The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3.

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•-), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•-, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Knowledge, attitudes and practices regarding children with ICU-acquired weakness in pediatric intensive care unit among chinese medical staff: a cross-sectional survey.

BACKGROUND: ICU-AW (Intensive Care Unit Acquired Weakness) is characterized by significant muscle weakness and can be caused by a variety of factors, including immobility, medication use, and underlying medical conditions.ICU-AW can affect critically ill children who have been hospitalized in the PICU for an extended period of time.The knowledge, attitude and practice level of ICU-AW of PICU medical staff directly affect the treatment of critically ill children with ICU-AW.The aim to this study was to explore the knowledge, attitudes, and practices of Chinese medical staff regarding critically ill children with intensive care unit-acquired weakness (ICU-AW) and related factors. METHODS: A Knowledge, Attitudes, and Practices (KAP) Questionnaire regarding critically ill children with ICU-AW was distributed to a stratified sample of 530 pediatric intensive care unit (PICU) healthcare workers. The questionnaire consisted of 31 items-with scores of 45, 40, and 40 for each dimension and a total score of 125. RESULTS: The mean total score of Chinese PICU healthcare workers for the KAP questionnaire regarding children with ICU-AW was 87.36 ± 14.241 (53-121), with mean total knowledge, attitudes, and practices scores of 30.35 ± 6.317, 30.46 ± 5.632, and 26.54 ± 6.454, respectively. The population distribution indicated that 50.56%, 46.04%, and 3.4% of healthcare workers had poor, average, and good scores, respectively. Multiple linear regression showed that gender, education, and hospital level classification influenced the KAP level of PICU healthcare workers regarding critically ill children with ICU-AW. CONCLUSIONS: Overall, PICU healthcare workers in China have an average KAP level about ICU-AW, and the gender and education level of PICU healthcare workers, as well as the classification of hospitals where they work, predict the KAP status of healthcare workers regarding children with ICU-AW. Therefore, healthcare leaders should plan and develop specific training programs to improve the KAP level of PICU healthcare workers.

HDL and Surgery.

In addition to the well-known functions, plasma HDL also plays an important role in postsurgery periods. In this chapter, we summarized the changes of HDL after surgery like bariatric surgery and cardiac surgery. Not only the amount of HDL changed, the HDL components or functions have also been altered after various surgeries. Furthermore, a few HDL-related indexes have been recognized as important clinical predictors after surgery, such as HDL cholesterol efflux capacity, HDL pro-inflammatory index, HDL cholesterol (HDL-C) concentration, and monocyte count to HDL ratio (MHR).

Simvastatin inhibits POVPC-mediated induction of endothelial-to-mesenchymal cell transition.

Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine, is a proinflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein ECs with POVPC, simvastatin, or both, and determined their effect on EC viability, morphology, tube formation, proliferation, and generation of NO and superoxide anion (O2•-). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect EC viability but altered cellular morphology from cobblestone-like ECs to a spindle-like mesenchymal cell morphology. POVPC increased O2- generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-ß), TGF-ß receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production and expression of CD31 and endothelial NO synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O2•- and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-ß/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-ß/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.

Supplementary Bovine Colostrum Feedings to Formula-Fed Preterm Pigs Improve Gut Function and Reduce Necrotizing Enterocolitis.

OBJECTIVES: Exclusive feeding with bovine colostrum (BC) protects preterm pigs against necrotizing enterocolitis (NEC) and BC has recently been tested as a supplement to a mother's own milk or formula (FOR) for very preterm infants. Using preterm pigs as a model for infants, we investigated if BC has gut- and NEC-protective effects at different proportions of the daily enteral intake given as BC. METHODS: Sixty-eight caesarean-delivered preterm piglets (90% gestation) were allocated into four groups with increasing proportions of eight daily bolus feedings as BC: BC00 (only FOR feeding), BC25 (25% BC), BC50 (50% BC), or BC75 (75% BC). On day 5, the gut was collected for biochemical analyses. RESULTS: Body growth was increased in BC50 and BC75 piglets (2-fold, P < 0.05 vs BC00). The incidence of mild NEC-like lesions was similar among groups (67-86%), but BC75 reduced severe NEC-like lesions (27% vs 79% in BC00, P < 0.05). BC50 and BC75 improved hexose absorption and mucosal structure and reduced gut permeability (P < 0.05 vs BC00), while enzyme activities (lactase, aminopeptidase N and A, dipeptidyl peptidase IV) were improved in all pigs fed BC (P < 0.05). Across the measured variables, beneficial effects were most clear for the BC75 group, including reductions in colon tissue cytokine levels (interleukin 8, interleukin 1ß, tumor necrosis factor α) and expression of immune- and apoptosis-related genes (LBP, TLR4, TLR2, IL8, STAT3, IL17, C3, all P < 0.05, relative to BC00). CONCLUSION: A proportion of 50-75% of daily enteral intake as BC is required to improve the intestinal structure, function, immunology, and NEC resistance in preterm piglets also fed formula. Further studies are required to show if and how supplementary BC may support gut development in preterm infants during the immediate postnatal period. It is challenging to translate results on optimal feeding regimens between species, and preterm infants would not receive a majority of their daily enteral intake as BC.

Circulating extracellular vesicles from patients with valvular heart disease induce neutrophil chemotaxis via FOXO3a and the inhibiting role of dexmedetomidine.

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.

Overexpression of inducible nitric oxide synthase in the diabetic heart compromises ischemic postconditioning.

Ischemia postconditioning (PTC) can reduce myocardial ischemia/reperfusion injury. However, the effectiveness of PTC cardioprotection is reduced or lost in diabetes and the mechanisms are largely unclear. Hyperglycemia can induce overexpression of inducible nitric oxide synthesis (iNOS) in the myocardium of diabetic subjects. However, it is unknown whether or not iNOS especially its overexpression plays an important role in the loss of cardioprotection of PTC in diabetes. C57BL6 and iNOS-/- mice were treated with streptozotocin to induce diabetes. Part of diabetic C57BL6 mice were also treated with an iNOS specific inhibitor, 1400 W. Mice were subjected to myocardial ischemia/ reperfusion with/without PTC. The hemodynamic parameters, plasma levels of cardiac troponin T (cTnT), TNF-α, IL-6 and nitric oxide (NO) were monitored. The myocardial infarct size, superoxide anion (O2-) generation, nitrotyrosine production and apoptosis were measured. The expression of phosphorylated Akt, endothelial NOS (eNOS), iNOS and Erk1/2 in ischemic heart were detected by immunoblot analysis. In diabetic C57BL6 and iNOS-/- mice, the post-ischemic hemodynamics were impaired, the cTnT, TNF-α, IL-6 level, myocardial infarct size, apoptotic index, O2- and nitrotyrosine generation were increased and the Akt/eNOS signal pathways were inhibited. PTC improved hemodynamic parameters, reduced cTnT level, myocardial infarct size, apoptotic index, O2- and nitrotyrosine generation and activated Akt/eNOS and Erk1/2 signal pathways in both non-diabetic C57BL6 and iNOS-/- mice as well as diabetic iNOS-/- mice, but not in diabetic C57BL6 mice. PTC also increased NO production in both non-diabetic and diabetic C57BL6 and iNOS-/- mice, and enhanced iNOS expression in non-diabetic C57BL6 mice. 1400 W restored the cardioprotection of PTC in diabetic C57BL6 mice. Our data demonstrated that PTC reduced myocardial ischemia/reperfusion injury in non-diabetic mice but not C57BL6 diabetic mice. Deletion of iNOS restored the cardioprotection of PTC in diabetic mice. Our findings suggest that iNOS plays a key role in the reduction of cardioprotection of PTC in diabetes and may provide a therapeutic target for diabetic patients.

Exploring the symptoms and psychological experiences among lung cancer convalescence patients after radical lobectomy: A qualitative study.

OBJECTIVE: This study aims to explore the symptom experiences and psychological feelings of lung cancer patients after radical lobectomy in China. METHODS: A qualitative study was conducted using face-to-face semistructured interviews with lung cancer patients who had a radical lobectomy for treatment of their cancer during the convalescence period. Participants (n = 18) were recruited from a general hospital in China, and patients were selected using purposive sampling from September 2021 to February 2022. Interviews were recorded and transcribed verbatim, and Colaizzi's seven-step method of phenomenology was used. The Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist was conducted to report the study. RESULTS: Four themes were extracted from the interview data: physiological dimensions (fatigue, cough or sputum, chest tightness and shortness of breath, daily activities affected, sleep disturbance, lack of appetite); psychological dimensions (negative emotion, fear of cancer recurrence, learning to accept reality, strengthened faith and hope); family dimensions (heavy economic burden, perceived family care, improved health management behavior); and social dimensions (perceived support of medical staff, decreased sense of social value and self-identity, changes in social and working style). CONCLUSION: Lung cancer patients are still troubled by many problems during the postoperative recovery period. Medical staff should design and implement effective evaluations and targeted interventions for patients' physical and mental health as soon as possible to improve patients' physical and mental health, as well as their quality of life.

High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p.

We previously demonstrated that normal high-density lipoprotein (nHDL) can promote angiogenesis, whereas HDL from patients with coronary artery disease (dHDL) is dysfunctional and impairs angiogenesis. Autophagy plays a critical role in angiogenesis, and HDL regulates autophagy. However, it is unclear whether nHDL and dHDL regulate angiogenesis by affecting autophagy. Endothelial cells (ECs) were treated with nHDL and dHDL with or without an autophagy inhibitor. Autophagy, endothelial nitric oxide synthase (eNOS) expression, miRNA expression, nitric oxide (NO) production, superoxide anion (O2•-) generation, EC migration, and tube formation were evaluated. nHDL suppressed the expression of miR-181a-5p, which promotes autophagy and the expression of eNOS, resulting in NO production and the inhibition of O2•- generation, and ultimately increasing in EC migration and tube formation. dHDL showed opposite effects compared to nHDL and ultimately inhibited EC migration and tube formation. We found that autophagy-related protein 5 (ATG5) was a direct target of miR-181a-5p. ATG5 silencing or miR-181a-5p mimic inhibited nHDL-induced autophagy, eNOS expression, NO production, EC migration, tube formation, and enhanced O2•- generation, whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of dHDL. ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null (LDLr-/-) mice when compared to C57BL/6 mice. ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Taken together, nHDL was able to stimulate autophagy by suppressing miR-181a-5p, subsequently increasing eNOS expression, which generated NO and promoted angiogenesis. In contrast, dHDL inhibited angiogenesis, at least partially, by increasing miR-181a-5p expression, which decreased autophagy and eNOS expression, resulting in a decrease in NO production and an increase in O2•- generation. Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for dHDL-impaired angiogenesis.

Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1.

Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles (eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass, remains unclear. Plasma plasminogen-activated inhibitor-1 (PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice (C57BL/6, Toll-like receptor 4 knockout (TLR4-/-) and inducible nitric oxide synthase knockout (iNOS-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3 (JAK2/3)-signal transducer and activator of transcription 3 (STAT3)-interferon regulatory factor 1 (IRF-1) pathway, along with iNOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors (AG490 or S3I-201, respectively), and was relieved in TLR4-/- and iNOS-/- mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1 (FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.

Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice.

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

Antenatal depression is associated with perceived stress, family relations, educational and professional status among women in South of China: a multicenter cross-sectional survey.

Background: Antenatal depression is a commonly seen mental health concern for women. This study introduced a multicenter cross-sectional survey with a large sample to provide new insights into pregnant women's depression, its socio-demographic and obstetric characteristics correlates, and its perceived stress among Chinese pregnant women. Methods: This study conducted an observational survey according to the STROBE checklist. The multicenter cross-sectional survey was performed from August 2020 to January 2021 by distributing paper questionnaires among pregnant women from five tertiary hospitals in South China. The questionnaire included socio-demographic and obstetrics information, the Edinburgh Postnatal Depression Scale, and the 10-item Perceived Stress Scale. For the analyses, the Chi-square test and Multivariate logistic regression were utilized. Results: Among 2014 pregnant women in their second/third trimester, the prevalence of antenatal depression was 36.3%. 34.4% of pregnant women reported AD in their second trimester of pregnancy, and 36.9% suffered from AD in third trimester of pregnancy. A multivariate logistic regression model indicated that unemployed women, lower levels of education, poor marital relationships, poor parents-in-law relationships, concerns about contracting COVID-19, and higher perceived stress could aggravate antenatal depression among participants (p<0.05). Conclusion: There is a high proportion of antenatal depression among pregnant women in South China, so integrating depression screening into antenatal care services is worthwhile. Maternal and child health care providers need to evaluate pregnancy-related risk factors (perceived stress), socio-demographic factors (educational and professional status), and interpersonal risk factors (marital relations and relationship with Parents-in-law). In future research, the study also emphasized the importance of providing action and practical support to reduce the experience of antenatal depression among disadvantaged sub-groups of pregnant women.

Anxiety, depression, and insomnia among nurses during the full liberalization of COVID-19: a multicenter cross-sectional analysis of the high-income region in China.

Introduction: Frontline nurses fighting against the epidemic were under great psychological stress. However, there is a lack of studies assessing the prevalence rates of anxiety, depression, and insomnia among frontline nurses after the full liberalization of COVID-19 in China. This study demonstrates the impact of the full liberalization of COVID-19 on the psychological issues and the prevalence rate and associated factors of depressive symptoms, anxiety, and insomnia among frontline nurses. Methods: A total of 1766 frontline nurses completed a self-reported online questionnaire by convenience sampling. The survey included six main sections: the 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder (GAD-7), the 7-item Insomnia Severity Index (ISI), the 10-item Perceived Stress Scale (PSS-10), sociodemographic information, and work information. Multiple logistic regression analyses were applied to identify the potential significantly associated factors for psychological issues. The study methods were compliant with the STROBE checklist. Results: 90.83% of frontline nurses were infected with COVID-19, and 33.64% had to work while infected COVID-19. The overall prevalence of depressive symptoms, anxiety and insomnia among frontline nurses was 69.20%, 62.51%, and 76.78%, respectively. Multiple logistic analyses revealed that job satisfaction, attitude toward the current pandemic management, and perceived stress were associated with depressive symptoms, anxiety, and insomnia. Conclusions: This study highlighted that frontline nurses were suffering from varying degrees of depressive symptoms, anxiety, and insomnia during full liberalization of COVID-19. Early detection of mental health issues and preventive and promotive interventions should be implemented according to the associated factors to prevent a more serious psychological impact on frontline nurses.

Bovine colostrum to supplement the first feeding of very preterm infants: The PreColos randomized controlled trial.

BACKGROUND & AIMS: Gut immaturity leads to feeding difficulties in very preterm infants (<32 weeks gestation at birth). Maternal milk (MM) is the optimal diet but often absent or insufficient. We hypothesized that bovine colostrum (BC), rich in protein and bioactive components, improves enteral feeding progression, relative to preterm formula (PF), when supplemented to MM. Aim of the study is to determine whether BC supplementation to MM during the first 14 days of life shortens the time to full enteral feeding (120 mL/kg/d, TFF120). METHODS: This was a multicenter, randomized, controlled trial at seven hospitals in South China without access to human donor milk and with slow feeding progression. Infants were randomly assigned to receive BC or PF when MM was insufficient. Volume of BC was restricted by recommended protein intake (4-4.5 g/kg/d). Primary outcome was TFF120. Feeding intolerance, growth, morbidities and blood parameters were recorded to assess safety. RESULTS: A total of 350 infants were recruited. BC supplementation had no effect on TFF120 in intention-to-treat analysis [n (BC) = 171, n (PF) = 179; adjusted hazard ratio, aHR: 0.82 (95% CI: 0.64, 1.06); P = 0.13]. Body growth and morbidities did not differ, but more cases of periventricular leukomalacia were detected in the infants fed BC (5/155 vs. 0/181, P = 0.06). Blood chemistry and hematology data were similar between the intervention groups. CONCLUSIONS: BC supplementation during the first two weeks of life did not reduce TFF120 and had only marginal effects on clinical variables. Clinical effects of BC supplementation on very preterm infants in the first weeks of life may depend on feeding regimen and remaining milk diet. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov: NCT03085277.

High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA.

Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.

Co-bedding of Preterm Newborn Pigs Reduces Necrotizing Enterocolitis Incidence Independent of Vital Functions and Cortisol Levels.

Background: Preterm infants are born with immature organs, leading to morbidities such as necrotizing enterocolitis (NEC), a gut inflammatory disease associated with adverse feeding responses but also hemodynamic and respiratory instability. Skin-to-skin contact including "kangaroo care" may improve infant survival and health via improved vital functions (e.g., pulmonary, cardiovascular) and endocrine influences by adrenal glucocorticoids. Clinical effects of skin-to-skin contact for newborn siblings ("co-bedding") are not known. Using NEC-susceptible Preterm pigs as models, we hypothesized that co-bedding and exogenous glucocorticoids improve vital functions and NEC resistance. Methods: In experiment 1, cesarean-delivered, formula-fed Preterm pigs were reared in incubators with (co-bedding, COB, n = 30) or without (single-bedding, SIN, n = 29) a sibling until euthanasia and tissue collection on day four. In experiment 2, single-bedded Preterm pigs were treated postnatally with a tapering dose of hydrocortisone (HC, n = 19, 1-3 mg/kg/d) or saline (CON, n = 19). Results: Co-bedding reduced NEC incidence (38 vs. 65%, p < 0.05) and increased the density of colonic goblet cells (+20%, p < 0.05) but had no effect on pulmonary and cardiovascular functions (respiration, blood pressure, heart rate, blood gases) or cortisol levels. There were limited differences in intestinal villous architecture and digestive enzyme activities. In experiment 2, HC treatment increased NEC lesions in the small intestine without any effects on pulmonary or cardiovascular functions. Conclusion: Co-bedding may improve gut function and NEC resistance independently of cardiorespiratory function and cortisol levels, but pharmacological cortisol treatment predispose to NEC. Preterm pigs may be a useful tool to better understand the physiological effects of co-bedding, neonatal stressors and their possible interactions with morbidities in Preterm neonates.

