Iron absorption in adults with sickle cell anemia: a stable-isotope approach.

PURPOSE: Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration. METHODS: SCA patients (n = 13; SCAtotal) and control participants (n = 10) ingested an oral stable iron isotope (57Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n = 3) and others classified without IO (SCAio-; n = 10). RESULTS: Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0-31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3-7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6-9.3 ng/mL) in control. Iron absorption was associated with ferritin level (r = - 0.641; p = 0.018) and liver iron concentration (LIC; r = - 0.786; p = 0.036) in the SCAtotal group. CONCLUSION: Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients. TRIAL REGISTRATION: This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt).

Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.

The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.

Altered IgG glycosylation at COVID-19 diagnosis predicts disease severity.

The nature of the immune responses associated with COVID-19 pathogenesis and disease severity, as well as the breadth of vaccine coverage and duration of immunity, is still unclear. Given the unpredictability for developing a severe/complicated disease, there is an urgent need in the field for predictive biomarkers of COVID-19. We have analyzed IgG Fc N-glycan traits of 82 SARS-CoV-2+ unvaccinated patients, at diagnosis, by nano-LC-ESI-MS. We determined the impact of IgG Fc glyco-variations in the induction of NK cells activation, further evaluating the association between IgG Fc N-glycans and disease severity/prognosis. We found that SARS-CoV-2+ individuals display, at diagnosis, variations in the glycans composition of circulating IgGs. Importantly, levels of galactose and sialic acid structures on IgGs are able to predict the development of a poor COVID-19 disease. Mechanistically, we demonstrated that a deficiency on galactose structures on IgG Fc in COVID-19 patients appears to induce NK cells activation associated with increased release of IFN-γ and TNF-α, which indicates the presence of pro-inflammatory immunoglobulins and higher immune activation, associated with a poor disease course. This study brings to light a novel blood biomarker based on IgG Fc glycome composition with capacity to stratify patients at diagnosis.

Endothelial c-Myc knockout enhances diet-induced liver inflammation and fibrosis.

Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control the pro-inflammatory response depend on the type of inflammatory stimuli, endothelial cell origin, and tissue involved. In the present study, we investigated the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium. At a systemic level, circulating monocytes, the chemokine CCL7, and the extracellular-matrix protein osteopontin were significantly increased in endothelial c-Myc knockout (EC-Myc KO) mice, whereas the cytokine TNFSF11 was downregulated. Using an experimental model of steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response, characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration, and worsened liver fibrosis. Transcriptome analysis identified enhanced expression of genes associated with inflammation, fibrosis, and hepatocellular carcinoma in EC-Myc KO mice relative to control (CT) animals after short-exposure to high-fat diet. Analysis of a single-cell RNA-sequencing dataset of human cirrhotic livers indicated downregulation of MYC in endothelial cells relative to healthy controls. In summary, our results suggest a protective role of endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may constitute a potential strategy for the treatment of inflammatory disease.

SARS-CoV-2 Infection Drives a Glycan Switch of Peripheral T Cells at Diagnosis.

COVID-19 is a highly selective disease in which SARS-CoV-2 infection can result in different clinical manifestations ranging from asymptomatic/mild to severe disease that requires hospitalization. In this study, we demonstrated that SARS-CoV-2 infection results in a glycosylation reprogramming of circulating lymphocytes at diagnosis. We identified a specific glycosignature of T cells, defined upon SARS-CoV-2 infection and apparently triggered by a serological factor. This specific glycan switch of T cells is detected at diagnosis being more pronounced in asymptomatic patients. We further demonstrated that asymptomatic patients display an increased expression of a viral-sensing receptor through the upregulation of DC-SIGN in monocytes. We showed that higher levels of DC-SIGN in monocytes at diagnosis correlates with better COVID-19 prognosis. This new evidence pave the way to the identification of a novel glycan-based response in T cells that may confer protection against SARS-CoV-2 infection in asymptomatic patients, highlighting a novel prognostic biomarker and potential therapeutic target.

Efficacy of sonic and ultrasonic activation during endodontic treatment: a Meta-analysis of in vitro studies.

