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5-iodotubercidin sensitizes cells to RIPK1-dependent necroptosis by interfering with NFκB signaling
(2023)
Receptor-interacting protein kinases (RIPK) −1 and −3 are master regulators of cell fate decisions in response to diverse stimuli and are subjected to multiple checkpoint controls. Earlier studies have established the presence of distinct IKK1/2 and p38/MK2-dependent checkpoints which suppress RIPK1 activation by directly phosphorylating it at different residues. In the present study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and show that MK2-deficiency or inactivation predominantly results in necroptotic cell death, even in the absence of caspase inhibition. While MK2-deficient cells can be rescued from necroptosis by RIPK1 inhibitors, RIPK3 inhibition seems to revert the process triggering apoptosis. To understand the mechanism of this necroptosis switch, we screened a 149-compound kinase inhibitor library for compounds which preferentially sensitize MK2-deficient MEFs to TNF-induced cell death. The most potent inhibitor identified was 5-Iodotubericidin, an adenosine analogue acting as adenosine kinase and protein kinase inhibitor. 5-ITu also potentiated LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-Iodotubericidin induces RIPK1-dependent necroptosis in the absence of MK2 activity by suppressing IKK signaling. The identification of this role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis will have potential implications in RIPK1-targeted therapies.
The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.
Osteosynthesematerialien aus resorbierbaren Materialien finden aufgrund ihrer zunehmenden biomechanischen Stabilität eine immer höhere Akzeptanz. Die vorgelegte Untersuchung vergleicht die knöcherne und okklusale Stabilität von solchen Osteosynthesesystemen aus resorbierbaren Materialien im Vergleich mit konventionellen Titanminiplatten in der orthognathen Chirurgie. Untersucht wurden 100 Patienten in einem Nachsorgezeitraum von bis zu 4 Jahren. Die Beurteilung erfolgte klinisch und röntgenologisch anhand von Fernröntgen-Seiten-Aufnahmen. In die Studie gingen ein fünfzig Patienten, die mit resorbierbaren Platten versorgt worden waren, 16 davon mit Polylactid-Polyglycolid Copolymer Platten und 34 Patienten mit 70:30 Poly-L/DL-Lactid Copolymer Platten; fünfzig weitere Patienten, versorgt mit einem Titanminiplattensystem wurden als Kontrollgruppe gewertet. Zunächst konnte gezeigt werden, dass die Gruppen zueinander homogen waren, es unterschieden sich die effektiven intraoperativen Bewegungen von Studien und Kontrollgruppe statistisch nicht signifikant, gleiches galt im Vergleich der resorbierbaren Platten untereinander. Bei der Datenauswertung konnte nachgewiesen werden, dass die absolute und relative Instabilität weder zwischen den Studiengruppen noch der Kontrollgruppe noch zwischen den resorbierbaren Plattensystemen untereinander signifikant unterschiedlich war. Die postoperative 1-Jahres Stabilität unterschied sich dabei ebenfalls nicht signifikant von der 4-Jahres Stabilität. Alle untersuchten Osteosynthesesysteme zeigten im Oberkiefer eine höhere Stabilität als im Unterkiefer und gleichzeitig eine größere Stabilität in der anterior-posterioren Richtung als in der inferior-superioren Richtung. Es wurden keine signifikanten Unterschiede zwischen der klinischen Stabilität von PLGA oder P(L/DL)LA-Miniplatten gefunden. Allerdings konnte auch belegt werden, dass der Einsatz resorbierbarer Unterkieferosteosynthesen eine sehr gute Compliance des Patienten bezüglich geführter Okklusion und Nachsorge voraussetzte. Als nachteilig bei den resorbierbaren Systemen konnte sowohl für den Oberkiefer als auch für den Unterkiefer eine leicht erhöhte Mobilität bis zu 6 Wochen nach der Operation festgestellt werden, die jedoch in keinem Fall das operative Ergebnis beeinflusste. Vielmehr ermöglichten resorbierbare Osteosynthesen eine bessere postoperative okklusale Einstellung. Weiteren Nachteil der resorbierbaren Osteosynthesesysteme bedeuten die hohen Kosten, die heute noch weit über denen von Titanminiplatten liegen. Zukünftige Entwicklungen gehen dahin, das Plattendesign weiter zu optimieren, wie z.B. neuartige pinbasierte Fixationssysteme einzusetzen, wie sie in der Extremitätenchirurgie teils bereits benutzt werden. Fernziel für die Zukunft ist die Entwicklung eines resorbierbaren Osteosynthesesystems, das sich bei geringen Herstellungskosten und miniaturisiertem Plattendesign auch minimalinvasiv einbringen lässt.
Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre-existing disease condition. Therapy remains predominantly symptom-based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
Purpose of the study: There is a clinical need for antiretroviral therapy (ART) regimens that simplify dosing and make adherence easier for specific patient groups such as former intravenous drug users (IVDU) receiving opiate substitution. Availability of tenofovir DF (TDF) and other once-daily (OD) agents could offer a viable OD regimen. The 3OD study was designed to evaluate the use of OD HAART in IVDU patients.
Methods: 3OD was a single-arm, multicentre, 48-weeks trial to assess efficacy, tolerability and adherence to a OD TDF-containing HAART regimen in former IVDU patients receiving opiate substitution. Of 67 patients enrolled, 27 were antiretroviral treatment naïve, 10 were virologically suppressed (<400 copies/mL), and 30 were re-starting HAART without prior virological failure. Opiate substitution was adjusted according to subject symptoms of opiate overdosing or withdrawal. Various methods were used to assess adherence: besides pill count, patients were asked to fill in a MASRI (Medication Adherence Self-Report Inventory) questionnaire and an electronic log pad diary. Calculation of adherence by pill count assumed that unreturned pills had been taken by the subjects.
Summary of results: Overall, 55% (n = 37, ITT, M = F) of patients had viral load <400 copies/mL at week 48. Using an ITT, M = E analysis, 90% (37/41) of patients reached undetectable VL (<400 copies/mL), 56% (23/41 patients) had plasma HIV-1 RNA concentrations <50 copies/mL at week 48. Only 30 patients (45%) completed the full study and the follow-up period. In 51% of patients, TDF adherence was >100% using pill count. MASRI showed adherence rates of 80–100% in 83–85% of patients; however, 15 patients never entered any data. Diary data were entered by 57 patients; diary data were entered for fewer days than patients received treatment (mean difference 113 days, calculated from treatment start and stop dates).
Conclusion: TDF in combination with other OD antiretrovirals in former IVDU patients showed comparable efficacy to that seen in the average HIV-1 infected population. However, measurement of adherence to self-administered HAART via pill count, MASRI or diary may be misleading in this population.
Background: Recent advances in 3D printing technology have enabled the emergence of new educational and clinical tools for medical professionals. This study provides an exemplary description of the fabrication of 3D‐printed individualised patient models and assesses their educational value compared to cadaveric models in oral and maxillofacial surgery.
Methods: A single‐stage, controlled cohort study was conducted within the context of a curricular course. A patient's CT scan was segmented into a stereolithographic model and then printed using a fused filament 3D printer. These individualised patient models were implemented and compared against cadaveric models in a curricular oral surgery hands‐on course. Students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out. P‐values were calculated using the Mann‐Whitney U test.
Results: Thirty‐eight fourth‐year dental students participated in the study. Overall, significant differences between the two models were found in the student assessment. Whilst the cadaveric models achieved better results in the haptic feedback of the soft tissue, the 3D‐printed individualised patient models were regarded significantly more realistic with regard to the anatomical correctness, the degree of freedom of movement and the operative simulation. At 3.46 € (compared to 6.51 €), the 3D‐printed patient individualised models were exceptionally cost‐efficient.
Conclusions: 3D‐printed patient individualised models presented a realistic alternative to cadaveric models in the undergraduate training of operational skills in oral and maxillofacial surgery. Whilst the 3D‐printed individualised patient models received positive feedback from students, some aspects of the model leave room for improvement.
In Bone Tissue Engineering (BTE), autologous bone-regenerative cells are combined with a scaffold for large bone defect treatment (LBDT). Microporous, polylactic acid (PLA) scaffolds showed good healing results in small animals. However, transfer to large animal models is not easily achieved simply by upscaling the design. Increasing diffusion distances have a negative impact on cell survival and nutrition supply, leading to cell death and ultimately implant failure. Here, a novel scaffold architecture was designed to meet all requirements for an advanced bone substitute. Biofunctional, porous subunits in a load-bearing, compression-resistant frame structure characterize this approach. An open, macro- and microporous internal architecture (100 µm–2 mm pores) optimizes conditions for oxygen and nutrient supply to the implant’s inner areas by diffusion. A prototype was 3D-printed applying Fused Filament Fabrication using PLA. After incubation with Saos-2 (Sarcoma osteogenic) cells for 14 days, cell morphology, cell distribution, cell survival (fluorescence microscopy and LDH-based cytotoxicity assay), metabolic activity (MTT test), and osteogenic gene expression were determined. The adherent cells showed colonization properties, proliferation potential, and osteogenic differentiation. The innovative design, with its porous structure, is a promising matrix for cell settlement and proliferation. The modular design allows easy upscaling and offers a solution for LBDT.
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.
Popular media now often present 3D printing as a widely employed technology for the production of dental prostheses. This article aims to show, based on factual information, to what extent 3D printing can be used in dental laboratories and dental practices at present. It attempts to present a rational evaluation of todays´ applications of 3D printing technology in the context of dental restorations. In addition, the article discusses future perspectives and examines the ongoing viability of traditional dental laboratory services and manufacturing processes. It also shows which expertise is needed for the digital additive manufacturing of dental restorations.