dosificación , Bencilaminas/administración & dosificación , Trasplante de Hígado/efectos adversos , Receptores X del Hígado/agonistas , Daño por Reperfusión/prevención & control , Transportador 1 de Casete de Unión a ATP/metabolismo , Aloinjertos/efectos de los fármacos , Aloinjertos/enzimología , Aloinjertos/patología , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Pruebas de Función Hepática , Trasplante de Hígado/métodos , Receptores X del Hígado/metabolismo , Masculino , FN-kappa B/metabolismo , Ratas , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
The aim of this study is to investigate the protective effect and the mechanism of tauroursodeoxycholic acid (TUDCA) against hepatic ischemia reperfusion (IR) injury. Male Balb/c mice were intraperitoneally injected with tauroursodeoxycholic acid (400â¯mg/kg) or saline solution, once per day for 3 days before surgery, and then the model of hepatic I/R injury was established. Blood and liver samples were collected from each group at 3, 6, and 24â¯h after surgery. Liver pathological changes, liver function, hepatocyte apoptosis and proinflammatory factors were detected. KCs were extracted, cultured and treated with TUDCA or phosphate-buffered saline (PBS) for 24â¯h, and then viability and phagocytosis were examined. Additionally, IRE1α/TRAF2/NF-κB pathway activity and AML cell apoptosis were detected. The results showed that TUDCA alleviated hepatic I/R injury, the level of liver function markers, and hepatocyte apoptosis in vivo. Furthermore, the proinflammatory effects of KCs were suppressed by down-regulating IRE1α/TRAF2/NF-κB pathway activity in vivo. TUDCA dose-dependently suppressed the expression of inflammatory factors and IRE1α/TRAF2/NF-κB pathway activity in vitro, consistent with the in vivo results. Therefore, TUDCA can effectively alleviate hepatic IR injury by down-regulating the activity of the IRE1α/TRAF2/NF-κB pathway to suppress the function of KCs.
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Macrófagos del Hígado/efectos de los fármacos , Hepatopatías/prevención & control , Hígado/efectos de los fármacos , Daño por Reperfusión/prevención & control , Ácido Tauroquenodesoxicólico/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Citocinas/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Hígado/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacos , Factor 2 Asociado a Receptor de TNF/metabolismo , Factores de TiempoRESUMEN
An acute reaction response (AR) following liver transplantation (LT) is caused by immune responses that are primarily mediated by T lymphocytes. Kupffer cells (KCs) are the largest antigen presenting cell (APC) group in vivo and are the primary modulators of the inflammatory or tolerogenic immune response in liver tissues. T cell immunoglobulindomain and mucindomain-4 (TIM4), the only TIM protein not expressed on T cells, is expressed on APCs; suggesting that it mediates the various immune responses. However, to the best of our knowledge, the role of TIM4 expressed by KCs in LT injury remains unknown. The present study aimed to explore whether and how TIM4 expressed by KCs is involved in the AR of liver allografts. Orthotopic liver transplantation (OLT) was performed in mice to establish a model of AR and results demonstrated that LT may lead to the augmented expression of TIM4 in activated KCs. It was also revealed that TIM4 blockade markedly attenuated AR injury in vivo via the nuclear factorκB (NFκB) and p38 mitogenactivated protein kinase (p38 MAPK) signaling pathways. In addition, levels of transforming growth factorß (TGFß) were increased following TIM4 blockade. Furthermore, in a KC/cluster of differentiation (CD)4+ T cell coculture system, blocking TIM4 inhibited T helper 2 (Th2) differentiation, stimulated the conversion of naive (CD)4+ T cells into CD4+CD25+Forkhead box protein p3+ T regulatory cells and suppressed interleukin4/signal transducer and activator of transcription 6/transcription factor gata3 signaling. These effects were enhanced following the addition of TGFß. It was also demonstrated that LT mouse models treated with TIM4 blockade in combination with exogenous TGFß injections, increased the survival times of mice and enhanced the amelioration of AR in LT. These results indicate that blocking the expression of TIM4 by KCs via exogenous TGFß injection may be an effective therapeutic strategy to inhibit the AR of liver allografts.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/patología , Macrófagos del Hígado/metabolismo , Trasplante de Hígado , Proteínas de la Membrana/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Femenino , Factor de Transcripción GATA3/metabolismo , Rechazo de Injerto/inmunología , Mediadores de Inflamación/metabolismo , Inyecciones , Interleucina-4/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Sistema de Señalización de MAP Quinasas , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Factor de Transcripción STAT6/metabolismo , Análisis de Supervivencia , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Células Th2/citología , Células Th2/efectos de los fármacos , Células Th2/metabolismo , Factor de Crecimiento Transformador beta/administración & dosificación , Factor de Crecimiento Transformador beta/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Our objective was to comparatively profile the metabolite composition of primary hepatocellular carcinoma (HCC) tumors from alcoholic liver disease (ALD), hepatitis B virus (HBV)-infected, and hepatitis C virus (HCV)-infected cirrhotic patients. Primary HCC tumors were collected from ALD, HBV-infected, and HCV-infected cirrhotic patients (n=20 each). High-resolution magic-angle spinning proton nuclear magnetic resonance spectroscopy and metabonomic data analysis were performed to compare HCC tumors from the three groups. Sensitivity analyses were performed to determine the effects of diabetes, high body mass index, and smoking status. Metabonomic pathway analyses were conducted to identify dysregulated pathways. Three metabolites were significantly differentiated between ALD and HBV-infected patients, which were distinguishable by changes in ketone body, glycerolipid, and phenylalanine metabolism. Five metabolites were significantly differentiated between ALD and HCV-infected patients, which were distinguishable by changes in ketone body, alanine/aspartate/glutamate, and phenylalanine metabolism. Six metabolites were significantly differentiated between HBV-infected and HCV-infected patients, which were distinguishable by changes in ketone body, tyrosine, and alanine/aspartate/glutamate metabolism. In conclusion, this is the first study to demonstrate that the metabolic phenotypes of primary HCC tumors vary significantly across ALD, HBV-infected, and HCV-infected cirrhotic patients.