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Objective: Interventional stroke therapy made thrombi available for histological analysis. Unfortunately, simple composition aspects such as erythrocyte versus fibrin/platelet rich did not allow a feasible allocation to thrombi's cardiac or carotid origin. Since the mentioned criteria represent characteristics of thrombus age, we used established histological criteria for determining thrombus age in patients who had an atherosclerotic (TOAST (Trial of Org 10172 in Acute stroke Treatment) 1) stroke versus patients who had a cardioembolic (TOAST 2) stroke. Methods: We assessed prospectively data from stroke patients presenting with occlusion of the middle cerebral artery eligible for catheter-based intervention. Besides patient characteristics and stroke workup, extracted thrombi were classified into different age categories according to their cellular to fibrotic transition. Thrombi were collected in an erythrocyte lysing solution to reduce acute clotting effects. Statistics were done with a non-parametric Kolmogorov-Smirnov test. Results: 170 patients were included, of which 50 (38 men; 73±12 years) had a TOAST 1 and 99 (59 women; 75±10 years) had a TOAST 2 categorised stroke. Age, National Institutes of Health Stroke Score (13±7 vs 15±7), Alberta Stroke Program Early CT Score (9±3 vs 9±2), Thrombolysis in Cerebral Infarction Score (2.9±0.2 vs 2.9±0.3), modified Rankin Score on discharge (3.2±2 vs 3.2±2), number of vascular risk factors (0.9±1.4 vs 1.0±1.1) or time span between symptom onset to reperfusion (266±115 vs 260±128 min) remained non-significant. Also, thrombus age did not differ between the groups. The mean age of thrombi was 5-8 days. However, the male-female ratio differed significantly (p<0.0005) between groups, with more men in TOAST 1 group and more women in TOAST 2 group. Conclusion: Age aspects of thrombi seem not feasible to allow reliable source allocation. However, the young age of thrombi points to a rapid detachment. The difference in sex relation is in line with previous reports.
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There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.
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PURPOSE: The impact of psychological factors on the incidence of hepatocellular carcinoma (HCC) in humans remains unclear. Mendelian randomization (MR) study is a novel approach aimed at unbiased detection of causal effects. Therefore, we conducted a two-sample MR to determine if there is a causal relationship between psychological distress (PD), participation in leisure/social activities of religious groups (LARG), and HCC. METHODS: The genetic summary data of exposures and outcome were retrieved from genome-wide association studies (GWAS). We used PD and LARG as exposures and HCC as outcome. Five MR methods were used to investigate the causal relationship between PD, LARG, and HCC. The result of inverse variance weighted (IVW) method was deemed as principal result. Besides, we performed a comprehensive sensitivity analysis to verify the robustness of the results. RESULTS: The IVW results showed that PD [odds ratio (OR) 1.006, 95% confidence interval (CI) 1.000-1.011, P = 0.033] and LARG (OR 0.994, 95% CI 0.988-1.000, P = 0.035) were causally associated with the incidence of HCC. Sensitivity analysis did not identify any bias in the results. CONCLUSION: PD turned out to be a mild risk factor for HCC. In contrast, LARG is a protective factor for HCC. Therefore, it is highly recommended that people with PD are seeking positive leisure activities such as participation in formal religious social activities, which may help them reduce the risk of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/genética , Factores de RiesgoRESUMEN
BACKGROUND: Patients with angina are often suffering from comorbidities such as varying degrees of hepatic dysfunction. However, the impact of angina on the incidence of hepatic failure (HF) remains unclear. METHODS: The genetic data were retrieved from genome-wide association studies. Five Mendelian randomization methods were used to investigate the causal relationship between unstable angina (UA), stable angina (SA), and HF. The result of the Inverse variance weighted (IVW) method was deemed the principal result. In addition, we performed a comprehensive sensitivity analysis to verify the robustness of the results. RESULTS: The IVW results showed that UA (Odds ratio (OR): 2.055, 95% confidence interval (CI): 1.171-3.606, p = 0.012) was causally associated with the incidence of HF. SA (OR: 1.122, 95% CI: 0.738-1.706, p = 0.591) was not causally associated with the incidence of HF. Sensitivity analysis did not identify any bias in the results. CONCLUSIONS: UA turned out to be a risk factor for HF. SA does not have a significant causal effect on HF. Therefore, it is highly recommended that patients with chronic liver disease seek prompt medical attention and undergo regular monitoring of liver function when experiencing UA. This may help them to reduce the risk of HF.
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This protocol presents an optimized erythrocytes-free NEVLP system using mouse livers. Ex vivo preservation of mouse livers was achieved by employing modified cannulas and techniques adapted from conventional commercial ex vivo perfusion equipment. The system was utilized to evaluate the preservation outcomes following 12 h of perfusion. C57BL/6J mice served as liver donors, and the livers were explanted by cannulating the portal vein (PV) and bile duct (BD), and subsequently flushing the organ with warm (37 °C) heparinized saline. Then, the explanted livers were transferred to the perfusion chamber and subjected to normothermic oxygenated machine perfusion (NEVLP). Inlet and outlet perfusate samples were collected at 3 h intervals for perfusate analysis. Upon completion of the perfusion, liver samples were obtained for histological analysis, with morphological integrity assessed using modified Suzuki-Score through Hematoxylin-Eosin (HE) staining. The optimization experiments yielded the following findings: (1) mice weighing over 30 g were deemed more suitable for the experiment due to the larger size of their bile duct (BD). (2) a 2 Fr (outer diameter = 0.66 mm) polyurethane cannula was better suited for cannulating the portal vein (PV) when compared to a polypropylene cannula. This was attributed to the polyurethane material's enhanced grip, resulting in reduced catheter slippage during the transfer from the body to the organ chamber. (3) for cannulation of the bile duct (BD), a 1 Fr (outer diameter = 0.33 mm) polyurethane cannula was found to be more effective compared to the polypropylene UT - 03 (outer diameter = 0.30 mm) cannula. With this optimized protocol, mouse livers were successfully preserved for a duration of 12 h without significant impact on the histological structure. Hematoxylin-Eosin (HE) staining revealed a well-preserved morphological architecture of the liver, characterized by predominantly viable hepatocytes with clearly visible nuclei and mild dilation of hepatic sinusoids.
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Trasplante de Hígado , Polipropilenos , Ratones , Animales , Eosina Amarillenta-(YS) , Hematoxilina , Poliuretanos , Trasplante de Hígado/métodos , Preservación de Órganos/métodos , Ratones Endogámicos C57BL , Hígado/patología , Perfusión/métodosRESUMEN
Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms.
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Hígado Graso , Midazolam , Ratones , Animales , Midazolam/farmacología , Cafeína/farmacocinética , Tasa de Depuración Metabólica , Sistema Enzimático del Citocromo P-450/metabolismoRESUMEN
BACKGROUND: In previous studies, five vasoactive drugs were investigated for their effect on the recovery process after extended liver resection without observing relevant improvements. We hypothesized that an analysis of gene expression could help to identify potentially druggable pathways and could support the selection of promising drug candidates. METHODS: Liver samples obtained from rats after combined 70% partial hepatectomy and right median hepatic vein ligation (n = 6/group) sacrificed at 0 h, 24 h, 48 h, and 7days were selected for this study. Liver samples were collected from differentially perfused regions of the median lobe (obstruction-zone, border-zone, normal-zone). Gene expression profiling of marker genes regulating hepatic hemodynamics, vascular remodeling, and liver regeneration was performed with microfluidic chips. We used 3 technical replicates from each sample. Raw data were normalized using LEMming and differentially expressed genes were identified using LIMMA. RESULTS: The strongest differences were found in obstruction-zone at 24 h and 48 h postoperatively compared to all other groups. mRNA expression of marker genes from hepatic hemodynamics pathways (iNOS,Ptgs2,Edn1) was most upregulated. CONCLUSION: These upregulated genes suggest a strong vasoconstrictive effect promoting arterial hypoperfusion in the obstruction-zone. Reducing iNOS expression using selective iNOS inhibitors seems to be a promising approach to promote vasodilation and liver regeneration.
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Hepatectomía , Regeneración Hepática , Animales , Ciclooxigenasa 2 , Perfilación de la Expresión Génica , Hígado/metabolismo , Regeneración Hepática/genética , ARN Mensajero/metabolismo , RatasRESUMEN
PURPOSE: The autophagy inhibitor chloroquine enhances the effect of targeted therapy using tyrosine kinase inhibitor in liver cancer. We would like to further understand the specific mechanism by which chloroquine inhibits the proliferation of tumor cells. METHODS: We used a human hepatocarcinoma cell line (HepG2) as cell culture model. In contrast to the control groups (treated only with complete medium), cells in experimental groups were treated either with complete medium + 40 ng/ml Hepatocyte growth factor (HGF), or with complete medium + 60 µM chloroquine or with complete medium + 40 ng/ml HGF + 60 µM chloroquine for 24 h. Cell number and ATP content were investigated using spectrophotometric assays. Cell proliferation and apoptosis were detected by immunohistochemistry. Cell morphological alterations were examined by Giemsa and H&E staining. Cellular lipid content was determined by Oil Red O staining and Triglyceride quantification assay. Autophagy-related proteins (LC3B and p62) and hepatocyte proliferation-related protein (S6K1) were examined using western blot. The autophagic flux of cells was assessed by mRFP-EGFP-LC3 transfection assay. RESULTS: We found that chloroquine inhibited the proliferation of HepG2 cells, as evidenced by a decrease in cellular ATP content, Ki-67 and S6K1 protein expression and a reduction in cell number. This finding was associated with an increase in lipid content. As expected, chloroquine inhibited autophagy of HepG2 cells, as evidenced by the accumulation of LC3B-II and the significant upregulation of p62. mRFP-EGFP-LC3 transfection assay showed that indeed chloroquine blocked the autophagic flux in HepG2 cells. CONCLUSION: Chloroquine impaired proliferation of HepG2 cells might be due to intracellular accumulation of lipids and inhibition of energy synthesis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Cloroquina/farmacología , Carcinoma Hepatocelular/patología , Factor de Crecimiento de Hepatocito/farmacología , Neoplasias Hepáticas/patología , Antígeno Ki-67 , Línea Celular Tumoral , Proteínas Asociadas a Microtúbulos/metabolismo , Autofagia , Proteínas Relacionadas con la Autofagia , Inhibidores de Proteínas Quinasas/farmacología , Triglicéridos/farmacología , Lípidos , Adenosina TrifosfatoRESUMEN
[This corrects the article DOI: 10.1155/2010/436145.].
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Portal vein ligation (PVL) has been adopted to induce hypertrophy of the future liver remnant (FLR) in patients with primarily irresectable liver tumor. However, regeneration of the FLR is not always sufficient to allow curative resection of the portally-deprived tumor-bearing liver lobe. We hypothesize that simultaneous hepatectomy (PHx) and PVL augments regeneration of the FLR and that the effect is related to the extent of the additional resection. Seventy-two Lewis rats were enrolled into 3 groups: 20%PVL + 70%PHx; 70%PVL + 20%PHx; 90%PVL. Animals were observed for 1, 2, 3 and 7 days postoperatively (n = 6/time point). Liver enzymes, caudate liver/body-weight-ratio, BrdU-proliferation-index (PI), proliferating-cell-nuclear-antigen (PCNA)-mRNA-expression level and autophagy-related-proteins were evaluated. Compared with 90% PVL, additional PHx induced significantly more hypertrophy during the observation time, which was confirmed by significantly higher PI and higher level of PCNA-mRNA expression. Similarly, the additional PHx induced more autophagy in the FLR compared with PVL alone. However, both effects were not clearly related to the extent of additional resection. Additional resection augmented liver regeneration and autophagy substantially compared with PVL alone. Therefore, we concluded that autophagy might play a critical role in regulating hepatocyte proliferation and the size of the FLR after simultaneous PVL + PHx.
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Hepatectomía , Ligadura , Regeneración Hepática , Vena Porta/cirugía , Autofagia , Biomarcadores , Proliferación Celular , Expresión Génica , Hepatectomía/métodos , Hepatocitos/metabolismo , Ligadura/métodos , Hígado/metabolismo , Hígado/cirugíaRESUMEN
Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for "rejuvenation" of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.
