Canine mesenchymal stem cell-derived exosomes attenuate renal ischemia-reperfusion injury through miR-146a-regulated macrophage polarization.

Introduction: The most common factor leading to renal failure or death is renal IR (ischemia-reperfusion). Studies have shown that mesenchymal stem cells (MSCs) and their exosomes have potential therapeutic effects for IR injury by inhibiting M1 macrophage polarization and inflammation. In this study, the protective effect and anti-inflammatory mechanism of adipose-derived mesenchymal stem cell-derived exosomes (ADMSC-Exos) after renal IR were investigated. Method: Initially, ADMSC-Exos were intravenously injected into IR experimental beagles, and the subsequent assessment focused on inflammatory damage and macrophage phenotype. Furthermore, an in vitro inflammatory model was established by inducing DH82 cells with LPS. The impact on inflammation and macrophage phenotype was then evaluated using ADMSC and regulatory miR-146a. Results: Following the administration of ADMSC-Exos in IR canines, a shift from M1 to M2 macrophage polarization was observed. Similarly, in vitro experiments demonstrated that ADMSC-Exos enhanced the transformation of LPS-induced macrophages from M1 to M2 type. Notably, the promotion of macrophage polarization by ADMSC-Exos was found to be attenuated upon the inhibition of miR-146a in ADMSC-Exos. Conclusion: These findings suggest that miR-146a plays a significant role in facilitating the transition of LPS-induced macrophages from M1 to M2 phenotype. As a result, the modulation of macrophage polarization by ADMSC-Exos is achieved via the encapsulation and conveyance of miR-146a, leading to diminished infiltration of inflammatory cells in renal tissue and mitigation of the inflammatory reaction following canine renal IR.

Plasma Proteomics to Identify Drug Targets and Potential Drugs for Retinal Artery Occlusion: An Integrated Analysis in the UK Biobank.

Retinal artery occlusion (RAO), which is positively correlated with acute ischemic stroke (IS) and results in severe visual impairment, lacks effective intervention drugs. This study aims to perform integrated analysis using UK Biobank plasma proteome data of RAO and IS to identify potential targets and preventive drugs. A total of 7191 participants (22 RAO patients, 1457 IS patients, 8 individuals with both RAO and IS, and 5704 healthy age-gender-matched controls) were included in this study. Unique 1461 protein expression profiles of RAO, IS, and the combined data set, extracted from UK Biobank Plasma proteomics projects, were analyzed using both differential expression analysis and elastic network regression (Enet) methods to identify shared key proteins. Subsequent analyses, including single cell type expression assessment, pathway enrichment, and druggability analysis, were conducted for verifying shared key proteins and discovery of new drugs. Five proteins were found to be shared among the samples, with all of them showing upregulation. Notably, adhesion G-protein coupled receptor G1 (ADGRG1) exhibited high expression in glial cells of the brain and eye tissues. Gene set enrichment analysis revealed pathways associated with lipid metabolism and vascular regulation and inflammation. Druggability analysis unveiled 15 drug candidates targeting ADGRG1, which demonstrated protective effects against RAO, especially troglitazone (-8.5 kcal/mol). Our study identified novel risk proteins and therapeutic drugs associated with the rare disease RAO, providing valuable insights into potential intervention strategies.

Synthesis, Crystal Structure, Fluorescence and Theoretical Calculations of Three Zn(II)/Cd(II) Complexes with Bis-dentate N,N-Quinoline Schiff Base.

Three d10 metal complexes, ZnL(OAc)2 (1), CdL(OAc)2 (2) and [CdL2(NO3)2]·CH3CN (3) were synthesized using the ligand (E)-N-(3-methoxy-4-methylphenyl)-1-(quinolin-2-yl)methanimine (L) and characterized by FT-IR spectra, NMR spectra, and CHN elemental analysis. Single-crystal X-ray diffraction analysis revealed that complexes 1 and 2 are isostructural, with the central metal adopting a hexacoordinate octahedral geometry, while complex 3 adopts a triangular dodecahedron geometry. Thermal gravimetric analysis showed that these complexes exhibit good thermal stability. Solid-state fluorescence spectroscopy measurements demonstrated that complexes 1-3 exhibit bright yellow-green fluorescence (λem = 564 nm for 1; 524 nm for 2; 542 nm for 3), suggesting their potential as photoluminescent materials. Furthermore, DFT calculations, including frontier molecular orbitals, energy levels, and surface electrostatic potential, provided insights into the structural and electronic spectral properties of complexes 1-3.

Analysis of Prognostic Factors and Cancer-Specific Survival in Patients with Undifferentiated and Dedifferentiated Endometrial Carcinoma Undergoing Various Postoperative Adjuvant Therapies.

Purpose: To investigate prognostic factors affecting cancer-specific survival (CSS) and to analyze the survival outcomes of patients with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) who underwent various postoperative adjuvant therapies. Methods: The independent risk factors affecting CSS were studied using univariate and multivariate Cox regression analysis, and CSS in the presence of various postoperative treatments was evaluated using Kaplan-Meier method based on the cohort with pathologically confirmed UDEC from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, the study included 18 cases with UDEC in our center and explored their molecular characteristics and prognosis. Results: Between 2000 and 2019, a total of 443 patients were included from the SEER database. The median CSS duration was 14 months, with corresponding 3- and 5-year CSS rates of 45.9% and 44.0%, respectively. Factors such as pTNM stage, surgical resection of primary lesion, and chemoradiation independently influenced CSS. Postoperative chemotherapy alone improved CSS in patients with initial tumor spread beyond the uterus (pT3 and pT4), or lymph node (LN) invasion, or distant metastases. Additionally, postoperative radiotherapy enhanced CSS in patients who had undergone postoperative chemotherapy, those with primary tumors progressing to stage pT3, and those with LN involvement but without distant metastases. Of the 18 patients diagnosed at our center, with a median follow-up of 15.5 months, one experienced relapse and two succumbed to UDEC, who exhibited aberrant p53 expression in immunohistochemical staining. Conclusion: Postoperative chemotherapy and radiotherapy are beneficial for UDEC patients with tumors extending beyond the uterus or involving lymph nodes.

Tardiphaga alba sp. nov., a heavy-metal-tolerant bacterium isolated from garden soil.

A previously undescribed, heavy-metal-tolerant, motile, Gram-negative bacterium, designated strain SK50-23T, was characterized using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SK50-23T was closely related to Tardiphaga robiniae LMG 26467T and the non-phototrophic 'Rhodopseudomonas boonkerdii' NS23T (98.1 and 97.3 % 16S rRNA gene sequence similarity, respectively). Strain SK50-23T possessed a circular genome of 5.86 Mb, with a DNA G+C content of 61.9 mol%. Digital DNA-DNA hybridization showed 20.8-21.6 % similarity between strain SK50-23T and related species. In addition, the whole-genome average nucleotide identity values between strain SK50-23T and related species ranged from 75.1 to 83.5 %. The major cellular fatty acid identified in strain SK50-23T was C18 : 1ω7c, and the main isoprenoid quinone present was ubiquinone Q-10. Strain SK50-23T could be assigned to the genus Tardiphaga with the species name Tardiphaga alba sp. nov. based on morphological, chemotaxonomic and genome-based taxonomic characteristics, and 16S rRNA gene-based phylogenetic characteristics. The type strain of the proposed novel species is SK50-23T (=NBRC 108825T=CGMCC No. 1.12037T).

Trim21 Regulates the Postnatal Development and Thermogenesis of Brown Adipose Tissue.

Brown adipose tissue undergoes rapid postnatal development to mature and plays a crucial role in thermoregulation and energy expenditure, which protects against cold and obesity. Herein, it is shown that the expression of Trim21 mRNA level of interscapular brown adipose tissue elevates after birth, and peaks at P14 (postnatal day 14). Trim21 depletion severely impairs the maturation of interscapular brown adipose tissue, decreases the expression of a series of thermogenic genes, and reduces energy expenditure. Consistently, the loss of Trim21 also leads to a suppression of white adipose tissue "browning", in response to cold exposure and a ß-adrenergic agonist, CL316,243. In addition, Trim21-/- mice are more prone to high-fat diet-induced obesity compared with the control littermates. Taken together, the study for the first time reveals a critical role of Trim21 in regulating iBAT postnatal development and thermogenesis.

Volatile oil of Angelica sinensis Radix improves cognitive function by inhibiting miR-301a-3p targeting Ppp2ca in cerebral ischemia mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Angelica Sinensis Radix (ASR) is a commonly used Chinese medicine known for its effects on tonifying blood, promoting blood circulation, and alleviating pain associated with menstrual regulation. Additionally, it has been used in the treatment of vascular cognitive impairment (VCI). The primary pharmacodynamic agent within ASR is volatile oil of Angelica Sinensis Radix (VOASR), which has demonstrated efficacy in combating cognitive impairment, although its mechanism remains unclear. OBJECTIVE: This study aimed to elucidate the potential molecular mechanisms underlying VOASR's improvement of cognitive function in cerebral ischemic mice. METHODS: A model of cerebral ischemic mice was established through unilateral common carotid artery occlusion (UCCAO) surgery, followed by intervention with VOASR. Cognitive function was assessed using the Morris water maze (MWM) test, while RT-qPCR was utilized to measure the differential expression of miR-301a-3p in the hippocampus. To evaluate cognitive function and hippocampal protein differences, wild-type mice and miR-301a-3p knockout mice were subjected to the MWM test and iTRAQ protein profiling. The relationship between miR-301a-3p and potential target genes was validated through a Dual-Luciferase Reporter experiment. RT-qPCR and Western blot were employed to determine the differential expression of Ppp2ca and synaptic plasticity-related proteins in the mouse hippocampus. RESULTS: Intervention with VOASR significantly improved cognitive impairment in cerebral ischemic mice and reduced the expression of miR-301a-3p in the hippocampus. Our findings suggest that miR-301a-3p may regulate cognitive function by targeting Ppp2ca. Furthermore, VOASR intervention led to an increase in the expression of Ppp2ca and synaptic plasticity-related proteins. CONCLUSION: Our study indicates that VOASR may be involved in regulating cognitive function by inhibiting miR-301a-3p, consequently increasing the expression of Ppp2ca and synaptic plasticity proteins. These results provide a new target and direction for the treatment of cognitive dysfunction.

Novel-miR-81 Promotes the Chondrocytes Differentiation of Bone Marrow Mesenchymal Stem Cells Through Inhibiting Rac2 Expression.

OBJECTIVE: MicroRNAs (miRNAs) play a key role in the differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes. Our previous study found that novel-miR-81 can relieve osteoarthritis, but its role in chondrogenic differentiation of BMSCs remains unclear. The purpose of this study was to explore the role of novel-miR-81 in chondrogenic differentiation of BMSCs. METHODS: We used a model in which transforming growth factor (TGF)-ß3-induced BMSCs differentiation into chondrocytes. We detected the expression Sox9, Collagen Ⅱ, Aggrecan, novel-miR-81, and Rac2 by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blot was performed to detect the expression of Sox9, Collagen Ⅱ, and Rac2. Dual-luciferase reporter gene assay confirmed that the association between novel-miR-81 and Rac2. In addition, the ectopic chondrocyte differentiation of BMSCs was performed subcutaneously in nude mice. The effect of novel-miR-81 and Rac2 on ectopic chondrogenic differentiation of BMSCs was determined by immunohistochemical staining. RESULTS: Novel-miR-81 upregulated in chondrogenic differentiation of BMSCs. Rac2 was a key target of novel-miR-81. Mimic novel-miR-81 and siRac2 upregulated the expression of Sox9, Collagen Ⅱ, and Aggrecan. CONCLUSION: Novel-miR-81 promotes the chondrocytes differentiation of BMSCs by inhibiting the expression of target gene Rac2, which provides potential targets for BMSCs transplantation to repair cartilage defects.

The influence of dust on extreme precipitation at a large city in North China.

In recent decades, the Beijing-Tianjin-Hebei city cluster is experiencing rapid urbanization along with economic booming. Meanwhile, these cities are suffering the influence of extreme precipitation and dust storms. In this study, the impact of dust aerosol on extreme precipitation that occurred in Beijing during 19-21 July 2016 is investigated using both satellite retrievals and Weather Research and Forecasting model coupled to Chemistry (WRF-Chem) model simulations. Results reveal that the dust particles can increase extreme precipitation by promoting the formation of ice clouds and enhancing convections. The dust is lifted into the upper troposphere (>10 km) via strong convection and affects the physical process of precipitation after long-range transport. It further transforms the supercooled water into the middle and high levels of ice nuclei (IN). These promote the formation of ice clouds according to the decreased effective radius of IN and increased ice water path, respectively. Along with sufficient water vapor transport and strong convergence, the formation of IN could release more latent heat and further strengthen convection development. Thus, the precipitation amount in southern Beijing is almost enhanced by 40 % (>80 mm). This study will provide a deep insight into understanding the causes of urban extreme precipitation.

Neuroprotective effect of aloe emodin against Huntington's disease-like symptoms in R6/1 transgenic mice.

Aloe emodin is a natural anthraquinone derived from aloe or rhubarb, showing anti-renal fibrosis, anti-atherosclerosis and anti-cancer effects. Aloe emodin also shows neuroprotective effects in ischemic stroke rats. Naturally, anthraquinone derivatives generally have the effect of inhibiting the transforming growth factor-ß1 (TGF-ß1) pathway. There is an increase in the calcium/calmodulin-dependent protein kinase II (CaMKII) and TGF-ß1 levels in both Huntington's disease (HD) patients' brains and HD transgenic mice. Thus, we hypothesized that aloe emodin may inhibit the phosphorylation of CaMKII (p-CaMKII) and TGF-ß1/sma- and mad-related protein (Smad) signaling in the brain, further preventing motor and cognitive dysfunction. Aloe emodin was orally administered to 10- to 20-week-old HD R6/1 transgenic mice. Aloe emodin improved the motor coordination of R6/1 transgenic mice in the rotarod test and attenuated visual recognition impairment in the novel object recognition test. Aloe emodin downregulated levels of the mutant huntingtin protein, p-CaMKII and TGF-ß1, but not the TGF-ß2 or TGF-ß3 levels, in the brains of R6/1 mice. Aloe emodin could also inhibit neuronal apoptosis in the hippocampus of R6/1 mice. Altogether, these results indicated that aloe emodin prevents several HD-like symptoms through the inhibition of CaMKII/Smad and TGF-ß1/Smad signaling in mice.

Cervical lymph node metastasis of bladder cancer: a case report and review of literature.

OBJECTIVE: To report an extremely rare case of bladder cancer patient with cervical lymph nodes, abdominal lymph nodes, and bone metastases at the same time. METHODS AND RESULTS: The case was investigated by follow-up and immunohistochemistry was used in the pathological part. RESULT: The patient was diagnosed with bladder cancer (high-grade urothelial metastatic epithelial cell carcinoma) by pathology and immunohistochemistry after transurethral resection of bladder tumor (TURBT) and metastatic bladder cancer by pathology and immunohistochemistry after cervical lymph node aspiration due to neck lymph node enlargement 1 year later, and a CT of the chest and abdomen suggested that the patient also had abdominal lymph node and bone metastases.At the 2.5-year regular chemotherapy follow-up, the patient showed that the abdominal lymph node metastasis disappeared, the cervical lymph node fusion shrank, and the bone metastasis still existed. CONCLUSION: 1. Regular postoperative review is particularly important; 2.For patients with UCB who undergo TURBT, a effective regular perfusion program should be performed throughout the postoperative period; 3. For patients with postoperative metastatic symptoms of UCB, Complex treatment has a positive effect on patient prognosis; 4.The presence of enlarged head and neck lymph nodes in patients with bladder cancer should also be considered as metastatic of UCB.

Paenibacillus sedimenti sp. nov., isolated from freshwater wetland sediment.

A Gram-stain-positive, motile, rod-shaped, facultatively anaerobic bacterium, designated strain WST5T, isolated from sediment was characterized using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain WST5T was most closely related to Paenibacillus aestuarii CJ25T (96.8 % similarity). The genome size of the WST5T was 6.5 Mb, contained 4500 predicted protein-coding genes, and had a DNA G+C content of 46.6%. The values of whole-genome average nucleotide identity analysis and digital DNA-DNA hybridization between strain WST5T and its closely related type strains were less than 76 and 25.6 %, respectively. The predominant cellular fatty acids (>10 %) were anteiso-C15 : 0 and C16 : 1 ω5c and the main menaquinone was MK-7. The major polar lipids were identified as diphospholidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and two unknown aminophospholipids. Based on the results of phenotypic, genotypic, chemotaxonomic and phylogenetic analyses, strain WST5T is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus sedimentum sp. nov. is proposed. The type strain is WST5T (=NBRC 115194 T=CGMCC 1.18706T).

Bioinformatics analysis reveals lipid metabolism may play an important role in the SiO2-stimulated rat model.

Silicosis is a progressive and irreversible common occupational disease caused by long-term inhalation of a large amount of free silica dust. Its pathogenesis is complex, and the existing prevention and treatment methods can not effectively improve silicosis injury. To uncover potential differential genes in silicosis, SiO2-stimulated rats and their control original transcriptomic data sets GSE49144, GSE32147 and GSE30178 were downloaded for further bioinformatics analysis. We used R packages to extract and standardize transcriptome profiles, then screened differential genes, and enriched GO and KEGG pathways through clusterProfiler packages. In addition, we investigated the role of lipid metabolism in the progression of silicosis by qRT-PCR validation and transfection with si-CD36. A total of 426 differential genes were identified in this study. Based on GO and KEGG enrichment analysis, it was found that lipid and atherosclerosis were significantly enriched. qRT-PCR was used to detect the relative expression level of differential genes in this signaling pathway of silicosis rat models. mRNA levels of Abcg1, Il1b, Sod2, Cyba, Cd14, Cxcl2, Ccl3, Cxcl1, Ccl2 and CD36 increased, mRNA levels of Ccl5, Cybb and Il18 decreased. In addition, at the cellular level, SiO2-stimulated lead to lipid metabolism disorder in NR8383, and silencing CD36 inhibited SiO2-induced lipid metabolism disorder. These results indicate that lipid metabolism plays an important role in the progression of silicosis, and the genes and pathways reported in this study may provide new ideas for the pathogenesis of silicosis.

ZmCIPK32 positively regulates germination of stressed seeds via gibberellin signal.

Calcineurin B-like proteins (CBLs) as specific calcium sensors that interact with CBL-interacting protein kinases (CIPKs) play a key role in the regulation of plant development and abiotic stress tolerance. In this study, we isolated and characterized the CIPK32 gene from Zea mays. ZmCIPK32 showed that it comprised 440 amino acids and a conserved NAF motif responsible for the interaction with CBLs localized in the cytoplasm and cell membrane. The interaction of ZmCIPK32 with ZmCBL1 and ZmCBL9 demonstrated using yeast two-hybrid system and bimolecular fluorescence complementation assay required the presence of the NAF domain. Overexpression of ZmCIPK32 promoted early germination in transgenic Arabidopsis seeds relative to that observed in wild-type (WT) plants under mannitol treatment. In addition, ZmCIPK32-overexpressing plants were insensitive to treatments with exogenous abscisic acid and paclobutrazol (PBZ) at seed germination and early seedling stages. Expression levels of the key genes GA20ox and GA3ox involved in the synthesis of gibberellin (GA) were increased, whereas expression levels of genes involved in the conversion of active GA to inactive forms and GA signaling were reduced in ZmCIPK32-overexpressing plants relative to those in WT plants under mannitol and PBZ treatments. Furthermore, overexpression of ZmCIPK32 increased GA level but decreased abscisic acid level in transgenic lines compared to the respective levels in WT plants under PBZ or mannitol treatments. Our results suggest that ZmCIPK32 positively regulates seed germination under stressed conditions by modulating GA signals.

Neutral amino acid transporter SLC38A2 protects renal medulla from hyperosmolarity-induced ferroptosis.

Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.

Homologous cancer cell membrane-camouflaged nanoparticles target drug delivery and enhance the chemotherapy efficacy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common digestive tract malignancy that seriously threatens human life and health. Early HCC may be treated by intervention, surgery, and internal radiotherapy, while the choice for late HCC is primarily chemotherapy to prolong patient survival. Lenvatinib (LT) is a Food and Drug Administration (FDA)-approved frontline drug for the treatment of advanced liver cancer and has achieved excellent clinical efficacy. However, its poor solubility and severe side effects cannot be ignored. In this study, a bionic nanodrug delivery platform was successfully constructed. The platform consists of a core of Lenvatinib wrapped with a pH-sensitive polymer, namely, poly(ß-amino ester)-polyethylene glycol-amine (PAE-PEG-NH2), and a shell formed by a cancer cell membrane (CCM). The prepared nanodrugs have high drug loading capacity, long-term stability, good biocompatibility, and a long retention time. In addition, the targeting effect of tumor cell membranes and the pH-responsive characteristics of the polymer materials enable them to precisely target tumor cells and achieve responsive release in the tumor microenvironment, which makes them suitable for effective drug delivery. In vivo experiments revealed that the nanodrug showed superior tumor accumulation and therapeutic effects in subcutaneous tumor mice model and could effectively eliminate tumors within 21 days. As a result, it opens up a new way to reduce side effects and improve the specific therapeutic effect of first-line clinical medications to treat tumors.

rno-miR-90 promotes chondrogenic differentiation of bone marrow mesenchymal stem cells by targeting SPARC-related modular calcium binding 2.

Bone marrow mesenchymal stem cells (BMSCs) have the ability to differentiate into chondrocytes. In the differentiation of BMSCs into chondrocytes, micro-RNAs (miRNAs) play an important role. rno-miR-90 is a new miRNA discovered by our research team, and its role in chondrogenic differentiation of BMSCs is unknown. This study aimed to investigate whether rno-miR-90 could promote chondrogenic differentiation of BMSCs by regulating secreted protein acidic and rich in cysteine-related modular calcium binding 2 (Smoc2). First, BMSCs chondroblast differentiation was successfully induced in vitro by classical induction method of transforming growth factor (TGF)-ß3. On this basis, we transfected rno-miR-90 mimic and inhibitor, and confirmed that rno-miR-90 mimic could promote the differentiation of BMSCs into chondrocytes by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. In addition, we demonstrated that Smoc2 was a target gene of rno-miR-90 by dual-luciferase reporter assay, and confirmed that rno-miR-90 mimic could inhibit the expression of Smoc2 by RT-qPCR and western blotting. In order to further prove the targeting relationship between rno-miR-90 and Smoc2, we constructed three interfering fragments of Smoc2, and proved that silencing Smoc2 could promote the differentiation of BMSCs into chondrocytes at the transcriptional and protein levels. Finally, we constructed a carrier scaffold for ectopic chondrogenic differentiation in vivo, and confirmed that rno-miR-90 mimic and siSmoc2 could promote chondrogenic differentiation of BMSCs by Alcian blue staining and immunohistochemistry. In summary, our results suggested that rno-miR-90 could promote chondrogenic differentiation of BMSCs by down-regulating the expression of Smoc2. rno-miR-90 mimic and Smoc2 may be therapeutic targets of osteoarthritis.

Constructing a competitive endogenous RNA network of EndMT-related atherosclerosis through weighted gene co-expression network analysis.

Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction and plaque formation. Under pro-inflammatory conditions, endothelial cells can undergo endothelial-to-mesenchymal transition (EndMT), contributing to atherosclerosis development. However, the specific regulatory mechanisms by which EndMT contributes to atherosclerosis remain unclear and require further investigation. Dan-Shen-Yin (DSY), a traditional Chinese herbal formula, is commonly used for cardiovascular diseases, but its molecular mechanisms remain elusive. Emerging evidence indicates that competing endogenous RNA (ceRNA) networks play critical roles in atherosclerosis pathogenesis. In this study, we constructed an EndMT-associated ceRNA network during atherosclerosis progression by integrating gene expression profiles from the Gene Expression Omnibus (GEO) database and weighted gene co-expression network analysis. Functional enrichment analysis revealed this EndMT-related ceRNA network is predominantly involved in inflammatory responses. ROC curve analysis showed the identified hub genes can effectively distinguish between normal vasculature and atherosclerotic lesions. Furthermore, Kaplan-Meier analysis demonstrated that high expression of IL1B significantly predicts ischemic events in atherosclerosis. Molecular docking revealed most DSY bioactive components can bind key EndMT-related lncRNAs, including AC003092.1, MIR181A1HG, MIR155HG, WEE2-AS1, and MIR137HG, suggesting DSY may mitigate EndMT in atherosclerosis by modulating the ceRNA network.

Network pharmacology and experimental analysis to reveal the mechanism of Dan-Shen-Yin against endothelial to mesenchymal transition in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaque and endothelial dysfunction. Under pro-inflammatory conditions, endothelial cells adopt a mesenchymal phenotype by a process called endothelial-to-mesenchymal transition (EndMT) which plays an important role in the pathogenesis of atherosclerosis. Dan-Shen-Yin (DSY) is a well-known traditional Chinese medicine used in the treatment of cardiovascular disease. However, the molecular mechanism whereby DSY mitigates atherosclerosis remains unknown. Therefore, we employed a network pharmacology-based strategy in this study to determine the therapeutic targets of DSY, and in vitro experiments to understand the molecular pharmacology mechanism. The targets of the active ingredients of DSY related to EndMT and atherosclerosis were obtained and used to construct a protein-protein interaction (PPI) network followed by network topology and functional enrichment analysis. Network pharmacology analysis revealed that the PI3K/AKT pathway was the principal signaling pathway of DSY against EndMT in atherosclerosis. Molecular docking simulations indicated strong binding capabilities of DSY's bioactive ingredients toward PI3K/AKT pathway molecules. Experimentally, DSY could efficiently modify expression of signature EndMT genes and decrease expression of PI3K/AKT pathway signals including integrin αV, integrin ß1, PI3K, and AKT1 in TGF-ß2-treated HUVECs. LASP1, which is upstream of the PI3K/AKT pathway, had strong binding affinity to the majority of DSY's bioactive ingredients, was induced by EndMT-promoting stimuli involving IL-1ß, TGF-ß2, and hypoxia, and was downregulated by DSY. Knock-down of LASP1 attenuated the expression of integrin αV, integrin ß1, PI3K, AKT1 and EndMT-related genes induced by TGF-ß2, and minimized the effect of DSY. Thus, our study showed that DSY potentially exerted anti-EndMT activity through the LASP1/PI3K/AKT pathway, providing a possible new therapeutic intervention for atherosclerosis.

A facile method for anti-cancer drug encapsulation into polymersomes with a core-satellite structure.

Polymersomes possess the self-assembly vesicular structure similar to liposomes. Although a variety of comparisons between polymersomes and liposomes in the aspects of physical properties, preparation and applications have been elaborated in many studies, few focus on their differences in drug encapsulation, delivery and release in vitro and in vivo. In the present work, we have provided a modified direct hydration method to encapsulate anti-cancer drug paclitaxel (PTX) into PEG-b-PCL constituted polymersomes (PTX@PS). In addition to advantages including narrow particle size distribution, high colloid stability and moderate drug-loading efficiency, we find that the loaded drug aggregate in small clusters and reside through the polymersome membrane, representing a unique core-satellite structure which might facilitate the sustained drug release. Compared with commercial liposomal PTX formulation (Lipusu®), PTX@PS exhibited superb tumor cell killing ability underlain by multiple pro-apoptotic mechanisms. Moreover, endocytic process of PTX@PS significantly inhibits drug transporter P-gp expression which could be largely activated by free drug diffusion. In glioma mice models, it has also confirmed that PTX@PS remarkably eradicate tumors, which renders polymersomes as a promising alternative to liposomes as drug carriers in clinic.