OBJECTIVE: To ensure a successful endodontic treatment, it is important to have a proper disinfection of the root canal. The current study compares the root canal cleanliness and smear layer score between sonic and ultrasonic activation. METHOD: Systematic literature review was implemented, using 12 databases. All in vitro studies comparing the efficacy of sonic and ultrasonic activation and reporting at least one outcome of interest were included. RESULTS: At the apical level, pooling the data in the random-effects model (I2=64%, p = .1) revealed a statistically significant lower smear layer score within the sonic activation group (MD-0.48; 95% CI-0.92, -0.04; p = .03). Furthermore, there was a statistically significant lower push-out bond strength value among the sonic group, in contrast to the ultrasonic group at the middle (MD-0.69; 95% CI-1.13, -0.25; p = .002) and at the apical levels (MD-0.78; 95% CI-1.09, -0.46; p < .0001) of the root canal. CONCLUSIONS: Sonic activation accomplished advancement relative to ultrasonic agitation in removing the smear layer, while ultrasonic activation resulted in significant cohesion between the sealers and the dentine tubules, decreasing the vulnerability of apical leakage and tooth fracture.

CFTR, Cell Junctions and the Cytoskeleton.

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP regulated chloride (Cl-) and bicarbonate (HCO3-) ion channel expressed at the apical plasma membrane (PM) of epithelial cells. Reduced CFTR protein results in decreased Cl- secretion and excessive sodium reabsorption in epithelial cells, which consequently leads to epithelial dehydration and the accumulation of thick mucus within the affected organs, such as the lungs, pancreas, gastrointestinal (GI) tract, reproductive system and sweat glands. However, CFTR has been implicated in other functions besides transporting ions across epithelia. The rising number of references concerning its association to actin cytoskeleton organization, epithelial cell junctions and extracellular matrix (ECM) proteins suggests a role in the formation and maintenance of epithelial apical basolateral polarity. This review will focus on recent literature (the last 10 years) substantiating the role of CFTR in cell junction formation and actin cytoskeleton organization with its connection to the ECM.

A Novel Detection Method of Breast Cancer through a Simple Panel of Biomarkers.

Circulating tumor cells (CTCs) have been identified as responsible for the spread of tumors to other organs of the body. In this sense, the development of sensitive and specific assays for their detection is important to reduce the number of deaths due to metastases. Here, we assessed whether the detection of CTCs in peripheral blood can serve in the construction of a panel of diagnosis and monitoring treatments of breast cancer (BC), focusing on the expression of markers of epithelial-mesenchymal transition. Through analyzing the blood from women without breast alterations (control), women with benign alterations, women with breast cancer without chemotherapy, and women with breast cancer with chemotherapy, we identified the best markers by transcriptional levels and determined three profiles of CTCs (mesenchymal, intermediate, and epithelial) by flow cytometry which, combined, can be used for diagnosis and therapy monitoring with sensitivity and specificity between 80% and 100%. Therefore, we have developed a method for detecting breast cancer based on the analysis of CTC profiles by epithelial-mesenchymal transition markers which, combined, can be used for the diagnosis and monitoring of therapy.

Risk factors for cage subsidence and clinical outcomes after transforaminal and posterior lumbar interbody fusion.

BACKGROUND: Cage subsidence is a very common complication after lumbar interbody fusion. It may compromise vertebral interbody fusion through progressive spinal deformity and consequently cause compression of neural elements. Clinical relevance remains, however, unclear, with few studies on this subject and even less information regarding its correlation with clinical findings. The aim of this study was to identify risk factors for cage subsidence and clinical evaluation after transforaminal (TLIF) and posterior (PLIF) lumbar interbody fusion. METHODS: A retrospective study in patients submitted to TLIF and PLIF between 2008 and 2017 was conducted. RESULTS: A total of 165 patients were included (123 TLIF and 42 PLIF). Univariate analysis showed an increased risk of cage subsidence in spondylolisthesis comparing with degenerative disk disease (p = 0.007). A higher preoperative lumbar lordosis angle (p = 0.014) and cage placement in L2-L3 (p = 0.012) were associated with higher risk of subsidence. The posterior cage positioning on vertebral endplate was associated with a higher risk of subsidence (p = 0.028) and significant subsidence (p = 0.005), defined as cage migration > 50% of cage height. PLIF presented a higher risk when comparing with TLIF (p = 0.024). Hounsfield unit (HU) values < 135 (OR6; 95% CI [1.95-34]) and posterior positioning (OR7; 95% CI [1.7-27.3]) were independent risk factors for cage subsidence and significant subsidence, respectively, in multivariate analysis. There was a tendency for significant subsidence in degrees ≥ 2 of Meyerding spondylolisthesis (OR4; 95% CI [0.85-21.5]). Significant cage subsidence was not associated with worse clinical results. Other analyzed factors, such as age (p = 0.008), low bone mineral density (BMD) (p = 0.029) and type of surgery (TLIF) (p = 0.004), were associated with worse results. CONCLUSION: The present study shows that lower BMD and posterior cage positioning are relevant risk factors for lumbar cage subsidence. Low BMD is also a predictor of poor clinical results, so it must be properly evaluated and considered, through HU values measurement in CT scan, a feasible and reliable tool in perioperative planning.

Low Annexin A1 level in HTLV-1 infected patients is a potential biomarker for the clinical progression and diagnosis of HAM/TSP.

BACKGROUND: Human T-lymphotropic virus 1 (HTLV-1) is etiologically associated with the chronic inflammatory neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) Annexin A1 (AnxA1) is an anti-inflammatory protein with proposed neuroprotective and anti-neuroinflammatory functions. We hypothesized that ANXA1 gene expression may be dysregulated in HTLV-1-infected HAM/TSP patients. METHODS: This study involved 37 individuals infected with HTLV-1, including 21 asymptomatic (AS) carriers and 16 with HAM/TSP, and a control group of 30 individuals negative for HTLV-1 and HTLV-2. For AS HTLV-1-positive and HAM/TSP patients, ANXA1 and formyl peptide receptor (FPR1, FPR2 and FPR3) expression and HTLV-1 proviral load (PVL) in peripheral blood cells were evaluated by real-time quantitative PCR (qPCR), and plasma AnxA1 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: ANXA1 gene expression was increased in the AS group compared with the HAM/TSP and control groups, but the differences were not statistically significant. FPR1 gene expression was higher in patients with HTLV-1 than in controls (AS, p = 0.0032; HAM/TSP, p < 0.0001). Plasma AnxA1 levels were higher in the AS group than in the HAM/TSP group (p = 0.0045), and PVL was higher in patients with HAM/TSP than in AS individuals (p = 0.0162). The use of a combined ROC curve using Annexin 1 levels and proviral load significantly increased the sensitivity and specificity to predict progression to HAM/TSP (AUC = 0.851 and AUC = 0.937, respectively, to AUC = 1000). CONCLUSIONS: Our results suggest that AnxA1 may be dysregulated in HAM/TSP patients. Serological detection of AnxA1 in association with proviral load may provide a prognostic biomarker for HTLV-1-associated neurodegenerative disease.

The Role of Glycosylation in Inflammatory Diseases.

The diversity of glycan presentation in a cell, tissue and organism is enormous, which reflects the huge amount of important biological information encoded by the glycome which has not been fully understood. A compelling body of evidence has been highlighting the fundamental role of glycans in immunity, such as in development, and in major inflammatory processes such as inflammatory bowel disease, systemic lupus erythematosus and other autoimmune disorders. Glycans play an instrumental role in the immune response, integrating the canonical circuits that regulate innate and adaptive immune responses. The relevance of glycosylation in immunity is demonstrated by the role of glycans as important danger-associated molecular patterns and pathogen-associated molecular patterns associated with the discrimination between self and non-self; also as important regulators of the threshold of T cell activation, modulating receptors signalling and the activity of both T and other immune cells. In addition, glycans are important determinants that regulate the dynamic crosstalk between the microbiome and immune response. In this chapter, the essential role of glycans in the immunopathogenesis of inflammatory disorders will be presented and its potential clinical applications (diagnosis, prognosis and therapeutics) will be highlighted.

Reasons for never receiving a pap test among Brazilian women: National health survey.

