Transplantation von hepatozytenähnlichen Zellen (NeoHep Zellen) verbessert das Überleben in einem Modell akuten Leberversagens

OBJECTIVE: Investigation of the efficacy of implantation of monocyte-derived hepatocyte-like cells (NeoHep cells) in acute liver failure. SUMMARY BACKGROUND DATA: Extended liver resection or split liver transplantation is still associated with high morbidity and mortality due to postoperative liver insufficiency. In view of liver support systems, implantation of isolated hepatocytes or hepatocyte-like cells such as NeoHep cells is increasingly under discussion. METHODS: 24 hours prior to subtotal hepatectomy, cells of different origin (A: human mononuclear cells (24x106); B: NeoHep cells (16x106); C: NeoHep cells (24x106); D: rat hepatocytes (24x106)) were injected into the spleen of male Wistar rats. Following an observation period of 5 days, animal survival, postoperative weight, and signs of encephalopathy were recorded. At the end of the observation period, blood was collected for laboratory analysis (serum levels of ALT, bilirubin, albumin). RESULTS: Transplantation of both rat hepatocytes and NeoHep cells significantly improved animal survival when compared to control animals (group A: 21%), reaching 72% in group D (p=.001), 50% in group C (p=.04), and 36% in group B (p=.22). Moreover, animals in these groups postoperatively experienced less frequently signs of encephalopathy, they also showed an earlier weight increase when compared to group A. CONCLUSION: Hepatocyte transplantation is a practicable and successful treatment option in the case of liver insufficiency since implantation of NeoHep cells or primary rat hepatocytes had an improving effect on survival. Based on this study, we believe that pre-treatment of patients with autologous monocyte-derived hepatocyte-like cells (NeoHep cells) by ‘own cell donation’ may represent an effective tool to markedly reduce morbidity and mortality due to postoperative liver failure.ZIEL: Untersuchung der Effizienz der Implantation von von Monozyten stammenden, hepatozytenähnlichen Zellen (NeoHep Zellen) bei akutem Leberversagen. HINTERGRUND: Ausgedehnte Leberresektionen oder Teillebertransplantationen sind immer noch mit hoher Morbidität und Mortalität wegen der Gefahr einer postoperativen Leberinsuffizienz assoziiert. Mit Blick auf Leberunterstützungssysteme ist die Implantation von isolierten Hepatozyten oder hepatozytenähnlichen Zellen wie NeoHep Zellen zunehmend in der Diskussion. METHODIK: 24 Stunden vor einer subtotalen Hepatektomie wurden Zellen unterschiedlichen Ursprungs (A: humane mononukleäre Zellen (24x106); B: NeoHep Zellen (16x106); C: NeoHep Zellen (24x106); D: Ratten Hepatozyten (24x106)) in die Milz von männlichen Wistar Ratten gespritzt. Während einer Beobachtungszeit von 5 Tagen wurden das Überleben, postoperative Gewicht und Zeichen der Enzephalopathie gemessen. Am Ende der Beobachtungszeit wurde Blut für Laboranalysen (Serumspiegel von ALT, Bilirubin und Albumin) abgenommen. ERGEBNISSE: Die Transplantation sowohl von Ratten Hepatozyten als auch von NeoHep Zellen erbrachte ein statistisch signifikant höheres Überleben (72% in Gruppe D (p=.001), 50% in Gruppe C (p=.04), 36% in Gruppe B (p=.22)) verglichen mit der Kontrollgruppe (Gruppe A: 21%). Darüberhinaus zeigten die Tiere in diesen Gruppen seltener Zeichen einer postoperativen Enzephalopathie und wiesen eine schnellere postoperative Gewichtszunahme auf als in Gruppe A. ZUSAMMENFASSUNG: Die Hepatozytentransplantation ist eine praktikable und erfolgreiche Behandlungsoption bei Vorliegen einer Leberinsuffizienz, da sowohl die Implantation von primären Rattenhepatozyten als auch von NeoHep Zellen das Überleben deutlich verbessern konnten. Basierend auf den Ergebnissen dieser Studie halten wir eine Vorbehandlung von Patienten mit autologen, von Monozyten abstammenden hepatozytenähnlichen Zellen (NeoHep Zellen) durch ,,Eigen-Zell-Spende’’ für ein wirksames Instrument, um die durch postoperative Leberinsuffizienz bedingte Morbidität und Mortalität deutlich zu reduzieren

Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation

It is critical to understand the molecular mechanisms of hepatocarcinogenesis in order to prevent or treat hepatocellular carcinoma (HCC). The development of HCC is commonly associated with hepatocyte death and compensatory proliferation. However, the role of Caspase-3, a key apoptotic executor, in hepatocarcinogenesis is unknown. In this study, we used Caspase-3-deficient mice to examine the role of Caspase-3 in hepatocarcinogenesis in a chemical (diethylnitrosamine, DEN)-induced HCC model. We found that Caspase-3 deficiency significantly increased DEN-induced HCC. Unexpectedly, Caspase-3 deficiency increased apoptosis induced by DEN and the subsequent compensatory proliferation. Intriguingly, we discovered that Caspase-3 deficiency increased the activation of p38 with and without DEN treatment. Moreover, we demonstrated that TNFα and IL1α stimulated increased activation of p38 in Caspase-3 KO hepatocytes compared with wild-type hepatocytes. Finally, we found that inhibition of p38 by SB202190 abrogated enhanced hepatocyte death, compensatory proliferation and HCC induced by DEN in Caspase-3-deficient mice. Overall, our data suggest that Caspase-3 inhibits chemical-induced hepatocarcinogenesis by suppressing p38 activation and hepatocyte death

A study of the dynamic relation between physiological changes and spontaneous expressions

Recent progress in Affective Computing (AC) has enabled integration of physiological cues and spontaneous expressions to reveal a subject’s emotional state. Due to the lack of an effective technique for evaluating multimodal correlations, experience and intuition play a main role in present AC studies when fusing affective cues or modalities, resulting in unexpected outcomes. This study seeks to demonstrate a dynamic correlation between two such affective cues, physiological changes and spontaneous expressions, which were obtained by a combination of stereo vision based tracking and imaging photoplethysmography (iPPG), with a designed protocol involving 20 healthy subjects. The two cues obtained were sampled into a Statistical Association Space (SAS) to evaluate their dynamic correlation. It is found that the probability densities in the SAS increase as the peaks in two cues are approached. Also the complex form of the high probability density region in the SAS suggests a nonlinear correlation between two cues. Finally the cumulative distribution on the zero time-difference surface is found to be small (<0.047) demonstrating a lack of simultaneity. These results show that the two cues have a close interrelation, that is both asynchronous and nonlinear, in which a peak of one cue heralds a peak in the other

Surgical strategies for treatment of malignant pancreatic tumors: extended, standard or local surgery?

Tumor related pancreatic surgery has progressed significantly during recent years. Pancreatoduodenectomy (PD) with lymphadenectomy, including vascular resection, still presents the optimal surgical procedure for carcinomas in the head of pancreas. For patients with small or low-grade malignant neoplasms, as well as small pancreatic metastases located in the mid-portion of pancreas, central pancreatectomy (CP) is emerging as a safe and effective option with a low risk of developing de-novo exocrine and/or endocrine insufficiency. Total pancreatectomy (TP) is not as risky as it was years ago and can nowadays safely be performed, but its indication is limited to locally extended tumors that cannot be removed by PD or distal pancreatectomy (DP) with tumor free surgical margins. Consequently, TP has not been adopted as a routine procedure by most surgeons. On the other hand, an aggressive attitude is required in case of advanced distal pancreatic tumors, provided that safe and experienced surgery is available. Due to the development of modern instruments, laparoscopic operations became more and more successful, even in malignant pancreatic diseases. This review summarizes the recent literature on the abovementioned topics

