Class I and II Histone Deacetylase Inhibitors as Therapeutic Modulators of Dilated Cardiac Tissue-Derived Mesenchymal Stem/Stromal Cells.

The prevalence of dilated cardiomyopathy (DCM) is increasing globally, highlighting the need for innovative therapeutic approaches to prevent its onset. In this study, we examined the energetic and epigenetic distinctions between dilated and non-dilated human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) and assessed the effects of class I and II HDAC inhibitors (HDACi) on these cells and their cardiomyogenic differentiation. Cells were isolated from myocardium biopsies using explant outgrowth methods. Mitochondrial and histone deacetylase activities, ATP levels, cardiac transcription factors, and structural proteins were assessed using flow cytometry, PCR, chemiluminescence, Western blotting, and immunohistochemistry. The data suggest that the tested HDAC inhibitors improved acetylation and enhanced the energetic status of both types of cells, with significant effects observed in dilated myocardium-derived hmMSCs. Additionally, the HDAC inhibitors activated the cardiac transcription factors Nkx2-5, HOPX, GATA4, and Mef2C, and upregulated structural proteins such as cardiac troponin T and alpha cardiac actin at both the protein and gene levels. In conclusion, our findings suggest that HDACi may serve as potential modulators of the energetic status and cardiomyogenic differentiation of human heart hmMSCs. This avenue of exploration could broaden the search for novel therapeutic interventions for dilated cardiomyopathy, ultimately leading to improvements in heart function.

Human nasal microbiota shifts in healthy and chronic respiratory disease conditions.

BACKGROUND: An increasing number of studies investigate various human microbiotas and their roles in the development of diseases, maintenance of health states, and balanced signaling towards the brain. Current data demonstrate that the nasal microbiota contains a unique and highly variable array of commensal bacteria and opportunistic pathogens. However, we need to understand how to harness current knowledge, enrich nasal microbiota with beneficial microorganisms, and prevent pathogenic developments. RESULTS: In this study, we have obtained nasal, nasopharyngeal, and bronchoalveolar lavage fluid samples from healthy volunteers and patients suffering from chronic respiratory tract diseases for full-length 16 S rRNA sequencing analysis using Oxford Nanopore Technologies. Demographic and clinical data were collected simultaneously. The microbiome analysis of 97 people from Lithuania suffering from chronic inflammatory respiratory tract disease and healthy volunteers revealed that the human nasal microbiome represents the microbiome of the upper airways well. CONCLUSIONS: The nasal microbiota of patients was enriched with opportunistic pathogens, which could be used as indicators of respiratory tract conditions. In addition, we observed that a healthy human nasal microbiome contained several plant- and bee-associated species, suggesting the possibility of enriching human nasal microbiota via such exposures when needed. These candidate probiotics should be investigated for their modulating effects on airway and lung epithelia, immunogenic properties, neurotransmitter content, and roles in maintaining respiratory health and nose-brain interrelationships.

The Effect of CaV1.2 Inhibitor Nifedipine on Chondrogenic Differentiation of Human Bone Marrow or Menstrual Blood-Derived Mesenchymal Stem Cells and Chondrocytes.

Cartilage is an avascular tissue and sensitive to mechanical trauma and/or age-related degenerative processes leading to the development of osteoarthritis (OA). Therefore, it is important to investigate the mesenchymal cell-based chondrogenic regenerating mechanisms and possible their regulation. The aim of this study was to investigate the role of intracellular calcium (iCa2+) and its regulation through voltage-operated calcium channels (VOCC) on chondrogenic differentiation of mesenchymal stem/stromal cells derived from human bone marrow (BMMSCs) and menstrual blood (MenSCs) in comparison to OA chondrocytes. The level of iCa2+ was highest in chondrocytes, whereas iCa2+ store capacity was biggest in MenSCs and they proliferated better as compared to other cells. The level of CaV1.2 channels was also highest in OA chondrocytes than in other cells. CaV1.2 antagonist nifedipine slightly suppressed iCa2+, Cav1.2 and the proliferation of all cells and affected iCa2+ stores, particularly in BMMSCs. The expression of the CaV1.2 gene during 21 days of chondrogenic differentiation was highest in MenSCs, showing the weakest chondrogenic differentiation, which was stimulated by the nifedipine. The best chondrogenic differentiation potential showed BMMSCs (SOX9 and COL2A1 expression); however, purposeful iCa2+ and VOCC regulation by blockers can stimulate a chondrogenic response at least in MenSCs.

The Effects of Mechanical Load on Chondrogenic Responses of Bone Marrow Mesenchymal Stem Cells and Chondrocytes Encapsulated in Chondroitin Sulfate-Based Hydrogel.

Articular cartilage is vulnerable to mechanical overload and has limited ability to restore lesions, which leads to the development of chronic diseases such as osteoarthritis (OA). In this study, the chondrogenic responses of human bone marrow mesenchymal stem cells (BMMSCs) and OA cartilage-derived chondrocytes in 3D chondroitin sulfate-tyramine/gelatin (CS-Tyr)/Gel) hydrogels with or without experimental mechanical load have been investigated. Chondrocytes were smaller in size, had slower proliferation rate and higher level of intracellular calcium (iCa2+) compared to BMMSCs. Under 3D chondrogenic conditions in CS-Tyr/Gel with or without TGF-ß3, chondrocytes more intensively secreted cartilage oligomeric matrix protein (COMP) and expressed collagen type II (COL2A1) and aggrecan (ACAN) genes but were more susceptible to mechanical load compared to BMMSCs. ICa2+ was more stably controlled in CS-Tyr/Gel/BMMSCs than in CS-Tyr/Gel/chondrocytes ones, through the expression of L-type channel subunit CaV1.2 (CACNA1C) and Serca2 pump (ATP2A2) genes, and their balance was kept more stable. Due to the lower susceptibility to mechanical load, BMMSCs in CS-Tyr/Gel hydrogel may have an advantage over chondrocytes in application for cartilage regeneration purposes. The mechanical overload related cartilage damage in vivo and the vague regenerative processes of OA chondrocytes might be associated to the inefficient control of iCa2+ regulating channels.

Chondroitin Sulfate-Tyramine-Based Hydrogels for Cartilage Tissue Repair.

The degradation of cartilage, due to trauma, mechanical load or diseases, results in abundant loss of extracellular matrix (ECM) integrity and development of osteoarthritis (OA). Chondroitin sulfate (CS) is a member of the highly sulfated glycosaminoglycans (GAGs) and a primary component of cartilage tissue ECM. In this study, we aimed to investigate the effect of mechanical load on the chondrogenic differentiation of bone marrow mesenchymal stem cells (BM-MCSs) encapsulated into CS-tyramine-gelatin (CS-Tyr/Gel) hydrogel in order to evaluate the suitability of this composite for OA cartilage regeneration studies in vitro. The CS-Tyr/Gel/BM-MSCs composite showed excellent biointegration on cartilage explants. The applied mild mechanical load stimulated the chondrogenic differentiation of BM-MSCs in CS-Tyr/Gel hydrogel (immunohistochemical collagen II staining). However, the stronger mechanical load had a negative effect on the human OA cartilage explants evaluated by the higher release of ECM components, such as the cartilage oligomeric matrix protein (COMP) and GAGs, compared to the not-compressed explants. Finally, the application of the CS-Tyr/Gel/BM-MSCs composite on the top of the OA cartilage explants decreased the release of COMP and GAGs from the cartilage explants. Data suggest that the CS-Tyr/Gel/BM-MSCs composite can protect the OA cartilage explants from the damaging effects of external mechanical stimuli. Therefore, it can be used for investigation of OA cartilage regenerative potential and mechanisms under the mechanical load in vitro with further perspectives of therapeutic application in vivo.

Human airway and lung microbiome at the crossroad of health and disease (Review).

The evolving field of the microbiome and microbiota has become a popular research topic. The human microbiome is defined as a new organ and is considered a living community of commensal, symbiotic and pathogenic microorganisms within a certain body space. The term 'microbiome' is used to define the entire genome of the microbiota. Bacteria, archaea, fungi, algae and small protists are all members of the microbiota, followed by phages, viruses, plasmids and mobile genetic elements. The composition, heterogeneity and dynamics of microbiomes in time and space, their stability and resistance, essential characteristics and key participants, as well as interactions within the microbiome and with the host, are crucial lines of investigation for the development of successful future diagnostics and therapies. Standardization of microbiome studies and harmonized comparable methodologies are required for the transfer of knowledge from fundamental science into the clinic. Human health is dependent on microbiomes and achieved by nurturing beneficial resident microorganisms and their interplay with the host. The present study reviewed scientific knowledge on the major components of the human respiratory microbiome, i.e. bacteria, viruses and fungi, their symbiotic and parasitic roles, and, also, major diseases of the human respiratory tract and their microbial etiology. Bidirectional relationships regulate microbial ecosystems and host susceptibility. Moreover, environmental insults render host tissues and microbiota disease-prone. The human respiratory microbiome reflects the ambient air microbiome. By understanding the human respiratory microbiome, potential therapeutic strategies may be proposed.

The Effect of Heat Shock on Myogenic Differentiation of Human Skeletal-Muscle-Derived Mesenchymal Stem/Stromal Cells.

Muscle injuries, degenerative diseases and other lesions negatively affect functioning of human skeletomuscular system and thus quality of life. Therefore, the investigation of molecular mechanisms, stimulating myogenic differentiation of primary skeletal-muscle-derived mesenchymal stem/stromal cells (SM-MSCs), is actual and needed. The aim of the present study was to investigate the myogenic differentiation of CD56 (neural cell adhesion molecule, NCAM)-positive and -negative SM-MSCs and their response to the non-cytotoxic heat stimulus. The SM-MSCs were isolated from the post operation muscle tissue, sorted by flow cytometer according to the CD56 biomarker and morphology, surface profile, proliferation and myogenic differentiation has been investigated. Data show that CD56(+) cells were smaller in size, better proliferated and had significantly higher levels of CD146 (MCAM) and CD318 (CDCP1) compared with the CD56(-) cells. At control level, CD56(+) cells significantly more expressed myogenic differentiation markers MYOD1 and myogenin (MYOG) and better differentiated to the myogenic direction. The non-cytotoxic heat stimulus significantly stronger stimulated expression of myogenic markers in CD56(+) than in CD56(-) cells that correlated with the multinucleated cell formation. Data show that regenerative properties of CD56(+) SM-MSCs can be stimulated by an extracellular stimulus and be used as a promising skeletal muscle regenerating tool in vivo.

Oxidative Properties of Blood-Derived Extracellular Vesicles in 15 Patients After Myocardial Infarction.

BACKGROUND In this study, we investigated the yield and composition of extracellular vesicles (EVs) derived from 40- to 60-year-old healthy male controls and post-myocardial infarction (post-MI) patients' blood samples and assessed their pro-inflammatory and oxidative-related properties. Our study aimed to determine the EV yield and composition differences between both groups and to find out if there were differences between EV-mediated oxidative stress reactions. MATERIAL AND METHODS Fifteen post-MI patients and 25 healthy individuals were included. EVs were isolated by ultracentrifugation and analyzed using nanotracking analysis (NTA), western blotting and fluorescent flow cytometry (FFC). Oxidative stress (OS) in blood samples was identified by measuring malondialdehyde concentration from serum, while EVs-induced OS was measured in the human vein endothelium cells (HUVEC) using H2DCFDA (2',7'-dichlorodihydrofluorescein diacetate) fluorescence as a marker. RESULTS We found higher EVs concentration in healthy controls than in the post-MI group (7.07±3.1 E+10 ml vs 3.1±1.9 E+10 ml, P<0.001) and a higher level of CD9-positive exosomes (MFI 275±39.5 vs 252±13, P<0.001). Post-MI patients' EVs carry pro-oxidative nicotinamide adenine dinucleotide phosphate (NADPH) oxidases isoforms NOX1 (NADPH oxidase 1), NOX5 (NADPH oxidase 5) and NOX2 (NADPH oxidase 2) and anti-oxidative thioredoxin, extracellular signal-regulated kinases 1/2 (ERK1/2), and protein kinase B (Akt B). In the post-MI EVs, there was a higher predominance of enzymes with anti-oxidative effects, leading to weaker OS-inducing properties in the HUVEC cells. CONCLUSIONS We conclude that post-MI patient blood sample EVs have stronger anti- than pro-oxidative properties and these could help fight against post-MI consequences.

Molecular Mechanisms behind Persistent Presence of Parvovirus B19 in Human Dilated Myocardium.

The role of parvovirus B19 (PVB19) in the pathogenesis of idiopathic dilated cardiomyopathy (DCM) remains poorly understood. Therefore, we have measured the levels of inflammation, fibrosis, apoptosis, and necrosis in endomyocardial biopsies (EMBs) and sera of nonischemic PVB19-positive (n = 14) and PVB19-negative (n = 18) DCM patients. Chronic persistence of PVB19 in myocardium did not induce significant infiltration of T cells (CD3 and CD45Ro) and macrophages (CD68), and did not secrete TNFα, IL-6, and CRB. The fibrosis in PVB19-positive EMBs was also lower compared to the virus-negative ones, while ECM degrading matrix metalloproteinase MMP1 and gelatinase MMP2 were significantly (by twofold) upregulated. In addition, there was no activation of neither apoptotic nor necrotic pathways. However, levels of antiapoptotic mitochondrial Bcl-2 and heat shock protein 60 (Hsp60) in PVB19-positive biopsies were almost threefold lower than in PVB19-negative ones revealing impairment of mitochondria. Altogether, data indicate that persistence of PVB19 in myocardiums of nonischemic DCM patients can cause myocardial ECM remodeling through the MMPs, such as MMP1 and MMP2, and mitochondrial impairment. The correlative analysis of measured biomarkers suggested likely further activation of apoptotic cell death pathways rather than fibrosis. Data also suggest that antiviral therapy could be beneficial for PVB19-positive DCM patients by managing further pathological myocardial remodeling.

Cardiomyogenic Differentiation Potential of Human Dilated Myocardium-Derived Mesenchymal Stem/Stromal Cells: The Impact of HDAC Inhibitor SAHA and Biomimetic Matrices.

Dilated cardiomyopathy (DCM) is the most common type of nonischemic cardiomyopathy characterized by left ventricular or biventricular dilation and impaired contraction leading to heart failure and even patients' death. Therefore, it is important to search for new cardiac tissue regenerating tools. Human mesenchymal stem/stromal cells (hmMSCs) were isolated from post-surgery healthy and DCM myocardial biopsies and their differentiation to the cardiomyogenic direction has been investigated in vitro. Dilated hmMSCs were slightly bigger in size, grew slower, but had almost the same levels of MSC-typical surface markers as healthy hmMSCs. Histone deacetylase (HDAC) activity in dilated hmMSCs was 1.5-fold higher than in healthy ones, which was suppressed by class I and II HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) showing activation of cardiomyogenic differentiation-related genes alpha-cardiac actin (ACTC1) and cardiac troponin T (TNNT2). Both types of hmMSCs cultivated on collagen I hydrogels with hyaluronic acid (HA) or 2-methacryloyloxyethyl phosphorylcholine (MPC) and exposed to SAHA significantly downregulated focal adhesion kinase (PTK2) and activated ACTC1 and TNNT2. Longitudinal cultivation of dilated hmMSC also upregulated alpha-cardiac actin. Thus, HDAC inhibitor SAHA, in combination with collagen I-based hydrogels, can tilt the dilated myocardium hmMSC toward cardiomyogenic direction in vitro with further possible therapeutic application in vivo.

Cardiovascular Drugs and Osteoarthritis: Effects of Targeting Ion Channels.

Osteoarthritis (OA) and cardiovascular diseases (CVD) share many similar features, including similar risk factors and molecular mechanisms. A great number of cardiovascular drugs act via different ion channels and change ion balance, thus modulating cell metabolism, osmotic responses, turnover of cartilage extracellular matrix and inflammation. These drugs are consumed by patients with CVD for many years; however, information about their effects on the joint tissues has not been fully clarified. Nevertheless, it is becoming increasingly likely that different cardiovascular drugs may have an impact on articular tissues in OA. Here, we discuss the potential effects of direct and indirect ion channel modulating drugs, including inhibitors of voltage gated calcium and sodium channels, hyperpolarization-activated cyclic nucleotide-gated channels, ß-adrenoreceptor inhibitors and angiotensin-aldosterone system affecting drugs. The aim of this review was to summarize the information about activities of cardiovascular drugs on cartilage and subchondral bone and to discuss their possible consequences on the progression of OA, focusing on the modulation of ion channels in chondrocytes and other joint cells, pain control and regulation of inflammation. The implication of cardiovascular drug consumption in aetiopathogenesis of OA should be considered when prescribing ion channel modulators, particularly in long-term therapy protocols.

Mechanotransducive Biomimetic Systems for Chondrogenic Differentiation In Vitro.

Osteoarthritis (OA) is a long-term chronic joint disease characterized by the deterioration of bones and cartilage, which results in rubbing of bones which causes joint stiffness, pain, and restriction of movement. Tissue engineering strategies for repairing damaged and diseased cartilage tissue have been widely studied with various types of stem cells, chondrocytes, and extracellular matrices being on the lead of new discoveries. The application of natural or synthetic compound-based scaffolds for the improvement of chondrogenic differentiation efficiency and cartilage tissue engineering is of great interest in regenerative medicine. However, the properties of such constructs under conditions of mechanical load, which is one of the most important factors for the successful cartilage regeneration and functioning in vivo is poorly understood. In this review, we have primarily focused on natural compounds, particularly extracellular matrix macromolecule-based scaffolds and their combinations for the chondrogenic differentiation of stem cells and chondrocytes. We also discuss different mechanical forces and compression models that are used for In Vitro studies to improve chondrogenic differentiation. Summary of provided mechanical stimulation models In Vitro reviews the current state of the cartilage tissue regeneration technologies and to the potential for more efficient application of cell- and scaffold-based technologies for osteoarthritis or other cartilage disorders.

The Effect of a Unique Region of Parvovirus B19 Capsid Protein VP1 on Endothelial Cells.

Parvovirus B19 (B19V) is a widespread human pathogen possessing a high tropism for erythroid precursor cells. However, the persistence or active replication of B19V in endothelial cells (EC) has been detected in diverse human pathologies. The VP1 unique region (VP1u) of the viral capsid has been reported to act as a major determinant of viral tropism for erythroid precursor cells. Nevertheless, the interaction of VP1u with EC has not been studied. We demonstrate that recombinant VP1u is efficiently internalized by rats' pulmonary trunk blood vessel-derived EC in vitro compared to the human umbilical vein EC line. The exposure to VP1u was not acutely cytotoxic to either human- or rat-derived ECs, but led to the upregulation of cellular stress signaling-related pathways. Our data suggest that high levels of circulating B19V during acute infection can cause endothelial damage, even without active replication or direct internalization into the cells.

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Improves Energetic Status and Cardiomyogenic Differentiation of Human Dilated Myocardium-Derived Primary Mesenchymal Cells.

BACKGROUND: In this study the effect of histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on the energetic status and cardiomyogenic differentiation of human healthy and dilated myocardium-derived mesenchymal stromal cells (hmMSC) have been investigated. METHODS: The hmMSC were isolated from the healthy and dilated post-operation heart biopsies by explant outgrowth method. Cell proliferation, HDAC activity, mitochondrial membrane potential, and level of adenosine triphosphate (ATP) were evaluated. The effect of SAHA on mitochondrial parameters has been investigated also by Seahorse XF analyzer and cardiomyogenic differentiation was confirmed by the expression of transcription factor NK2 Homeobox 5 (Nkx2.5), cardiac troponin T and alpha cardiac actin at gene and protein levels. RESULTS: Dilated myocardium-derived hmMSC had almost 1.5 folds higher HDAC activity compared to the healthy cells and significantly lower mitochondrial membrane potential and ATP level. HDAC class I and II inhibitor SAHA improved energetic status of mitochondria in dilated myocardium-isolated hmMSC and increased expression of cardiac specific proteins during 14 days of exposure of cells to SAHA. CONCLUSIONS: HDAC inhibitor SAHA can be a promising therapeutic for dilated cardiomyopathy (DCM). Dilated hmMSC exposed to SAHA improved energetic status and, subsequently, cardiomyogenic differentiation. Data suggest that human dilated myocardium-derived MSC still have cardio tissue regenerative potential, which might be stimulated by HDAC inhibitors.

Biomatrices for Heart Regeneration and Cardiac Tissue Modelling In Vitro.

Cardiac muscle is the hardest working muscle in the body, pumping approximately 70 g of blood with every heartbeat, circulating 9500 l of blood daily and contracting over 3 billion times during the average human's life. Heart failure - a heterogeneous syndrome - is a major and increasing health care problem worldwide and a leading cause of hospitalization and morbidity in elderly. Adequate heart tissue regeneration in human is lacking. Challenges to engineer heart tissue and employ it in vitro or in regenerative medicine remain to be solved. First of all, cardiac tissue bioengineering requires robust and powerful cells capable of differentiating into cardiomyogenic lineages in combination with effective, safe and highly specialized biomaterials, hydrogels and/or scaffolds for recreating the native extracellular microenvironment. Advances in stem cell and biomaterial science already provided an increasing array of cell resources, their cultivation technologies and biomatrices for efficient and safe cardiac tissue reconstruction. In order to develop new cardiac tissue mimicking technologies in vitro, it is necessary to analyze the advantages and drawbacks of already established biosystems. Therefore, in this paper, we provide a comprehensive overview of recently employed cells, 2D and 3D biomatrices for cardiac tissue engineering and review the current state-of-the-art in this field as well as future directions.

The Role of Cardiac T-Cadherin in the Indicating Heart Failure Severity of Patients with Non-Ischemic Dilated Cardiomyopathy.

Background and objectives: T-cadherin (T-cad) is one of the adiponectin receptors abundantly expressed in the heart and blood vessels. Experimental studies show that T-cad sequesters adiponectin in cardiovascular tissues and is critical for adiponectin-mediated cardio-protection. However, there are no data connecting cardiac T-cad levels with human chronic heart failure (HF). The aim of this study was to assess whether myocardial T-cad concentration is associated with chronic HF severity and whether the T-cad levels in human heart tissue might predict outcomes in patients with non-ischemic dilated cardiomyopathy (NI-DCM). Materials and Methods: 29 patients with chronic NI-DCM and advanced HF were enrolled. Patients underwent regular laboratory investigations, echocardiography, coronary angiography, and right heart catheterization. TNF-α and IL6 in serum were detected by enzyme-linked immunosorbent assay (ELISA). Additionally, endomyocardial biopsies were obtained, and the levels of T-cad were assessed by ELISA and CD3, CD45Ro, CD68, and CD4- immunohistochemically. Mean pulmonary capillary wedge pressure (PCWP) was used as a marker of HF severity, subdividing patients into two groups: mean PCWP > 19 mmHg vs. mean PCWP < 19 mmHg. Patients were followed-up for 5 years. The study outcome was composite: left ventricular assist device implantation, heart transplantation, or death from cardiovascular causes. Results: T-cad shows an inverse correlation with the mean PCWP (rho = -0.397, p = 0.037). There is a tendency towards a lower T-cad concentration in patients with more severe HF, as indicated by the mean PCWP > 19 mmHg compared to those with mean PCWP ≤ 19 mmHg (p = 0.058). Cardiac T-cad levels correlate negatively with myocardial CD3 cell count (rho = -0.423, p = 0.028). Conclusions: Univariate Cox regression analysis did not prove T-cad to be an outcome predictor (HR = 1, p = 0.349). However, decreased T-cad levels in human myocardium can be an additional indicator of HF severity. T-cad in human myocardium has an anti-inflammatory role. More studies are needed to extend the role of T-cad in the outcome prediction of patients with NI-DCM.

Homeobox Genes and Homeodomain Proteins: New Insights into Cardiac Development, Degeneration and Regeneration.

Cardiovascular diseases are the most common cause of human death in the developing world. Extensive evidence indicates that various toxic environmental factors and unhealthy lifestyle choices contribute to the risk, incidence and severity of cardiovascular diseases. Alterations in the genetic level of myocardium affects normal heart development and initiates pathological processes leading to various types of cardiac diseases. Homeobox genes are a large and highly specialized family of closely related genes that direct the formation of body structure, including cardiac development. Homeobox genes encode homeodomain proteins that function as transcription factors with characteristic structures that allow them to bind to DNA, regulate gene expression and subsequently control the proper physiological function of cells, tissues and organs. Mutations in homeobox genes are rare and usually lethal with evident alterations in cardiac function at or soon after the birth. Our understanding of homeobox gene family expression and function has expanded significantly during the recent years. However, the involvement of homeobox genes in the development of human and animal cardiac tissue requires further investigation. The phenotype of human congenital heart defects unveils only some aspects of human heart development. Therefore, mouse models are often used to gain a better understanding of human heart function, pathology and regeneration. In this review, we have focused on the role of homeobox genes in the development and pathology of human heart as potential tools for the future development of targeted regenerative strategies for various heart malfunctions.

