Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure ...hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure.
The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin.
Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low‐density lipoprotein (LDL) levels. This study was undertaken to ...investigate the role of LDL composition in promoting early vascular aging in SLE patients.
Methods
Plasma LDL from 45 SLE patients (SLE‐LDL) and from 37 normal healthy controls (N‐LDL) was chromatographically divided into 5 subfractions (L1–L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid‐mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE−/− mice.
Results
The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE‐L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima‐media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix‐assisted laser desorption ionization–time‐of‐flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet‐activating factor (PAF) were increased in SLE‐LDL and in the SLE‐L5 plasma subfraction. Injecting SLE‐LDL, SLE‐L5, or LPC into young, male apoE−/− mice caused increases in plasma CX3CL1 levels, aortic fatty‐streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N‐LDL or SLE‐L1 had negligible effects (n = 3–8 mice per group). In vitro, SLE‐L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE‐LDL and SLE‐L5 induced the expression of CX3CL1 and enhanced monocyte–endothelial cell adhesion in assays with bovine aortic endothelial cells.
Conclusion
An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.
Summary
Dysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), ...induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.
It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain ...largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.
•Both intraperitoneal and intra-vlPAG administration of (2R,6R)-HNK rescue chronic stress-induced depression-like behavior.•(2R,6R)-HNK rapidly rescues chronic stress-induced depression-like behavior.•Antidepressant effects of (2R,6R)-HNK persist for up to 21 days.•(2R,6R)-HNK increases glutamate release presynaptically and surface GluR1 expression postsynaptically in the vlPAG.•Blockage of AMPAR in the vlPAG antagonizes antidepressant effects of (2R,6R)-HNK.
This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac ...dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25
regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.
This study aimed to investigate the affective Kansei/affective design elements of Taiwanese wooden furniture and the consumer demand and perception for the design using Kansei engineering methodology ...and fuzzy theory. An online survey was conducted to carry out triangular fuzzy linguistic analysis from fuzzy theory and understand the consumers’ demands and perceptions of the design elements of wooden seat shapes. The research results showed that consumers agreed with “sturdy” the most, indicating the element needs to comply with the demand and purchase intention of consumers. In terms of the Kansei design elements of a rectangular seat shape, consumers’ agreement on “elegant” was medium, while consumers agreed with “novel” the least. The research results provide the Taiwanese wooden furniture industry and designers with a reference for decision-making, design, and manufacturing.
High-resolution geochemical and sedimentological data have been obtained for a lacustrine sediment record from Lagoa Dourada (South Brazil). Four distinctly different depositional processes were ...determined: (1) Suspension fallout of fine-grained minerogenic particles transferred via fluvial activity dominates the Early Holocene and relates to open grassland in the catchment area; (2) Activation of the karst hydrological system with deposition of massive sand layers indicates increased precipitation at the onset of the Middle Holocene; (3) Minerogenic sediments are replaced by organic deposition due to wetter climatic conditions with the expansion of woodlands in combination with release of dissolved nutrients due to enhanced pedogenesis during the Middle to Late Holocene; (4) Human-induced land-use change caused destabilization of soils in the catchment area with resulting cultural soil erosion between 1800 and 1950 CE. These depositional trends are linked to intensity variations of the South American Monsoon System (SAMS). Century-long climatic events detected by data of high-resolution XRF scanning confirm this relationship and provide signals of the 8.2 and 4.2 ka events as well as of the Little Ice Age. These events document increased rainfall with complex responses of the environmental system. Our SAMS-induced consequences of past hydroclimatic variability on the environment of South Brazil provide background information for better evaluating model projections of future climate change.
Display omitted
•Hydroclimatic variability detected at the margin of the South American Monsoon System.•Sedimentation of river flooding superseded by karst discharge and lacustrine productivity.•8.2 and 4.2 ka events as well as Little Ice Age reflect increased rainfall.•Onset of cultural soil erosion with agricultural activities since 1800 CE ± 50.
Aims/Introduction
Electronegative low‐density lipoprotein (L5) is the most atherogenic fraction of low‐density lipoprotein and is elevated in people with metabolic syndrome (MetS), whereas the ...retinol‐binding protein 4 receptor (stimulated by retinoic acid 6 STRA6) cascade is disrupted in various organs of patients with obesity‐related diseases. Our objective was to investigate whether L5 from MetS patients capably induces pathogenesis of aorta through disrupting the STRA6 cascade.
Material and Methods
We examined the in vivo and in vitro effects of L5 on the STRA6 cascade and aortic atherogenic markers. To investigate the role of this cascade on atherosclerotic formation, crbp1 transfection was carried out in vitro.
Results
This study shows that L5 activates atherogenic markers (p38 mitogen‐activated protein kinases, pSmad2 and matrix metallopeptidase 9) and simultaneously suppresses STRA6 signals (STRA6, cellular retinol‐binding protein 1, lecithin‐retinol acyltransferase, retinoic acid receptor‐α and retinoid X receptor‐α) in aortas of L5‐injected mice and L5‐treated human aortic endothelial cell lines and human aortic smooth muscle cell lines. These L5‐induced changes of the STRA6 cascade and atherogenic markers were reversed in aortas of LOX1−/− mice and in LOX1 ribonucleic acid‐silenced human aortic endothelial cell lines and human aortic smooth muscle cell lines. Furthermore, crbp1 gene transfection reversed the disruption of the STRA6 cascade, the phosphorylation of p38 mitogen‐activated protein kinases and Smad2, and the elevation of matrix metallopeptidase 9 in L5‐treated human aortic endothelial cell lines.
Conclusions
This study shows that L5 from MetS patients induces atherogenic markers by disrupting STRA6 signaling. Suppression of STRA6 might be one novel pathogenesis of aorta in patients with MetS.
Dyslipoproteinemia can cause aortic injuries by utilizing electronegative low‐density lipoprotein caused disruption of stimulated by retinoic acid 6 signaling. The suppression of stimulated by retinoic acid 6 might be one novel pathogenesis of aorta in people with metabolic syndrome.
This study aims to investigate the sensory preferences of children aged 8–12 regarding the material and characteristics of wooden toys. Taking wooden rocking horses as research samples, this study ...selected three types of wood, respectively Pinus taiwanensis, Fagus sylvatica, and Juglans nigra, which are significantly different in appearance from solid wood commonly used to make wooden toys. The experiment was conducted through on-site observation and questionnaire surveys to record children’s preferences for wood characteristics, such as the characteristic factors of wood texture, color and luster, touch, weight, smell, and overall preference. Descriptive statistics and analysis were performed using SPSS 25V, and the experimental results were analyzed and interpreted using fuzzy trigonometric functions. The findings reveal that Taiwan pine had the highest average worth score among the various evaluation characteristics in terms of wood surface performance preferences. Other types of wood also showed different favorability results in different characteristics. This study also analyzes the correlation and significant differences in favorability evaluation using fuzzy theory. This study provides insights that can be useful for toy designers and children’s teaching aid developers to purchase and match wooden toys effectively while promoting the efficient use of wood resources.
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