To estimate the effects of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) on proteinuria and oxidative stress expression in type 2 diabetes patients.
68 patients with type 2 diabetes mellitus ...(T2DM) were divided into three groups according urinary albumin-to-creatinine ratio (UACR), including T2DM with non-albuminuria group (UACR < 30 mg/g), T2DM with microalbuminuria group (30 ≤ UACR ≤ 300 mg/g), T2DM with macroalbuminuria group (UACR>300 mg/g). They all received SGLT2 inhibitors (SGLT2i) treatment for 12 weeks. The expression of advanced glycation end products (AGEs) in plasma and 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine were measured as indications of oxidative stress. The 24-hour urine samples were collected to measure the concentration of proteinuria and 8-OHdG before and after 12 weeks SGLT2i treatment. Plasma renin activity (PRA), angiotensin II (Ang II) and Aldosterone (ALD) were measured to evaluate renin angiotensin aldosterone system (RASS) levels.
After 12 weeks SGLT2 inhibitors treatment, the median values of 24-hour proteinuria decreased in macroalbuminuria compared to baseline (970 vs. 821 mg/d, P = 0.006). The median values of AGEs and 8-OHdG decreased in microalbuminuria and macroalbuminuria groups when compared to baseline, AGEs (777 vs. 136 ug/ml, P = 0.003) and (755 vs. 210 ug/ml, P = 0.001), 8-OHdG (8.00 vs. 1.88 ng/ml, P = 0.001) and (11.18 vs. 1.90 ng/ml, P < 0.001), respectively. Partial correlations showed that 8-OHdG were relevant to the baseline 24-h proteinuria (r = 0.389, p = 0.001), the reduction of OHdG (Δ8-OHdG) were positively correlated with the decrease of 24-h proteinuria (Δ24-h proteinuria) after 12 weeks of SGLT2i treatment (r = 0.283, P = 0.031). There was no significant correlation between 24-h proteinuria and AGEs in baseline (r = -0.059, p = 0.640) as well as between ΔAGEs and Δ24-h proteinuria (r = 0.022, p = 0.872) after12 weeks of SGLT2i treatment in T2DM patients.
SGLT2i may reduce proteinuria in diabetic nephropathy patients, potentially by inhibiting renal oxidative stress, but not through the AGEs pathway and does not induce RAAS activation.
This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.
Background and Purpose
Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro‐immune communication. Neuronal mechanism‐based therapeutic treatments remain ...lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro‐immune mechanism.
Experimental Approach
Pharmacological intervention, immunofluorescence, RNA‐sequencing, genetic modification and immunoassay were performed to dissect the neuro‐immune basis of itch and inflammation in atopic dermatitis‐like mouse model and in patients.
Key Results
Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)‐induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX‐314, a charged NaV blocker that enters through pathologically activated large‐pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV1.8‐expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1‐positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity‐dependent release of calcitonin gene‐related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model.
Conclusion and Implications
NaV1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti‐inflammatory and anti‐pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.
Metal nanoparticles (NPs) stabilized by MOFs are very promising for catalysis, whereas introduction of C60 into MOFs has been very rarely used, and there was no report for their cooperative catalysis ...in organic syntheses. In this work, C60@UiO‐67 was synthesized by a one‐pot method, so that C60 is uniformly distributed on UiO‐67 in molecular form. Pd NPs coordinating with C60 have been successfully embedded into the framework. The obtained multifunctional C60Pdn@UiO‐67 catalyst exhibits remarkable synergistic catalytic activity in cascade reactions under mild conditions, where UiO‐67 affords Lewis acidity and C60Pdn offers higher hydrogenation activity relative to solely Pd NPs.
Composite catalyst: A new material consisting of Pd, C60 and MOF was designed and synthesized, and showed high catalytic activity in a tandem hydrogenation reaction. The different components of the material acted synergistically to improve the conversion performance.
Realizing blue‐hazard‐free emission is an important goal for white organic light‐emitting diodes (OLEDs) toward healthy lighting applications. However, conventional blue organic emitters with broad ...emission spectra would generally cover the high‐energy emission region and thus cannot meet the demand. Here a blue multiple resonance type thermally activated delayed fluorescence (TADF) emitter DPMX‐CzDABNA is newly designed. The DPMX‐CzDABNA‐based OLEDs can realize blue narrowband emission peaked at 484 nm with a full width at half maximum of 29 nm, and external quantum efficiencies (EQEs) around 26%, which allows DPMX‐CzDABNA to precisely avoid the high‐energy photon contribution and thus be a promising blue component to construct high‐performance white OLEDs with human‐eye‐friendly emission spectra. Using DPMX‐CzDABNA and a reported TADF emitter BPPZ‐DPXZ, respectively, as blue and orange components in white OLEDs, the single‐emitting‐layer devices approach white emission with outstanding EQE up to 35.8%; the double‐emitting‐layer OLEDs achieve blue‐hazard‐free white emissions with a maximum EQE of 26.5% and very stable Commission Internationale de l'Eclairage coordinates of ≈(0.38,0.43) over a wide luminance range from 100 to 10 000 cd m−2. It is expected that this strategy can pave a new way for developing highly efficient all‐TADF white OLEDs without blue‐hazard emission.
By using a novel multiple resonance type emitter DPMX‐CzDABNA and a high‐performance thermally activated delayed fluorescence emitter BPPZ‐DPXZ as blue and orange components, respectively, in double‐emitting‐layer organic light‐emitting diodes, high‐performance blue‐hazard‐free white electroluminescence is achieved with a maximum external quantum efficiency of 26.5% and stable Commission Internationale de l'Eclairage coordinates of (0.38,0.43).
Abstract
Aims
Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after ...myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.
Methods and results
MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.
Conclusion
IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.
Higher-order interactions are ubiquitous in the real world and play a critical role in maintaining the overall function of complex systems. To investigate the effects of higher-order interactions on ...cascading dynamics, we propose a threshold model of cascading failure on hypergraphs that describes the propagation mechanism of failures among nodes and hyperedges. We assume that a hyperedge fails when the fraction of failed nodes within the hyperedge exceeds a specified threshold. Additionally, once a hyperedge fails, all its remaining nodes also fail. Through numerical simulations and theoretical analysis, we reveal a dual effect of hyperedges on the robustness of hypergraphs: they can not only strengthen the connections among nodes and promote the emergence of giant components in the hypergraph but also increase the risk of failure transmission among nodes and debilitate the hypergraph. Our work provides a theoretical framework for understanding the cascading failure of complex systems with high-order interactions and offers a useful tool for designing robust complex systems with such interactions.
•A threshold model of cascading failure with higher-order interactions has been proposed.•Hyperedges have a dual effect on the robustness of hypergraphs.•A proper average hyperdegree or average cardinality can lead to the optimal robustness of a hypergraph.•hypergraphs may collapse in the manners of the first-order, second-order, or double phase transition.
There are many factors affecting decisions to persistent participation in sports and various approaches have been used to frame these antecedents. The aim of this paper was to systematically review ...and quantify the primary factors of persistent participation and to assess their respective strengths of association with persistent participation in youth sport. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guidelines, a comprehensive search was implemented on 31st December 2021 in five databases and meta-analytic procedures were applied to data from studies meeting inclusion criteria. The results revealed that sports enjoyment (meta
r
= 0.45, 95%CI 0.42, 0.49) was highly correlated with persistent intention, while persistent intention (SMD = 1.13, 95%CI 0.70, 1.56) was highly correlated with persistent behavior. In addition, parental support, coach support, peer support, basic psychological needs and sports competence were the primary factors associated with persistent intention and persistent behavior, respectively. This study identified the key factors related to persistent participation and provide a complete understanding of children and adolescents' decisions to continue their participation in organized sports. Referring to the key factors, it can provide information for sports clubs and policy makers to develop strategies to increase youth participation in organized sport.
Systematic Review Registration
PROSPERO, identifier: CRD42021229397.
Background
Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence ...in residential Shanghai, China.
Methods
Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid‐Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world.
Results
In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015‐2017) was 7.01 (95% CI 5.65‐8.37) cases per million, and the mean annual incidence was 2.33 (1.97‐3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 9.23‐19.50 cases per million) and incidence (3.55 0.72 3.74 cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3‐40 cases per million and annual incidence ranging 0.34‐2.4 cases per million.
Conclusions
The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.
Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although ...precise mechanisms remain obscure.
To investigate the mechanism of miR-30d-mediated cardioprotection in HF.
In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems.
These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.
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