Apolipoprotein A-I mimetic peptide inhibits atherosclerosis by increasing tetrahydrobiopterin via regulation of GTP-cyclohydrolase 1 and reducing uncoupled endothelial nitric oxide synthase activity.

BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: Low-density lipoprotein (LDL) receptor null (LDLr-/-) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.

Circulating endothelial microparticles: a promising biomarker of acute kidney injury after cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Current diagnostic strategies for acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB) are nonspecific and limited. Previously, we demonstrated that circulating microparticles (MPs) in patients with valve heart disease (VHD) and congenital heart diseases (CHD) induce endothelial dysfunction and neutrophil chemotaxis, which may result in kidney injury. We also found that circulating MPs increase after cardiac surgery with CPB and are related to cardiac function. However, the relationship between circulating MPs and AKI after CPB is unknown. METHODS: Eighty-five patients undergoing cardiac surgery with CPB were enrolled. Patients were divided into AKI and non-AKI groups based on the serum creatinine levels at 12 h and 3 d post-CPB. Circulating MPs were isolated from plasma, and their levels including its subtypes were detected by flow cytometer. Independent risk factors for the CPB-associated AKI (CPB-AKI) were determined by multivariate logistic regression analysis. Receiver operating characteristic (ROC) analysis was used to measure the prognostic potential of CPB-AKI. RESULTS: The morbidity of AKI at 12 h and 3 d after cardiac surgery with CPB was 40% and 31.76%, respectively. The concentrations of total MPs and platelet-derived MPs (PMP) remained unchanged at 12 h and then increased at 3 d post-CPB, while that of endothelial-derived MPs (EMP) increased at both time points. In patients with AKI, PMP and EMP were elevated compared with the patients without AKI. However, no significant change was detected on monocyte-derived MPs (MMP) at 12 h and 3 d post-CPB. The logistic regression analysis showed that EMP was the independent risk factor for AKI both at 12 h and 3 d post-CPB. The area under ROC for the concentrations of EMP at 12 h and 3 d post-CPB was 0.86 and 0.91, with the specificity up to 0.88 and 0.91, respectively. CONCLUSIONS: Circulating EMP may serve as a potential biomarker of AKI after cardiac surgery with CPB.

Density functional theory study of the free and tetraprotonated spheroidal macrotricyclic ligands and the complexes with halide anions: F(-), Cl(-), Br(-).

Theoretical studies of the macrotricyclic tetramine hexaether (SC), its tetraprotonated form SC-4H(+), and the corresponding complexes X(-) subsetSC-4H(+) (This expression represents the structural properties of the halide inclusion complex formed though the free ligand SC-4H(+) and the halide anion X(-): the spherical halide anion X(-) is held by a tetrahedral array of (+)N--H...X(-) hydrogen bonds inside the intramolecular cavity of the tetraprotonated form SC-4H(+)) of SC-4H(+) with the halide anions: F(-), Cl(-), and Br(-) have been performed using density functional theory (DFT) with B3LYP/6-31G method implemented in the Gaussian 03 program package. The optimized geometric structures obtained from DFT calculations are used to perform Natural Bond Orbital (NBO) analysis. The three main types of hydrogen bonds (+)N--H...F(-), (+)N--H...Cl(-), and (+)N--H...Br(-) are investigated. The results indicate that hydrogen bonding interactions are dominant and the halide anions: F(-), Cl(-), and Br(-) offer lone pair electrons to the contacting sigma* (N--H) antibond orbital of SC-4H(+). For all the structures, the most pronounced changes in geometric parameters upon interaction are observed in the proton-donor molecule. The intermolecular interaction energies are predicted by using B3LYP/6-31G methods with basis set superposition error (BSSE) and zero-point energy (ZPE) correction.