OBJECTIVE: To identify reasons among Brazilian women for never having a Pap test. DESIGN: We designed a cross-sectional study that used data from the National Health Survey. SAMPLE: Two thousand four hundred and two women 25-64 years old who never had a pap test. MEASURES: Variables were age, race, education, marital status, housing condition, primary health care access, health insurance, self-perceived health, and social support network. We calculated the prevalence of different reasons and odds ratios for each. RESULTS: The most frequent reason for never having a test were linked to women thinking the test was unnecessary (42.3%) which had a significant association with marital status (OR = 1.52; 95% CI = 1.07-1.91), age (OR = 1.56; 95% CI = 1.21-1.99), area of residence (OR = 1.15; 95% CI = 1.02-1.39), having a health insurance (OR = 1.18; 95% CI = 1.01-1.36), and self-perceived health (OR = 1.42; 95% CI = 1.28-1.56). The second most frequent reason was not knowing they needed a test (22.9%) which was associated with age (OR = 1.95; 95% CI = 1.74-2.16) and self-perceived health (OR = 1.56; 95% CI = 1.33-1.80). CONCLUSIONS: The findings suggest lack of knowledge about cervical cancer and its prevention among Brazilian women. We consider it essential that the health service can provide the test, as well as the necessary guidelines for raising the awareness of the target audience.

Low intake of dietary fibre among Brazilian adolescents and association with nutritional status: cross-sectional analysis of Study of Cardiovascular Risks in Adolescents data.

OBJECTIVE: To evaluate dietary fibre intake in Brazilian adolescents and its association with nutritional status. DESIGN: This was a cross-sectional study including data from the Brazilian multicentre Study of Cardiovascular Risks in Adolescents (ERICA). Data analysed were geographic region, sex, age, nutritional status, sexual maturation stage, socioeconomic status, school type and level of physical activity. For nutritional status classification, BMI/age was used by sex. Dietary intake was assessed by 24-h recall. Dietary fibre intake was expressed in g/d, and adequacy was determined using dietary reference intake (DRI) values. Complex sample design was considered in statistical analysis, and logistic regression was used to estimate OR for fibre intake and nutritional status. SETTING: Brazilian municipalities with more than 100 000 inhabitants. PARTICIPANTS: A total of 71 740 adolescents aged 12-17 years were included. RESULTS: The average total dietary fibre intake was 19·1 g/d (95 % CI 18·5, 19·7), and only 13·1 % (95 % CI 11·6, 14·7) of Brazilian adolescents reached the recommendations. The results of logistic regression analysis adjusted for geographic region, sex and type of school showed that overweight and obese adolescents were 1·6 and 1·8 times more likely, respectively, to have inadequate dietary fibre intake (P < 0·0001). CONCLUSIONS: Brazilian adolescents had a significantly inadequate dietary fibre intake. This was particularly notable in adolescents with excess weight. Education policies on nutrition must be implemented, as dietary fibre plays an important role in the prevention and treatment of obesity and other chronic diseases.

Oral and cranio-maxillofacial trauma in children and adolescents in an emergency setting at a Brazilian hospital.

BACKGROUND/AIMS: Very few studies have been performed to evaluate cranio-maxillofacial trauma diagnosed in hospitals in children and adolescents. The aim of this study was to perform an analysis of oral and cranio-maxillofacial trauma in the aforementioned population. MATERIALS AND METHODS: A hospital-based retrospective study, which reviewed 1438 patient records, was conducted at the "Teresina Emergency Hospital", Brazil. Data regarding demographics, day of the week on which trauma occurred, type of injury, etiology, anatomic trauma site, time of hospital admission, and associated comorbidities (or injuries) were collected. RESULTS: There were 1092 (75.9%) males and 346 (24.1%) females. The largest group was adolescents aged between 13 and 18 years (956, 66.5%). The majority lived in urban areas (69%). Trauma occurred most frequently during the week. The most prevalent etiology was road traffic accidents involving motorcycles (771, 53.6%) causing facial and skull fractures (598, 41%). The most prevalent soft tissue lesions were facial abrasions (49%), followed by injuries to the cheek (16.7%). Comorbidities associated with craniofacial trauma were present in 82%, with complications from traumatic brain injuries being the most prevalent (65.6%) Dental trauma was recorded in only 81 cases (5.6%). CONCLUSION: Male adolescents living in urban areas were most affected by craniofacial trauma. The most common cause was road traffic accidents involving motorcycles, resulting in facial and skull fractures. Complications from traumatic brain injuries were the most common associated injuries.

