Vitamin A as a Transcriptional Regulator of Cardiovascular Disease

Vitamin A is a micronutrient and signaling molecule that regulates transcription, cellular differentiation, and organ homeostasis. Additionally, metabolites of Vitamin A are utilized as differentiation agents in the treatment of hematological cancers and skin disorders, necessitating further study into the effects of both nutrient deficiency and the exogenous delivery of Vitamin A and its metabolites on cardiovascular phenotypes. Though vitamin A/retinoids are well-known regulators of cardiac formation, recent evidence has emerged that supports their role as regulators of cardiac regeneration, postnatal cardiac function, and cardiovascular disease progression. We here review findings from genetic and pharmacological studies describing the regulation of both myocyte- and vascular-driven cardiac phenotypes by vitamin A signaling. We identify the relationship between retinoids and maladaptive processes during the pathological hypertrophy of the heart, with a focus on the activation of neurohormonal signaling and fetal transcription factors (Gata4, Tbx5). Finally, we assess how this information might be leveraged to develop novel therapeutic avenues

Towards adipose tissue-derived stromal cells-based therapy for diabetic retinopathy

In this thesis, we investigated the impact of hyperglycemia on adipose tissue-derived stromal cells (ASC) as a prelude to their use in the future therapeutic treatment of diabetic retinopathy (DR). Ultrastructure analyses of co-cultured ASC-endothelial cells featured the pericytic role of ASC in the maintenance of the vascular architecture under normal and high glucose conditions. The ROS-induced mitochondrial dysfunction and hyperglycemia-induced apoptosis partially influenced the pericytic functions of ASC. Injected ASC into an angiogenic mouse models, were detected at pericytic positions on newly formed vessels. Our recommendation is to preculturing of ASC under ‘chronic’ hyperglycemia, before injecting into a hyperglycemic environment to reduce their expression of pro-inflammatory and pro-angiogenic genes. ASC-conditioned medium (ASC-Cme) delivered from ASC cultured in chronically HG, protected bovine retinal endothelial cells (BREC) from hyperglycemia-induced apoptosis and inflammatory activation. This effect on BREC was evoked by the ROS-neutralizing capacity of ASC-Cme in culture that was associated with a reduced NF-κB activation which showed as a downmodulation of HG-upregulated pro-inflammatory genes in BREC. Towards using ASC for treatment of DR, we present a new hypothermic storing technique of cells in their own culture medium to well-maintain and transport the prepared cells to their clinical destination. The new pharmacologic compound, (6-hydroxyl-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl) methanone (SUL-109) shields ASC during cell preservation from hypothermic cell death without influencing their multi-potency capacity and proliferation through maintenance of the mitochondrial membrane potential and promoting the activation of mitochondrial complexes I and IV, consequently sustaining ATP production and preventing the overproduction of ROS under hypothermic conditions

Influence of cell culture conditions and enhanced expression of genes of interest in optimization of dopaminergic neuron generation

Parkinsonova bolest (PB) je neurološki poremećaj koji je karakteriziran gubitkom mezencefaličkih dopaminergičkih (DA) neurona. Proizvodnja ovog tipa stanica omogućit će novi terapijski pristup koji trenutno nedostaje. Naime, trenutni farmakološki i kirurški tretmani ublažavaju simptome Parkinsonove bolesti, ali niti jedna terapija ne može spriječiti ili zaustaviti progresivni patološki učinak. Živčane matične stanice izolirane iz ventralnog mezencefaličkog ljudskog tkiva predstavljaju snažan istraživački alat i kandidati su za terapiju transplantacije stanica u PD. Istraživačka grupa dr. Martinez-Serrana razvila je besmrtnu staničnu liniju hNSCs uvođenjem gena v-myc ptičjeg retrovirusa u stanice. Ove stanične linije sadrže sva izvorna svojstva neuralnih matičnih stanica koje su u mogućnosti proliferirati u DAn. Ranije je pokazano da se prisiljenom ekspresijom gena Bcl-XL povećava razina dopaminergičnih neurona, no anti-apoptotička priroda Bcl-XL čini ga protoonkogenom pa se ne može koristiti u kliničke svrhe. Stoga je potrebno pronaći sigurnije gene sličnog učinka. Testirani geni od interesa su CDKN1C, GADD45G, GFRA1, INSM1 i NHLH1. Imunocitokemijska analiza pokazala je da geni GADD45G, GFRA1, INSM1 induciraju ekspresiju DA biljega, tirozin hidroksilaze i predstavljaju obećavajuću zamjenu za Bcl-xL. Dodatci za medije, B-27, N-2 i SCM005, testirani su kako bi se optimiziralo kultiviranje hNSC-a. Nije bilo značajnih razlika u učinkovitosti navedenih medijskih dodataka.Parkinson’s disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. The generation of this cell type will fulfill a currently unmet therapeutic need. Current pharmacological and surgical treatments alleviate parkinsonian symptoms, but none can prevent or stop the progressive pathology effect. Human neural stem cells derived from the ventral mesencephalon are powerful research tools and candidates for cell therapies in PD. The Dr. Martinez-Serrano research group were able to develop an immortalized cell line of hNSCs by introducing the avian retroviral v-myc gene into the cells. The cell lines provide all the genuine properties of NSC that act as precursors of human DAn. Previous studies proved that a forced expression of Bcl-xL enhance the generation of dopaminergic neurons. The anti-apoptotic nature of Bcl-xL makes it a protooncogene that cannot be used for clinical applications. Therefore it is necessary to find an alternative and safer genes which can work in a similar way. The selected genes of interest that were tested were CDKN1C, GADD45G, GFRA1, INSM1 and NHLH1. Immunocytochemical analysis demonstrated that GADD45G, GFRA1, INSM1 genes induced the expression of the DA marker, tyrosine hydroxylase, and could be good substitutes of Bcl-xL. Media supplements, B-27, N-2 and SCM005, were tested to optimize hNSC culturing. No substantial difference was recorded between media supplements

Untersuchungen zu pathophysiologischen Merkmalen des Morbus Niemann-Pick Typ C1

Morbus Niemann-Pick Typ C1 (NPC1) ist eine seltene autosomal rezessive, lysosomale Lipidose, die sich durch eine Akkumulation von Cholesterol in den Lysosomen auszeichnet. Ziel der Arbeiten war es, ein humanes neuronales in vitro Zellmodellsystem für NPC1 zu entwickeln. Hierzu wurden NPC1 patientenspezifische Fibroblasten in patientenspezifische IPS-Zellen reprogrammiert. Diese wurden in Neurone und Gliazellen differenziert und hinsichtlich der Ausprägung von pathophysiologischen Merkmalen, als Beleg für die Verwendbarkeit der Zellen als NPC1 in vitro Modellsystem, untersucht.Niemann-Pick type C1 (NPC1) disease is a rare autosomal recessive lysosomal lipidosis, characterized by an accumulation of cholesterol in the lysosomes. The aim of the work was to develop a human neural in vitro cell model system for NPC1. For this purpose NPC1 patient-specific fibroblasts were reprogrammed into patient-specific induced pluirpotent stem cells (IPSCs). These IPSCs were differentiated into neurons and glial cells and examined with regard to the expression of pathophysiological features of NPC1, to evidence the feasibility of the cells as a NPC1 in vitro model system

Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury

Characterisation of calcium signalling and functional development in an immortalised human neural progenitor cell line

The development of an immortalised hNPC line, ReNcell VM, was investigated in standard cell cultures and after transplantation on to hippocampal organotypical brain slice cultures. Whole cell patch clamp recordings and Calcium imaging were used to characterise the functional development during proliferation and differentiation. The findings of this study provide insights into the functional properties of hNPCs, and identify a new method by which their development might be controlled in culture

Neuronal stem cell-drug interactions : a systematic review and meta-analysis

Stem cell therapy is a promising treatment option for neurodegenerative diseases that mostly affect geriatric patients who often suffer from comorbidities requiring multiple medications. However, not much is known about the interactions between stem cells and drugs. Here, we focus on the potential interactions between drugs used to treat the comorbidities or sequelae of neurodegenerative diseases and neuronal stem cells to reveal potential effects on drug safety and efficacy. To determine the potential effects of drugs frequently used in geriatric patients (analgesic, antibiotic, antidepressant, antidiabetic, antihyperlipidemic, and antihypertensive drugs) on neuronal stem cell differentiation and proliferation, we systematically searched PubMed to identify nonreview articles published in English in peer‐reviewed journals between January 1, 1991, and June 7, 2018. We identified 5,954 publications, of which 214 were included. Only 62 publications provided the complete data sets required for meta‐analysis. We found that antidepressants stimulated neuronal stem cell proliferation but not differentiation under physiologic conditions and increased the proliferation of stem cells in the context of stress. Several other potential interactions were identified, but the limited number of available data sets precludes robust conclusions. Although available data were in most cases insufficient to perform robust meta‐analysis, a clear interaction between antidepressants and neuronal stem cells was identified. We reveal other potential interactions requiring further experimental investigation. We recommend that future research addresses such interactions and investigates the best combination of pharmacological interventions and neuronal stem cell treatments for more efficient and safer patient care. Stem Cells Translational Medicine 2019;8:1202–121