Experimental Models of Abdominal Aortic Aneurysms

Despite being a leading cause of death in the West, the pathophysiology of abdominal aortic aneurysms (AAA) is still incompletely understood. Pharmacotherapy to reduce the growth of small AAAs is limited and techniques for repairing aneurysms continue to evolve. Experimental models play a key role in AAA research, as they allow a detailed evaluation of the pathogenesis of disease progression. This review focuses on in vivo experimental models, which have improved our understanding of the potential mechanisms of AAA development and contributed to the advancement of new treatments

The Emerging Role of TLR and Innate Immunity in Cardiovascular Disease

Cardiovascular disease is a complex disorder involving multiple pathophysiological processes, several of which involve activation of toll-like receptors (TLRs) of the innate immune system. As sentinels of innate immunity TLRs are nonclonally germline-encoded molecular pattern recognition receptors that recognize exogenous as well as tissue-derived molecular dangers signals promoting inflammation. In addition to their expression in immune cells, TLRs are found in other tissues and cell types including cardiomyocytes, endothelial and vascular smooth muscle cells. TLRs are differentially regulated in various cell types by several cardiovascular risk factors such as hypercholesterolemia, hyperlipidemia, and hyperglycemia and may represent a key mechanism linking chronic inflammation, cardiovascular disease progression, and activation of the immune system. Modulation of TLR signaling by specific TLR agonists or antagonists, alone or in combination, may be a useful therapeutic approach to treat various cardiovascular inflammatory conditions such as atherosclerosis, peripheral arterial disease, secondary microvascular complications of diabetes, autoimmune disease, and ischemia reperfusion injury. In this paper we discuss recent developments and current evidence for the role of TLR in cardiovascular disease as well as the therapeutic potential of various compounds on inhibition of TLR-mediated inflammatory responses

Polyhexamethylene Biguanide: Polyurethane Blend Nanofibrous Membranes for Wound Infection Control

Polyhexamethylene biguanide (PHMB) is a broad-spectrum antiseptic which avoids many efficacy and toxicity problems associated with antimicrobials, in particular, it has a low risk of loss of susceptibility due to acquired antimicrobial resistance. Despite such advantages, PHMB is not widely used in wound care, suggesting more research is required to take full advantage of PHMB’s properties. We hypothesised that a nanofibre morphology would provide a gradual release of PHMB, prolonging the antimicrobial effects within the therapeutic window. PHMB:polyurethane (PU) electrospun nanofibre membranes were prepared with increasing PHMB concentrations, and the effects on antimicrobial activities, mechanical properties and host cell toxicity were compared. Overall, PHMB:PU membranes displayed a burst release of PHMB during the first hour following PBS immersion (50.5–95.9% of total released), followed by a gradual release over 120 h (≤25 wt % PHMB). The membranes were hydrophilic (83.7–53.3°), gradually gaining hydrophobicity as PHMB was released. They displayed superior antimicrobial activity, which extended past the initial release period, retained PU hyperelasticity regardless of PHMB concentration (collective tensile modulus of 5–35% PHMB:PU membranes, 3.56 ± 0.97 MPa; ultimate strain, >200%) and displayed minimal human cell toxicity (<25 wt % PHMB). With further development, PHMB:PU electrospun membranes may provide improved wound dressings

Comparison of gene expression between human and mouse iPSC-derived cardiomyocytes for stem cell therapies of cardiovascular defects via bioinformatic analysis

Background: Preclinical studies have demonstrated the potential use of induced pluripotent stem cells (iPSCs) to treat cardiovascular disease (CVD). In vivo preclinical studies conducted on animal models (murine, porcine, guinea pig, etc.) have employed either syngeneic or human-derived iPSCs. However, no study has been carried out to investigate and report the key genetic differences between the human and animal-derived iPSCs. Our study analysed the gene expression profile and molecular pathway patterns underlying the differentiation of both human and mouse iPSCs to iPSC-cardiomyocytes (iPSC-CMs), and the differences between them via bioinformatic analysis. Method: Data sets were downloaded from the Gene Expression Omnibus (GEO) database and included both human and mouse models, and the data for undifferentiated iPSCs and iPSC-CMs were isolated from each. Differentially expressed genes (DEGs) were screened and then analysed. The website g:Profiler was used to obtain the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Protein-protein interaction (PPI) networks of the DEGs were constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and Cytoscape software. The subclusters were then extracted from the PPI network for further analysis. Results: iPSC-derived cardiomyocytes expressed many genes related to vascular, endothelial, and smooth muscle repair in the human iPSC-CMs, and prevention of calcification in the mouse iPSC-CMs with clear differences in gene expression, which will affect how iPSCs act in research. Especially in the human iPSC-CMs, and also prevention of calcification processes in the mouse data. The identified differences in gene expression of iPSCs derived from the two species suggests that in vivo studies using mouse iPSC-CMs may not reflect those in humans. Conclusion: The study provides new insights into the key genes related to the iPSCs, including genes related to angiogenesis, calcification, and striated muscle, endothelium, and bone formation. Moreover, the clear differences between both mouse and human-derived iPSCs have been identified, which could be used as new evidence and guidance for developing novel targeted therapy strategies to improve the therapeutic effects of iPSC treatment in cardiovascular defects

The importance of inflammation control for the treatment of chronic diabetic wounds

Diabetic chronic wounds cause massive levels of patient suffering and economic problems worldwide. The state of chronic inflammation arises in response to a complex combination of diabetes mellitus-related pathophysiologies. Advanced treatment options are available; however, many wounds still fail to heal, exacerbating morbidity and mortality. This review describes the chronic inflammation pathophysiologies in diabetic ulcers and treatment options that may help address this dysfunction either directly or indirectly. We suggest that treatments to reduce inflammation within these complex wounds may help trigger healing

Potential of Novel EPO Derivatives in Limb Ischemia

Erythropoietin (EPO) has tissue-protective properties, but it increases the risk of thromboembolism by raising the haemoglobin concentration. New generation of EPO derivatives is tissue protective without the haematopoietic side effects. Preclinical studies have demonstrated their effectiveness and safety. This paper summarizes the development in EPO derivatives with emphasis on their potential use in critical limb ischaemia

Nitric Oxide Manipulation: A Therapeutic Target for Peripheral Arterial Disease?

Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD

Toll-Like Receptors in Ischaemia and Its Potential Role in the Pathophysiology of Muscle Damage in Critical Limb Ischaemia

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI