Exploring the impact of coffee consumption on liver health: A comprehensive bibliometric analysis.

The study indicates that while research has demonstrated the potential of coffee to mitigate liver damage, a comprehensive quantitative analysis of its effects has yet to be conducted. This study seeks to explore the current landscape and focal points of research on coffee consumption's impact on the liver from 2013 to 2023. Articles published within this timeframe were retrieved from the Web of Science database and subjected to analysis using R software, VOSviewer, and CiteSpace software. A total of 1106 articles primarily focused on coffee's impact on liver health were analyzed. The frequency of publication exhibited a significant increase from 2013 to 2023. The United States emerged as the leading contributor in publications and international collaborations, particularly with institutions such as Harvard Medical School and Harvard T.H. Chan School of Public Health. Noteworthy journals in this domain included "Nutrients" and "Hepatology" Commonly occurring keywords encompassed components, chlorogenic acids, oxidative stress, and liver. The study highlighted coffee's potential benefits in preventing cardiovascular and liver diseases, attributed to mechanisms such as antioxidant activity and modulation of hepatic cells. Through bibliometric analysis, this study offers valuable insights into the research status and emphasis on coffee's effects on liver health, serving as a significant reference for future investigations in this area.

Association between Impaired Renal Function and Subclinical Myocardial Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction: Assessment Using Noninvasive Pressure-Strain Loop.

INTRODUCTION: The objective of this study was to evaluate the abnormal myocardial function in HFpEF patients with renal dysfunction (RD) and investigate the relationship between renal function and myocardial mechanical characteristics in patients with HFpEF. METHODS: 134 patients with HFpEF and 32 control subjects were enrolled in our study. Clinical and echocardiography data were collected for offline analysis. Global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE) were measured after noninvasive pressure-strain loop analysis. Univariate and multivariate analyses were used to determine the correlation between renal function and myocardial function in patients with HFpEF. RESULTS: In comparison to control subjects, patients with HFpEF tend to have higher GWW (78 [50-115] vs. 108 [65-160] mm Hg%, p < 0.05) and lower GWE (96 [95-97] vs. 95 [92-96] %, p < 0.05), while left ventricular ejection fraction (65.5 ± 3.3 vs. 64.3 ± 4.6%, p < 0.05) was comparable between them. Besides, increased GWW (86 [58-152] vs. 125 [94-187] mm Hg%, p < 0.05) and decreased GWE (96 [93-97] vs. 94 [92-96] %, p < 0.05) were detected in patients with RD compared to those with normal renal function. An independent correlation was found between estimated glomerular filtration rate and GWW after multivariate analysis. DISCUSSION/CONCLUSION: More severely impaired myocardial function was detected in HFpEF patients with RD compared to those with normal renal function. Estimated glomerular filtration rate was independently correlated to GWW in patients with HFpEF.

Effects of 3-month dapagliflozin on left atrial function in treatment-naïve patients with type 2 diabetes mellitus: Assessment using 4-dimensional echocardiography.

BACKGROUND: The sodium-glucose transporter-2 (SGLT-2) inhibitor dapagliflozin can improve left ventricular (LV) performance in patients with type 2 diabetes mellitus (T2DM). However, the effects on left atrial (LA) function in treatment-naïve T2DM patients remain unclear. The aim of our study was 1) to investigate the effects of 3-month treatment with dapagliflozin on LA function in treatment-naïve patients with T2DM using 4-dimensional automated LA quantification (4D Auto LAQ) and 2) to explore linked covariation patterns of changes in clinical and LA echocardiographic variables. METHODS: 4D Auto LAQ was used to evaluate LA volumes, longitudinal and circumferential strains in treatment-naïve T2DM patients at baseline, at follow-up, and in healthy control (HC). Sparse canonical correlation analysis (sCCA) was performed to capture the linked covariation patterns between changes in clinical and LA echocardiographic variables within the treatment-naïve T2DM patient group. RESULTS: This study finally included 61 treatment-naïve patients with T2DM without cardiovascular disease and 39 healthy controls (HC). Treatment-naïve T2DM patients showed reduced LA reservoir and conduit function at baseline compared to HC, independent of age, sex, BMI, and blood pressure (LASr: 21.11 ± 5.39 vs. 27.08 ± 5.31 %, padjusted = 0.017; LAScd: -11.51 ± 4.48 vs. -16.74 ± 4.51 %, padjusted = 0.013). After 3-month treatment with dapagliflozin, T2DM patients had significant improvements in LA reservoir and conduit function independent of BMI and blood pressure changes (LASr: 21.11 ± 5.39 vs. 23.84 ± 5.74 %, padjusted < 0.001; LAScd: -11.51 ± 4.48 vs. -12.75 ± 4.70 %, padjusted < 0.001). The clinical and LA echocardiographic parameters showed significant covariation (r = 0.562, p = 0.039). In the clinical dataset, changes in heart rate, insulin, and BMI were most associated with the LA echocardiographic variate. In the LA echocardiographic dataset, changes in LAScd, LASr, and LASr_c were most associated with the clinical variate. CONCLUSION: Compared with HC, treatment-naïve patients with T2DM had lower LA function, and these patients benefited from dapagliflozin administration, particularly in LA function.

Diagnostic potential of myocardial early systolic lengthening for patients with suspected non-ST-segment elevation acute coronary syndrome.

BACKGROUND: During early systole, ischemic myocardium with reduced active force experiences early systolic lengthening (ESL). This study aimed to explore the diagnostic potential of myocardial ESL in suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with normal wall motion and left ventricular ejection fraction (LVEF). METHODS: Overall, 195 suspected NSTE-ACS patients with normal wall motion and LVEF, who underwent speckle tracking echocardiography (STE) before coronary angiography, were included in this study. Patients were stratified into the coronary artery disease (CAD) group when there was ≥ 50% stenosis in at least one major coronary artery. The CAD patients were further stratified into the significant (≥ 70% reduction of vessel diameter) stenosis group or the nonsignificant stenosis group. Myocardial strain parameters, including global longitudinal strain (GLS), duration of early systolic lengthening (DESL), early systolic index (ESI), and post-systolic index (PSI), were analyzed using STE and compared between groups. Receiver operating characteristic curve (ROC) analysis was performed to determine the diagnostic accuracy. Logistic regression analysis was conducted to establish the independent and incremental determinants for the presence of significant coronary stenosis. RESULTS: The DESL and ESI values were higher in patients with CAD than those without CAD. In addition, CAD patients with significant coronary stenosis had higher DESL and ESI than those without significant coronary stenosis. The ROC analysis revealed that ESI was superior to PSI for identifying patients with CAD, and further superior to GLS and PSI for predicting significant coronary stenosis. Moreover, ESI could independently and incrementally predict significant coronary stenosis in patients with CAD. CONCLUSIONS: The myocardial ESI is of great value for the diagnosis and risk stratification of clinically suspected NSTE-ACS patients with normal LVEF and wall motion.

Association between left ventricular geometry and global myocardial work in patients with heart failure with preserved ejection fraction: assessment using strain-pressure loop.

Concentric LV remodeling and hypertrophy are common structural abnormalities in patients with heart failure with preserved ejection fraction (HFpEF) and tend to be accompanied by impaired LV function. Assessment of global myocardial work (GMW) using strain-pressure loop may provide more comprehensive assessment of LV myocardial function, overcoming the limitations of the conventional parameters. We investigated the value of GMW in patients with HFpEF and assessed the relationship of GMW with concentric remodeling and hypertrophy. Consecutive patients with HFpEF (n = 107) and sex-matched healthy controls (n = 32) were prospectively enrolled. Clinical and conventional echocardiography variables were obtained. Further analyses of offline data were performed to obtain GMW indices including global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE). Association of concentric remodeling and hypertrophy with GMW was analyzed by univariate and multivariate analysis. HFpEF patients showed lower GWE (94% vs 96%, P < 0.001) and higher GWW (114 mmHg% vs 78 mmHg%, P = 0.003) than control group, while GWI (2111 mmHg% vs 2146 mmHg%, P = 0.877) and GCW (2369 mmHg% vs 2469 mmHg%, P = 0.733) were comparable in the two groups. HFpEF patients with relative wall thickness (RWT) > 0.42 had reduced GWE (94% vs 95%, P = 0.034) compared to HFpEF patients with RWT ≤ 0.42, while GWI, GCW, and GWW were comparable between these two subgroups. Multivariate analysis showed an independent association of RWT with GWI, GCW, and GWE, respectively. Impaired global myocardial work was detected in patients with HFpEF. Impaired LV GMW may be associated with increased RWT.

Usefulness of layer-specific strain for evaluating and predicting recovery of left ventricular myocardial function in patients undergoing hybrid coronary revascularization.

PURPOSE: This study aimed to determine if layer-specific strain (LSS) can be used to evaluate and predict left ventricular (LV) recovery in patients with multi-vessel coronary artery disease (CAD) undergoing hybrid coronary revascularization (HCR) using speckle tracking echocardiography (STE). METHODS: A total of 187 consecutive CAD patients who received HCR in our hospital were prospectively enrolled. 30 healthy individuals with matched age and gender were enrolled as a control group. Echocardiography was performed for CAD patients before and 1, 2, and 6 months after HCR. Comprehensive conventional and LSS echocardiography parameters were collected. LV recovery was defined as improvement in LV ejection fraction (LVEF) > 5% at 6-months follow-up compared with baseline. Logistic regression analysis was used to test the correlates of LV recovery. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of correlates for predicting LV recovery. RESULTS: LVEF and LV strain in CAD patients were significantly decreased compared with control subjects. Endocardial global longitudinal strain (Endo-GLS) improved significantly at 1-month follow-up (14.2 ± 1.6% vs. 13.8 ± 1.5%, P < 0.05), and LVGLS and global circumferential strain (GCS) improved significantly at 2-months follow-up. Multivariate regression revealed that Endo-GLS, GLS, and SYNTAX score before HCR were independently correlated to LV recovery. Endo-GLS had an optimal cutoff value of 13.2% for predicting LV recovery with sensitivity of 91% and specificity of 78%. CONCLUSION: LV myocardial systolic function in CAD patients was impaired before HCR and significantly improved after HCR. Endo-GLS was independently correlated to and has optimal predictive value for LV recovery.

Subclinical left ventricular myocardial dysfunction in patients with obstructive sleep apnea syndrome: insights from noninvasive left ventricular myocardial work analysis.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with various cardiovascular diseases and has aroused public concern. Early detection for declining myocardial function is of great significance. This study was aimed at noninvasively evaluating the subclinical left ventricular (LV) myocardial dysfunction with LV pressure-strain loop (PSL) in patients with OSAS having normal LV ejection fraction. METHODS: We enrolled 200 patients with OSAS who visited the Beijing Chaoyang Hospital between February 2021 and December 2021. According to the apnea-hypopnea index (AHI), patients were divided into mild, moderate, and severe groups. The global longitudinal strain (GLS) of the left ventricle was analyzed by two-dimensional speckle tracking echocardiography. The LV PSL was used to assess global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE), and comparisons were made among groups. RESULTS: GLS was significantly lower in the severe group than in mild and moderate group. GWI, GCW, and GWE were lower in the severe group than in mild and moderate groups. GWW was significantly higher in the severe group than in the mild group. GLS, GWI, and GWE were moderately correlated with AHI (Spearman's ρ = -0.468, -0.321, and -0.319, respectively; P < 0.001), whereas GCW and GWW showed a weak correlation with AHI (Spearman's ρ = -0.226 and 0.255 respectively; P < 0.001). Multiple regression analyses revealed AHI was independently associated with GWI after adjusting for SBP, GLS, e', etc. AHI was independently associated with GCW after adjusting for SBP, GLS, etc. CONCLUSIONS: The LV PSL is a new technique to noninvasively detect myocardial function deterioration in patients with OSAS and preserved LV ejection fraction. Increased severity of OSAS was independent associated with both decreased GWI and GCW.

Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway.

The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 µM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein.

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 µM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

The Effects of Leaders' Prosocial Orientation on Employees' Organizational Citizenship Behavior - The Roles of Affective Commitment and Workplace Ostracism.

