Angiotensin II type 2 receptor ligand PD123319 attenuates hyperoxia-induced lung and heart injury at a low dose in newborn rats

Intervening in angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for bronchopulmonary dysplasia (BPD) by attenuating lung inflammation and preventing arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with PD123319 (0.5 and 2 mg·kg−1·day−1) on the beneficial effect of AT2 agonist LP2–3 (5 μg/kg twice a day) on RVH in newborn rats with hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of PD123319 (0.1 mg·kg−1·day−1) in two models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression. Ten days of coadministration of LP2–3 and PD123319 abolished the beneficial effects of LP2–3 on RVH in experimental BPD. In the early treatment model PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular collagen III deposition, and by preventing RVH. In the late treatment model PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations PD123319 blocks the beneficial effects of the AT2-agonist LP2–3 on RVH. At low concentrations PD123319 attenuates cardiopulmonary injury by reducing pulmonary inflammation and fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.

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Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

10.21203/rs.3.rs-16134/v1 ◽

2020 ◽

Author(s):

Yongfa Sun ◽

Lili Song ◽

Yong Zhang ◽

Hongjun Wang ◽

Xiao Dong

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Skin Damage ◽

Impaired Wound Healing ◽

Collagen Iii

Abstract BACKGROUND: Diabetic patients suffer from impaired wound healing. Mesenchymal stem cell (MSC) therapy represents a promising approach toward improving skin wound healing through release of soluble growth factors and cytokines that stimulate new vessel formation and modulate inflammation. Whether adipose-derived MSCs (ASCs) from type 2 diabetes donors are suitable for skin damage repair remains largely unknown. METHODS: In this study, we compared the phenotype and functionality of ASCs harvested from high fat diet (HFD) and streptozotocin (STZ)-induced T2D or control mice, and assessed their abilities to promote wound healing in an excisional wound splinting mouse model with T2D. RESULTS: T2D ASCs expressed similar cellular markers as control ASCs, but secreted less hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β). T2D ASCs were somewhat less effective in promoting healing of the wound, as manifested by slightly reduced re-epithelialization, cutaneous appendage regeneration, and collagen III deposition in wound tissues. In vitro, T2D ASCs promoted proliferation and migration of skin fibroblasts to a comparable extent as control ASCs via suppression of inflammation and macrophage infiltration. CONCLUSIONS: From these findings, we conclude that, although ASCs from T2D mice are marginally inferior to control ASCs, they possess comparable therapeutic effects in wound healing.

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Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00073.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. L264-L275 ◽

Cited By ~ 14

Author(s):

Gerry T. M. Wagenaar ◽

El Houari Laghmani ◽

Yvonne P. de Visser ◽

Rozemarijn M. A. Sengers ◽

Paul Steendijk ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Lung Injury ◽

Arterial Hypertension ◽

Right Ventricular ◽

Early Treatment ◽

Vascular Development ◽

Treatment Model ◽

Neonatal Rats ◽

Late Treatment ◽

Pulmonary Arterial

Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1–20 mg·kg−1·day−1) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with Nω-nitro-l-arginine methyl ester (l-NAME; 25 mg·kg−1·day−1) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by l-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.

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Metabolomic Approaches to Investigate the Effect of Metformin: An Overview

International Journal of Molecular Sciences ◽

10.3390/ijms221910275 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10275

Author(s):

Hyun Woo Kim

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Therapeutic Potential ◽

Metformin Treatment ◽

First Line ◽

Antidiabetic Drug ◽

Metabolic Alterations ◽

Beneficial Effects

Metformin is the first-line antidiabetic drug that is widely used in the treatment of type 2 diabetes mellitus (T2DM). Even though the various therapeutic potential of metformin treatment has been reported, as well as the improvement of insulin sensitivity and glucose homeostasis, the mechanisms underlying those benefits are still not fully understood. In order to explain the beneficial effects on metformin treatment, various metabolomics analyses have been applied to investigate the metabolic alterations in response to metformin treatment, and significant systemic metabolome changes were observed in biofluid, tissues, and cells. In this review, we compare the latest metabolomic research including clinical trials, animal models, and in vitro studies comprehensively to understand the overall changes of metabolome on metformin treatment.

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Adipose Stem Cells from Type 2 Diabetic Mice Exhibit Therapeutic Potential in Wound Healing

10.21203/rs.3.rs-16134/v2 ◽

2020 ◽

Author(s):

Yongfa Sun ◽

Lili Song ◽

Yong Zhang ◽

Hongjun Wang ◽

Xiao Dong

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Skin Damage ◽

Impaired Wound Healing ◽

Collagen Iii

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Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00360.2012 ◽

2013 ◽

Vol 305 (5) ◽

pp. L341-L351 ◽

Cited By ~ 46

Author(s):

Gerry T. M. Wagenaar ◽

El Houari Laghmani ◽

Melissa Fidder ◽

Rozemarijn M. A. Sengers ◽

Yvonne P. de Visser ◽

...

Keyword(s):

Angiotensin Ii ◽

Pulmonary Inflammation ◽

Renin Angiotensin System ◽

Inflammatory Cells ◽

Continuous Exposure ◽

Neonatal Rats ◽

Fibrin Deposition ◽

Beneficial Effects ◽

Stimulation Of

Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10–50 μg·kg−1·day−1] and AT2 [dKcAng-(1-7); 5–20 μg·kg−1·day−1]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with Nω-nitro-l-arginine methyl ester (25 mg·kg−1·day−1) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.

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Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22105351 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5351

Author(s):

Pascual Sanz ◽

José Maria Serratosa ◽

Marina P. Sánchez

Keyword(s):

Therapeutic Potential ◽

Neurological Diseases ◽

Special Focus ◽

Lafora Disease ◽

Beneficial Effects ◽

Progressive Myoclonus Epilepsy ◽

The Family ◽

Myoclonus Epilepsy ◽

The Central Nervous System

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

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Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects

International Journal of Molecular Sciences ◽

10.3390/ijms22115863 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5863

Author(s):

Giuseppe Palmiero ◽

Arturo Cesaro ◽

Erica Vetrano ◽

Pia Clara Pafundi ◽

Raffaele Galiero ◽

...

Keyword(s):

Heart Failure ◽

Glucose Transporter ◽

The Elderly ◽

Intracellular Sodium ◽

Clinical Effects ◽

Glucose Lowering ◽

Beneficial Effects ◽

Glucose Transporter 2 ◽

Function Impairment

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients’ exposure to gliflozins’ treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.

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