The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway impairment promotes oxidative stress-induced endothelial cell apoptosis in diabetes.

BACKGROUND: Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. METHODS: Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. RESULTS: UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. CONCLUSION: Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.

Effects of simulated multi-sensory stimulation integration on physiological and psychological restoration in virtual urban green space environment.

Virtual urban green environment images and audio stimuli had been proven to have restorative effects on subjects' physical and mental health. In this area, researchers predominantly focused on visual, auditory and olfactory aspects, while tactile and gustatory senses have been minimally explored. However, the optimal combination of sensory stimuli for promoting physical and mental recovery remains unclear. Therefore, a simulated sensory stimulation approach involving 240 participants was employed, with 30 individuals included in each of the eight experimental groups: the visual-auditory (VA), visual-auditory-olfactory (VAO), visual-auditory-tactile (VAT), visual-auditory-gustatory(VAG), visual-auditory-olfactory-tactile (VAOT), visual-auditory-olfactory-gustatory (VAOG), visual-auditory-tactile-gustatory (VATG), and visual-auditory-olfactory-tactile-gustatory (VAOTG) groups. This study aimed to explore the differences in participants' physiological and psychological health recovery after exposure to different combinations of simulated sensory stimuli in virtual UGSs. The results indicated that the following: (1) In terms of physiological recovery, the blood pressure of the 8 experimental groups decreased significantly after the experiment, indicating that the virtual urban green space environment has a certain recovery effect on physiological state. The combination of VAOTG stimuli in the multisensory group resulted in the best blood pressure recovery (p < 0.05). Tactile is an important sense to enhance the physiological recovery effect. Olfactory-tactile or tactile-gustatory stimuli interactions significantly enhance physiological recovery, emphasizing the importance of tactile stimulation in improving physiological recovery. (2) In terms of psychological recovery, the common trigger of olfactory-gustatory is the most key element to enhance psychological recovery through multi-sensory stimulation of virtual urban green space environment. VAOG stimulation had the best effect on psychological recovery (p < 0.05), followed by VAOTG stimulation (p < 0.05). Gustatory is an important sense to enhance the psychological recovery effect, and both the tactile-gustatory interaction and the olfactory-gustatory interaction significantly enhance the recovery effect. At the same time, the psychological recovery effect obtained by four or more sensory combinations was higher than that obtained by two or three sensory stimulation groups. This study confirms more possibilities for ways to restore physical and mental health through virtual natural environments. It expands the research on the benefits of virtual nature experience and provides theoretical support for the application of this method.

Toxic effects of acetochlor on mortality, reproduction and growth of Caenorhabditis elegans and Pristionchus pacificus.

The effects of acetochlor on the mortality, growth and reproduction of two nematode species were assessed. The LC50 values for Caenorhabditis elegans and Pristionchus pacificus were 1,296 and 210.7 mg/L at 24 h, and 540.0 and 126.4 mg/L at 48 h exposure, respectively. In three succession generations, reproductive capacity was more sensitive in P. pacificus than in C. elegans. Moreover, the sublethal test endpoint of final length was more sensitive with P. pacificus. This study suggested that acetochlor had no long-term effects on C. elegans at lower concentrations. The higher concentrations of acetochlor (from 40 to 160 mg/L) revealed sublethal toxicity to the two tested species, with P. pacificus being more sensitive than C. elegans.

Pien-tze-huang promotes wound healing in streptozotocin-induced diabetes models associated with improving oxidative stress via the Nrf2/ARE pathway.

Diabetic foot ulcers are a serious complication of diabetes, with high mortality and a lack of effective clinical treatment, which leads to a considerable financial burden. Pien-Tze-Huang (PZH) is a Chinese traditional medicine with a long history that has been found to be an effective and convenient treatment for inflammatory diseases such as skin abscesses and ulcers. In this study, we assessed the effects of PZH on diabetic wounds and the underlying mechanisms. The wounds were established on the backs of streptozotocin-induced type 1 diabetic rats and type 2 diabetic mouse models. We found that PZH treatment used locally or by gavage significantly promoted wound healing, accelerated re-epithelialization and vasculature in the wound tissue, upregulated the expression of the growth factors VEGF-A, PDGF, and EGF, and activated the Nrf2/ARE pathway in the wound tissue. In vitro assays showed that PZH improved the proliferation, migration and angiogenic function of human umbilical vein endothelial cells (HUVECs) cultured in palmitic acid, reduced the expression of the apoptotic proteins p53, Bax, and cleaved-caspase3, and activated Nrf2/ARE signaling; however, these protective effects were abrogated after Nrf2 was knocked down by specific siRNA. In addition, the levels of the serum inflammatory cytokines IL-1ß, TNF-α, and IL-6 were reduced after PZH gavage treatment. In conclusion, the positive role of PZH in diabetic wound healing might be related to the activation of the Nrf2/ARE pathway to regulate the level of oxidative stress in vivo and increase the expression of growth factors to improve angiogenesis.

Macitentan treatment of portopulmonary hypertension with hepatopulmonary syndrome: a case report and literature review.

Pulmonary arterial hypertension-targeted therapies in portopulmonary hypertension (PoPH) are scarce, let alone for patients with chronic liver failure (CLF) and hepatopulmonary syndrome (HPS). A 48-year male was admitted to the hospital because of cirrhosis for 18 years, systemic oedema, and chest distress after exercise for 1 week. He was diagnosed with CLF, PoPH, and HPS. After 7 weeks of macitentan treatment, the patient's activity tolerance, pulmonary artery systolic pressure, arterial partial pressure of oxygen (PaO2 ), cTNI, and NT-proBNP changes indicated gradual recovery, without hepatic safety concerns. This case indicated that administering macitentan in patients diagnosed as PoPH (with CLF and HPS) may be efficient and safe enough in a clinical setting.

Geriatric syndromes, chronic inflammation, and advances in the management of frailty: A review with new insights.

As people age, geriatric syndromes characterized by frailty significantly impact both clinical practice and public health. Aging weakens people's immune functions, leading to chronic low-grade inflammation that ultimately contributes to the development of frailty. Effectively managing geriatric syndromes and frailty can help alleviate the economic burden of an aging population. This review delves into the intricate relationship among aging, infection-induced inflammation, chronic inflammation, and frailty. In addition, it analyzes various approaches and interventions to address frailty, such as smart rehabilitation programs and stem-cell treatments, offering promising solutions in this new era. Given the importance of this topic, further research into the mechanisms of frailty is crucial. Equally essential is the devising of relevant measures to delay its onset and the formulation of comprehensive clinical, research, and public health strategies to enhance the quality of life for elderly individuals.

Comprehensive Analysis of Differential Immunocyte Infiltration and Potential ceRNA Networks Involved in the Development of Atrial Fibrillation.

This study is aimed at identifying potential molecular mechanisms and candidate biomarkers in the left atrial regions for the diagnosis and treatment of valvular atrial fibrillation (VAF). Multibioinformatics methods, including linear models for microarray analysis (LIMMA), an SVA algorithm, CIBERSORT immune infiltration, and DNA methylation analysis, were employed. In addition, the protein-protein interaction (PPI) network, Gene Ontology (GO), and molecular pathways of differentially expressed genes (DEGs) or differential methylation regions were constructed. In all, compared with the normal rhythm group, 243 different mRNAs (29 downregulated and 214 upregulated) and 26 different lncRNAs (3 downregulated and 23 upregulated) were detected in the left atrium (LA) of atrial fibrillation (AF) patients, and the neutrophil and CD8+ T cell were infiltrated. Additionally, 199 different methylation sites (107 downregulated and 92 upregulated) were also identified based on DNA methylation analysis. After integration, ELOVL2, CCR2, and WEE1 were detected for differentially methylated and differentially transcribed genes. Among them, WEE1 was also a core gene identified by the competing endogenous RNA (ceRNA) network that included WEE1-KRBOX1-AS1-hsa-miR-17-5p, in VAF left atrial tissue. We combined the DNA methylation and transcriptional expression differential analysis and found that WEE1 (cg13365543) may well be a candidate gene regulated by DNA methylation modification. Moreover, KRBOX1-AS1 and WEE1 can compete endogenously and may mediate myocardial tissue infiltration into CD8+ T cells and participate in the AF process.

A Simple and Fast Hypervolume Indicator-Based Multiobjective Evolutionary Algorithm.

To find diversified solutions converging to true Pareto fronts (PFs), hypervolume (HV) indicator-based algorithms have been established as effective approaches in multiobjective evolutionary algorithms (MOEAs). However, the bottleneck of HV indicator-based MOEAs is the high time complexity for measuring the exact HV contributions of different solutions. To cope with this problem, in this paper, a simple and fast hypervolume indicator-based MOEA (FV-MOEA) is proposed to quickly update the exact HV contributions of different solutions. The core idea of FV-MOEA is that the HV contribution of a solution is only associated with partial solutions rather than the whole solution set. Thus, the time cost of FV-MOEA can be greatly reduced by deleting irrelevant solutions. Experimental studies on 44 benchmark multiobjective optimization problems with 2-5 objectives in platform jMetal demonstrate that FV-MOEA not only reports higher hypervolumes than the five classical MOEAs (nondominated sorting genetic algorithm II (NSGAII), strength Pareto evolutionary algorithm 2 (SPEA2), multiobjective evolutionary algorithm based on decomposition (MOEA/D), indicator-based evolutionary algorithm, and S-metric selection based evolutionary multiobjective optimization algorithm (SMS-EMOA)), but also obtains significant speedup compared to other HV indicator-based MOEAs.

Consistencies and contradictions of performance metrics in multiobjective optimization.

An important consideration of multiobjective optimization (MOO) is the quantitative metrics used for defining the optimality of different solution sets, which is also the basic principle for the design and evaluation of MOO algorithms. Although a plethora of performance metrics have been proposed in the MOO context, there has been a lack of insights on the relationships between metrics. In this paper, we first group the major MOO metrics proposed to date according to four core performance criteria considered in the literature, namely, capacity, convergence, diversity, and convergence-diversity. Then, a comprehensive study is conducted to investigate the relationships among representative group metrics, including generational distance, ϵ-indicator (I(1)ϵ+), spread (∆), generalized spread (∆∗), inverted generational distance, and hypervolume. Experimental results indicated that these six metrics show high consistencies when Pareto fronts (PFs) are convex, whereas they show certain contradictions on concave PFs.