Research on the toxicological prognostic significance of age-related genes in endometrial cancer unveiling key factors in patient prognosis.

This study investigates the influence of aging-related genes on endometrial cancer, a prominent gynecological malignancy with rising incidence and mortality. By analyzing gene expression differences between cancerous and normal endometrial tissues, 42 aging-related genes were identified as differentially expressed. Utilizing the TCGA-UCEC sample, consensus clustering divided the samples into two molecular subgroups, Aging low and Aging high, based on their expression profiles. These subgroups showed distinct prognoses and survival rates, with the Aging high group associated with DNA repair and cell cycle pathways, and the Aging low group showing suppressed metabolic pathways and increased immune cell infiltration, suggesting a potential for better immunotherapy outcomes. Mutation analysis did not find significant differences in mutation frequencies between the groups, but a high Tumor Mutation Burden (TMB) correlated with better prognosis. A risk score model was also developed, showcasing significant prognostic power. Further analysis of the SIX1 gene revealed its overexpression in cancer cells. Drug sensitivity tests indicated that the low-risk group might respond better to chemotherapy. This research underscores the significance of aging-related genes in endometrial cancer, offering insights into their prognostic value and therapeutic potential, which could lead to personalized treatment approaches and enhanced patient management.

Ultrathin 2D Cerium-Based Metal-Organic Framework Nanosheet That Boosts Selective Oxidation of Inert C(sp3 )H Bond through Multiphoton Excitation.

The development of methodologies for inducing and tailoring activities of catalysts is an important issue in various catalysis. The ultrathin 2D monolayer metal-organic framework (MOF) nanosheets with more accessible active sites and faster diffusion obtained by exfoliating 3D layered MOFs are of great potential as heterogeneous catalysts, but the rational design and preparation of 3D layered MOFs remains a grand challenge. Herein, a novel weak electrostatic interaction strategy to construct a 3D layered cerium-bearing MOF by coordinating chlorine-capped cerium nodes and linear photoactive methyl viologen (MV+ ) organic linkers is used. Under multiphoton excitation, the MV+ ligands and CeCl chromophores are triggered consecutively to form the high activity chlorine radical (Cl• ) for activation of inert C(sp3 )H bond through a hydrogen atom transfer. Benefiting from framework confinement effects, synergistic effects of two active sites and/or flexibility of the ultrathin framework nanosheets with high surface utilization, the observed activities increase in the order CeCl3 /MV+  < bulk 3D MOF crystals < 2D MOF nanosheets in photocatalysis. This work not only contributes a new strategy to construct 3D layered MOFs and their ultrathin nanosheets but also paves the way to use nanostructured MOFs to handle synergy of multiple molecular catalysts.

HIF-1α mediates CXCR4 transcription to activate the AKT/mTOR signaling pathway and augment the viability and migration of activated B cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy with a high relapse rate. We previously found that C-X-C motif chemokine receptor 4 (CXCR4) was highly expressed in DLBCL and associated with poor prognosis. This study focused on the effect of hypoxia-inducible factor-1α (HIF-1α) on CXCR4 expression and the DLBCL progression. Two activated B cell-like DLBCL cell lines Ly-3 and SUDHL2 were transfected with overexpression and knockdown plasmids or HIF-1α. The viability and migration of DLBCL cells were significantly increased under hypoxic conditions, or upon HIF-1α overexpression under normoxic conditions, but the HIF-1α downregulation led to inverse trends. However, the promoting effects of HIF-1α overexpression on DLBCL cells were suppressed by Plerixafor (a CXCR4 inhibitor). The luciferase and chromatin immunoprecipitation assays revealed that HIF-1α bound to the functional site HRE1 on CXCR4 promoter to activate its transcription. HIF-1α-mediated CXCR4 activation further led to increased phosphorylation of AKT/mTOR under hypoxic conditions. Taken together, this work reports that HIF-1α promotes viability and migration of activated B cell-like cells under hypoxia, which might involve the transcription of CXCR4 and the activation of the AKT/mTOR pathway. The finding may provide novel lights in the management of DCBCL.

MYC-targeted genes predict distant recurrence in patients with ocular adnexal extranodal marginal zone lymphoma.

Ocular adnexal extranodal marginal zone lymphoma (OA-EMZL) is the most frequent subtype of ocular adnexal lymphoma, with a high propensity for recurrence. Distant recurrence (DR) as an essential prognostic event has unique clinical risk factors, but whether distinct molecular features exist remains poorly understood. Here, we identified potential biomarkers using proteomic analysis of 27 OA-EMZL samples. The MYC-targeted genes PCNA, MCM6, and MCM4 were identified as candidates. MYC-targeted genes were further identified as the most significantly activated gene set in patients with DR. The candidate genes were verified in samples from 11 patients with DR and 33 matched controls using immunohistochemistry. The 3-year and 5-year AUC values of MCM6 (0.699 and 0.757) were higher than those of Ki-67 (0.532 and 0.592). High expressions of MCM6 and MCM4 were significantly associated with shorter distant recurrence-free survival (Log-rank p = 0.017, Log-rank p = 0.0053). Multivariate Cox regression identified MCM6 expression as an independent risk factor for DR (HR, 6.86; 95% CI, 1.32-35.79; P = 0.02). Knockdown of c-Myc in B cells resulted in decreased MCM6 and MCM4 expression and reduced proliferative capacity. Our results suggest that activation of the MYC-targeted gene is a distinct molecular feature of DR in OA-EMZL. MYC-targeted gene, MCM6, is a promising pathological biomarker for DR.

Vibration phases estimation based on orthogonal interferometry of inner view field for ISAL imaging and detection.

Inverse synthetic aperture ladar (ISAL) has the capability to achieve high-resolution imaging of long-distance targets in a short time because of the laser's short wavelength. However, the unexpected phases introduced by target vibration in the echo can cause defocused imaging results of the ISAL. How to estimate the vibration phases has always been one of the difficulties in ISAL imaging. In this paper, in view of the echo's low signal-to-noise ratio, the orthogonal interferometry method based on time-frequency analysis is proposed to estimate and compensate the vibration phases of ISAL. The method can effectively suppress the influence of noise on the interferometric phases and accurately estimate vibration phases using multichannel interferometry in the inner view field. The effectiveness of the proposed method is validated through simulations and experiments, including a 1200 m distance cooperative vehicle experiment and a 250 m distance noncooperative unmanned aerial vehicle experiment.

Engineering the Active Site Lid Dynamics to Improve the Catalytic Efficiency of Yeast Cytosine Deaminase.

Conformational dynamics is important for enzyme catalysis. However, engineering dynamics to achieve a higher catalytic efficiency is still challenging. In this work, we develop a new strategy to improve the activity of yeast cytosine deaminase (yCD) by engineering its conformational dynamics. Specifically, we increase the dynamics of the yCD C-terminal helix, an active site lid that controls the product release. The C-terminal is extended by a dynamical single α-helix (SAH), which improves the product release rate by up to ~8-fold, and the overall catalytic rate kcat by up to ~2-fold. It is also shown that the kcat increase is due to the favorable activation entropy change. The NMR H/D exchange data indicate that the conformational dynamics of the transition state analog complex increases as the helix is extended, elucidating the origin of the enhanced catalytic entropy. This study highlights a novel dynamics engineering strategy that can accelerate the overall catalysis through the entropy-driven mechanism.

Cellular heterogeneity and immune microenvironment revealed by single-cell transcriptome in venous malformation and cavernous venous malformation.

Venous malformation (VM) and cavernous venous malformation (CVM) are two types of vascular malformations. Even if the two diseases are similar in appearance and imaging, the distinct cellular components and signaling pathways between them might help distinguish the two from a molecular perspective. Here, we performed single-cell profiling of 35,245 cells from two VM samples and three CVM samples, with a focus on endothelial cells (ECs), smooth muscle cells (SMCs) and immune microenvironment (IME). Clustering analysis based on differential gene expression unveiled 11 specific cell types, and determined CVM had more SMCs. Re-clustering of ECs and SMCs indicated CVM was dominated by arterial components, while VM is dominated by venous components. Gene set variation analysis suggested the activation of inflammation-related pathways in VM ECs, and upregulation of myogenesis pathway in CVM SMCs. In IME analysis, immune cells were identified to accounted for nearly 30% of the total cell number, including macrophages, monocytes, NK cells, T cells and B cells. Notably, more macrophages and monocytes were discovered in VM, indicating innate immune responses might be more closely related to VM pathogenesis. In addition, angiogenesis pathway was highlighted among the significant pathways of macrophages & monocytes between CVM and VM. In VM, VEGFA was highly expressed in macrophages & monocytes, while its receptors were all abundantly present in ECs. The close interaction of VEGFA on macrophages with its receptors on ECs was also predicted by CellPhoneDB analysis. Our results document cellular composition, significant pathways, and critical IME in CVM and VM development.

Comprehensive circular RNA expression profiling with associated ceRNA network in orbital venous malformation.

Purpose: Orbital venous malformation (OVM), the most common type of vascular malformation in adults, has a great impact on both visual and cosmetic factors. Circular RNAs (circRNAs) play important roles in various ophthalmological diseases; however, little is known about their function in the pathogenesis of OVM. Methods: We obtained differentially expressed circRNAs, mRNAs, and miRNAs based on RNA sequencing of four OVM tissues and four normal orbital vascular tissues. The circRNA-mRNA coexpression network and circRNA-miRNA-mRNA and competing endogenous RNA (ceRNA) networks were constructed using miRanda software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the up- and downregulated mRNAs in the circRNA-miRNA-mRNA ceRNA network. Results: Overall, we identified 45 upregulated and 144 downregulated circRNAs, as well as 2,175 upregulated and 1,274 downregulated mRNAs and 156 upregulated and 168 downregulated miRNAs in OVM samples compared with normal orbital vascular tissues. The expression changes of mRNAs and circRNAs detected by quantitative real-time PCR (qRT-PCR) were in line with the RNA-seq results. Then, a ceRNA regulatory network was constructed with these differentially expressed circRNAs, mRNAs, and miRNAs. GO functional analysis revealed that most related biological processes involved extracellular matrix organization, positive regulation of actin nucleation, and so on, which were thought to be involved in the evolution of OVM. KEGG pathway analysis of upregulated mRNAs showed that mucin-type O-glycan biosynthesis, glycosaminoglycan degradation, and the PI3K (Gene ID: 5290; OMIM: 613089)-AKT (Gene ID: 207; OMIM: 114500) signaling pathway were all enriched in OVM samples. Conclusions: Our study provides novel insight into the regulatory mechanism of circRNAs, miRNAs, and mRNAs in the pathogenesis of OVM.

Eosin Y-Containing Metal-Organic Framework as a Heterogeneous Catalyst for Direct Photoactivation of Inert C-H Bonds.

Xanthene dyes as a class of ideal organic homogeneous photocatalyst have received significant attention in C-H bond activation; however, the inherent nature of fast carrier recombination/deactivation and low stability limits their practical applications. Herein, by the ingenious decoration of eosin Y into a porous metal-organic framework (MOF), a high-performance heterogeneous MOF-based photocatalyst was prepared to efficiently activate inert C-H bonds on the reactants via the hydrogen atom transfer pathway for the functionalization of the C-H bonds. Taking advantage of the fixation effect of a rigid framework, the incorporation of eosin Y into MOF leads to great enhancement of their chemical durability. More importantly, by the introduction of the second auxiliary ligand, the carbonyl groups of xanthene on the eosin Y dyes were perfectly retained and periodically aligned within the confined channels of this rigid framework, which could effectively form excited state radicals to prompt inert C-H bond activation, promoting reaction efficiency by the host-guest supramolecular interaction. New eosin Y-based MOFs were recyclable for six times without reducing photocatalytic activity. This eosin Y functionalized MOF-based heterogeneous photocatalytic system provides an availably catalytic avenue to develop a scalable and sustainable synthetic strategy for the practical application of organic dyes.

Intralesional diode laser pretreatment facilitates surgery for orbital venous malformations: initial experience with 23 consecutive patients.

PURPOSE: This study aims to evaluate the efficacy and safety of intralesional diode laser pretreatment for facilitating surgery for orbital venous malformations (OVMs). METHODS: This is a retrospective, non-comparative, interventional cohort involving 23 consecutive OVM patients undergoing intralesional laser pretreatment followed by surgical excision. The main outcome measures included volumetric changes, exophthalmometry, cosmesis, and symptom scores as well as treatment-related adverse events. RESULTS: Following intralesional diode laser, the mean volume dropped significantly from 2366 ± 1887 to 129 ± 119 mm3 (t = 5.716; p < 0.001). After a single treatment session, a mean 90 ± 13% volume shrinkage was achieved in all 23 OVM. The mean Hertel exophthalmometry decreased significantly from 14 ± 3 to 13 ± 1 mm (t = 2.515; P < 0.02). The resolution of periocular dyschromasia and swelling were evident in 20 patients (87%). Symptom scores improved significantly from 6.5 ± 1.4 (very intense discomfort or effect on daily living) to 1.2 ± 1.0 (very mild discomfort or effect on daily living; p < 0.001). Short-term bruises and swelling were reported in 20 patients (87%). CONCLUSION: Intralesional laser pretreatment is effective to facilitate surgery especially for the deep involving orbital venous malformations.

Moving target imaging of a dual-channel ISAL with binary phase shift keying signals and large squint angles.

A dual-channel inverse synthetic aperture ladar imaging experimental system based on wide-pulse binary phase coded signals and its moving target imaging are introduced. The analysis, simulation, and experimental data processing results of binary phase coded signal Doppler compensation and pulse compression are included. The method of motion phase error estimation based on interferometric processing and the imaging method with small computation in the case of large squint angles are proposed, and the simulation results are presented. The effectiveness of the imaging method is verified by experimental data processing. Doppler frequency curves are estimated based on time-frequency analysis of echo signals, and the coarse compensation of motion phase error is realized. According to the interferometric phase and coherence coefficient of dual-channel echo signals' time-frequency analysis, the coherence of the dual-channel echo signals is checked, and along-track interferometry can be applied to the precise compensation. The stable interferometric phase and increased coherence coefficient of actual dual-channel data imaging results indicate the effectiveness of the motion phase error compensation method proposed. Considering characteristics of inverse synthetic aperture ladar (ISAL) imaging, after dividing echo signals into multiple sub-apertures, range-Doppler algorithm and sub-aperture stitching are adopted, the stitched image is corrected geometrically through Stolt transformation, and the computation is reduced.

Detecting the Hydrogen Bond Cooperativity in a Protein ß-Sheet by H/D Exchange.

The hydrogen bond (H-bond) cooperativity in the ß-sheet of GB3 is investigated by a NMR hydrogen/deuterium (H/D) exchange method. It is shown that the weakening of one backbone N-H…O=C H-bond between two ß-strands, ß1 and ß2, due to the exchange of NH to ND of the H-bond donor in ß1, perturbs the chemical shift of 13Cα, 13Cß, 1Hα, 1HN, and 15N of the H-bond acceptor and its following residue in ß2. Quantum mechanical calculations suggest that the -H-bond chemical shift isotope effect is caused by the structural reorganization in response to the H-bond weakening. This structural reorganization perturbs four neighboring H-bonds, with three being weaker and one being stronger, indicating that three H-bonds are cooperative and one is anticooperative with the perturbed H-bond. The sign of the cooperativity depends on the relative position of the H-bonds. This H-bond cooperativity, which contributes to ß-sheet stability overall, can be important for conformational coupling across the ß-sheet.

Demulsification of Heavy Oil-in-Water Emulsion by a Novel Janus Graphene Oxide Nanosheet: Experiments and Molecular Dynamic Simulations.

Various nanoparticles have been applied as chemical demulsifiers to separate the crude-oil-in-water emulsion in the petroleum industry, including graphene oxide (GO). In this study, the Janus amphiphilic graphene oxide (JGO) was prepared by asymmetrical chemical modification on one side of the GO surface with n-octylamine. The JGO structure was verified by Fourier-transform infrared spectra (FTIR), transmission electron microscopy (TEM), and contact angle measurements. Compared with GO, JGO showed a superior ability to break the heavy oil-in-water emulsion with a demulsification efficiency reaching up to 98.25% at the optimal concentration (40 mg/L). The effects of pH and temperature on the JGO's demulsification efficiency were also investigated. Based on the results of interfacial dilatational rheology measurement and molecular dynamic simulation, it was speculated that the intensive interaction between JGO and asphaltenes should be responsible for the excellent demulsification performance of JGO. This work not only provided a potential high-performance demulsifier for the separation of crude-oil-in-water emulsion, but also proposed novel insights to the mechanism of GO-based demulsifiers.

A Review of Recent Advances in the Inhibition of Sweet Corrosion.

This review paper discusses the research work published in the last decade on the use of organic compounds and natural products as corrosion inhibitors for steel in CO2 and CO2 /H2 S coexisting environments. The carbon and mild steel samples tested are mostly immersed in CO2 -saturated NaCl/brine solutions or simulated oilfield waters. The influence of temperature, immersion time, CO2 partial pressure, pre-corrosion, flow rate/rotation speed, and the synergistic effect of other compounds on the corrosion inhibition effectiveness of organic compounds and natural products is presented. Primarily, weight loss and electrochemical techniques were used to evaluate the corrosion inhibition effectiveness of these compounds.

Predictors for Surgeries With the Endoscope-Navigation System for Traumatic Optic Neuropathy and its Clinical Assessment.

BACKGROUND: To assess surgeries with the endoscope-navigation system (ENS) in patients who underwent traumatic optic neuropathy (TON) and find predictors for best corrected visual acuity (BCVA) outcomes. METHODS: The clinical data of 96 consecutive TON patients (96 eyes) who underwent decompression surgery with ENS in the Department of Ophthalmology, Shanghai Ninth People's Hospital, from January 2013 to December 2019 were retrospectively reviewed and analyzed. A binary logistic regression was performed to establish a predictive model for BCVA after treatment as TON outcome. RESULTS: By practicing ENS, 49/96 (51.0%) TON patients got improvement in BCVA, whereas the improvement rate of patients with BCVA of light perception or better was 72.5% (29/40). Hemorrhage within the postethmoid and/or sphenoid sinus, orbital fracture, time interval between trauma and treatment, and BCVA before treatment were predictors for BCVA improvement in TON patients by practicing ENS surgery. The area under raw current curves of the predictive model was 0.826. CONCLUSIONS: Surgeries with the ENS showed positive outcomes for TON patients, especially for those with better BCVA before treatment, shorter time interval between trauma and treatment, without orbital fracture or hemorrhage within the postethmoid and/or sphenoid sinus.

[Evidence of clinical randomized controlled trial study in treatment of acute cerebral infarction with traditional Chinese medicine in recent five years].

To systematically search and sort out the clinical randomized controlled trial(RCT) on the prevention and treatment of acute cerebral infarction with traditional Chinese medicine(TCM) by using the method of evidence map, and to understand the evidence distribution of related studies. CNKI, Wanfang, VIP, CBM, PubMed, EMbase, Cochrane Library and Web of Science were retrieved from January 2016 to September 2020, and literatures related to the prevention and treatment of acute cerebral infarction with traditional Chinese medicine were included. Text description combined with table and bubble chart were used to analyze the distribution characteristics of evidence. A total of 1 102 clinical articles in recent five years were retrieved. The annual trend of clinical study publication, study size, TCM therapy category and main scheme, and study literature quality were analyzed. We find that TCM treatment of acute cerebral infarction has become a hot topic of clinical research, the number of literature showed a trend of increased year by year, various means of intervention of TCM in the treatment of the advantages of increasingly highlight. Follow-up clinical research should highlight the characteristics of TCM: in the analysis of outcome indicators; increase the neuropsychological patients after stroke and cognitive ability, and the theory of combined treatment of TCM disease when thoughts; At the same time, the quality of clinical research needs to be improved. At present, there is still a lack of unified standards for the production of evidence map. This study is the first to explore the application of evidence map to summarize and display the clinical research status of TCM treatment of acute cerebral infarction, and combine it with the setting of priority areas of TCM clinical research, so as to provide a reference basis for determining the priority topic selection of TCM treatment optimization research.

[Analysis of status quo of outcome indicators of randomized controlled trials in treatment of acute ischemic stroke with acupuncture in recent three years].

To analyze the use of outcome indicators of randomized controlled trial(RCT) of acupuncture in the treatment of acute ischemic stroke in recent three years, so as to provide a basis for building a study on the core outcome indicators for the treatment of acute ischemic stroke with acupuncture. The RCTs of acupuncture treatment for acute ischemic stroke in recent three years were collec-ted through computer retrieval of eight Chinese and English databases and two clinical trial registries at home and abroad. Literature was screened out, and data was extracted. Risk of assessment bias tool Cochrane 6.1 was used for bias risk assessment, outcome indicators were summarized and analyzed. A total of 47 RCTs were included, and 3 studies were trials registration scheme. Outcome indicators were divided into 6 categories according to functional attributes, namely physical symptoms/signs, physical and chemical examination, quality of life, traditional Chinese medicine symptoms/syndromes, safety events and long-term prognosis. The study found that in addition to the common problems in previous studies covered by the status quo of outcome indicators selection of RCT of acupuncture in the treatment of acute ischemic stroke, there were also the other problems as follows: emphasis on macroscopic efficacy indicators but neglect of acupuncture specific indicators, lack of characteristic indicators and economic indicators of traditional Chinese medicine therapy, and unification of indicators measurement tool and measurement time point. In the future, the outcome indicators set for the treatment of acute ischemic stroke with acupuncture shall be established, and the core outcome indicators set shall be in line with the characteristics of traditional Chinese medicine treatment.

[Overview of systematic reviews/Meta-analysis of Xingnaojing Injection in treatment of cerebral ischaemic stroke].

There have been many clinical trials, systematic reviews/Meta-analysis proving that Xingnaojing Injection has a good clinical efficacy in treatment of cerebral ischaemic stroke, but with fewer comprehensive descriptions. In this study, an overview of systematic reviews/Meta-analysis of Xingnaojing Injection in treating cerebral ischaemic stroke was performed to provide current situation of evidences and basis for clinical practice. CNKI, Wanfang, VIP, CBM, EMbase, PubMed, Cochrane Library, Web of Science were retrieved through computers. A total of 6 literatures were included in this study. By AMSTAR-2 checklist and GRADE, the quality of included systematic reviews and the efficacy of Xingnaojing Injection were evaluated. The results of AMSTAR-2 checklist showed an extremely low quality for all of the 6 systematic reviews. According to the results of GRADE evaluation, among 55 outcomes, there were 2 outcomes with a medium quality, 4 outcomes with a low quality and 49 outcomes with an extremely low quality. The 6 systematic reviews reached a consistent conclusion that Xingnaojing Injection was effective in the treatment of cerebral ischaemic stroke. This therapy could improve the total efficacy, neurological deficit scores, hemodynamic and hemodynamic parameters. However, the methodolo-gical quality of all literatures was extremely low. The evidence levels of outcomes were between extremely low to medium. The effectiveness of Xingnaojing Injection in the treatment of cerebral ischaemic stroke still needs to be further verified by more high-quality studies. In the future, relevant clinical studies and systematic reviews/Meta-analysis shall be carried out in a strict accordance with relevant regulations.

[Overview of systematic reviews of Panax notoginseng saponins in treatment of acute cerebral infarction].

To overview the systematic reviews of Panax notoginseng saponins in the treatment of acute cerebral infarction. CNKI, CBM, Wanfang, VIP, PubMed, Cochrane Library and EMbase databases were retrieved to collect the systematic reviews of the efficacy of P. notoginseng saponins in the treatment of acute cerebral infarction. The retrieval time was from the time of database establishment to January 2021. After two researchers independently screened out the literature and extracted the data, AMSTAR-2 scale was used to evaluate the methodological quality of the included systematic reviews, GRADE system was used to grade the quality of evidences of the outcome indicators, and the efficacy evaluation was summarized. A total of 5 systematic reviews were included. AMSTAR-2 evaluation results showed that 3 items were relatively complete, while 4 items had a poor overall quality. P. notoginseng saponins combined with conventional Western medicine therapy was superior to single conventional therapy in the recovery of neurological function, enhancement of the total effective rate in clinic, and improvement of activities of daily living. GRADE evaluation results showed that the quality of evidence was from low quality to very low quality. In conclusion, in the treatment of acute cerebral infarction, P. notoginseng saponins can improve the clinical efficacy, with a good safety but a not high methodological quality and a low evidence quality. It is suggested that high-quality clinical studies shall be further carried out to provide evidence-based basis for the application of P. notoginseng saponins in the treatment of acute cerebral infarction.

BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway.

Venous malformation (VM) is a type of vascular morphogenic defect in humans with an incidence of 1%. Although gene mutation is considered as the most common cause of VM, the pathogenesis of those without gene mutation remains to be elucidated. Here, we aimed to explore the relation of bone morphogenetic protein 9 (BMP9) and development of VM. At first, we found serum and tissue BMP9 expression in VM patients was significantly lower than that in healthy subjects, detected via enzyme-linked immunosorbent assay. Next, with wound healing assay, transwell assay and tube formation assay, we discovered BMP9 could inhibit migration and enhance tube formation activity of human umbilical vein endothelial cells (HUVECs) via receptor activin receptor-like kinase 1 (ALK1). Besides, BMP9 improved the expression of structural proteins alpha-smooth muscle actin (α-SMA) and Desmin in human umbilical vein smooth muscle cells (HUVSMCs) via activation of the SMAD1/5-ID1 pathway, determined by RNA-based next-generation sequencing, qPCR, immunofluorescence and western blotting. Intriguingly, this effect could be blocked by receptor ALK1 inhibitor, SMAD1/5 inhibitor and siRNAs targeting ID1, verifying the BMP9/ALK1/SMAD1/5/ID1/α-SMA pathway. Meanwhile, knocking out BMP9 in C57BL/6 mice embryo led to α-SMA scarcity in walls of lung and mesenteric vessels, as well as walls of small trachea. BMP9-/- zebrafish also exhibited abnormal vascular maturity, indicating a critical role of BMP9 in vascular maturity and remodeling. Finally, a VM mice model revealed that BMP9 might have therapeutic effect in VM progression. Our study discovered that BMP9 might inhibit the occurrence of VM by strengthening the vessel wall and maintaining endothelium quiescence. These findings provide promising evidences of new therapeutic targets that might be used for the management of VM.