PURPOSE: According to leadership trait theory, leaders' personality traits are stable factors in organizational situations and exert significant effects on employees' organizational behaviors. However, studies related to this topic are very limited. In this study, from the leadership trait perspective and based on social identity theory and social exchange theory, the influencing mechanisms of leaders' prosocial tendencies on affiliation-oriented and challenge-oriented organizational citizenship behaviors are investigated. Specifically, leadership prosocial tendency, affective commitment and workplace ostracism are selected as the independent variable, mediating variable and moderating variable, respectively. METHODS: The data collection is conducted in two stages in which the leader-employee pairing method is adopted. Ultimately, 347 valid questionnaires are collected from 73 teams. Later, the hierarchical regression analysis and bootstrap methods are used to test the study's hypotheses. RESULTS: Leadership prosocial tendencies have significant positive effects on affective commitment (ß = 0.282, p < 0.001), affiliation-oriented (ß = 0.648, p < 0.001) and challenge-oriented organizational citizenship behaviors (ß = 0.521, p < 0.001). There is a significant positive effect of affective commitment on affiliation-oriented (ß = 0.103, p < 0.05) and challenge-oriented organizational citizenship behaviors (ß = 0.122, p < 0.05). At the same time, the influence of leadership prosocial tendencies on affiliation-oriented (ß = 0.619, p < 0.001) and challenge-oriented organizational citizenship behaviors (ß = 0.487, p < 0.001) remains significant. In other words, affective commitment partially mediates the relationships between leaders' prosocial tendencies and affiliation-oriented, challenge-oriented organizational citizenship behaviors. Workplace ostracism plays a negative moderating role between leaders' prosocial tendencies and affective commitment (ß = -0.098, p < 0.05). Furthermore, workplace ostracism can also mediate the mediating role of affective commitment with 95% bias-corrected confidence intervals [-0.146, -0.017] and [-0.114, -0.003]. CONCLUSION: The results show that leaders' prosocial tendencies have significant positive effects on both affiliation-oriented and challenge-oriented organizational citizenship behaviors. Affective commitment partially mediates the relationships between leaders' prosocial tendencies and affiliation-oriented and challenge-oriented organizational citizenship behaviors. Workplace ostracism significantly negatively moderates the relationship between leaders' prosocial tendencies and affective commitment. Moreover, the study verifies that the mediating effect of workplace ostracism on affective commitment has a significant moderating effect.

Reduced mechanical function of the left atrial predicts adverse outcome in pregnant women with clustering of metabolic risk factors.

INTRODUCTION: The left atrial (LA) strain and strain rate are sensitive indicators of LA function. However, they are not widely used for the evaluation of pregnant women with metabolic diseases. The aim of this study was to assess the LA strain and strain rate of pregnant women with clustering of metabolic risk factors and to explore its prognostic effect on adverse pregnancy outcomes. MATERIALS AND METHODS: Sixty-three pregnant women with a clustering of metabolic risk factors (CMR group), fifty-seven women with pregnancy-induced hypertension (PIH group), fifty-seven women with gestational diabetes mellitus (GDM group), and fifty matched healthy pregnant women (control group) were retrospectively evaluated. LA function was evaluated with two-dimensional speckle-tracking imaging. Iatrogenic preterm delivery caused by severe preeclampsia, placental abruption, and fetal distress was regarded as the primary adverse outcome. RESULTS: The CMR group showed the lowest LA strain during reservoir phase (LASr), strain during contraction phase (LASct) and peak strain rate during conduit phase (pLASRcd) among the three groups (P < 0.05). LA strain during conduit phase (LAScd) and peak strain rate during reservoir phase (pLASRr) in the CMR group were lower than those in the control and GDM groups (P < 0.05). Multivariable Cox regression analysis demonstrated systolic blood pressure (HR = 1.03, 95% CI 1.01-1.05, p = 0.001) and LASr (HR = 0.86, 95% CI 0.80-0.92, p < 0.0001) to be independent predictors of iatrogenic preterm delivery. An LASr cutoff value ≤ 38.35% predicted the occurrence of iatrogenic preterm delivery. CONCLUSIONS: LA mechanical function in pregnant women with metabolic aggregation is deteriorated. An LASr value of 38.35% or less may indicate the occurrence of adverse pregnancy outcomes.

Roflumilast prevents ischemic stroke-induced neuronal damage by restricting GSK3ß-mediated oxidative stress and IRE1α/TRAF2/JNK pathway.

Inhibition of phosphodiesterase 4 (PDE4) protects against neuronal apoptosis induced by cerebral ischemia. However, the exact mechanisms responsible for the protection of PDE4 inhibition have not been completely clarified. Roflumilast (Roflu) is an FDA-approved PDE4 inhibitor for the treatment of chronic obstructive pulmonary disease. The potential protective role of Roflu against ischemic stroke-associated neuronal injury remains unexplored. In this study, we investigated the effect and mechanism of Roflu against ischemic stroke using in vitro oxygen-glucose deprivation reperfusion (OGD/R) and in vivo rat middle cerebral artery occlusion (MCAO) models. We demonstrated that Roflu significantly reduced the apoptosis of HT-22 cells exposed to OGD/R, enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2), and reduced oxidative stress. Treatment with Roflu increased the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3ß (GSK3ß) but decreased the level of phosphorylated inositol requiring enzyme 1α (IRE1α). Interestingly, constitutively active GSK3ß (S9A) mutation abolished the effects of Roflu on oxidative stress and IRE1α phosphorylation. Moreover, Roflu decreased the binding of IRE1α to tumor necrosis factor receptor-associated factor 2 (TRAF2) and attenuated the phosphorylation of c-Jun N-terminal kinase (JNK). We also found that PDE4B knockdown reduced the phosphorylation of both IRE1α and JNK, while overexpression of PDE4B antagonized the role of PDE4B knockdown on the activation of IRE1α and JNK. Besides, the inhibition of PDE4 by Roflu produced similar effects in primary cultured neurons. Finally, Roflu ameliorated MCAO-induced cerebral injury by decreasing infarct volume, restoring neurological score, and reducing the phosphorylation of IRE1α and JNK. Collectively, these data suggest that Roflu protects neurons from cerebral ischemia reperfusion-mediated injury via the activation of GSK3ß/Nrf-2 signaling and suppression of the IRE1α/TRAF2/JNK pathway. Roflu has the potential as a protective drug for the treatment of cerebral ischemia.

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress.

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1ß. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.

Value of territorial work efficiency estimation in non-ST-segment-elevation acute coronary syndrome: a study with non-invasive left ventricular pressure-strain loops.

Non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) patients with normal left ventricular (LV) ejection fraction (LVEF) and wall motion require a non-invasive tool to detect LV risk areas. This study utilized non-invasive LV pressure-strain loops to evaluate territorial myocardial work efficiency (WE) for identifying obstructive coronary artery stenosis, in patients with non-obstructive or obstructive coronary artery stenosis NSTE-ACS, the latter with or without occlusion. Global and territorial longitudinal strain (LS) analyses were performed via speckle-tracking imaging before coronary angiography. LV pressure-strain loops estimated global and territorial myocardial work index (MWI), constructive work (CW), wasted work (WW), and WE. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of independent parameters to detect obstructive coronary artery stenosis. Compared with non-obstructive, obstructive coronary artery stenosis showed significantly lower global and territorial LS, MWI, CW, and WE, and higher WW. Territorial LS, MWI, CW, and WE were significantly worse in territories of coronary occlusion. Territorial WE was the best parameter for predicting obstructive coronary artery stenosis (AUC 0.80, cutoff < 96%, sensitivity 73%, specificity 70%, P < 0.001). In patients with NSTE-ACS with normal wall motion and LVEF, territorial WE is more accurate than territorial LS or MWI to identify LV risk areas.

Roflupram, a novel phosphodiesterase 4 inhibitor, inhibits lipopolysaccharide-induced neuroinflammatory responses through activation of the AMPK/Sirt1 pathway.