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Envejecimiento/fisiología , Autofagia , Regeneración Hepática/fisiología , Hígado/fisiología , Animales , Humanos , Mitocondrias/metabolismo , Transducción de SeñalRESUMEN
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide with a steadily increasing mortality rate. Fast diagnosis at early stages of HCC is of key importance for the improvement of patient survival rates. In this regard, we combined two imaging techniques with high potential for HCC diagnosis in order to improve the prediction of liver cancer. In detail, Raman spectroscopic imaging and matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) were applied for the diagnosis of 36 HCC tissue samples. The data were analyzed using multivariate methods, and the results revealed that Raman spectroscopy alone showed a good capability for HCC tumor identification (sensitivity of 88% and specificity of 80%), which could not be improved by combining the Raman data with MALDI IMS. In addition, it could be shown that the two methods in combination can differentiate between well-, moderately- and poorly-differentiated HCC using a linear classification model. MALDI IMS not only classified the HCC grades with a sensitivity of 100% and a specificity of 80%, but also showed significant differences in the expression of glycerophospholipids and fatty acyls during HCC differentiation. Furthermore, important differences in the protein, lipid and collagen compositions of differentiated HCC were detected using the model coefficients of a Raman based classification model. Both Raman and MALDI IMS, as well as their combination showed high potential for resolving concrete questions in liver cancer diagnosis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico , Detección Precoz del Cáncer , Humanos , Neoplasias Hepáticas/diagnóstico , Imagen Molecular , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría RamanRESUMEN
BACKGROUND: Prostate cancer (PCa) is the most common type of cancer among men in Western countries. Despite numerous therapeutic options, few treatments are available for patients with end-stage disease. In the present study, different somatostatin receptors (SSTs) and the chemokine receptor CXCR4 were evaluated for their suitability as novel therapeutic targets in PCa. MATERIALS AND METHODS: The expression of SST subtypes 1, 2A, 3, and 5 and of CXCR4 was evaluated in 276 PCa tumor samples on a tissue microarray (TMA) in 23 whole-block tumor samples and in 3 PCa cell lines by immunohistochemistry using well-characterized monoclonal antibodies. RESULTS: Overall, the frequency and intensity of expression of SSTs and CXCR4 were very low among the PCa samples investigated. Specifically, SST5, SST2A, and SST3 were expressed, albeit at low intensity, in 10.5%, 9.1%, and 0.7% of the TMA samples, respectively. None of the TMA samples showed SST1 or CXCR4 expression. Only a single small-cell-type neuroendocrine carcinoma that was coincidentally included among the whole-block samples exhibited strong SST2A, SST5, and CXCR4 and moderate SST3 expression. Independent of the tumor cells, the tumor capillaries in many of the PCa samples were strongly positive for SST2A, SST3, SST5, or CXCR4 expression. SST expression in the tumor cells was associated with advanced tumor grade and stage. CONCLUSION: Overall, SST and CXCR4 expression levels are clearly of no therapeutic relevance in PCa. SST- or CXCR4-based therapy might be feasible, however, in rare cases of small-cell-type neuroendocrine carcinoma of the prostate.
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Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.
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Envejecimiento/patología , Autofagia , Regeneración Hepática , Hígado/metabolismo , Envejecimiento/metabolismo , Animales , Humanos , Hígado/crecimiento & desarrollo , Hígado/fisiologíaRESUMEN
The liver has the ability to maintain its total size by adjusting the size of the individual liver lobes differently in response to regeneration- and atrophy-stimuli. Portal vein ligation (PVL) drives the ligated lobe to undergo atrophy whereas partial hepatectomy (PHx) drives the total remnant liver to regenerate. We hypothesize that the size of the PVL-lobe is dependent on the balance between the extent of PVL and the extent of PHx inducing a complex interplay between hepatocyte proliferation, apoptosis and autophagy. Lewis-rats were subjected to either 20%PVL + 70%PHx or 70%PVL + 20%PHx. Control groups consisted of 20%PVL and 70%PVL. Liver lobe weight, BrdU-proliferation-index, proliferating-cell-nuclear-antigen-mRNA-expression level, apoptotic density and autophagy-related-proteins were investigated. The PVL-liver lobe adjusted its weight differently, increasing by 40% after 20%PVL + 70%PHx, but decreasing by 25% after 70%PVL + 20%PHx. Additional resection induced a low, but substantial size-dependent hepatocyte proliferation rate (maximal 6.3% and 3.6% vs. 0.3% and significantly suppressed apoptotic density in the deportalized-liver-lobe (3 and 14 cells/mm2 comparing with above 26 cells/mm2, p < 0.01). Autophagy was more activated in PVL-liver lobe after simultaneous PHx than after PVL only. In summary, atrophy of the PVL-liver lobe after simultaneous PHx was counteracted by promoting hepatocyte proliferation, inducing autophagy and suppressing apoptosis in a PHx-extent-dependent manner.
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Hepatectomía/métodos , Hígado/cirugía , Vena Porta/cirugía , Animales , Apoptosis/fisiología , Autofagia/fisiología , Proliferación Celular/fisiología , Hepatocitos/citología , Hepatocitos/metabolismo , Inmunohistoquímica , Ligadura , Masculino , Ratas , Ratas Endogámicas LewRESUMEN
In vivo liver decellularization has become a promising strategy to study in vivo liver engineering. However, long-term survival after in vivo liver decellularization has not yet been achieved due to anatomical and technical challenges. This study aimed at establishing a survival model of in vivo partial liver lobe perfusion-decellularization in rats. We compared three decellularization protocols (1% Triton X100 followed by 1% sodium dodecyl sulfate [SDS], 1% SDS vs. 1% Triton X100, n = 6/group). Using the optimal one as judged by macroscopy, histology and DNA content, we characterized the structural integrity and matrix proteins by using histology, scanning electron microscopy, computed tomography scanning, and immunohistochemistry (IHC). We prevented contamination of the abdominal cavity with the corrosive detergents by using polyvinylidene chloride (PVDC) film + dry gauze in comparison to PVDC film + dry gauze + aspiration tube (n = 6/group). Physiological reperfusion was assessed by histology. Survival rate was determined after a 7-day observation period. Only perfusion with 1% SDS resulted in an acellular scaffold (fully translucent without histologically detectable tissue remnants, DNA concentration is <2% of that in native lobe) with remarkable structural and ultrastructural integrity as well as preservation of main matrix proteins (IHC positive for collagen IV, laminin, and elastin). Contamination of abdominal organs with the potentially toxic SDS solution was achieved by placing a suction tube in addition to the PVDC film + dry gauze and allowed a 7-day survival of all animals without severe postoperative complications. On reperfusion, the liver turned red within seconds without any leakage from the surface of the liver. About 12 h after reperfusion, not only blood cells but also some clots were visible in the portal vein, sinusoidal matrix network, and central vein, suggesting physiological perfusion. In conclusion, our results of this study show the first available data on generation of a survival model of in vivo parenchymal organ decellularization, creating a critical step toward in vivo organ engineering. Impact Statement Recently, in vivo liver decellularization has been considered a promising approach to study in vivo liver repopulation of a scaffold compared with ex vivo liver repopulation. However, long-term survival of in vivo liver decellularization has not yet been achieved. Here, despite anatomical and technical challenges, we successfully created a survival model of in vivo selected liver lobe decellularization in rats, providing a major step toward in vivo organ engineering.
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Hígado/citología , Modelos Biológicos , Ingeniería de Tejidos , Animales , Cuidados Intraoperatorios , Estimación de Kaplan-Meier , Hígado/irrigación sanguínea , Hígado/cirugía , Masculino , Perfusión , Ratas Endogámicas Lew , Andamios del Tejido/químicaRESUMEN
Ventral or incisional hernia are a common disease pattern in general surgery. Mostcommonly, a mesh repair is used for reconstruction, whereby the mesh itself might causecomplications, like infections or adhesions. Biological materials, like biocellulose, might reducethese clinical problems substantially. In this prospective rodent study, a biocellulose mesh(produced by Gluconacetobacter xylinus) was implanted either by a sublay technique or assupplementation of the abdominal wall. After an observation period of 90 days, animals weresacrificed. The adhesions after the reconstruction of the abdominal wall were moderate. Thehistologic investigations revealed that the biocellulose itself was inert, with a minimal regenerativeresponse surrounding the mesh. The explanted mesh showed a minimal shrinkage (around 15%) aswell as a minimal loss of tear-out force, which might be without clinical relevance. This is the firstin vivo study describing biocellulose as a suitable mesh for the repair of ventral hernia in twodifferent hernia models. The material seems to be a promising option for solving actual problems inmodern hernia surgery.
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Aging is often associated with a decreased autophagic activity that contributes to the high sensitivity of aged livers to ischemia reperfusion injury (IRI). Blood from young animals can positively affect aged animals. This study was designed to evaluate the effect of young plasma in a model of liver IRI in aged rats. Aged rats were treated with pooled plasma collected from young rats before ischemia. Administration of young plasma restored aging-induced suppression in hepatic autophagic activity and reduced liver IRI. Inhibition of the young-plasma-restored autophagic activity abrogated the beneficial effect of young plasma against liver IRI. Similarly, young serum restored autophagic activity and reduced cellular injury after hypoxia/reoxygenation (H/R) in primary old rat hepatocytes. Mechanistic studies showed thatadministration of young plasma increased AMPK phosphorylation and led to unc-51-like autophagy activating kinase (ULK)1 activation. Furthermore, AMPK-inhibition abrogated the young serum-induced ULK1 activation and autophagic activity and diminished the protective action of young serum against H/R injury in primary old rat hepatocytes, whereas AMPK-activation potentiated the effects of young serum. Young plasma could restore age-impaired autophagy, at least in part, via AMPK/ULK1 signaling. Restoration of age-impaired autophagic activity may be a critical contributing mechanism to young-plasma-afforded protection against liver IRI in aged rats.-Liu, A., Yang, J., Hu, Q., Dirsch, O., Dahmen, U., Zhang, C., Gewirtz, D. A., Fang, H., Sun, J. Young plasma attenuates age-dependent liver ischemia reperfusion injury.