Lung alveolar tissue destruction and protein citrullination in diesel exhaust-exposed mouse lungs.

Humanity faces an increasing impact of air pollution worldwide, including threats to human health. Air pollutants prompt and promote chronic inflammation, tumourigenesis, autoimmune and other destructive processes in the human body. Post-translational modification of proteins, for example citrullination, results from damaging attacks of pollutants, including smoking, air pollution and others, rendering host tissues immunogenic. Citrullinated proteins and citrullinating enzymes, deiminases, are more prevalent in patients with COPD and correlate with ongoing inflammation and oxidative stress. In this study, we installed an in-house-designed diesel exhaust delivery and cannabidiol vaporization system where mice were exposed to relevant, urban traffic-related levels of diesel exhaust for 14 days and assessed integrity of alveolar tissue, gene expression shifts and changes in protein content in the lungs and other tissues of exposed mice. Systemic presence of modified proteins was also tested. The protective effect of phytocannabinoids was investigated as well. Data obtained in our study show subacute effects of diesel exhaust on mouse lung integrity and protein content. Emphysematous changes are documented in exposed mouse lungs. In parallel, increased levels of citrulline were detected in the alveolar lung tissue and peripheral blood of exposed mice. Pre-treatment with vaporized cannabidiol ameliorated some damaging effects. Results reported hereby provide new insights into subacute lung tissue changes that follow diesel exhaust exposure and suggest possible dietary and/or other therapeutic interventions for maintaining lung health and healthy ageing.

Cytoprotective Effects of Mangiferin and Z-Ligustilide in PAH-Exposed Human Airway Epithelium in Vitro.

According to World Health Organisation (WHO) air pollution increases the risk of cardiovascular disorders, respiratory diseases, including COPD, lung cancer and acute respiratory infections, neuro-degenerative and other diseases. It is also known that various phytochemicals may mitigate such risks. This study tested if phytochemicals mangiferin (MNG) and Z-ligustilide (Z-LG) may protect PAH-exposed human lung bronchial epithelial cells (BEAS-2B). Organic PAH extract was obtained from the urban fine PM with high benzo(a)pyrene content collected in Eastern European mid-sized city during winter heating season. Cell proliferation traits and levels of intracellular oxidative stress were examined. Effect of MNG (0.5 µg/mL) alone or in combination with PAH on bronchial epithelium wound healing was evaluated. Both phytochemicals were also evaluated for their antioxidant properties in acellular system. Treatment with MNG produced strong cytoprotective effect on PAH-exposed cells (p < 0.01) while Z-LG (0.5 µg/mL) exhibited strong negative effect on cell proliferation in untreated and PAH-exposed cells (p < 0.001). MNG, being many times stronger antioxidant than Z-LG in chemical in vitro assays (p < 0.0001), was also able to decrease PAH-induced oxidative stress in the cell cultures (p < 0.05). Consequently MNG ameliorates oxidative stress, speeds up wound healing process and restores proliferation rate in PAH-exposed bronchial epithelium. Such protective effects of MNG in air pollution affected airway epithelium stimulate further research on this promising phytochemical.

Pro-inflammatory effects of extracted urban fine particulate matter on human bronchial epithelial cells BEAS-2B.

Atmospheric particulate matter (PM) constitutes the major part of urban air pollution and is a heterogeneous mixture of solid and liquid particles of different origin, size, and chemistry. Human exposure to PM in urban areas poses considerable and significant adverse effects on the respiratory system and human health in general. Major contributors to PM content are combustion-related sources such as diesel vehicles, household, and industrial heating. PM is composed of thousands of different high molecular weight organic compounds, including poly-aromatic hydrocarbons (PAHs). The aim of this study was to clarify the cytotoxic effects of the extract of actual urban PM1 with high benzo[a]pyrene (BaP) content collected in Eastern European mid-sized city during winter heating season on human bronchial epithelial cells (BEAS-2B). Decreased cell viability, alteration of cell layer integrity, increased apoptosis, and oxidative stress were observed during the 3-day exposure to the PM extract. In addition, following PM exposure pro-inflammatory cytokine expression was upregulated at gene and protein levels. Morphology and motility changes, i.e., decreased cells' ability to cover scratch area, were also documented. We report here that the extract of urban PM1 may induce bronchial epithelium changes and render it pro-inflammatory and compromised within 3 days.