Assessment of neuroprotective effects of gamma-hydroxybutyrate and neurosteroids on cellular models of Alzheimer’s disease

This PhD work showed that GHB and neurosteroids efficiently protect neuroblastoma cells against nerve cell death caused by Alzheimer's disease etiological factors including amyloid precursor protein overexpression and oxidative stress. Interestingly, an additive action of GHB and allopregnanolone was identified that may result from the combination of partial stimulation of anti-apoptotic protein expression induced by both compounds. GHB protective effect was blocked by aromatase inhibitors, suggesting that GHB may also induce neuroprotection via the activation of neurosteroidogenesis. Finally, we have used a yeast-based MMP activity assay to check whether GHB and neurosteroids can regulate the activity of human MMP-2 and MMP-9, which both control Aβ peptide degradation. Although we cannot yet conclude from our preliminary results, further improvement of the experimental setup in combination with RT-qPCR and western analyzes in human neuroblastoma cells will help to determine the modulatory action of GHB and neurosteroids on MMP activity and/or expression. Together, our data suggest that GHB and neurosteroids may be used to develop combined neuroprotective strategies against neuronal loss in Alzheimer disease.In der vorliegenden Doktorarbeit konnte gezeigt werden, dass Gamma-Hydroxybutyrat (GHB) und Neurosteroide effektiv in der Lage sind, Neuroblastoma Zellen vor den ätiologischen Faktoren der Alzheimer-Krankheit, darunter insbesondere durch oxidativen Stress und Überexpression von Amyloid-Precursor-Proteinen verursachten Zelltod, zu schützen. Interessanterweise wurde eine additive neuroprotektive Wirkung von GHB und Allopregnanolon gegen den durch oxidativen Stress induzierten Zelltod beobachtet. Diese additive Wirkung ist vermutlich auf eine spezifische Aktivierung von anti-apoptotischen Signalwegen durch GHB und Allopregnanolon zurückzuführen. Die Schutzwirkung von GHB wurde durch Aromatase-Inhibitoren blockiert, was darauf schließen lässt, dass GHB möglicherweise die Neurosteroidogenese aktiviert. Abschließend wurde mit Hilfe eines Hefe-basierten MMP-Aktivitätstests überprüft, ob GHB und/oder Neurosteroide die Aktivität von humanem MMP-2 bzw. MMP-9, welche den Abbau von Aβ-Peptiden kontrollieren, direkt beeinflussen. Auch wenn mit dem verwendeten Testsystem noch kein signifikanter Effekt von GHB und Neurosteroiden beobachtet wurde, sollte eine weitere Optimierung des Testsystems kombiniert mit RT-qPCR und Western-Analysen an humanen Neuroblastoma Zellen dazu beitragen, mögliche regulatorische Effekte von GHB und Neurosteroiden auf die MMP-Aktivitat und -Expression zu bestimmen. Zusammenfassend deuten die vorliegenden Daten darauf hin, dass GHB und Neurosteroide möglicherweise als kombinierte Neuroprotektiva in der Alzheimer-Therapie Anwendung finden könnten

Assessment of neuroprotective effects of gamma-hydroxybutyrate and neurosteroids on cellular models of Alzheimer’s disease

This PhD work showed that GHB and neurosteroids efficiently protect neuroblastoma cells against nerve cell death caused by Alzheimer's disease etiological factors including amyloid precursor protein overexpression and oxidative stress. Interestingly, an additive action of GHB and allopregnanolone was identified that may result from the combination of partial stimulation of anti-apoptotic protein expression induced by both compounds. GHB protective effect was blocked by aromatase inhibitors, suggesting that GHB may also induce neuroprotection via the activation of neurosteroidogenesis. Finally, we have used a yeast-based MMP activity assay to check whether GHB and neurosteroids can regulate the activity of human MMP-2 and MMP-9, which both control Aβ peptide degradation. Although we cannot yet conclude from our preliminary results, further improvement of the experimental setup in combination with RT-qPCR and western analyzes in human neuroblastoma cells will help to determine the modulatory action of GHB and neurosteroids on MMP activity and/or expression. Together, our data suggest that GHB and neurosteroids may be used to develop combined neuroprotective strategies against neuronal loss in Alzheimer disease.In der vorliegenden Doktorarbeit konnte gezeigt werden, dass Gamma-Hydroxybutyrat (GHB) und Neurosteroide effektiv in der Lage sind, Neuroblastoma Zellen vor den ätiologischen Faktoren der Alzheimer-Krankheit, darunter insbesondere durch oxidativen Stress und Überexpression von Amyloid-Precursor-Proteinen verursachten Zelltod, zu schützen. Interessanterweise wurde eine additive neuroprotektive Wirkung von GHB und Allopregnanolon gegen den durch oxidativen Stress induzierten Zelltod beobachtet. Diese additive Wirkung ist vermutlich auf eine spezifische Aktivierung von anti-apoptotischen Signalwegen durch GHB und Allopregnanolon zurückzuführen. Die Schutzwirkung von GHB wurde durch Aromatase-Inhibitoren blockiert, was darauf schließen lässt, dass GHB möglicherweise die Neurosteroidogenese aktiviert. Abschließend wurde mit Hilfe eines Hefe-basierten MMP-Aktivitätstests überprüft, ob GHB und/oder Neurosteroide die Aktivität von humanem MMP-2 bzw. MMP-9, welche den Abbau von Aβ-Peptiden kontrollieren, direkt beeinflussen. Auch wenn mit dem verwendeten Testsystem noch kein signifikanter Effekt von GHB und Neurosteroiden beobachtet wurde, sollte eine weitere Optimierung des Testsystems kombiniert mit RT-qPCR und Western-Analysen an humanen Neuroblastoma Zellen dazu beitragen, mögliche regulatorische Effekte von GHB und Neurosteroiden auf die MMP-Aktivitat und -Expression zu bestimmen. Zusammenfassend deuten die vorliegenden Daten darauf hin, dass GHB und Neurosteroide möglicherweise als kombinierte Neuroprotektiva in der Alzheimer-Therapie Anwendung finden könnten

Transcatheter aortic valve replacement in the management of aortic insufficiency secondary to left ventricular assist device implantation: a case report

background: left ventricular assist device (LVAD) is considered either a destination therapy for patients with end-stage heart failure or heart transplantation bridging. LVAD implantation often causes aortic insufficiency (AI), which requires aortic valve repair. however, severe acute aI does not respond well to medication, and re-operation means higher risk to the patients; the most effective therapeutic strategies for LVAD-induced AI still need further exploration. In this report, we present the first described case of new-onset, severe LVAD-induced aI in china with a patient who underwent transcatheter aortic valve replacement (TAVR) and achieved significant improvement in functional capacity and symptoms with lower operation risk. case description: a 55-year-old male patient was diagnosed with dilated cardiomyopathy for 14 years. The effect of the medication gradually deteriorated, LVAD (HeartCon®) was implanted one year earlier. the patient complained of intermittent chest tightness for one week, which had been aggravated for two days before hospitalization. echocardiographic findings revealed new-onset, severe LVAD-induced AI. TAVR was performed with a self-expandable stent-valve (TAV30, vitaflow Liberty). within minutes, the patient recovered with rapid disappearance of chest tightness and stable vital signs. before discharge, the position of the artificial valve was fixed without incomplete closure nor thrombus attachment, yielding a left ventricular ejection fraction (LVEF) of 35%. the patient was hospitalized for 38 days, and followed up with outpatient treatment, the condition was stable until 19 June 2023. conclusions: TAVR could be an effective, safe, and less invasive means of restoring ejection fraction for patients with a LVAD who develop severe AI

The role of hemoadsorption in cardiac surgery - a systematic review

BACKGROUND: Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting. METHODS: A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms "cardiac surgery" and "hemoadsorption". The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view. RESULTS: The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb$^{®}$ therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability. CONCLUSIONS: The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy