Role of EZH2-mediated epigenetic modification on vascular smooth muscle in cardiovascular diseases: A mini-review.

Vascular smooth muscle cells (VSMCs) are integral to the pathophysiology of cardiovascular diseases (CVDs). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, plays a crucial role in epigenetic regulation of VSMCs gene expression. Emerging researches suggest that EZH2 has a dual role in VSMCs, contingent on the pathological context of specific CVDs. This mini-review synthesizes the current knowledge on the mechanisms by which EZH2 regulates VSMC proliferation, migration and survival in the context of CVDs. The goal is to underscore the potential of EZH2 as a therapeutic target for CVDs treatment. Modulating EZH2 and its associated epigenetic pathways in VSMCs could potentially ameliorate vascular remodeling, a key factor in the progression of many CVDs. Despite the promising outlook, further investigation is warranted to elucidate the epigenetic mechanisms mediated by EZH2 in VSMCs, which may pave the way for novel epigenetic therapies for conditions such as atherosclerosis and hypertension.

Flavor release from walnut kernels in an in-vitro mastication model with decoupled oral parameters.

Consumer preferences for walnut products are largely determined by the flavors released during mastication. In this study, a peeled walnut kernel (PWK) model was established with oral parameters decoupled using a Hutchings 3D model. The model explored in vitro variations using head-space solid-phase microextraction-gas chromatography-mass spectrometry and intelligent sensory techniques. The fracture strength, hardness, particle size, adhesiveness, springiness, gumminess, and chewiness were significantly reduced during mastication. We identified 61 volatile compounds and found that 2,5-dimethyl-3-ethylpyrazine is a key component, releasing predominantly baking and milky notes. Glutamic acid, alanine, arginine, and sucrose were identified as the key compounds in taste perception. The method can help establish a mastication model for nuts and facilitate breakthroughs in the development of walnut products and processing methods.

Hybrid fiber-based time synchronization and vibration detection system.

We propose a hybrid fiber-based time synchronization and vibration detection system. The vibration is detected by exploring the idle light of the time synchronization system, i.e., the Rayleigh backscattering of the timing pulse disseminated in the fiber link. The addition of a sensing function does not affect the performance of time synchronization. In the multiuser experimental demonstration, time deviation results are 3.6 ps at τ = 1 s and 1.4 ps at τ = 104 s on the 40-km fiber link. Meanwhile, the hybrid system can accurately detect and locate vibrations occurring on the link. This method enables multiple functions of the optical fiber network without occupying extra optical channels. Moreover, it gives a possible solution for enhancing the security of the time synchronization network through vibration detection.

DEAD-box helicase 17 (DDX17) protects cardiac function by promoting mitochondrial homeostasis in heart failure.

DEAD-box helicase 17 (DDX17) is a typical member of the DEAD-box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice (Ddx17-cKO), cardiomyocyte-specific Ddx17 transgenic mice (Ddx17-Tg), and various models of cardiomyocyte injury and heart failure (HF). DDX17 is downregulated in the myocardium of mouse models of heart failure and cardiomyocyte injury. Cardiomyocyte-specific knockout of Ddx17 promotes autophagic flux blockage and cardiomyocyte apoptosis, leading to progressive cardiac dysfunction, maladaptive remodeling and progression to heart failure. Restoration of DDX17 expression in cardiomyocytes protects cardiac function under pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor B-cell lymphoma 6 (BCL6) and inhibit the expression of dynamin-related protein 1 (DRP1). When DDX17 expression is reduced, transcriptional repression of BCL6 is attenuated, leading to increased DRP1 expression and mitochondrial fission, which in turn leads to impaired mitochondrial homeostasis and heart failure. We also investigated the correlation of DDX17 expression with cardiac function and DRP1 expression in myocardial biopsy samples from patients with heart failure. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway in heart failure.

Identification of the Immune Landscapes and Follicular Helper T Cell-Related Genes for the Diagnosis of Age-Related Macular Degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is a progressive ocular ailment causing age-associated vision deterioration, characterized by dysregulated immune cell activity. Notably, follicular helper T (Tfh) cells have emerged as pivotal contributors to AMD pathogenesis. Nonetheless, investigations into Tfh-associated gene biomarkers for this disorder remain limited. METHODS: Utilizing gene expression data pertinent to AMD procured from the Gene Expression Omnibus (GEO) repository, we employed the "DESeq2" R software package to standardize and preprocess expression levels. Concurrently, CIBERSORT analysis was utilized to compute the infiltration proportions of 22 distinct immune cell types. Subsequent to weighted gene correlation network analysis (WGCNA), coupled with differential expression scrutiny, we pinpointed genes intricately linked with Tfh cells. These potential genes underwent further screening using the MCODE function within Cytoscape software. Ultimately, a judicious selection of pivotal genes from these identified clusters was executed through the LASSO algorithm. Subsequently, a diagnostic nomogram was devised based on these selected genes. RESULTS: Evident Tfh cell disparities between AMD and control cohorts were observed. Our amalgamated analysis, amalgamating differential expression data with co-expression patterns, unveiled six genes closely associated with Tfh cells in AMD. Subsequent employment of the LASSO algo-rithm facilitated identification of the most pertinent genes conducive to predictive modeling. From these, GABRB3, MFF, and PROX1 were elected as prospective diagnostic biomarkers for AMD. CONCLUSIONS: This investigation discerned three novel biomarker genes, linked to inflammatory mechanisms and pivotal in diagnosing AMD. Further exploration of these genes holds potential to foster novel therapeutic modalities and augment comprehension of AMD's disease trajectory.

A Case of Pyoderma Gangrenosum after Partial Small Bowel Resection.

ABSTRACT: Pyoderma gangrenosum (PG) is a rare, noninfectious inflammatory disease of unknown etiology that affects the skin and mucous membranes. The development of PG after partial small bowel resection is very rare and can initially resemble an infectious complication, although it is an inflammatory disease.This report presents the case of a 55-year-old man who underwent partial small bowel resection for incomplete intestinal obstruction and developed postoperative infection-like manifestations, including redness and swelling of the incision, severe pain, and yellow-green turbid fluid from the drainage tube. After completing a skin biopsy that suggested massive neutrophil infiltration, multiple secretion cultures for Pseudomonas aeruginosa (+), and systemic screening without other comorbidities, a diagnosis of postoperative PG and P aeruginosa infection was determined.Early detection of this complication is essential for patient recovery because primary surgical treatment, which is contraindicated in such cases, can worsen PG. Therefore, PG should be treated conservatively with corticosteroids.

Malignant ascites supernatant enhances the proliferation of gastric cancer cells partially via the upregulation of asparagine synthetase.

Malignant ascites (MA) is a common manifestation of advanced gastric cancer (GC) with peritoneal metastasis (PM), which usually indicates a poor prognosis. The present study aimed to explore the effects of MA, a unique microenvironment of PM, on the proliferation of cancer cells and investigate the underlying mechanisms. Ex vivo experiments demonstrated that GC cells treated with MA exhibited enhanced proliferation. RNA sequencing indicated that asparagine synthetase (ASNS) was one of the differentially expressed genes in GC cells following incubation with MAs. Furthermore, the present study suggested that MA induced an upregulation of ASNS expression and the stimulatory effect of MA on cancer cell proliferation was alleviated upon ASNS downregulation. Activating transcription factor 4 (ATF4), a pivotal transcription factor regulating ASNS, was upregulated when cells were treated with MA supernatant. After ATF4 knockdown, the proliferation of MA-treated GC cells and the expression of ASNS decreased. In addition, the decline in the proliferation of the ATF4-downregulated AGS GC cell line was rescued by ASNS upregulation. The findings indicated that MA could promote the proliferation of GC cells via activation of the ATF4-ASNS axis. Hence, it may be a potential target for treating GC with PM and MA.

