The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target.

Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.

Targeting endothelial thioredoxin-interacting protein (TXNIP) protects from metabolic disorder-related impairment of vascular function and post-ischemic revascularisation.

INTRODUCTION: Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo. METHODS AND RESULTS: To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation. CONCLUSION: Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders.

Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo.

Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biologic functions, the contribution of endothelial TXNIP has not been well defined. To investigate the endothelial function of TXNIP, we generated a TXNIP knockout mouse on the Cdh5-cre background (TXNIPfl/fl cdh5cre). Control (TXNIPfl/fl) and TXNIPfl/fl cdh5cre mice were fed a high protein-low carbohydrate (HP-LC) diet for 3 mo to induce metabolic stress. We found that TXNIPfl/fl and TXNIPfl/fl cdh5cre mice on an HP-LC diet displayed impaired glucose tolerance and dyslipidemia concretizing the metabolic stress induced. We evaluated the impact of this metabolic stress on mice with reduced endothelial TXNIP expression with regard to arterial structure and function. TXNIPfl/fl cdh5cre mice on an HP-LC diet exhibited less endothelial dysfunction than littermate mice on an HP-LC diet. These mice were protected from decreased aortic medial cell content, impaired aortic distensibility, and increased plasminogen activator inhibitor 1 secretion. This protective effect came with lower oxidative stress and lower inflammation, with a reduced NLRP3 inflammasome expression, leading to a decrease in cleaved IL-1ß. We also show the major role of TXNIP in inflammation with a knockdown model, using a TXNIP-specific, small interfering RNA included in a lipoplex. These findings demonstrate a key role for endothelial TXNIP in arterial impairments induced by metabolic stress, making endothelial TXNIP a potential therapeutic target.-Bedarida, T., Domingues, A., Baron, S., Ferreira, C., Vibert, F., Cottart, C.-H., Paul, J.-L., Escriou, V., Bigey, P., Gaussem, P., Leguillier, T., Nivet-Antoine, V. Reduced endothelial thioredoxin-interacting protein protects arteries from damage induced by metabolic stress in vivo.

Potential Clinical Applications of Stem Cells in Regenerative Medicine.

The field of regenerative medicine is looking for a pluripotent/multipotent stem cell able to differentiate across germ layers and be safely employed in therapy. Unfortunately, with the exception of hematopoietic stem/progenitor cells (HSPCs) for hematological applications, the current clinical results with stem cells are somewhat disappointing. The potential clinical applications of the more primitive embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have so far been discouraging, as both have exhibited several problems, including genomic instability, a risk of teratoma formation, and the possibility of rejection. Therefore, the only safe stem cells that have so far been employed in regenerative medicine are monopotent stem cells, such as the abovementioned HSPCs or mesenchymal stem cells (MSCs) isolated from postnatal tissues. However, their monopotency, and therefore limited differentiation potential, is a barrier to their broader application in the clinic. Interestingly, results have accumulated indicating that adult tissues contain rare, early-development stem cells known as very small embryonic-like stem cells (VSELs), which can differentiate into cells from more than one germ layer. This chapter addresses different sources of stem cells for potential clinical application and their advantages and problems to be solved.

[Impact of Geriatric Drug Guidelines on the Quality Requirement of Elderly Patients]. / Impact d'un livret thérapeutique sur la qualité des prescriptions médicamenteuses des résidents d'EHPAD.

OBJECTIVE: Elderly with several pathologies are usually treated with many drugs, and are exposed to a majored risk of drug-induced adverse effects. A network of local nursing homes (EHPAD) in the south Seine-Saint-Denis area (France) created a geriatric drug guidelines to improve the quality of the drugs prescriptions. This study assesses the conformity of prescriptions in elderly patients prior and after the distribution of the booklet. METHODS: This before and after design study focused on the drug prescriptions for patients in eight EHPAD followed for two randomly given days in 2012 (n = 503) and 2013 (n = 334). The geriatric drug guidelines included a list of medicines suitable for the elderly (conformity list) and recommendations for prescription and monitoring. Data collection was conducted from medical records and interviews with coordinators doctors and nursing staff in nursing homes. A 6 items-quality score was calculated, ranging from 0 (lowest quality) to 6 (highest quality). RESULTS: Median age, weight and creatinine level were respectively 88 years, 61.0 kg, and 74.9 µmol/L (prior) and 88 years, 59.6 kg, and 77.0 µmol/L (after). Median times of latest serum creatinine dosage were 112 days (prior) and 108 days (after). The median number of prescribed drugs was 8 per resident during the two period of study. The conformity rate of prescription was better prior the distribution of the guidelines, respectively 87.5% and 80.0% (p<10⁻³). The average formal quality score was better after the distribution of the booklet increasing form 4.23 to 4.40 points (p<10⁻4). For high risk inducing drugs, monitoring was prescribed in 34.2% (prior) and 32.4% (after). CONCLUSIONS: This study shows that the drug geriatric guidelines does not improve prescription conformity and monitoring for high risk drugs, but it does significantly improve the median formal quality score.

Combined Transplantation of Human MSCs and ECFCs Improves Cardiac Function and Decrease Cardiomyocyte Apoptosis After Acute Myocardial Infarction.

BACKGROUND: Ischemic heart disease, often caused by an acute myocardial infarction (AMI) is one of the leading causes of morbidity and mortality worldwide. Despite significant advances in medical and procedural therapies, millions of AMI patients progress to develop heart failure every year. METHODS: Here, we examine the combination therapy of human mesenchymal stromal cells (MSCs) and endothelial colony-forming cells (ECFCs) to reduce the early ischemic damage (MSCs) and enhance angiogenesis (ECFCs) in a pre-clinical model of acute myocardial infarction. NOD/SCID mice were subjected to AMI followed by transplantation of MSCs and ECFCs either alone or in combination. Cardiomyocyte apoptosis and cardiac functional recovery were assessed in short- and long-term follow-up studies. RESULTS: At 1 day after AMI, MSC- and ECFC-treated animals demonstrated significantly lower cardiomyocyte apoptosis compared to vehicle-treated animals. This phenomenon was associated with a significant reduction in infarct size, cardiac fibrosis, and improvement in functional cardiac recovery 4 weeks after AMI. CONCLUSIONS: The use of ECFCs, MSCs, and the combination of both cell types reduce cardiomyocyte apoptosis, scar size, and adverse cardiac remodeling, compared to vehicle, in a pre-clinical model of AMI. These results support the use of this combined cell therapy approach in future human studies during the acute phase of ischemic cardiac injury.

Neuropilin 1 Regulation of Vascular Permeability Signaling.

The vascular endothelium acts as a selective barrier to regulate macromolecule exchange between the blood and tissues. However, the integrity of the endothelium barrier is compromised in an array of pathological settings, including ischemic disease and cancer, which are the leading causes of death worldwide. The resulting vascular hyperpermeability to plasma molecules as well as leukocytes then leads to tissue damaging edema formation and inflammation. The vascular endothelial growth factor A (VEGFA) is a potent permeability factor, and therefore a desirable target for impeding vascular hyperpermeability. However, VEGFA also promotes angiogenesis, the growth of new blood vessels, which is required for reperfusion of ischemic tissues. Moreover, edema increases interstitial pressure in poorly perfused tumors, thereby affecting the delivery of therapeutics, which could be counteracted by stimulating the growth of new functional blood vessels. Thus, targets must be identified to accurately modulate the barrier function of blood vessels without affecting angiogenesis, as well as to develop more effective pro- or anti-angiogenic therapies. Recent studies have shown that the VEGFA co-receptor neuropilin 1 (NRP1) could be playing a fundamental role in steering VEGFA-induced responses of vascular endothelial cells towards angiogenesis or vascular permeability. Moreover, NRP1 is involved in mediating permeability signals induced by ligands other than VEGFA. This review therefore focuses on current knowledge on the role of NRP1 in the regulation of vascular permeability signaling in the endothelium to provide an up-to-date landscape of the current knowledge in this field.

Novel view of the adult stem cell compartment - a developmental story of germline and parental imprinting.

Evidence has accumulated that postnatal tissues contain developmentally early stem cells that remain in a dormant state as well as stem cells that are more proliferative, supplying tissue-specific progenitor cells and thus playing a more active role in the turnover of adult tissues. The most primitive, dormant, postnatal tissue-derived stem cells, called very small embryonic like stem cells (VSELs), are regulated by epigenetic changes in the expression of certain parentally imprinted genes, a molecular phenomenon previously described for maintaining primordial germ cells (PGCs) in a quiescent state. Specifically, they show erasure of parental imprinting at the Igf2-H19 locus, which keeps them in a quiescent state in a similar manner as migrating PGCs. To date, the presence of these cells in adult postnatal tissues have been demonstrated by at least 25 independent laboratories. We envision that similar changes in expression of parentally imprinted genes may also play a role in the quiescence of dormant VSELs present in other non-hematopoietic tissues. Recent data indicate that VSELs expand in vivo and in vitro after reestablishment of somatic imprinting at the Igf2-H19 locus by nicotinamide treatment in response to stimulation by pituitary gonadotrophins (follicle stimulating factor, luteinizing hormone and prolactin) and gonadal androgens and estrogens. These cells could be also successfully expanded ex vivo in the presence of the small molecule UM177.

ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking.

Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to a local "sterile" inflammation of brain or due to a systemic inflammation process that affects the central nervous system. This is supported by the observation that in peripheral blood of psychotic patients are detectable several mediators and markers of inflammation as well as clinical data on correlations between systemic chronic inflammatory processes and psychiatric disorders. This may explain why some reported anti-inflammatory treatment strategies have beneficial effects on ameliorating psychotic events. In this review we will present a concept that aberrant purinergic signaling and increases in extracellular level of adenosine triphosphate (ATP) in the brain parenchyma may lead to activation of Nlrp3 inflammasome in microglia cells and as a consequence microglia released danger associated molecular pattern (DAMP) proteins activate complement cascade (ComC) in mannan binding lectin (MBL) - dependent manner. Activation of ATP-Nlrp3 inflammasome-ComC axis may also orchestrate trafficking of stem cells released from bone marrow into peripheral blood observed in psychotic patients. Based on this, the ATP-Nlrp3 inflammasome-ComC axis may become a target for new therapeutic approaches, which justifies the development and clinical application of efficient anti-inflammatory treatment strategies targeting this axis in psychiatry.