Constitutive, Basal, and β-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor D Induces Release of the Inflammatory Cytokine IL-6 and Is Dependent on NF-κB Signaling

G protein-coupled receptors (GPCRs) have emerged as key players in regulating (patho)physiological processes, including inflammation. Members of the Mas-related G protein coupled receptors (MRGPRs), a subfamily of GPCRs, are largely expressed by sensory neurons and known to modulate itch and pain. Several members of MRGPRs are also expressed in mast cells, macrophages, and in cardiovascular tissue, linking them to pseudo-allergic drug reactions and suggesting a pivotal role in the cardiovascular system. However, involvement of the human Mas-related G-protein coupled receptor D (MRGPRD) in the regulation of the inflammatory mediator interleukin 6 (IL-6) has not been demonstrated to date. By stimulating human MRGPRD-expressing HeLa cells with the agonist β-alanine, we observed a release of IL-6. β-alanine-induced signaling through MRGPRD was investigated further by probing downstream signaling effectors along the Gαq/Phospholipase C (PLC) pathway, which results in an IkB kinases (IKK)-mediated canonical activation of nuclear factor kappa-B (NF-κB) and stimulation of IL-6 release. This IL-6 release could be blocked by a Gαq inhibitor (YM-254890), an IKK complex inhibitor (IKK-16), and partly by a PLC inhibitor (U-73122). Additionally, we investigated the constitutive (ligand-independent) and basal activity of MRGPRD and concluded that the observed basal activity of MRGPRD is dependent on the presence of fetal bovine serum (FBS) in the culture medium. Consequently, the dynamic range for IL-6 detection as an assay for β-alanine-mediated activation of MRGPRD is substantially increased by culturing the cells in FBS free medium before treatment. Overall, the observation that MRGPRD mediates the release of IL-6 in an in vitro system, hints at a role as an inflammatory mediator and supports the notion that IL-6 can be used as a marker for MRGPRD activation in an in vitro drug screening assay.

Polylactic Acid Piezo-Biopolymers: Chemistry, Structural Evolution, Fabrication Methods, and Tissue Engineering Applications

Polylactide acid (PLA), as an FDA-approved biomaterial, has been widely applied due to its unique merits, such as its biocompatibility, biodegradability, and piezoelectricity. Numerous utilizations, including sensors, actuators, and bio-application—its most exciting application to promote cell migration, differentiation, growth, and protein–surface interaction—originate from the piezoelectricity effect. Since PLA exhibits piezoelectricity in both crystalline structure and an amorphous state, it is crucial to study it closely to understand the source of such a phenomenon. In this respect, in the current study, we first reviewed the methods promoting piezoelectricity. The present work is a comprehensive review that was conducted to promote the low piezoelectric constant of PLA in numerous procedures. In this respect, its chemistry and structural origins have been explored in detail. Combining any other variables to induce a specific application or to improve any PLA barriers, namely, its hydrophobicity, poor electrical conductivity, or the tuning of its mechanical properties, especially in the application of cardiovascular tissue engineering, is also discussed wherever relevant.

Graphene-Based Scaffolds: Fundamentals and Applications for Cardiovascular Tissue Engineering

Cardiac tissue engineering requires materials that can faithfully recapitulate and support the native in vivo microenvironment while providing a seamless bioelectronic interface. Current limitations of cell scaffolds include the lack of electrical conductivity and suboptimal mechanical properties. Here we discuss how the incorporation of graphene into cellular scaffolds, either alone or in combination with other materials, can affect morphology, function, and maturation of cardiac cells. We conclude that graphene-based scaffolds hold great promise for cardiac tissue engineering.

Decellularized bovine aorta as a promising 3D elastin scaffold for vascular tissue engineering applications

Aim: To evaluate the suitability of using aorta elastin scaffold, in combination with human adipose-derived mesenchymal stem cells (hAd-MSCs), as an approach for cardiovascular tissue engineering. Materials & Methods: Human adipose-derived MSCs were seeded on elastin samples of decellularized bovine aorta. The samples were cultured in vitro to investigate the inductive effects of this scaffold on the cells. The results were evaluated using histological, and immunohistochemical methods, as well as MTT assay, DNA content, reverse transcription-PCR and scanning electron microscopy. Results: Histological staining and DNA content confirmed the efficacy of decellularization procedure (82% DNA removal). MTT assay showed the construct’s ability to support cell viability and proliferation. Cell differentiation was confirmed by reverse transcription-PCR and positive immunohistochemistry for alfa smooth muscle actin and von Willebrand. Conclusion: The prepared aortic elastin samples act as a potential scaffold, in combination with MSCs, for applications in cardiovascular tissue engineering. Further experiments in animal models are required to confirm this.

Future Perspectives of Cardiovascular Biomarker Utilization in Cancer Survivors: A Scientific Statement From the American Heart Association

Improving cancer survival represents the most significant effect of precision medicine and personalized molecular and immunologic therapeutics. Cardiovascular health becomes henceforth a key determinant for the direction of overall outcomes after cancer. Comprehensive tissue diagnostic studies undoubtedly have been and continue to be at the core of the fight against cancer. Will a systemic approach integrating circulating blood-derived biomarkers, multimodality imaging technologies, strategic panomics, and real-time streams of digitized physiological data overcome the elusive cardiovascular tissue diagnosis in cardio-oncology? How can such a systemic approach be personalized for application in day-to-day clinical work, with diverse patient populations, cancer diagnoses, and therapies? To address such questions, this scientific statement approaches a broad definition of the biomarker concept. It summarizes the current literature on the utilization of a multitude of established cardiovascular biomarkers at the intersection with cancer. It identifies limitations and gaps of knowledge in the application of biomarkers to stratify the cardiovascular risk before cancer treatment, monitor cardiovascular health during cancer therapy, and detect latent cardiovascular damage in cancer survivors. Last, it highlights areas in biomarker discovery, validation, and clinical application for concerted efforts from funding agencies, scientists, and clinicians at the cardio-oncology nexus.

Nesfatin-1 inhibits free fatty acids (FFAs)-induced endothelial inflammation via Gfi1/NF-κB signaling

Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFAs mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFAs-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase (LDH) release and production of inflammatory factors were observed in FFAs treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFAs treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFAs-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFAs-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.

Extracellular Matrix-Based Biomaterials for Cardiovascular Tissue Engineering

Regenerative medicine and tissue engineering strategies have made remarkable progress in remodeling, replacing, and regenerating damaged cardiovascular tissues. The design of three-dimensional (3D) scaffolds with appropriate biochemical and mechanical characteristics is critical for engineering tissue-engineered replacements. The extracellular matrix (ECM) is a dynamic scaffolding structure characterized by tissue-specific biochemical, biophysical, and mechanical properties that modulates cellular behavior and activates highly regulated signaling pathways. In light of technological advancements, biomaterial-based scaffolds have been developed that better mimic physiological ECM properties, provide signaling cues that modulate cellular behavior, and form functional tissues and organs. In this review, we summarize the in vitro, pre-clinical, and clinical research models that have been employed in the design of ECM-based biomaterials for cardiovascular regenerative medicine. We highlight the research advancements in the incorporation of ECM components into biomaterial-based scaffolds, the engineering of increasingly complex structures using biofabrication and spatial patterning techniques, the regulation of ECMs on vascular differentiation and function, and the translation of ECM-based scaffolds for vascular graft applications. Finally, we discuss the challenges, future perspectives, and directions in the design of next-generation ECM-based biomaterials for cardiovascular tissue engineering and clinical translation.

Mechano-regulated cell–cell signaling in the context of cardiovascular tissue engineering

Cardiovascular tissue engineering (CVTE) aims to create living tissues, with the ability to grow and remodel, as replacements for diseased blood vessels and heart valves. Despite promising results, the (long-term) functionality of these engineered tissues still needs improvement to reach broad clinical application. The functionality of native tissues is ensured by their specific mechanical properties directly arising from tissue organization. We therefore hypothesize that establishing a native-like tissue organization is vital to overcome the limitations of current CVTE approaches. To achieve this aim, a better understanding of the growth and remodeling (G&R) mechanisms of cardiovascular tissues is necessary. Cells are the main mediators of tissue G&R, and their behavior is strongly influenced by both mechanical stimuli and cell–cell signaling. An increasing number of signaling pathways has also been identified as mechanosensitive. As such, they may have a key underlying role in regulating the G&R of tissues in response to mechanical stimuli. A more detailed understanding of mechano-regulated cell–cell signaling may thus be crucial to advance CVTE, as it could inspire new methods to control tissue G&R and improve the organization and functionality of engineered tissues, thereby accelerating clinical translation. In this review, we discuss the organization and biomechanics of native cardiovascular tissues; recent CVTE studies emphasizing the obtained engineered tissue organization; and the interplay between mechanical stimuli, cell behavior, and cell–cell signaling. In addition, we review past contributions of computational models in understanding and predicting mechano-regulated tissue G&R and cell–cell signaling to highlight their potential role in future CVTE strategies.

Protective effect of melatonin in atherosclerotic cardiovascular disease: A comprehensive review

Heart failure is characterized by the heart losing its capacity to pump sufficient blood to match the body’s demand. It is caused by a variety of cardiovascular impairments. Among them, atherosclerosis is the most common one. Although, a variety of medicines selectively target this pathology, the death rate due to atherosclerosis associated heart disorders remain high. To address this issue, the use of antioxidants combined with conventional therapy to achieve synergistic effects has gained popularity. Melatonin is one of such antioxidants. In addition to its potent antioxidant activity, this molecule acts in harmony to protect the cardiovascular tissue. This review explores the various mechanisms by which melatonin protects the cardiovascular tissue. This information will contribute further insights into the role of melatonin in maintaining cardiovascular homeostasis in normal as well as in pathological conditions. It will also help us to better understand the potential synergistic effects of melatonin with conventional therapy to successfully target the heart failure associated with atherosclerosis.