Corrigendum: DDX5 and DDX17-multifaceted proteins in the regulation of tumorigenesis and tumor progression.

[This corrects the article DOI: 10.3389/fonc.2022.943032.].

Mesoporous silica stabilized Cu-Fe bimetallic nanozymes for total antioxidant capacity assay of fruit foods.

Total antioxidant capacity (TAC) is currently considered as a vital indicator of food quality in antioxidant ability and attracts much attention for human healthcare. It is thus of great significance to realize the accurate and rapid detection of TAC in foods. Herein, we have constructed a preferable hybrid nanozyme based on the mesoporous silica-stabilized CuO composited Fe3O4 nanoparticles (Fe3O4@MSNs@CuO, FMC NPs), which possess the enhanced peroxidase (POD)-like activity via cascade response for specific and sensitive determination of TAC in fruit foods. The results showed the hybrid nanozyme displayed a remarkable POD-like activity, excellent selectivity and sensitivity, and the limit of detection (LOD) of the colorimetric sensor was 6.13 mM with the concentration range from 10 to 45 mM. Therefore, the fabricated hybrid nanozyme can be regarded as an effective biosensor for the evaluation of antioxidant quality in fruit foods in future. KEY POINTS: • The stabilized bimetallic nanozyme was constructed for TAC analysis in fruits. • The hybrid nanozyme possessed the enhanced POD-like activity by cascading effects. • The nanozyme was an effective biosensor for antioxidant quality evaluation in fruits.

Research on the evolution and the driving forces of land use classification for production, living, and ecological space in China's Qilian Mountains Nature Reserve from 2000 to 2020.

With the rapid development of the economy, problems such as resource depletion, environmental degradation, and increasingly strained human-land relations have become increasingly prominent. The rational layout of the production, living, and ecological spaces is the basis for solving the contradiction between economic development and environmental protection. This paper analyzed the spatial distribution pattern and evolution characteristics of the Qilian Mountains Nature Reserve based on the theory of production, living, and ecological space. The results show that the production and living function indexes are rising. The most advantaged areas are in the northern part of the research area, where the terrain is flat and transportation is convenient. The ecological function index rises, falls, then rises again. The high-value area is located in the south of the study area, and its ecological function is intact. The study area is dominated by ecological space. During the study period, the area of production space increased by 858.5 km2 and the living space area increased by 341.12 km2. The intensification of human activities has separated the continuity of ecological space. The area of ecological space has decreased by 233.68 km2. Among geographical factors, altitude has a significant impact on the evolution of living space. Population density is the main socioeconomic factor in changing the areas of production space and ecological space. This study is expected to provide a reference basis for land use planning and sustainable development of resources and environment in nature reserves.

Research on Mechanisms of Chinese Medicines in Prevention and Treatment of Postoperative Adhesion.

Postoperative adhesion (PA) is currently one of the most unpleasant complications following surgical procedures. Researchers have developed several new strategies to alleviate the formation of PA to a great extent, but so far, no single measure or treatment can meet the expectations and requirements of clinical patients needing complete PA prevention. Chinese medicine (CM) has been widely used for thousands of years based on its remarkable efficacy and indispensable advantages CM treatments are gradually being accepted by modern medicine. Therefore, this review summarizes the formating process of PA and the efficacy and action mechanism of CM treatments, including their pharmacological effects, therapeutic mechanisms and advantages in PA prevention. We aim to improve the understanding of clinicians and researchers on CM prevention in the development of PA and promote the in-depth development and industrialization process of related drugs.

ROCK inhibition enhanced hepatocyte liver engraftment by retaining membrane CD59 and attenuating complement activation.

Hepatocyte transplantation can be an effective treatment for patients with certain liver-based metabolic disorders and liver injuries. Hepatocytes are usually infused into the portal vein, from which hepatocytes migrate into the liver and integrate into the liver parenchyma. However, early cell loss and poor liver engraftment represent major hurdles to sustaining the recovery of diseased livers after transplantation. In the present study, we found that ROCK (Rho-associated kinase) inhibitors significantly enhanced in vivo hepatocyte engraftment. Mechanistic studies suggested that the isolation of hepatocytes caused substantial degradation of cell membrane proteins, including the complement inhibitor CD59, probably due to shear stress-induced endocytosis. ROCK inhibition by ripasudil, a clinically used ROCK inhibitor, can protect transplanted hepatocytes by retaining cell membrane CD59 and blocking the formation of the membrane attack complex. Knockdown of CD59 in hepatocytes eliminates ROCK inhibition-enhanced hepatocyte engraftment. Ripasudil can accelerate liver repopulation of fumarylacetoacetate hydrolase-deficient mice. Our work reveals a mechanism underlying hepatocyte loss after transplantation and provides immediate strategies to enhance hepatocyte engraftment by inhibiting ROCK.

Prediction of air pollutant concentrations based on TCN-BiLSTM-DMAttention with STL decomposition.

A model with high accuracy and strong generalization performance is conducive to preventing serious pollution incidents and improving the decision-making ability of urban planning. This paper proposes a new neural network structure based on seasonal-trend decomposition using locally weighted scatterplot smoothing (Loess) (STL) and a dependency matrix attention mechanism (DMAttention) based on cosine similarity to predict the concentration of air pollutants. This method uses STL for series decomposition, temporal convolution, a bidirectional long short-term memory network (TCN-BiLSTM) for feature learning of the decomposed series, and DMAttention for interdependent moment feature emphasizing. In this paper, the long short-term memory network (LSTM) and the gated recurrent unit network (GRU) are set as the baseline models to design experiments. At the same time, to test the generalization performance of the model, short-term forecasts in hours were performed using PM2.5, PM10, SO2, NO2, CO, and O3 data. The experimental results show that the model proposed in this paper is superior to the comparison model in terms of root mean square error (RMSE) and mean absolute percentage error (MAPE). The MAPE values of the 6 kinds of pollutants are 6.800%, 10.492%, 9.900%, 6.299%, 4.178%, and 7.304%, respectively. Compared with the baseline LSTM and GRU models, the average reduction is 49.111% and 43.212%, respectively.

Apigenin alleviates oxidative stress-induced myocardial injury by regulating SIRT1 signaling pathway.

Apigenin is a natural flavonoid which is widely found in vegetables and fruits. However, the mechanism of apigenin in oxidative stress-induced myocardial injury has not been fully elucidated. We established an isoproterenol (Iso)-induced myocardial injury mouse model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell injury model, followed by pretreatment with apigenin to explore its protective effects. Apigenin can significantly alleviate isoproterenol-induced oxidative stress, cell apoptosis and myocardial remodeling in vivo. Apigenin pretreatment can also significantly improve cardiomyocyte morphology, decrease H/R induced oxidative stress, and attenuate cell apoptosis and inflammation in vitro. Further mechanism study revealed that apigenin treatment reversed isoprenaline and H/R-induced decrease of Sirtuin1 (SIRT1). Molecular docking results proved that apigenin can form hydrogen bond with 230 Glu, a key site of SIRT1 activation, indicating that apigenin is an agonist of SIRT1. Moreover, SIRT1 knockdown by siRNA significantly reversed the protective effect of apigenin in H/R-induced myocardial injury. In conclusion, apigenin protects cardiomyocyte function from oxidative stress-induced myocardial injury by modulating SIRT1 signaling pathway, which provides a new potential therapeutic natural compound for the clinical treatment of cardiovascular diseases.

Rapid induction and long-term self-renewal of neural crest-derived ectodermal chondrogenic cells from hPSCs.