Nutritional Status, Nutrient Intake, and Food Diversity Among Children With Sickle Cell Anemia.

Children with sickle cell anemia (SCA) often exhibit nutritional deficiencies and are at high risk of dying before the age of 5 years. Ensuring adequate nutrition is a critical part of health care for such children. This study aimed to investigate the association between nutritional status, nutrient intake, and food diversity in children with SCA. A descriptive cross-sectional study was conducted on 74 children with SCA, between 24 and 71 months of age. Anthropometric measurements, food and nutrients consumption were determined. The prevalence of low weight, stunting, and overweight/obesity were 16.2%, 35.1%, and 16.2%, respectively. Mean folic acid intake was low (49.05%±51.22%), whereas the intakes of protein (426.71%±171.93%), retinol (292.97%±403.88%), phosphorus (204.55%±151.35%), magnesium (233.02%±151.14%), iron (250.76%±165.81%), and zinc (243.21%±148.40%) were high. The dietary phosphorus/protein ratio was high for 31.1% of the children, and 44.6% of the children had low dietary diversity score. No correlation was found between food diversity, nutrient adequacy, and nutritional status. Despite the adequacy of the intake of most micronutrients, diet quality was inadequate, constituting mainly ultraprocessed foods. Knowing the food consumption pattern of these children enables a more resolute nutritional intervention.

Construction of hypermedia to support the systematization of the nursing care education. / Construção de hipermídia para apoio ao ensino da sistematização da assistência de enfermagem.

OBJECTIVE: To describe the process of hypermedia construction to support the teaching of the Systematization of the Nursing Care (SNC). METHOD: Methodological research of educational technology development. The hypermedia construction stages were conducted from February 2015 to March 2016 and integrated theoretical studies, focus group with professors and educational technology development process in the light of the referential Theory of Significant Learning. RESULTS: Hypermedia consists of interactive content and shows a splash screen with a concept map that guides a free way of learning about four structuring aspects in the SNC learning: concept, history and benefits; ethical-legal aspects; operationalization; and nursing process: steps and technical integration in nursing. CONCLUSIONS: It was concluded that it is essential that the educational technologies are built from a pedagogical rationale to support your incorporation into educational environments.

Yeast aquaporin regulation by 4-hydroxynonenal is implicated in oxidative stress response.

Reactive oxygen species, especially hydrogen peroxide (H2 O2 ), contribute to functional molecular impairment and cellular damage, but also are necessary in normal cellular metabolism, and in low doses play stimulatory role in cell proliferation and stress resistance. In parallel, reactive aldehydes such as 4-hydroxynonenal (HNE), are lipid peroxidation breakdown products which also contribute to regulation of numerous cellular processes. Recently, channeling of H2 O2 by some mammalian aquaporin isoforms has been reported and suggested to contribute to aquaporin involvement in cancer malignancies, although the mechanism by which these membrane water channels are implicated in oxidative stress is not clear. In this study, two yeast models with increased levels of membrane polyunsaturated fatty acids (PUFAs) and aquaporin AQY1 overexpression, respectively, were used to evaluate their interplay in cell's oxidative status. In particular, the aim of the study was to investigate if HNE accumulation could affect aquaporin function with an outcome in oxidative stress response. The data showed that induction of aquaporin expression by PUFAs results in increased water permeability in yeast membranes and that AQY1 activity is impaired by HNE. Moreover, AQY1 expression increases cellular sensitivity to oxidative stress by facilitating H2 O2 influx. On the other hand, AQY1 expression has no influence on the cellular antioxidant GSH levels and catalase activity. These results strongly suggest that aquaporins are important players in oxidative stress response and could contribute to regulation of cellular processes by regulation of H2 O2 influx. © 2017 IUBMB Life, 69(5):355-362, 2017.

Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia.

BACKGROUND: Mesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis. METHODS: SDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 µl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21. RESULTS: Administration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH. CONCLUSIONS: The therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.

Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival.

The beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit(+) cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit(+) CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation.