The impact of psoriasis on idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study.

BACKGROUND: The association between psoriasis and pulmonary fibrosis has been reported in observational studies. However, the association is vulnerable to bias from using immunosuppressants such as methotrexate, which can cause fibrosis in multiple organs. The present study is to investigate whether psoriasis could independently increase the risk of idiopathic pulmonary fibrosis (IPF). METHODS: We conducted a two-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies. The random-effects inverse variance weighted analysis was used as the primary method. Some secondary analyses were further performed, including a sensitivity analysis using a genetic instrument that excluded extended single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) gene region. RESULTS: Our study included 9267 cases and 364,071 controls for psoriasis, 2018 cases, and 373,064 controls for IPF of European ancestry, respectively. Genetically predicted psoriasis was associated with a higher risk of IPF (odds ratio (OR), 1.14; 95% confidence interval (CI), 1.08-1.22; P < 0.001). Sensitivity analyses did not uncover any statistically significant evidence of bias resulting from pleiotropy or the genetic instruments, including SNPs in the MHC gene region. CONCLUSIONS: These MR analyses support that genetically predicted psoriasis was associated with the risk of IPF, implying that pulmonary fibrosis in patients with psoriasis should not be neglected, even if they are not receiving immunosuppressant therapy.

Activation of GPR30 Ameliorates Cerebral Ischemia-Reperfusion Injury by Suppressing Ferroptosis Through Nrf2/GPX4 Signaling Pathway.

The newly identified estrogen receptor, G protein-coupled receptor 30 (GPR30), is prevalent in the brain and has been shown to provide significant neuroprotection. Recent studies have linked ferroptosis, a newly characterized form of programmed cell death, closely with cerebral ischemia-reperfusion injury (CIRI), highlighting it as a major contributing factor. Consequently, our research aimed to explore the potential of GPR30 targeting in controlling neuronal ferroptosis and lessening CIRI impacts. Results indicated that GPR30 activation not only improved neurological outcomes and decreased infarct size in a mouse model but also lessened iron accumulation and malondialdehyde formation post-middle cerebral artery occlusion (MCAO). This protective effect extended to increased levels of Nrf2 and GPX4 proteins. Similar protective results were replicated in PC12 cells subjected to Oxygen Glucose Deprivation and Reoxygenation (OGD/R) using the GPR30-specific agonist G1. Importantly, inhibition of Nrf2 with ML385 curtailed the neuroprotective effects of GPR30 activation, suggesting that GPR30 mitigates CIRI primarily through inhibition of neuronal ferroptosis via upregulation of Nrf2 and GPX4.

Generation of an induced pluripotent stem cell line (NCHi016-A) from a 5-year-old female with pulmonary atresia with intact ventricular septum and one-and-half ventricle palliation.

Pulmonary atresia with intact ventricular septum (PA-IVS) is a rare congenital heart defect characterized by underdeveloped pulmonary valve and right ventricular hypoplasia. Neonates undergoing surgery to open pulmonary valve have a range of post-surgical ventricular recovery: single-ventricle (1v) palliation, one-and-half ventricle (1.5v) palliation, and bi-ventricular (2v) repair. PA-IVS-1.5v typically requires surgical intervention to install cavopulmonary shunt and entails partial right ventricle recovery. NCHi016-A is an iPSC line derived from a 5-year-old female with PA-IVS-1.5v using Sendai Virus reprogramming. This iPSC line shows typical iPSC morphology, has normal karyotype, expresses pluripotency markers, and has potential to differentiate into three germ layers.

[Application of ion chromatographic fingerprint analysis for quality evaluation of tobacco flavors].

Tobacco flavor, an important tobacco additive, is an essential raw material in cigarette production that can effectively improve the quality of tobacco products, add aroma and taste, and increase the suction flavor. The quality consistency of tobacco flavors affects the quality stability of branded cigarettes. Therefore, the quality control of tobacco flavors is a major concern for cigarette and flavor manufacturers. Physical and chemical indices, odor similarity, and sensory efficacy are employed to evaluate the quality of tobacco flavors, and the analysis of chemical components in tobacco flavors is usually conducted using gas chromatography (GC) and high performance liquid chromatography (HPLC). However, because the composition of tobacco flavors is complex, their quality cannot be fully reflected using a single component or combination of components. Therefore, establishing an objective analytical method for the quality control of tobacco flavors is of extreme importance. Chromatographic fingerprint analysis is routinely used for the discriminative analysis of tobacco flavors. Chromatographic fingerprints refer to the general characteristics of the concentration profiles of different chemical compounds. In the daily procurement process, fingerprints established by GC and HPLC are effective for the evaluation and identification of tobacco flavors. However, given continuous improvements in aroma-imitation technology, some flavors with high similarity cannot be directly distinguished using existing methods. In this study, a method for the determination of organic acids and inorganic anions in tobacco flavors based on ion chromatography (IC) was developed to ensure the quality consistency of tobacco flavors. A 1.0 g sample of tobacco flavors and 10 mL of deionized water were mixed and vibrated for 30 min. The aqueous sample solution was passed through a 0.45 µm membrane filter and RP pretreatment column in succession to eliminate interferences and then subjected to IC. Standard solutions containing nine organic acids and seven inorganic anions were used to identify the anions in the tobacco flavors, and satisfactory reproducibility was obtained. The relative standard deviations (RSDs) for retention times and peak areas were <0.71% and <6.02%, respectively. The chromatographic fingerprints of four types of tobacco flavors (samples A-D) from five different batches were obtained. Nine tobacco flavor samples from different manufacturers (samples AY1-AY3, BY1-BY2, CY1-CY2, DY1-DY2) were also analyzed to obtain their chromatographic fingerprints. Hierarchical cluster and similarity analyses were used to evaluate the quality of tobacco flavors from different manufacturers. Hierarchical clustering refers to the process of subdividing a group of samples into clusters that exhibit a high degree of intracluster similarity and intercluster dissimilarity. The dendrograms obtained using SPSS 12.0 indicated good quality consistency among the samples in different batches. Samples AY3, BY2, CY2, and DY1 clustered with the batches of standard tobacco flavors. Therefore, hierarchical cluster analysis can effectively distinguish the quality of products from different manufacturers. The Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (version 2.0) was used to evaluate the similarity between the standard tobacco flavors and products from different manufacturers. Among the samples analyzed, samples AY3, BY2, CY2, and DY1 showed the highest similarity values (>97.7%), which was consistent with the results of the hierarchical cluster analysis. This finding indicates that IC combined with chromatographic fingerprint analysis could accurately determine the quality of tobacco flavors. GC combined with ultrasonic-assisted liquid-liquid extraction was also used to analyze the tobacco flavors and verify the accuracy of the proposed method. Compared with GC coupled with ultrasonic-assisted liquid-liquid extraction, IC demonstrated more significant quality differences among certain tobacco flavors.

Low-light enhancement method with dual branch feature fusion and learnable regularized attention.

Restricted by the lighting conditions, the images captured at night tend to suffer from color aberration, noise, and other unfavorable factors, making it difficult for subsequent vision-based applications. To solve this problem, we propose a two-stage size-controllable low-light enhancement method, named Dual Fusion Enhancement Net (DFEN). The whole algorithm is built on a double U-Net structure, implementing brightness adjustment and detail revision respectively. A dual branch feature fusion module is adopted to enhance its ability of feature extraction and aggregation. We also design a learnable regularized attention module to balance the enhancement effect on different regions. Besides, we introduce a cosine training strategy to smooth the transition of the training target from the brightness adjustment stage to the detail revision stage during the training process. The proposed DFEN is tested on several low-light datasets, and the experimental results demonstrate that the algorithm achieves superior enhancement results with the similar parameters. It is worth noting that the lightest DFEN model reaches 11 FPS for image size of 1224×1024 in an RTX 3090 GPU.

Hydrogels for Nucleic Acid Drugs Delivery.

Nucleic acid drugs are one of the hot spots in the field of biomedicine in recent years, and play a crucial role in the treatment of many diseases. However, its low stability and difficulty in target drug delivery are the bottlenecks restricting its application. Hydrogels are proven to be promising for improving the stability of nucleic acid drugs, reducing the adverse effects of rapid degradation, sudden release, and unnecessary diffusion of nucleic acid drugs. In this review, the strategies of loading nucleic acid drugs in hydrogels are summarized for various biomedical research, and classify the mechanism principles of these strategies, including electrostatic binding, hydrogen bond based binding, hydrophobic binding, covalent bond based binding and indirect binding using various carriers. In addition, this review also describes the release strategies of nucleic acid drugs, including photostimulation-based release, enzyme-responsive release, pH-responsive release, and temperature-responsive release. Finally, the applications and future research directions of hydrogels for delivering nucleic acid drugs in the field of medicine are discussed.

A Review: Development of a Synthetic Lactoferrin Biological System.

Lactoferrin is an iron-binding glycoprotein with antibacterial, antitumor, and immunomodulatory functions derived from milk and mucosal secretions. Lactoferrin is used in various products, such as infant formula milk powder, nutritional supplements, and cosmetics. Researchers have developed new technologies to produce lactoferrin because there are limitations in the separation and purification of lactoferrin from milk that cannot compensate for the market demand. Therefore, synthetic systems of lactoferrin have been developed with the development of genetic engineering, and the structure of lactoferrin expressed in heterologous systems is very similar to that of natural lactoferrin. The structure and functions of lactoferrin and the design and construction of synthetic lactoferrin biological systems, especially microbial synthetic systems, including prokaryotic and eukaryotic host-expression systems, are described. On the basis of these results, we summarize the challenges and solutions for constructing systems of high-yield lactoferrin. The development directions of recombinant lactoferrin are discussed in this review. Overall, the design and development of these synthetic biological systems have allowed us to explore the great potential of the industrial large-scale preparation of lactoferrin.

Establishment of a nomogram model for predicting therapy complications in patients with polycythemia and deep venous thrombosis.

BACKGROUND: Patients with deep venous thrombosis (DVT) residing at high altitudes can only rely on anticoagulation therapy, missing the optimal window for surgery or thrombolysis. Concurrently, under these conditions, patient outcomes can be easily complicated by high-altitude polycythemia (HAPC), which increases the difficulty of treatment and the risk of recurrent thrombosis. To prevent reaching this point, effective screening and targeted interventions are crucial. Thus, this study analyzes and provides a reference for the clinical prediction of thrombosis recurrence in patients with lower-extremity DVT combined with HAPC. AIM: To apply the nomogram model in the evaluation of complications in patients with HAPC and DVT who underwent anticoagulation therapy. METHODS: A total of 123 patients with HAPC complicated by lower-extremity DVT were followed up for 6-12 months and divided into recurrence and non-recurrence groups according to whether they experienced recurrence of lower-extremity DVT. Clinical data and laboratory indices were compared between the groups to determine the influencing factors of thrombosis recurrence in patients with lower-extremity DVT and HAPC. This study aimed to establish and verify the value of a nomogram model for predicting the risk of thrombus recurrence. RESULTS: Logistic regression analysis showed that age, immobilization during follow-up, medication compliance, compliance with wearing elastic stockings, and peripheral blood D-dimer and fibrin degradation product levels were indepen-dent risk factors for thrombosis recurrence in patients with HAPC complicated by DVT. A Hosmer-Lemeshow goodness-of-fit test demonstrated that the nomogram model established based on the results of multivariate logistic regression analysis was effective in predicting the risk of thrombosis recurrence in patients with lower-extremity DVT complicated by HAPC (χ 2 = 0.873; P > 0.05). The consistency index of the model was 0.802 (95%CI: 0.799-0.997), indicating its good accuracy and discrimination. CONCLUSION: The column chart model for the personalized prediction of thrombotic recurrence risk has good application value in predicting thrombotic recurrence in patients with lower-limb DVT combined with HAPC after discharge.

PTX-RPPR, a conjugate of paclitaxel and NRP-1 peptide inhibitor to prevent tumor growth and metastasis.

Paclitaxel, a potent anti-tumor drug widely recognized for its therapeutic efficacy, has faced limitations in clinical application due to its poor solubility. The use of Cremophor EL (CrEL) as a cosolvent in paclitaxel injections has been associated with hypersensitivity reactions in some patients. To overcome these challenges, we have developed a novel conjugate by linking a neuropilin-1 targeting peptide, RPPR, to paclitaxel, resulting in PTX-RPPR. This innovative approach has significantly enhanced the solubility of paclitaxel, achieving a 3.8 mg/mL concentration, a remarkable 90-fold increase over the native drug. PTX-RPPR has shown potent anti-tumor activity, inhibiting tumor cell proliferation with an IC50 ranging from 0.26 to 1.64 µM and effectively suppressing migration, invasion, and angiogenesis at a concentration of 75 nM. Notably, in a 4T1 mammary carcinoma model, PTX-RPPR administered at a dose of 0.7 µmol/kg exhibited tumor growth inhibition comparable to that of paclitaxel at a higher dose of 3.5 µmol/kg, with superior efficacy in preventing lung metastasis. Furthermore, PTX-RPPR effectively reduced NRP-1 expression in both tumors and lungs post-treatment. In contrast to paclitaxel formulated with CrEL, PTX-RPPR did not induce IL-6 expression, suggesting a safer profile in terms of immunological response. Characterized by a particle size of 200 nm and a zeta potential of +30 mV, the nano-formulation of PTX-RPPR demonstrated remarkable stability over seven days. This study introduced PTX-RPPR as a promising peptide-drug conjugate that addresses the solubility and hypersensitivity issues associated with paclitaxel, offering a safer therapeutic strategy for cancer treatment.

Additional Hepatic Arterial Infusion Chemotherapy to Sorafenib Was Cost-Effective for Hepatocellular Carcinoma with Major Portal Vein Tumor Thrombosis.

Purpose: The combination of sorafenib and hepatic arterial infusion chemotherapy (SoHAIC) has shown to enhance overall survival rates in patients with advanced hepatocellular carcinoma and major portal vein tumor thrombosis (HCC-Vp3-4) compared to sorafenib alone. Our objective was to evaluate the cost-effectiveness of SoHAIC versus sorafenib for the treatment of HCC-Vp3-4, taking into account the viewpoint of Chinese healthcare payers. Methods: This pharmacoeconomic study employed a Markov model to assess the cost-effectiveness of treating HCC-Vp3-4 with SoHAIC in comparison to sorafenib. The patient characteristics were drawn from individuals from the trial conducted between June 2017 and November 2019, with cost and health value data sourced from published literature. The primary outcome measure in this research was the incremental cost-effectiveness ratio (ICER), which indicates the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold per QALY was set at $30,492.00. Furthermore, 1-way sensitivity and probabilistic sensitivity analyses were carried out to validate the consistency of the results. Results: In the baseline scenario, sorafenib resulted in 0.42 QALY at a cost of $10,507.89, while SoHAIC generated 1.66 QALY at a cost of $32,971.56. When comparing SoHAIC to sorafenib, the ICER was $18,237.20 per QALY, which was below the WTP threshold per QALY. Furthermore, the 1-way sensitivity analysis demonstrated that the ICER remained within the WTP threshold despite fluctuations in variables. In the probabilistic sensitivity analysis, SoHAIC had a 98.8% probability of being cost-effective at the WTP threshold, considering a wide range of parameters. Conclusion: In this cost-effectiveness evaluation, SoHAIC demonstrated cost-effectiveness over sorafenib for HCC with major portal vein tumor thrombosis, as observed from the perspective of a Chinese payer.

Blocking CTLA-4 promotes pressure overload-induced heart failure via activating Th17 cells.

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson's disease.

TFE3 and TFEB, as the master regulators of lysosome biogenesis and autophagy, are well characterized to enhance the synaptic protein α-synuclein degradation in protecting against Parkinson's disease (PD) and their levels are significantly decreased in the brain of PD patients. However, how TFE3 and TFEB are regulated during PD pathogenesis remains largely vague. Herein, we identified that programmed cell death 4 (PDCD4) promoted pathologic α-synuclein accumulation to facilitate PD development via suppressing both TFE3 and TFEB translation. Conversely, PDCD4 deficiency significantly augmented global and nuclear TFE3 and TFEB distributions to alleviate neurodegeneration in a mouse model of PD with overexpressing α-synuclein in the striatum. Mechanistically, like TFEB as we reported before, PDCD4 also suppressed TFE3 translation, rather than influencing its transcription and protein stability, to restrain its nuclear translocation and lysosomal functions, eventually leading to α-synuclein aggregation. We proved that the two MA3 domains of PDCD4 mediated the translational suppression of TFE3 through binding to its 5'-UTR of mRNA in an eIF-4A dependent manner. Based on this, we developed a blood-brain barrier penetrating RVG polypeptide modified small RNA drug against pdcd4 to efficiently prevent α-synuclein neurodegeneration in improving PD symptoms by intraperitoneal injections. Together, we suggest PDCD4 as a PD-risk protein to facilitate α-synuclein neurodegeneration via suppressing TFE3 and TFEB translation and further provide a potential small RNA drug against pdcd4 to treat PD by intraperitoneal injections.

Object-oriented multi-scale segmentation and multi-feature fusion-based method for identifying typical fruit trees in arid regions using Sentinel-1/2 satellite images.

Fruit tree identification that is quick and precise lays the groundwork for scientifically evaluating orchard yields and dynamically monitoring planting areas. This study aims to evaluate the applicability of time series Sentinel-1/2 satellite data for fruit tree classification and to provide a new method for accurately extracting fruit tree species. Therefore, the study area selected is the Tarim Basin, the most important fruit-growing region in northwest China. The main focus is on identifying several major fruit tree species in this region. Time series Sentinel-1/2 satellite images acquired from the Google Earth Engine (GEE) platform are used for the study. A multi-scale segmentation approach is applied, and six categories of features including spectral, phenological, texture, polarization, vegetation index, and red edge index features are constructed. A total of forth-four features are extracted and optimized using the Vi feature importance index to determine the best time phase. Based on this, an object-oriented (OO) segmentation combined with the Random Forest (RF) method is used to identify fruit tree species. To find the best method for fruit tree identification, the results are compared with three other widely used traditional machine learning algorithms: Support Vector Machine (SVM), Gradient Boosting Decision Tree (GBDT), and Classification and Regression Tree (CART). The results show that: (1) the object-oriented segmentation method helps to improve the accuracy of fruit tree identification features, and September satellite images provide the best time window for fruit tree identification, with spectral, phenological, and texture features contributing the most to fruit tree species identification. (2) The RF model has higher accuracy in identifying fruit tree species than other machine learning models, with an overall accuracy (OA) and a kappa coefficient (KC) of 94.60% and 93.74% respectively, indicating that the combination of object-oriented segmentation and RF algorithm has great value and potential for fruit tree identification and classification. This method can be applied to large-scale fruit tree remote sensing classification and provides an effective technical means for monitoring fruit tree planting areas using medium-to-high-resolution remote sensing images.

Optimization of saponin extraction from the leaves of Panax notoginseng and Panax quinquefolium and evaluation of their antioxidant, antihypertensive, hypoglycemic and anti-inflammatory activities.

Panax notoginseng and Panax quinquefolium are important economic plants that utilize dried roots for medicinal and food dual purposes; there is still insufficient research of their stems and leaves, which also contain triterpenoid saponins. The extraction process was developed with a total saponin content of 12.30 ± 0.34% and 12.19 ± 0.64% for P. notoginseng leaves (PNL) and P. quinquefolium leaves (PQL) extracts, respectively. PNL and PQL saponin extracts showed good antioxidant, antihypertensive, hypoglycemic, and anti-inflammatory properties in vitro and RAW264.7 cells. A total of 699 metabolites were identified in PNL and PQL saponin extracts, with the majority being triterpenoid saponins, flavonoids and amino acids. Fourteen ginsenosides, 18 flavonoids or alkaloids, and 16 amino acids were enriched in both saponin extracts. Overall, the utilization of saponins from medicinal plants PNL and PQL has been developed to facilitate systematic research in the functional food and natural product industries.

Characterization of an induced pluripotent stem cell line (NCHi013-A) from a 5-year-old male with pulmonary atresia with intact ventricular septum and a biventricular repair.

Pulmonary atresia with intact ventricular septum (PA/IVS) is a rare congenital heart defect that causes a significant decrease of blood outflow from the heart and is fatal if left untreated. iPSC line NCHi013-A was produced from peripheral blood mononuclear cells from a male child with PA/IVS using Sendai virus reprogramming. NCHi013-A displayed normal stem cell morphology, expressed markers for pluripotency, and presented ability to differentiate into cells of endoderm, ectoderm, and mesoderm lineages. The iPSC line also maintained normal karyotype, was validated for cell identity, and tested negative for transgenes and mycoplasma contamination.

Numerical simulation and in vitro experimental study of the hemodynamic performance of vena cava filters with helical forms.

Inferior vena cava filter (IVCF) implantation is a common method of thrombus capture. By implanting a filter in the inferior vena cava (IVC), microemboli can be effectively blocked from entering the pulmonary circulation, thereby avoiding acute pulmonary embolism (PE). Inspired by the helical flow effect in the human arterial system, we propose a helical retrievable IVCF, which, due to the presence of a helical structure inducing a helical flow pattern of blood in the region near the IVCF, can effectively avoid the deposition of microemboli in the vicinity of the IVCF while promoting the cleavage of the captured thrombus clot. It also reduces the risk of IVCF dislodging and slipping in the vessel because its shape expands in the radial direction, allowing its distal end to fit closely to the IVC wall, and because its contact structure with the inner IVC wall is curved, increasing the contact area and reducing the risk of the vessel wall being punctured by the IVCF support structure. We used ANSYS 2023 software to conduct unidirectional fluid-structure coupling simulation of four different forms of IVCF, combined with microthrombus capture experiments in vitro, to explore the impact of these four forms of IVCF on blood flow patterns and to evaluate the risk of IVCF perforation and IVCF dislocation. It can be seen from the numerical simulation results that the helical structure does have the function of inducing blood flow to undergo helical flow dynamics, and the increase in wall shear stress (WSS) brought about by this function can improve the situation of thrombosis accumulation to a certain extent. Meanwhile, the placement of IVCF will change the flow state of blood flow and lead to the deformation of blood vessels. In in vitro experiments, we found that the density of the helical support rod is a key factor affecting the thrombus trapping efficiency, and in addition, the contact area between the IVCF and the vessel wall has a major influence on the risk of IVCF displacement.

ALKBH5 deficiency attenuates oxygen-glucose deprivation-induced injury in mouse brain microvascular endothelial cells in an m6A dependent manner.

Structural and functional alterations in brain microvascular endothelial cells (BMECs) caused by oxygen-glucose deprivation (OGD) are involved in the pathogenesis of various brain disorders. AlkB homolog 5 (ALKBH5) is a primary m6A demethylase that regulates various cell processes, but its distinct roles in BMEC function remain to be clarified. In the present study, in mouse middle cerebral artery occlusion (MCAO) model, knockout of ALKBH5 reduced neurological deficits, infarct volumes and tissue apoptosis caused by ischemia/reperfusion injury. Evans blue leakage and decreased expression of the tight junction protein ZO-1 and Occludin were also attenuated by ALKBH5 knockout. During the exploration of the underlying mechanisms of the role of ALKBH5 in BMECs, we found that the expression of ALKBH5 was induced at both the mRNA and protein levels by hypoxia; however, its protein stability was impaired by OGD treatment. Knockdown of ALKBH5 expression increased total m6A levels and alleviated OGD-induced BMEC injury. At the same time, the selective ALKBH5 inhibitor Cpd 20m also exhibited a protective effect on cell injury. In contrast, overexpression of ALKBH5 increased the sensitivity of BMECs to OGD. Interestingly, the m6A sequencing data revealed that knockdown of ALKBH5altered the expression of many genes via m6A upregulation. The gene expression alterations were verified by real-time PCR. Taken together, our results suggest that ALKBH5, as well as its target genes, plays important roles in the regulation of brain microvascular endothelial cell function through its RNA demethylase activity.

The Megacomplex protects ER-alpha from degradation by Fulvestrant in epithelial ovarian cancer.

Ovarian cancer, a significant contributor to cancer-related mortality, exhibits limited responsiveness to hormonal therapies targeting the estrogen receptor (ERα). This study aimed to elucidate the mechanisms behind ERα resistance to the therapeutic drug Fulvestrant (ICI182780 or ICI). Notably, compared to the cytoplasmic version, nuclear ERα was minimally degraded by ICI, suggesting a mechanism for drug resistance via the protective confines of the nuclear substructures. Of these substructures, we identified a 1.3MDa Megacomplex comprising transcription factors ERα, FOXA1, and PITX1 using size exclusion chromatography (SEC) in the ovarian cancer cell line, PEO4. ChIP-seq revealed these factors colocalized at 6,775 genomic positions representing sites of Megacomplex formation. Megacomplex ERα exhibited increased resistance to degradation by ICI compared to cytoplasmic and nuclear ERα. A small molecule inhibitor of active chromatin and super-enhancers, JQ1, in combination with ICI significantly enhanced ERα degradation from Megacomplex as revealed by SEC and ChIP-seq. Interestingly, this combination degraded both the cytoplasmic as well as nuclear ERa. Pathway enrichment analysis showed parallel results for RNA-seq gene sets following Estradiol, ICI, or ICI plus JQ1 treatments as those defined by Megacomplex binding identified through ChIP-seq. Furthermore, similar pathway enrichments were confirmed in mass-spec analysis of the Megacomplex macromolecule fractions after modulation by Estradiol or ICI. These findings implicate Megacomplex in ERα-driven ovarian cancer chromatin regulation. This combined treatment strategy exhibited superior inhibition of cell proliferation and viability. Therefore, by uncovering ERα's resistance within the Megacomplex, the combined ICI plus JQ1 treatment elucidates a novel drug treatment vulnerability.

[Lysine Succinylation:A New Perspective in the Treatment of Cardiovascular Diseases].

With the continuous development of identification technologies such as mass spectrometry,omics,and antibody technology,post-translational modification (PTM) has demonstrated increasing potential in medical research.PTM as a novel chemical modification method provides new perspectives for the research on diseases.Succinylation as a novel modification has aroused the interest of more and more researchers.The available studies about succinylation mainly focus on a desuccinylase named sirtuin 5.This enzyme plays a key role in modification and has been preliminarily explored in cardiovascular studies.This paper summarizes the influencing factors and regulatory roles of succinylation and the links between succinylation and other PTMs and reviews the research progress of PTMs in the cardiovascular field,aiming to deepen the understanding about the role of this modification and give new insights to the research in this field.

Physicochemical and Rheological Properties of Degraded Konjac Gum by Abalone (Haliotis discus hannai) Viscera Enzyme.

In the present study, a new degraded konjac glucomannan (DKGM) was prepared using a crude enzyme from abalone (Haliotis discus hannai) viscera, and its physicochemical properties were investigated. After enzymatic hydrolysis, the viscosity of KGM obviously decreased from 15,500 mPa·s to 398 mPa·s. The rheological properties analysis of KGM and DKGMs revealed that they were pseudoplastic fluids, and pseudoplasticity, viscoelasticity, melting temperature, and gelling temperature significantly decreased after enzymatic hydrolysis, especially for KGM-180 and KGM-240. In addition, the molecular weight of KGM decreased from 1.80 × 106 Da, to 0.45 × 106 Da and the polydispersity index increased from 1.17 to 1.83 after 240 min of degradation time. Compared with natural KGM, the smaller particle size distribution of DKGM further suggests enzyme hydrolysis reduces the aggregation of molecular chains with low molecular weight. FT-IR and FESEM analyses showed that the fragmented KMG chain did not affect the structural characteristics of molecular monomers; however, the dense three-dimensional network microstructure formed by intermolecular interaction changed to fragment microstructure after enzyme hydrolysis. These results revealed that the viscosity and rheological properties of KGM could be controlled and effectively changed using crude enzymes from abalone viscera. This work provides theoretical guidance for the promising application of DKGM in the food industry.