Articular cartilage is highly specific and has limited capacity for regeneration if damaged. Human pluripotent stem cells (hPSCs) have the potential to generate any cell type in the body. Here, we report the dual-phase induction of ectodermal chondrogenic cells (ECCs) from hPSCs through the neural crest (NC). ECCs were able to self-renew long-term (over numerous passages) in a cocktail of growth factors and small molecules. The cells stably expressed cranial neural crest-derived mandibular condylar cartilage markers, such as MSX1, FOXC1 and FOXC2. Compared with chondroprogenitors from iPSCs via the paraxial mesoderm, ECCs had single-cell transcriptome profiles similar to condylar chondrocytes. After the removal of the cocktail sustaining self-renewal, the cells stopped proliferating and differentiated into a homogenous chondrocyte population. Remarkably, after transplantation, this cell lineage was able to form cartilage-like structures resembling mandibular condylar cartilage in vivo. This finding provides a framework to generate self-renewing cranial chondrogenic progenitors, which could be useful for developing cell-based therapy for cranial cartilage injury.

Microbiota in promoting liver regeneration.

Extensive work has revealed well-coordinated mechanisms that underlie liver regeneration, albeit with a focus on intrinsic interactions within hepatic cells. Here, Hess et al.1 demonstrate that Mycobacterium leprae infection can induce liver growth of nine-banded armadillo without obvious side effects.

AMPK activation is sufficient to increase skeletal muscle glucose uptake and glycogen synthesis but is not required for contraction-mediated increases in glucose metabolism.

The AMP-activated protein kinase (AMPK) is a cellular sensor of energetics and when activated in skeletal muscle during contraction can impart changes in skeletal muscle metabolism. Therapeutics that selectively activate AMPK have been developed to lower glucose levels through increased glucose disposal rates as an approach to abrogate the hyperglycemic state of diabetes; however, the metabolic fate of glucose following AMPK activation remains unclear. We have used a combination of in vivo evaluation of glucose homeostasis and ex vivo skeletal muscle incubation to systematically evaluate metabolism following pharmacological activation of AMPK with PF-739, comparing this with AMPK activation through sustained intermittent electrical stimulation of contraction. These methods to activate AMPK result in increased glucose uptake but divergent metabolism of glucose: pharmacological activation results in increased glycogen accumulation while contraction-induced glucose uptake results in increased lactate formation and glucose oxidation. These results provide additional evidence to support a role for AMPK in control of skeletal muscle metabolism and additional insight into the potential for AMPK stimulation with small molecule direct activators.

Compound Capecitabine Colon-Targeted Microparticle Prepared by Coaxial Electrospray for Treatment of Colon Tumors.

To improve the antitumor effect of combined capecitabine (CAP) and osimertinib (OSI) therapy and quickly and efficiently reduce tumor volumes for preoperative chemotherapy, we designed a compound CAP colon-targeted microparticle (COPMP) prepared by coaxial electrospray. COPMP is a core-shell microparticle composed of a Eudragit S100 outer layer and a CAP/OSI-loaded PLGA core. In this study, we characterized its size distribution, drug loading (DL), encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, formula ratio, cellular growth inhibition, and in vivo antitumor efficacy. COPMP is of spherical appearance with a size of 1.87 ± 0.23 µm. The DLs of CAP and OSI are 4.93% and 4.95%, respectively. The DSC showed that the phase state of CAP and OSI changed after encapsulation. The FTIR results indicated good compatibility between the drug and excipients. The release curve showed that CAP and OSI were released in a certain ratio. They were barely released prior to 2 h (pH 1.0), less than 50% was released between 3 and 5 h (pH 6.8), and sustained release of up to 80% occurred between 6 and 48 h (pH 7.4). CAP and OSI demonstrated a synergistic effect on HCT-116 cells. In a colon tumor model, the tumor inhibition rate after oral administration of COPMP reached 94% within one week. All the data suggested that COPMP promotes the sustained release of CAP and OSI in the colon, which provides a preoperative chemotherapy scheme for the treatment of colon cancer.

DDX5 and DDX17-multifaceted proteins in the regulation of tumorigenesis and tumor progression.

DEAD-box (DDX)5 and DDX17, which belong to the DEAD-box RNA helicase family, are nuclear and cytoplasmic shuttle proteins. These proteins are expressed in most tissues and cells and participate in the regulation of normal physiological functions; their abnormal expression is closely related to tumorigenesis and tumor progression. DDX5/DDX17 participate in almost all processes of RNA metabolism, such as the alternative splicing of mRNA, biogenesis of microRNAs (miRNAs) and ribosomes, degradation of mRNA, interaction with long noncoding RNAs (lncRNAs) and coregulation of transcriptional activity. Moreover, different posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, endow DDX5/DDX17 with different functions in tumorigenesis and tumor progression. Indeed, DDX5 and DDX17 also interact with multiple key tumor-promoting molecules and participate in tumorigenesis and tumor progression signaling pathways. When DDX5/DDX17 expression or their posttranslational modification is dysregulated, the normal cellular signaling network collapses, leading to many pathological states, including tumorigenesis and tumor development. This review mainly discusses the molecular structure features and biological functions of DDX5/DDX17 and their effects on tumorigenesis and tumor progression, as well as their potential clinical application for tumor treatment.

Elucidating the Novel Mechanism of Ligustrazine in Preventing Postoperative Peritoneal Adhesion Formation.

Postoperative peritoneal adhesion (PPA) is a major clinical complication after open surgery or laparoscopic procedure. Ligustrazine is the active ingredient extracted from the natural herb Ligusticum chuanxiong Hort, which has promising antiadhesion properties. This study is aimed at revealing the underlying mechanisms of ligustrazine in preventing PPA at molecular and cellular levels. Both rat primary peritoneal mesothelial cells (PMCs) and human PMCs were used for analysis in vitro. Several molecular biological techniques were applied to uncover the potential mechanisms of ligustrazine in preventing PPA. And molecular docking and site-directed mutagenesis assay were used to predict the binding sites of ligustrazine with PPARγ. The bioinformatics analysis was further applied to identify the key pathway in the pathogenesis of PPA. Besides, PPA rodent models were prepared and developed to evaluate the novel ligustrazine nanoparticles in vivo. Ligustrazine could significantly suppress hypoxia-induced PMC functions, such as restricting the production of profibrotic cytokines, inhibiting the expression of migration and adhesion-associated molecules, repressing the expression of cytoskeleton proteins, restricting hypoxia-induced PMCs to obtain myofibroblast-like phenotypes, and reversing ECM remodeling and EMT phenotype transitions by activating PPARγ. The antagonist GW9662 of PPARγ could restore the inhibitory effects of ligustrazine on hypoxia-induced PMC functions. The inhibitor KC7F2 of HIF-1α could repress hypoxia-induced PMC functions, and ligustrazine could downregulate the expression of HIF-1α, which could be reversed by GW9662. And the expression of HIF-1α inhibited by ligustrazine was dramatically reversed after transfection with si-SMRT. The results showed that the benefit of ligustrazine on PMC functions is contributed to the activation of PPARγ on the transrepression of HIF-1α in an SMRT-dependent manner. Molecular docking and site-directed mutagenesis tests uncovered that ligustrazine bound directly to PPARγ, and Val 339/Ile 341 residue was critical for the binding of PPARγ to ligustrazine. Besides, we discovered a novel nanoparticle agent with sustained release behavior, drug delivery efficiency, and good tissue penetration in PPA rodent models. Our study unravels a novel mechanism of ligustrazine in preventing PPA. The findings indicated that ligustrazine is a potential strategy for PPA formation and ligustrazine nanoparticles are promising agents for preclinical application.