Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation.

Rationale: WW domain-containing oxidoreductase ( ) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation.

Methods: mice, generated by CRISPR/Cas9, and mice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection.

Loss of Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the precapillary pulmonary arteries. Genomic variation within the T-box 4 (TBX4) transcription factor is the second most common genetic cause of PAH, and can also cause severe lung developmental disorders with neonatal PH. Currently, the effect of TBX4 loss-of-function on later stages of lung development and predisposition to lung disease, including PH, is not well understood.

Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Background: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.

Methods: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects.

Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction.

Background: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling.

Methods: Using skeletal muscle-specific knockout mice () and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF.

Effect of estrogen receptor α on cardiopulmonary adaptation to chronic developmental hypoxia in a rat model.

Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaptation to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA.

SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.

Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis.

Complex enameloid microstructure of †Ischyrhiza mira rostral denticles.

Serving in a foraging or self-defense capacity, pristiophorids, pristids, and the extinct sclerorhynchoids independently evolved an elongated rostrum lined with modified dermal denticles called rostral denticles. Isolated rostral denticles of the sclerorhynchoid Ischyrhiza mira are commonly recovered from Late Cretaceous North American marine deposits. Although the external morphology has been thoroughly presented in the literature, very little is known about the histological composition and organization of these curious structures.

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin.

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling.

Transcriptomic modifications in developmental cardiopulmonary adaptations to chronic hypoxia using a murine model of simulated high-altitude exposure.

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia.

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Objective: Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension.

Investigational new drug enabling angiotensin oral-delivery studies to attenuate pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1-7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality.

Complementary Embryonic and Adult Cell Populations Enhance Myocardial Repair in Rat Myocardial Injury Model.

We compared the functional outcome of Isl-1 cardiac progenitors, CD90 bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1 cells were isolated from embryonic day 12.5 (E12.

Therapeutic Use of Adipose-Derived Stromal Cells in a Murine Model of Acute Pancreatitis.

Background: No specific therapy exists for acute pancreatitis (AP), and current treatment remains entirely supportive. Adipose stem cells (ASCs) have significant immunomodulatory and regenerative activities. We hypothesized that systemic administration of ASCs would mitigate inflammation in AP.

Cigarette Smoking Impairs Adipose Stromal Cell Vasculogenic Activity and Abrogates Potency to Ameliorate Ischemia.

Cigarette smoking (CS) adversely affects the physiologic function of endothelial progenitor, hematopoietic stem and progenitor cells. However, the effect of CS on the ability of adipose stem/stromal cells (ASC) to promote vasculogenesis and rescue perfusion in the context of ischemia is unknown. To evaluate this, ASC from nonsmokers (nCS-ASC) and smokers (CS-ASC), and their activity to promote perfusion in hindlimb ischemia models, as well as endothelial cell (EC) survival and vascular morphogenesis in vitro were assessed.

Mucosal Perfusion Preservation by a Novel Shapeable Tissue Expander for Oral Reconstruction.

Background: There are few methods for expanding oral mucosa, and these often cause complications such as tissue necrosis and expander eruption. This study examines mucosal blood perfusion following insertion of a novel shapeable hydrogel tissue expander (HTE). The canine model used subgingival insertion of HTE following tooth extraction and alveolar bone reduction.

Human Adipose-Derived Stem Cells Suppress Elastase-Induced Murine Abdominal Aortic Inflammation and Aneurysm Expansion Through Paracrine Factors.

Abdominal aortic aneurysm (AAA) is a potentially lethal disease associated with immune activation-induced aortic degradation. We hypothesized that xenotransplantation of human adipose-derived stem cells (hADSCs) would reduce aortic inflammation and attenuate expansion in a murine AAA model. Modulatory effects of ADSCs on immune cell subtypes associated with AAA progression were investigated using human peripheral blood mononuclear cells (hPBMNCs) cocultured with ADSCs.

17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension.

17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve).

Pulmonary Retention of Adipose Stromal Cells Following Intravenous Delivery Is Markedly Altered in the Presence of ARDS.

Transplantation of mesenchymal stromal cells (MSCs) has been shown to effectively prevent lung injury in several preclinical models of acute respiratory distress syndrome (ARDS). Since MSC therapy is tested in clinical trials for ARDS, there is an increased need to define the dynamics of cell trafficking and organ-specific accumulation. We examined how the presence of ARDS changes retention and organ-specific distribution of intravenously delivered MSCs isolated from subcutaneous adipose tissue [adipose-derived stem cells (ADSCs)].

Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis.

Background: Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS.

Methods: To assess the effect of ASC-CM on ARDS indices, intravenous delivery of ASC and ASC-CM to C57Bl/6 mice was carried out 4 h after LPS oropharyngeal aspiration; Evans Blue Dye (EBD) was injected intravenously 1 h prior to animal sacrifice (48 h post-LPS).

Human adipose-derived stem cells ameliorate cigarette smoke-induced murine myelosuppression via secretion of TSG-6.

Objective: Bone marrow-derived hematopoietic stem and progenitor cells (HSC/HPC) are critical to homeostasis and tissue repair. The aims of this study were to delineate the myelotoxicity of cigarette smoking (CS) in a murine model, to explore human adipose-derived stem cells (hASC) as a novel approach to mitigate this toxicity, and to identify key mediating factors for ASC activities.

Methods: C57BL/6 mice were exposed to CS with or without i.

Muscle-derived Gr1(dim)CD11b(+) cells enhance neovascularization in an ischemic hind limb mouse model.

Gr1(+)CD11b(+) cells are characterized as myeloid-derived suppressor cells potentially involved in angiogenesis. We demonstrate that Gr1(+)CD11b(+) cells isolated from ischemic muscle in a hind-limb ischemic C57BL/6 mouse model play a role in vessel formation after ischemic injury. Gr1(dim)CD11b(+) cells, a subpopulation of Gr1(+)CD11b(+) cells, within skeletal muscle were increased in context of ischemia.

IFATS collection: Human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function.

The administration of therapeutic cell types, such as stem and progenitor cells, has gained much interest for the limitation or repair of tissue damage caused by a variety of insults. However, it is still uncertain whether the morphological and functional benefits are mediated predominantly via cell differentiation or paracrine mechanisms. Here, we assessed the extent and mechanisms of adipose-derived stromal/stem cells (ASC)-dependent tissue repair in the context of acute myocardial infarction.

Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization.

The use of adipose-derived stem/stromal cells (ASCs) for promoting repair of tissues is a promising potential therapy, but the mechanisms of their action are not fully understood. We and others previously demonstrated accelerated reperfusion and tissue salvage by ASCs in peripheral ischemia models and have shown that ASCs secrete physiologically relevant levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor. The specific contribution of HGF to ASC potency was determined by silencing HGF expression.

Sclerosing therapy as first line treatment for low flow vascular lesions of the orbit.

Purpose: To evaluate the outcome of sodium morrhuate 5% injections in patients with low flow vascular lesions, which consist of orbital lymphangiomas, and in one patient with intraosseous cavernous hemangioma.

Design: Prospective, interventional consecutive case series.

Methods: Intralesional sodium morrhuate 5% was injected under direct visualization or under radiographic guidance to six patients with orbital lymphangiomas and one patient with intraosseous cavernous hemangioma.