Roflupram (ROF) is a novel phosphodiesterase 4 inhibitor. We previously found that ROF suppressed the production of pro-inflammatory factors in microglial cells; however, the underlying mechanisms are largely unknown. The present study aimed to elucidate the underlying molecular mechanisms of the anti-neuroinflammatory effects of ROF in lipopolysaccharide (LPS)-activated microglial cells and LPS-challenged mice. Treatment with ROF suppressed LPS-induced expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in BV-2 microglia cell line. Immunofluorescence and Western blotting analysis showed that ROF significantly inhibited the activation of microglia, as evidenced by decreased expression of ionized calcium binding adaptor molecule-1 (Iba1). Similar results were obtained in primary cultured microglial cells. ROF induced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Sirtuin 1 (Sirt1). Interestingly, the AMPK inhibitor, compound C, blocked the role of ROF in both the phosphorylation of AMPK and the expression of Sirt1 in BV-2 cells stimulated with LPS. More importantly, the Sirt1 inhibitor, EX527, abolished the inhibitory role of ROF on the production of pro-inflammatory factors, and reactivated BV-2 cells. In mice challenged with LPS, ROF improved cognition and decreased the levels of IL-6 and TNF-α in both the cortex and hippocampus. In contrast, EX527 weakened the effects of ROF on cognitive enhancement and reduction of pro-inflammatory factors in the cortex and hippocampus. Furthermore, EX527 blocked the inhibitory role of ROF in the activation of microglial cells in both the hippocampus and cortex. Taken together, our results indicated that ROF attenuated LPS-induced neuroinflammatory responses in microglia, and the AMPK/Sirt1 pathway is essential for the anti-inflammatory effects of ROF.

LncRNA PVT1 induces aggressive vasculogenic mimicry formation through activating the STAT3/Slug axis and epithelial-to-mesenchymal transition in gastric cancer.

PURPOSE: Vasculogenic mimicry (VM), a vessel-like network formed by highly aggressive tumor cells, plays an important role in accelerating cancer progression. This special vascularization pattern is closely associated with a poor prognosis in various cancers. As yet, however, the regulatory mechanism of VM formation is largely unknown. In this study, we assess whether the long noncoding RNA PVT1 is involved in VM generation in gastric cancer. METHODS: VM formation was determined by immunohistochemistry using PAS/CD31 double staining in gastric cancers and Matrigel tube formation in vitro. qRT-PCR and Western blotting were used to assess mRNA and protein expression. Interaction between PVT1 and STAT3 was determined using a RNA pull-down assay. Luciferase reporter and chromatin immunoprecipitation assays were performed to evaluate transcriptional activity of STAT3 on the Slug gene promoter. RESULTS: We found that PVT1 can induce VM generation both in vitro and in vivo. Mechanistically, we found that PVT1 interacted with and activated STAT3 through a 850-1770 nt fragment. PVT1 facilitated STAT3 recruitment to the Slug promoter and transcriptionally enhanced Slug expression, thereby triggering epithelial-to-mesenchymal transition (EMT) and VM capillary formation. STAT3 inhibition effectively blocked PVT1-mediated VM. In primary gastric cancer samples, a positive correlation was found between PVT1 and Slug upregulation, and patients with a high PVT1 and Slug expression exhibited markedly shorter survival times. CONCLUSION: Our results shed light on the role of PVT1 in gastric cancer cell-dependent VM formation. Our findings provide valuable clues for the design of new anti-angiogenic therapeutic strategies. The PVT1/STAT3 axis may serve as a potential target in gastric cancer treatment.

Roflupram exerts neuroprotection via activation of CREB/PGC-1α signalling in experimental models of Parkinson's disease.

BACKGROUND AND PURPOSE: Roflupram improves cognition and limits neuroinflammation in the brain. However, the beneficial effects of roflupram on Parkinson's disease (PD) remain unknown. Therefore, we aimed to elucidate the pharmacological effects and mechanisms of action of ROF in experimental models of PD. EXPERIMENTAL APPROACH: We used an in vitro PD model of SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium iodide (MPP+ ). Cell viability and apoptosis were analysed via the MTT assay and flow cytometry. Mitochondrial morphology, mitochondrial respiratory capacity, and ROS were measured by a mitochondrial tracker, Seahorse Analyzer, and a MitoSOX-Red dye. For in vivo PD model, behavioural tests, Nissl staining, and immunohistochemistry were used to evaluate protection by roflupram. The levels of TH, cAMP response element-binding protein (CREB), and PPARγ coactivator-1α (PGC-1α) were analysed by western blotting. KEY RESULTS: Roflupram decreased MPP+ -induced apoptosis in SH-SY5Y cells and human dopaminergic neurons. Roflupram also increased mitochondrial respiratory capacity, decreased ROS production, and restored mitochondrial morphology. Roflupram reversed the MPP+ -induced reductions of phosphorylated CREB, PGC-1α and TH. These protective effects were blocked by the PKA inhibitor H-89 or by PGC-1α siRNA. In mice treated with MPTP, roflupram significantly improved motor functions. Roflupram prevented both dopaminergic neuronal loss and the reduction of phosphorylated CREB and PGC-1α in the substantia nigra and striatum. CONCLUSION AND IMPLICATIONS: Roflupram protected dopaminergic neurons from apoptosis via the CREB/PGC-1α pathway in PD models. Hence, roflupram has potential as a protective drug in the treatment of PD.

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway.

Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation of endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative stress is an inducer of ER stress. The present study aimed to determine whether suppression of ER stress is involved in the protective effects of PDE4 inhibition against cerebral ischemia. We found that exposing HT-22 cells to oxygen-glucose deprivation (OGD) significantly activated ER stress, as evidenced by increased expression of the 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), and C/EBP-homologous protein (CHOP). Overexpression of PDE4B increased ER stress, while knocking down PDE4B or treatment with the PDE4 inhibitor, FCPR03, prevented OGD-induced ER stress in HT-22 cells. Furthermore, FCPR03 promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus. Importantly, the Nrf-2 inhibitor, ML385, blocked the inhibitory role of FCPR03 on OGD-induced ER stress. ML385 also abolished the protective role of FCPR03 in HT-22 cells subjected to OGD. Knocking down heme oxygenase-1 (HO-1), which is a target of Nrf-2, also blocked the protective role of FCPR03, enhanced the level of reactive oxygen species (ROS), and increased ER stress and cell death. We then found that FCPR03 or the antioxidant, N-Acetyl-l-cysteine, reduced oxidative stress in cells exposed to OGD. This effect was accompanied by increased cell viability and decreased ER stress. In primary cultured neurons, we found that FCPR03 reduced OGD-induced production of ROS and phosphorylation of eIF2α. The neuroprotective effect of FCPR03 against OGD in neurons was blocked by ML385. These results demonstrate that inhibition of PDE4 activates Nrf-2/HO-1, attenuates the production of ROS, and thereby attenuates ER stress in neurons exposed to OGD. Additionally, we conclude that FCPR03 may represent a promising therapeutic agent for the treatment of ER stress-related disorders.

LncRNA PVT1 Mediates Antiapoptosis and 5-Fluorouracil Resistance via Increasing Bcl2 Expression in Gastric Cancer.

PURPOSE: Plasmacytoma variant translocation 1 (PVT1) is a long noncoding RNA encoded by the human PVT1 gene, which has been verified to mediate tumorigenesis in gastric cancer. However, the underlying molecular mechanisms of PVT1 in gastric cancer (GC) remain largely unknown. METHODS: The tumorigenic ability of PVT1 was verified by subcutaneous and orthotopic mouse models. Flow cytometry assay and TdT-mediated dUTP Nick-End Labeling staining were conducted to explore the effects of PVT1 on gastric cancer cell apoptosis. We investigated the relative gene and protein that are involved in apoptosis in real-time PCR and western blot assay. The resistance to 5- Fluorouracil (5-Fu) caused by PVT1 was evaluated using cell viability assay. Then, to confirm the effects of PVT1 on 5-Fu resistance, we conducted the Kaplan-Meier analysis based on three public databases. RESULTS: We confirmed that PVT1 can promote the progression of gastric cancer. PVT1 inhibited the apoptosis of GC cells, which may account for its promotion on GC. We confirmed that PVT1 can regulate the expression of Bcl2 and enhance drug-resistance of gastric cancer to 5-Fu. Kaplan-Meier analysis showed that patients with high PVT1 expression do not experience survival related benefits from 5-Fu based chemotherapy; instead, therapy containing no 5-Fu chemotherapy can improve the first progression survival and overall survival of high PVT1 expression GC patients significantly. CONCLUSION: Our results showed that PVT1 can inhibit the apoptosis and enhance the 5-Fu resistance of gastric cancer through the activation of Bcl2. PVT1 has the potential to serve as an indicator to predict 5-Fu treatment resistance.