TRPM2 promotes pancreatic cancer by PKC/MAPK pathway

Abstract The mechanism of pancreatic cancer (PA) is not fully understanded. In our last report, TRPM2 plays a promising role in pancreatic cancer. However, the mechanism of TRPM2 is still unknown in this dismal disease. This study was designed to investigate the role and mechanism of TRPM2 in pancreatic cancer. TRPM2 overexpressed and siRNA plasmid were created and transfected with pancreatic cancer cell line (BxPC-3) to construct the cell model. We employed CCK-8, Transwell, scratch wound, and nude mice tumor-bearing model to investigate the role of TRPM2 in pancreatic cancer. Besides, we collected the clinical data, tumor tissue sample (TT) and para-tumor sample (TP) from the pancreatic cancer patients treated in our hospital. We analyzed the mechanism of TRPM2 in pancreatic cancer by transcriptome analysis, western blot, and PCR. We blocked the downstream PKC/MEK pathway of TRPM2 to investigate the mechanism of TRPM2 in pancreatic cancer by CCK8, scratch wound healing, and transwell assays. Overexpressed TRPM2 could promote pancreatic cancer in proliferation, migration, and invasion ability in no matter the cell model or nude mice tumor-bearing model. TRPM2 level is highly negative correlated to the overall survival and progression-free survival time in PA patients, however, it is significantly increased in PA tissue as the tumor stage increases. The transcriptome analysis, GSEA analysis, western-blot, and PCR results indicate TRPM2 is highly correlated with PKC/MAPK pathways. The experiments of PKC/MEK inhibitors added to TRPM2 overexpressed BxPC-3 cell showed that significant inhibition of PA cells happened in CCK8, transwell, and wound-healing assay. TRPM2 may directly activate PKCα by calcium or indirectly activate PKCε and PKCδ by increased DAG in PA, which promote PA by downstream MAPK/MEK pathway activation

Detection of Simulated <i>In Vitro</i> Digestion Products of Fucoxanthin and Their Photodamage Alleviation Effect in Retinal Müller Cells Induced by Ultraviolet B Irradiation: A Proteomics Analysis

Our previous study reported that the marine dietary bioactive compound fucoxanthin (FX) has the potential to reduce the level of oxidation in retinal Müller cells (RMCs) induced by ultraviolet B (UVB) irradiation. However, the gastrointestinal environment can inhibit the bioavailability and absorption of FX in the cell systems. In the current study, FX was initially digested in a simulated in vitro gastrointestinal fluid. Nine main digestive products were identified, and the photoprotective activities of FX simulated in vitro gastrointestinal digestion products (FX-ID) were assessed in the same RMC model. FX-ID significantly reduced intracellular ROS and alleviated apoptosis. Western blot assays showed that FX-ID inhibited phosphorylated proteins in the MAPK and NF-κB signaling pathways. Our proteomics analysis revealed that the differentially expressed proteins were linked to biological networks associated with antioxidation and metabolic processes. The data may provide insight into the photoprotective mechanisms of FX-ID and promote the development of various functional foods to prevent retinal disorders

Managing Phase Orientation and Crystallinity of Printed Dion–Jacobson 2D Perovskite Layers via Controlling Crystallization Kinetics

Two-dimensional perovskites have attracted substantial attention for solar cell applications because of their higher stability as compared to their 3D analogs. To achieve efficient charge transport in thin-film devices, obtaining high crystalline perovskite crystals perpendicularly aligned to the substrate is of great importance. This article reports the scalable printing of high-quality Dion–Jacobson (DJ) perovskite thin films via tailoring crystallization kinetics. Introducing a small amount of 1-methyl-2-pyrrolidinone to the conventional N,N-dimethylformamide:dimethyl sulfoxide-based precursor, the strong coordination with ammonium spacers enables a notably retarded crystallization, which results in perovskite films with distinctly enhanced crystallinity, highly vertical orientation, and graded phase distribution. Accordingly, efficient charge generation and ultrafast interphase charge transfer are realized. The champion DJ perovskite device delivers a high current density of 17.10 mA cm–2, an impressive open-circuit voltage of 1.21 V, leading to a stabilized efficiency of 16.19%. In addition, the devices processed from the ternary solvent exhibit remarkably improved stability under stimuli with light, heat, and humidity, benefiting from their superb phase stability. This work demonstrates an important advancement in scalable deposition of DJ perovskite thin films for efficient and stable photovoltaic devices