SCOPE: Atherosclerosis is believed to be an independent predictor of cardiovascular diseases. A growing body of evidence suggests that quercetin is a potent antioxidant and anti‐inflammatory ...compound. The molecular mechanisms underlying its protective effects against oxidative stress in human endothelial cells remain unclear. This study was designed to confirm the hypothesis that quercetin inhibits oxidized LDL (oxLDL) induced endothelial oxidative damage by activating sirtuin 1 (SIRT1) and to explore the role of adenosine monophosphate activated protein kinase (AMPK), which is a negative regulator of Nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH oxidase) and free radicals. METHODS AND RESULTS: Human umbilical vein endothelial cells were treated with oxLDL with or without quercetin pretreatment. We found that quercetin pretreatment increased SIRT1 mRNA expression. In fact, quercetin protected against oxLDL‐impaired SIRT1 and AMPK activities and reduced oxLDL‐activated NOX2 and NOX4. However, silencing SIRT1 and AMPK diminished the protective function of quercetin against oxidative injuries. The results also indicated that oxLDL suppressed AKT/endothelial NO synthase, impaired mitochondrial dysfunction, and enhanced reactive oxygen species formation, activating the Nuclear Factor Kappa B (NF‐κB) pathway. CONCLUSION: These results provide new insight regarding the possible molecular mechanisms of quercetin. Quercetin suppresses oxLDL‐induced endothelial oxidative injuries by activating SIRT1 and modulating the AMPK/NADPH oxidase/AKT/endothelial NO synthase signaling pathway.
Scope
Endothelial dysfunction is an important mechanism in the development of atherosclerosis and is thought to be critical for predicting cardiovascular diseases. Previous reports suggested that ...chlorogenic acid (CGA) is a potent antioxidant and anti‐inflammatory compound. The molecular mechanisms underlying the inhibitory effects of CGA on oxLDL‐induced oxidative injuries in human endothelial cells are still largely unknown. This study is aimed to test the hypothesis that CGA protects against oxLDL‐facilitated oxidative stress by upregulating SIRT1 and to explore the role of AMPK/PGC‐1 pathway and mitochondrial biogenesis.
Methods and results
HUVECs were treated with oxLDL in the presence or absence of CGA pretreatment. Our data indicated that CGA pretreatment increased SIRT1 deacetylase activity levels. In addition, CGA reversed oxLDL‐impaired SIRT1 and AMPK/PGC‐1 activity and mitigated oxLDL‐induced oxidative stress and dysfunction of mitochondrial biogenesis. However, silencing SIRT1, AMPK, and PGC‐1 abated the ability of CGA to protect against oxidative stress. Results from the present study also suggested that CGA inhibits oxLDL‐induced endothelial apoptosis through modulating SIRT1 and AMPK/PGC‐1 function.
Conclusion
These findings provide new insights into possible molecular mechanisms by which CGA mitigates oxLDL‐induced endothelial oxidative stress and mitochondrial dysfunction by activating SIRT1 and modulating the AMPK/PGC‐1 signaling pathway.
Chlorogenic acid (CGA) is a potent antioxidant and anti‐inflammatory compound. This study found that CGA reduces oxLDL‐induced oxidative damage in human endothelial cells. The signaling transduction pathways of SIRT1‐mediated anti‐atherosclerotic effects involve maintaining mitochondrial biogenesis, thereby inhibiting ROS generation and oxidative stress and apoptosis.
Galectin-3, a biomarker linking oxidative stress and inflammation, participates in different mechanisms related to atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. ...Accumulating evidence indicates that galectin-3 may also promote atherogenesis through inducing endothelial dysfunction. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a receptor for oxLDL uptake, contributes to oxLDL-induced endothelial dysfunction. Whether galectin-3 induces endothelial dysfunction through modulation of LOX-1-mediated signaling remains unclear. In the present study, we explored the mechanisms underlying galectin-3 enhanced cytotoxicity of oxLDL in human umbilical vein endothelial cells (HUVECs) and the role of LOX-1. Incubation of HUVECs with galectin-3 increased the expression of LOX-1 in RNA and protein levels. In addition, the expression of LOX-1 induced by oxLDL was promoted by galectin-3. However, pretreatment of LOX-1 antibody reduced LOX-1 mRNA expression level in cells with oxLDL plus galectin-3 incubation. Compared to cells treated with oxLDL alone, reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and subsequent activation of p38 mitogen-activated protein kinases followed by nuclear factor kappa B (NF-κB) activation and related inflammatory responses including adhesion molecule expression, adhesiveness of monocytic cells, and IL-8 release were also aggravated in cells treated with galectin-3 combined with oxLDL. Compared to cells treated with galectin-3 plus oxLDL group. We found that LOX-1 antibody mitigated NADPH oxidase activity, p-38 up-regulation, NF-κB activation, and proinflammatory responses in cells treated with galectin-3 combined with oxLDL. We conclude that galectin-3 enhances endothelial LOX-1 expression and propose a new mechanism by which galectin-3 may promote endothelial dysfunction by inducing inflammation via LOX-1/ROS/p38/NF-κB-mediated signaling pathway.
Scope
Atherosclerotic cardiovascular disease is the most prevalent cause of mortality and morbidity. Fucoxanthin (FX) possesses anti‐hypertensive and anti‐obesity properties. However, the molecular ...mechanisms underlying the inhibitory effects of FX on oxidized low‐density lipoprotein (oxLDL)‐induced oxidative injuries in human endothelial cells are still largely unknown. This study aims to test the hypothesis that FX protects against oxLDL‐induced oxidative stress by upregulating AMP‐activated protein kinase (AMPK) and to explore the roles of cAMP response element binding protein (CREB) and peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α).
Methods and Results
Human umbilical vein endothelial cells are treated with oxLDL in the presence or absence of FX. FX significantly increases AMPK phosphorylation. In addition, FX diminishes oxLDL‐mediated nicotinamide adenine dinucleotide phosphate oxidase activation by inhibiting protein kinase C and subsequently inducing reactive oxygen species generation and impairing the activity of the endogenous antioxidant enzyme superoxidase dismutase. Furthermore, FX restores oxLDL‐mediated dephosphorylation of phosphoinositide‐3‐kinase/Akt and decreases CREB and PGC‐1α expression to nearly normal levels. Moreover, FX ameliorates the oxLDL‐mediated suppression of mitochondrial function and apoptosis.
Conclusion
These findings provide new insights into the possible molecular mechanisms by which FX mitigates oxLDL‐induced endothelial oxidative stress and mitochondrial dysfunction.
Fucoxanthin (FX) is a natural marine carotenoid derived from edible seaweeds such as brown seaweeds. In the present study, FX ameliorated oxidized low‐density lipoprotein‐induced oxidative damage to endothelial cells, as confirmed by the inhibition of nicotinamide adenine dinucleotide phosphate oxidase and subsequent reactive oxygen species generation and mitochondrial dysfunction.
Vaccination appears to be one of the effective strategies to control the COVID-19 pandemic. However, the challenge of vaccine hesitancy may lower the uptake rate and affect overall vaccine efficacy. ...Being a low-risk group in terms of serious consequences of infection, university students may possess low motivation to get vaccinated. Therefore, an expanded Protection Motivation Theory (PMT) incorporating perceived knowledge, adaptive response, and maladaptive response was proposed to investigate the COVID-19 vaccination intention among Taiwanese university students. University students (n = 924; 575 males; mean age = 25.29 years) completed an online survey during January to February 2021. The proposed expanded PMT model was examined using structural equation modeling (SEM). The results showed that perceived knowledge was significantly associated with coping appraisal (standardized coefficient (β) = 0.820; p < 0.001), and coping appraisal was significantly associated with adaptive response (β = 0.852; p < 0.001), maladaptive response (β = 0.300; p < 0.001) and intention (β = 0.533; p = 0.009). Moreover, maladaptive response (β = −0.173; p = 0.001) but not adaptive response (β = 0.148; p = 0.482) was significantly and negatively associated with intention. The present study’s results demonstrated a positive path between perceived knowledge, coping appraisal, and intention among university students. Therefore, improving knowledge among this population may increase the intention to uptake the vaccine.
Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin's antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease ...(fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts. We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (-358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs. In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.
Background: Vertebral compression fractures (VCFs) often occur in patients with osteoporosis. These fractures can also lead to postural changes. Several studies have shown that patients with ...vertebral compression fractures have a restrictive pattern in their pulmonary function. Percutaneous vertebroplasty (PVP) is the standard treatment for vertebral compression fractures, with the benefits of pain relief and enhancement of vertebral stability for partially collapsed vertebral bodies. However, the effects of PVP on short-term recovery of respiratory performance have not been investigated. Therefore, this study aimed to investigate the changes in pulmonary function, respiratory muscle strength, maximal voluntary ventilation (MVV), and chest mobility in patients with vertebral compression fractures after PVP.
Methods: This research was approved by the clinic committee of the E-DA Hospital Institutional Review Board (EMRP07109N) and registered in the Thai Clinical Trials Registry (TCTR20211029005). We recruited 32 VCF patients. Four-time points were measured: before and after PVP and 1 and 3 weeks after PVP. We measured pulmonary function and maximum voluntary ventilation (MVV) by using spirometry. Respiratory muscle strength was assessed by using a respiratory pressure meter. The chest expansion test was used to evaluate chest mobility. A visual analogue scale (VAS) was used to assess resting and aggravated back pain.
Results: Chest expansion and back pain improved at each time point after PVP. MVV showed significant progress at both 1 and 3 weeks after discharge. Forced expiratory volume in 1 second (FEV1) and maximal inspiratory muscle strength significantly improved 1 week after discharge.
Conclusion: Taking all the data together, PVP not only can resolve severe back pain but can also provide excellent improvements in MVV and chest mobility in patients with vertebral compression fractures.
This study observed the cutaneous analgesic effect of adrenergic agonists when combined with lidocaine. We aimed at the usefulness of four adrenergic agonists and epinephrine as analgesics or as ...tools to prolong the effect of local anesthetics using a model of cutaneous trunci muscle reflex (pinprick pain) in rats. We showed that subcutaneous four adrenergic agonists and epinephrine, as well as the local anesthetic bupivacaine and lidocaine, developed a concentration‐dependent cutaneous analgesia. The rank order of the efficacy of different compounds (ED50; median effective dose) was epinephrine 0.013 (0.012–0.014) μmol > oxymetazoline 0.25 (0.22–0.28) μmol > naphazoline 0.42 (0.34–0.53) μmol = bupivacaine 0.43 (0.37–0.50) μmol > xylometazoline 1.34 (1.25–1.45) μmol > lidocaine 5.86 (5.11–6.72) μmol > tetrahydrozoline 6.76 (6.21–7.36) μmol. The duration of full recovery caused by tetrahydrozoline, oxymetazoline, or xylometazoline was greater (P < 0.01) than that induced via epinephrine, bupivacaine, lidocaine, or naphazoline at equianesthetic doses (ED25, ED50, and ED75). Co‐administration of lidocaine (ED50) with four adrenergic agonists or epinephrine enhanced the cutaneous analgesic effect. We observed that four adrenergic agonists and epinephrine induce analgesia by themselves, and such an effect has a longer duration than local anesthetics. Co‐administration of lidocaine with the adrenergic agonist enhances the analgesic effect, and the cutaneous analgesic effect of lidocaine plus naphazoline (or oxymetazoline) is greater than that of lidocaine plus epinephrine.
Background
Relaxin/relaxin family peptide receptor 1 (RXFP1) signaling is important for both normal physiology and disease. Strong preclinical evidence supports relaxin as a potent antifibrotic ...molecule. However, relaxin‐based therapy failed in clinical trial in patients with systemic sclerosis. We and others have discovered that aberrant expression of RXFP1 may contribute to the abnormal relaxin/RXFP1 signaling in different diseases. Reduced RXFP1 expression and alternative splicing transcripts with potential functional consequences have been observed in fibrotic tissues. A relative decrease in RXFP1 expression in fibrotic tissues—specifically lung and skin—may explain a potential insensitivity to relaxin. In addition, receptor dimerization also plays important roles in relaxin/RXFP1 signaling.
Methods
This review describes the tissue specific expression, characteristics of the splicing variants, and homo/heterodimerization of RXFP1 in both normal physiological function and human diseases. We discuss the potential implications of these molecular features for developing therapeutics to restore relaxin/RXFP1 signaling and to harness relaxin's potential antifibrotic effects.
Results
Relaxin/RXFP1 signaling is important in both normal physiology and in human diseases. Reduced expression of RXFP1 in fibrotic lung and skin tissues surrenders both relaxin/RXFP1 signaling and their responsiveness to exogenous relaxin treatments. Alternative splicing and receptor dimerization are also important in regulating relaxin/RXFP1 signaling.
Conclusions
Understanding the molecular mechanisms that drive aberrant expression of RXFP1 in disease and the functional roles of alternative splicing and receptor dimerization will provide insight into therapeutic targets that may restore the relaxin responsiveness of fibrotic tissues.
The failure of antifibrotic effects in systemic sclerosis patients by relaxin may be the result of reduced expression of its receptor relaxin family peptide receptor 1 (RXFP1) in the fibrotic tissues. Alternative splicing and RXFP1 dimerization with other receptors also play roles in regulating relaxin/RXFP1 signaling. Molecular mechanisms underline the reduced RXFP1 expression and alternative splicing are potential therapeutic targets for restoring relaxin sensitivity in fibrotic diseases.
Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory ...muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery.
This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5-10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL).
We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care.
The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.
KEY MESSAGES
The fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.
The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.
The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.
The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.
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