Functional screening identifies miRNAs with a novel function inhibiting Vascular Smooth Muscle Cell proliferation.

Proliferation of vascular smooth muscle cells (vSMCs) is a crucial contributor to pathological vascular remodelling. MicroRNAs (miRNAs) are powerful gene regulators and attractive therapeutic agents. Here, we aim to systematically identify and characterise miRNAs with therapeutic potential in targeting vSMC proliferation.

Endothelial-to-mesenchymal transition enhances permissiveness to AAV vectors in cardiac endothelial cells.

A major obstacle in inducing therapeutic angiogenesis in the heart is inefficient gene transfer to endothelial cells (ECs). Here, we identify compounds able to enhance the permissiveness of cardiac ECs to adeno-associated virus (AAV) vectors, which stand as ideal tools for in vivo gene delivery. We screened a library of >1,500 US Food and Drug Administration (FDA)-approved drugs, in combination with AAV vectors, in cardiac ECs.

Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis.

Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung.

The p-rpS6-zone delineates wounding responses and the healing process.

The spatial boundaries of tissue response to wounding are unknown. Here, we show that in mammals, the ribosomal protein S6 (rpS6) is phosphorylated in response to skin injury, forming a zone of activation surrounding the region of the initial insult. This p-rpS6-zone forms within minutes after wounding and is present until healing is complete.

Ischemic wound revascularization by the stromal vascular fraction relies on host-donor hybrid vessels.

Nonhealing wounds place a significant burden on both quality of life of affected patients and health systems. Skin substitutes are applied to promote the closure of nonhealing wounds, although their efficacy is limited by inadequate vascularization. The stromal vascular fraction (SVF) from the adipose tissue is a promising therapy to overcome this limitation.

The role of senescence in cellular plasticity: Lessons from regeneration and development and implications for age-related diseases.

Senescence is a cellular state which involves cell cycle arrest and a proinflammatory phenotype, and it has traditionally been associated with cellular and organismal aging. However, increasing evidence suggests key roles in tissue growth and regrowth, especially during development and regeneration. Conversely, cellular plasticity-the capacity of cells to undergo identity change, including differentiation and dedifferentiation-is associated with development and regeneration but is now being investigated in the context of age-related diseases such as Alzheimer disease.

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction.

Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation.

Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice.

Promises and challenges of senolytics in skin regeneration, pathology and ageing.

The research of the last two decades has defined a crucial role of cellular senescence in both the physiology and pathology of skin, and senescent cells have been detected in conditions including development, regeneration, aging, and disease. The pathophysiology of cellular senescence in skin is complex as the phenotype of senescence pertains to several different cell types including fibroblasts, keratinocytes and melanocytes, among others. Paradoxically, the transient presence of senescent cells is believed to be beneficial in the context of development and wound healing, while the chronic presence of senescent cells is detrimental in the context of aging, diseases, and chronic wounds, which afflict predominantly the elderly.

A Polyphenol-Rich Extract of Olive Mill Wastewater Enhances Cancer Chemotherapy Effects, While Mitigating Cardiac Toxicity.

Cardiovascular toxicity remains one of the most adverse side effects in cancer patients receiving chemotherapy. Extra-virgin olive oil (EVOO) is rich in cancer preventive polyphenols endowed with anti-inflammatory, anti-oxidant activities which could exert protective effects on heart cells. One very interesting derivative of EVOO preparation is represented by purified extracts from olive mill waste waters (OMWW) rich in polyphenols.

miR-200 family members reduce senescence and restore idiopathic pulmonary fibrosis type II alveolar epithelial cell transdifferentiation.

Rationale: Alveolar type II (ATII) cells act as adult stem cells contributing to alveolar type I (ATI) cell renewal and play a major role in idiopathic pulmonary fibrosis (IPF), as supported by familial cases harbouring mutations in genes specifically expressed by these cells. During IPF, ATII cells lose their regenerative potential and aberrantly express pathways contributing to epithelial-mesenchymal transition (EMT). The microRNA miR-200 family is downregulated in IPF, but its effect on human IPF ATII cells remains unproven.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation.

Fibrosis is a hallmark in the pathogenesis of various diseases, with very limited therapeutic solutions. A key event in the fibrotic process is the expression of contractile proteins, including α-smooth muscle actin (αSMA) by fibroblasts, which become myofibroblasts. Here, we report the results of a high-throughput screening of a library of approved drugs that led to the discovery of haloperidol, a common antipsychotic drug, as a potent inhibitor of myofibroblast activation.

Is early detection of late-onset Pompe disease a pneumologist's affair? A lesson from an Italian screening study.

Background: Late-onset Pompe disease (LOPD) is a recessive disease caused by α-glucosidase (GAA) deficiency, leading to progressive muscle weakness and/or respiratory failure in children and adults. Respiratory derangement can be the first indication of LOPD, but the diagnosis may be difficult for pneumologists. We hypothesize that assessing the GAA activity in suspected patients by a dried blood spot (DBS) may help the diagnosis of LOPD in the pneumological setting.

HPV-16 virions can remain infectious for 2 weeks on senescent cells but require cell cycle re-activation to allow virus entry.

Successful infection with Human Papillomaviruses requires mitosis, when incoming viral genomes gain access to nuclear components. However, very little is known about how long HPV particles can remain infectious in non-dividing cells or in which cellular compartments these viruses may reside. To investigate these questions we have used BJ cells as a reversible model of senescence and show that HPV-16 can only infect early-passage proliferating cells.

Identification of HSP90 inhibitors as a novel class of senolytics.

Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging.

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.

Background: Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis.

Objectives: This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy.