Effectiveness and safety of PD-1/PD-L1 inhibitors monotherapy in patients with endometrial cancer.

BACKGROUND: Studies evaluating the effectiveness of immune checkpoint inhibitors (ICI) for endometrial cancer (EC) are limited. This study aimed to assess the efficacy of PD-1/PD-L1 inhibitors as monotherapy for EC by conducting a meta-analysis. The predictive significance of MMR status, a biomarker for ICI response, also required further investigation. METHODS: A systematic literature search was conducted in English databases until September 2023. The analysis included objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and odds ratios (OR), along with their corresponding 95% confidence intervals (CI). RESULTS: There were twelve trials totaling 685 individuals. PD-1/PD-L1 inhibitor monotherapy resulted in an ORR for 34% (95% CI = 24-44%) of the pooled EC patients. Subgroup analysis revealed a significantly higher ORR in dMMR EC (45%) compared to pMMR EC (8%), with an OR of 6.36 (95% CI = 3.64-11.13). The overall DCR was 42%, with dMMR EC at 51% and pMMR EC at 30% (OR = 2.61, 95% CI = 1.69-4.05). Grade three or higher adverse events (AEs) occurred in 15% of cases (95% CI = 9-24%) of the pooled incidence of AEs, which was 68% (95% CI = 65-72%). CONCLUSIONS: This meta-analysis provides significant evidence for the effectiveness of PD-1/PD-L1 inhibitors as monotherapy for EC. Notably, dMMR EC patients demonstrated superior treatment efficacy with PD-1/PD-L1 inhibitor immunotherapy. Further research is required to explore subclassifications of EC based on dMMR molecular subtypes, enabling improved treatment strategies and outcomes for EC patients.

The Effects of Perineural Dexamethasone on Rebound Pain After Nerve Block in Patients with Unicompartmental Knee Arthroplasty A Randomized Controlled Trial.

OBJECTIVES: A single nerve block provides excellent analgesia in a short time, but rebound pain after the nerve block disappears has attracted researchers' attention. The aim of this study is to evaluate the effect of perineural dexamethasone on rebound pain after sciatic nerve block and femoral nerve block in patients undergoing unicompartmental knee arthroplasty (UKA). METHODS: In a double-blinded fashion, We recruited 72 patients undergoing UKA, each of whom received sciatic and femoral nerve block. Patients were randomly assigned to two groups (n=36): X (ropivacaine only) and D (ropivacaine combined with dexamethasone). The primary outcome was the incidence of rebound pain. The secondary outcomes were rebound pain score, the duration of rebound pain, the duration of nerve block, pain score, sufentanil consumption and rescue analgesic, patient-controlled intravenous analgesia, distance walked, sleep quality score, C-reactive protein levels, and adverse effects. RESULTS: Compared with group X, the incidence of rebound pain in group D was higher, the rebound pain score was higher and the duration of nerve block was prolonged (P<0.05). At 12, 16, and 20 hours postoperatively, the pain scores at rest in group D was lower. At 32 and 36 hours postoperatively, the pain scores at rest in group D was higher (P<0.05). Moreover, patients in group D had lower levels of C-reactive protein after surgery (P<0.05). DISCUSSION: Addition of dexmedetomidine to ropivacaine for UKA effectively prolonged the duration of nerve block and decreased c-reactive protein levels, but increased the incidence of rebound pain and rebound pain score, and had no beneficial effects on the postoperative analgesia.

1-DNJ Alleviates Obesity-Induced Testicular Inflammation in Mice Model by Inhibiting IKKß/ NF-kB Pathway.

Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1ß (IL-1ß), and interleukin 6 (IL-6). The activation of IκB kinase ß (IKKß) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKß/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility.

A magnetic multi-layer soft robot for on-demand targeted adhesion.

Magnetic soft robots have shown great potential for biomedical applications due to their high shape reconfigurability, motion agility, and multi-functionality in physiological environments. Magnetic soft robots with multi-layer structures can enhance the loading capacity and function complexity for targeted delivery. However, the interactions between soft entities have yet to be fully investigated, and thus the assembly of magnetic soft robots with on-demand motion modes from multiple film-like layers is still challenging. Herein, we model and tailor the magnetic interaction between soft film-like layers with distinct in-plane structures, and then realize multi-layer soft robots that are capable of performing agile motions and targeted adhesion. Each layer of the robot consists of a soft magnetic substrate and an adhesive film. The mechanical properties and adhesion performance of the adhesive films are systematically characterized. The robot is capable of performing two locomotion modes, i.e., translational motion and tumbling motion, and also the on-demand separation with one side layer adhered to tissues. Simulation results are presented, which have a good qualitative agreement with the experimental results. The feasibility of using the robot to perform multi-target adhesion in a stomach is validated in both ex-vivo and in-vivo experiments.

A gradient mapping guided explainable deep neural network for extracapsular extension identification in 3D head and neck cancer computed tomography images.

BACKGROUND: Diagnosis and treatment management for head and neck squamous cell carcinoma (HNSCC) is guided by routine diagnostic head and neck computed tomography (CT) scans to identify tumor and lymph node features. The extracapsular extension (ECE) is a strong predictor of patients' survival outcomes with HNSCC. It is essential to detect the occurrence of ECE as it changes staging and treatment planning for patients. Current clinical ECE detection relies on visual identification and pathologic confirmation conducted by clinicians. However, manual annotation of the lymph node region is a required data preprocessing step in most of the current machine learning-based ECE diagnosis studies. PURPOSE: In this paper, we propose a Gradient Mapping Guided Explainable Network (GMGENet) framework to perform ECE identification automatically without requiring annotated lymph node region information. METHODS: The gradient-weighted class activation mapping (Grad-CAM) technique is applied to guide the deep learning algorithm to focus on the regions that are highly related to ECE. The proposed framework includes an extractor and a classifier. In a joint training process, informative volumes of interest (VOIs) are extracted by the extractor without labeled lymph node region information, and the classifier learns the pattern to classify the extracted VOIs into ECE positive and negative. RESULTS: In evaluation, the proposed methods are well-trained and tested using cross-validation. GMGENet achieved test accuracy and area under the curve (AUC) of 92.2% and 89.3%, respectively. GMGENetV2 achieved 90.3% accuracy and 91.7% AUC in the test. The results were compared with different existing models and further confirmed and explained by generating ECE probability heatmaps via a Grad-CAM technique. The presence or absence of ECE has been analyzed and correlated with ground truth histopathological findings. CONCLUSIONS: The proposed deep network can learn meaningful patterns to identify ECE without providing lymph node contours. The introduced ECE heatmaps will contribute to the clinical implementations of the proposed model and reveal unknown features to radiologists. The outcome of this study is expected to promote the implementation of explainable artificial intelligence-assiste ECE detection.

Metabolic and senescence characteristics associated with the immune microenvironment in ovarian cancer.

Ovarian cancer is a highly malignant gynecological cancer influenced by the immune microenvironment, metabolic reprogramming, and cellular senescence. This review provides a comprehensive overview of these characteristics. Metabolic reprogramming affects immune cell function and tumor growth signals. Cellular senescence in immune and tumor cells impacts anti-tumor responses and therapy resistance. Targeting immune cell metabolism and inducing tumor cell senescence offer potential therapeutic strategies. However, challenges remain in identifying specific targets and biomarkers. Understanding the interplay of these characteristics can lead to innovative therapeutic approaches. Further research is needed to elucidate mechanisms, validate strategies, and improve patient outcomes in ovarian cancer.

A brain MRI dataset and baseline evaluations for tumor recurrence prediction after Gamma Knife radiotherapy.

Prediction and identification of tumor recurrence are critical for brain cancer treatment design and planning. Stereotactic radiation therapy delivered with Gamma Knife has been developed as one of the common treatment approaches combined with others by delivering radiation that targets accurately on the tumor while not affecting nearby healthy tissues. In this paper, we release a fully publicly available brain cancer MRI dataset and the companion Gamma Knife treatment planning and follow-up data for the purpose of tumor recurrence prediction. The dataset contains original patient MRI images, radiation therapy data, and clinical information. Lesion annotations are provided, and inclusive preprocessing steps have been specified to simplify the usage of this dataset. A baseline framework based on a convolutional neural network is proposed companionably with basic evaluations. The release of this dataset will contribute to the future development of automated brain tumor recurrence prediction algorithms and promote the clinical implementations associated with the computer vision field. The dataset is made publicly available on The Cancer Imaging Archive (TCIA) ( https://doi.org/10.7937/xb6d-py67 ).

Synthesis of three-dimensional (3D) hierarchically porous iron-nickel nanoparticles encapsulated in boron and nitrogen-codoped porous carbon nanosheets for accelerated water splitting.

Designing two-dimensional (2D) porous carbon nanosheets is a promising strategy for enhancing the water-splitting activities of non-noble metal catalysts. In this study, we developed a novel method for synthesizing the novel three-dimensional (3D) hierarchically porous iron-nickel (FeNi) nanoparticles encapsulated in boron (B) and nitrogen (N)-codoped porous carbon nanosheets (denoted as FeNi@BNPCNS). Owing to the advantages of morphology and structure of B and N, 10.31 atom % of B/N active centers were successfully doped into the optimal FeNi@BNPCNS-800 nanosheets. FeNi@BNPCNS-800 exhibited better hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) electrocatalytic activities than control catalysts in an alkaline solution. However, the HER and OER electrocatalytic activities of FeNi@BNPCNS-800 were slightly lower than 20 wt% Pt/C and RuO2. The FeNi@BNPCNS-800||FeNi@BNPCNS-800 electrolyzer achieved 10 mA cm-2 at 1.514 V, which was 73 mV lower than that of 20 wt% Pt/C||RuO2 electrolyzer (1.587 V). The perfect 3D honeycomb-like architectures, abundant mesopores/defects, and abundant electrocatalytic active sites were attributed to the outstanding water-splitting performances of FeNi@BNPCNS-800 nanosheets. This study provides an efficient strategy for the large-scale, rapid, and low-cost fabrication of 2D porous carbon nanosheets without using any template, surfactant, or expensive raw material, thus presenting a simple approach to design advanced non-noble metal electrocatalysts for water splitting.

Cancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment.

Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting the activity of F0F1 ATPase complex V. However, its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue/cell uptake, leading to insufficient Gboxin accumulation at GBM sites, which limits its further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) by coating cancer cell-mitochondria hybrid membrane (HM) on the surface of Gboxin-loaded nanoparticles. An additional design element uses a reactive oxygen species responsive polymer to facilitate at-site Gboxin release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. The results suggest that HM-NPs@G achieve improved blood circulation (4.90 h versus 0.47 h of free Gboxin) and tumour accumulation (7.73% ID/g versus 1.06% ID/g shown by free Gboxin). Effective tumour inhibition in orthotopic U87MG GBM and patient derived X01 GBM stem cell xenografts in female mice with extended survival time and negligible side effects are also noted. We believe that the biomimetic Gboxin nanomedicine represents a promising treatment for brain tumours with clinical potential.

H2 O2 -Inducible DNA Cross-linking Agents Capable of Releasing Multiple DNA Alkylators as Anticancer Prodrugs.

Three compounds with arylboronate esters conjugated with two equivalent nitrogen mustards [bis(2-chloroethyl)methylamine, HN2] have been synthesized and characterized. These inactive small molecules selectively react with H2 O2 to produce multiple DNA cross-linkers, such as two HN2 molecules alongside a bisquinone methide (bisQM), leading to efficient DNA ICL formation. In comparison to other amine functional groups, using HN2 as a leaving group greatly improves the DNA cross-linking efficiency of these arylboronate esters as well as cellular activity. The introduction of HN2 in these arylboronate ester analogues favored the generation of bisQM that can directly cross-link DNA. Two equivalents of HN2 are also generated from these compounds upon treatment with H2 O2 , which directly produces DNA ICL products. The cumulative effects of HN2 and bisQM on DNA cross-linking makes these molecules highly effective H2 O2 -inducible DNA ICL agents. The three compounds with HN2 as a leaving group showed greatly enhanced cytotoxicity towards cancer cells in comparison to those containing trimethyl amine as a leaving group. This provides an effective strategy for further design of novel potential ROS-activated anticancer prodrugs.

PLCB1 Enhances Cell Migration and Invasion in Gastric Cancer Via Regulating Actin Cytoskeletal Remodeling and Epithelial-Mesenchymal Transition.

Phospholipase C Beta 1 (PLCB1) regulates the abundance of PI(4,5)P2 in the plasma membrane and is implicated in various kinds of cancers. This study aimed to investigate the role and underlying mechanisms of PLCB1 in gastric cancer. Herein, it was found that PLCB1 mRNA and protein were highly expressed in gastric cancer, and high levels of PLCB1 were correlated with poor outcomes of patients with gastric cancer via the GEPIA database. Moreover, our results revealed that PLCB1 depletion inhibited gastric cancer cell proliferation, migration, and invasion. Meanwhile, PLCB1 overexpression resulted in an inverse result. Furthermore, PLCB1 mediated actin cytoskeleton rearrangement and activated the RhoA/LIMK/Cofilin pathway. Besides, PLCB1 promoted the Epithelial-Mesenchymal transition process via activating ATK signaling. In conclusion, PLCB1 promoted gastric cancer cell migratory and invasive abilities via regulating actin cytoskeleton rearrangement and Epithelial-Mesenchymal transition process. These findings imply that targeting PLCB1 may be a potential strategy to improve the prognosis of gastric cancer patients.

Preoperative Prediction and Identification of Extracapsular Extension in Head and Neck Cancer Patients: Progress and Potential.

Background This study aimed to demonstrate both the potential and development progress in the identification of extracapsular nodal extension in head and neck cancer patients prior to surgery. Methodology A deep learning model has been developed utilizing multilayer gradient mapping-guided explainable network architecture involving a volume extractor. In addition, the gradient-weighted class activation mapping approach has been appropriated to generate a heatmap of anatomic regions indicating why the algorithm predicted extension or not. Results The prediction model shows excellent performance on the testing dataset with high values of accuracy, the area under the curve, sensitivity, and specificity of 0.926, 0.945, 0.924, and 0.930, respectively. The heatmap results show potential usefulness for some select patients but indicate the need for further training as the results may be misleading for other patients. Conclusions This work demonstrates continued progress in the identification of extracapsular nodal extension in diagnostic computed tomography prior to surgery. Continued progress stands to see the obvious potential realized where not only can unnecessary multimodality therapy be avoided but necessary therapy can be guided on a patient-specific level with information that currently is not available until postoperative pathology is complete.

Regulated cell death pathways in cardiomyopathy.

Heart disease is a worldwide health menace. Both intractable primary and secondary cardiomyopathies contribute to malignant cardiac dysfunction and mortality. One of the key cellular processes associated with cardiomyopathy is cardiomyocyte death. Cardiomyocytes are terminally differentiated cells with very limited regenerative capacity. Various insults can lead to irreversible damage of cardiomyocytes, contributing to progression of cardiac dysfunction. Accumulating evidence indicates that majority of cardiomyocyte death is executed by regulating molecular pathways, including apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Importantly, these forms of regulated cell death (RCD) are cardinal features in the pathogenesis of various cardiomyopathies, including dilated cardiomyopathy, diabetic cardiomyopathy, sepsis-induced cardiomyopathy, and drug-induced cardiomyopathy. The relevance between abnormity of RCD with adverse outcome of cardiomyopathy has been unequivocally evident. Therefore, there is an urgent need to uncover the molecular and cellular mechanisms for RCD in order to better understand the pathogenesis of cardiomyopathies. In this review, we summarize the latest progress from studies on RCD pathways in cardiomyocytes in context of the pathogenesis of cardiomyopathies, with particular emphasis on apoptosis, necroptosis, ferroptosis, autophagy, and pyroptosis. We also elaborate the crosstalk among various forms of RCD in pathologically stressed myocardium and the prospects of therapeutic applications targeted to various cell death pathways.

Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids-in specifically designed percentages-substituted for protein. METHODS AND RESULTS: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole-body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA-sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage-by improving mitochondrial fuel oxidation-in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet's cardioprotective impact. CONCLUSION: Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.

Sequencing and Assembly of Polyploid Genomes.

Polyploidy has been observed throughout major eukaryotic clades and has played a vital role in the evolution of angiosperms. Recent polyploidizations often result in highly complex genome structures, posing challenges to genome assembly and phasing. Recent advances in sequencing technologies and genome assembly algorithms have enabled high-quality, near-complete chromosome-level assemblies of polyploid genomes. Advances in novel sequencing technologies include highly accurate single-molecule sequencing with HiFi reads, chromosome conformation capture with Hi-C technique, and linked reads sequencing. Additionally, new computational approaches have also significantly improved the precision and reliability of polyploid genome assembly and phasing, such as HiCanu, hifiasm, ALLHiC, and PolyGembler. Herein, we review recently published polyploid genomes and compare the various sequencing, assembly, and phasing approaches that are utilized in these genome studies. Finally, we anticipate that accurate and telomere-to-telomere chromosome-level assembly of polyploid genomes could ultimately become a routine procedure in the near future.

Zhen Wu decoction represses renal fibrosis by invigorating tubular NRF2 and TFAM to fuel mitochondrial bioenergetics.

BACKGROUND: Zhen Wu Decoction (ZWD) is a prescription from the classical text "Treatise on Exogenous Febrile Disease" and has been extensively used to control kidney diseases since the time of the Eastern Han Dynasty. HYPOTHESIS: We hypothesized that ZWD limits tubular fibrogenesis by reinvigorating tubular bio-energetic capacity. STUDY DESIGN / METHODS: A mouse model of chronic kidney disease (CKD) was established using unilateral ureteral obstruction (UUO). Three concentrations of ZWD, namely 25.2 g/kg (high dosage), 12.6 g/kg (middle dosage), and 6.3 g/kg (low dosage), were included to study the dose-effect relationship. Real-time qPCR was used to observe gene transcription in blood samples from patients with CKD. Different siRNAs were designed to study the role of mitochondrial transcription factor A (TFAM) and nuclear factor (erythroid-derived 2)-related factor 2 (NRF2) in transforming growth factor (TGF)-ß1 induced fibrogenesis and mitochondrial damage. RESULTS: We showed that ZWD efficiently attenuates renal function impairment and reduces renal interstitial fibrosis. TFAM and NRF2 were repressed, and the stimulator of interferon genes (STING) was activated in CKD patient blood sample. We further confirmed that ZWD activated TFAM depended on NRF2 as an important negative regulator of STING in mouse kidneys. Treatment with ZWD significantly reduced oxidative stress and inflammation by regulating the levels of oxidative phosphorylation (OXPHOS) and pro-inflammatory factors, such as interleukin-6, interleukin-1ß, tumor necrosis factor receptor 1, and mitochondrial respiratory chain subunits. NRF2 inhibitors can weaken the ability of ZWD to increase TFAM expression and heal injured mitochondria, playing a similar role to that of STING inhibitors. Our study showed that ZWD elevates the expression of TFAM and mitochondrial respiratory chain subunits by promoting NRF2 activation, after suppressing mitochondrial membrane damage and cristae breakdown and restricting mitochondrial DNA (mtDNA) leakage into the cytoplasm to reduce STING activation. CONCLUSION: ZWD maintains mitochondrial integrity and improves OXPHOS which represents an innovative insight into "strengthening Yang-Qi" theory. ZWD limits tubular fibrogenesis by reinvigorating tubular bioenergetic capacity.

Metabolic status differentiates Trp53inp2 function in pressure-overload induced heart failure.

Cardiometabolic disorders encompass a broad range of cardiovascular complications associated with metabolic dysfunction. These conditions have an increasing share in the health burden worldwide due to worsening endemic of hypertension, obesity, and diabetes. Previous studies have identified Tumor Protein p53-inducible Nuclear Protein 2 (Trp53inp2) as a molecular link between hyperglycemia and cardiac hypertrophy. However, its role in cardiac pathology has never been determined in vivo. In this study, we generated a cardiac specific knockout model of Trp53inp2 (Trp53inp2-cKO) and investigated the impact of Trp53inp2 inactivation on the pathogenesis of heart failure under mechanic or/and metabolic stresses. Based on echocardiography assessment, inactivation of Trp53inp2 in heart led to accelerated onset of HFrEF in response to pressure-overload, with significantly reduced ejection fraction and elevated heart failure marker genes comparing to the control mice. In contrast, inactivation of Trp53inp2 ameliorated cardiac dysfunction induced by combined stresses of high fat diet and moderate pressure overload (Cardiometabolic Disorder Model). Moreover, Trp53inp2 inactivation led to reduced expression of glucose metabolism genes in lean, pressure-overloaded hearts. However, the same set of genes were significantly induced in the Trp53inp2-cKO hearts under both mechanical and metabolic stresses. In summary, we have demonstrated for the first time that cardiomyocyte Trp53inp2 has diametrically differential roles in the pathogenesis of heart failure and glucose regulation under mechanical vs. mechanical plus metabolic stresses. This insight suggests that Trp53inp2 may exacerbate the cardiac dysfunction during pressure overload injury but have a protective effect in cardiac diastolic function in cardiometabolic disease.

LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

RATIONALE: Vascular smooth muscle cells (VSMCs) phenotype switch from contractile to proliferative phenotype is a pathological hallmark in various cardiovascular diseases. Recently, a subset of long noncoding RNAs was identified to produce functional polypeptides. However, the functional impact and regulatory mechanisms of long noncoding RNAs in VSMCs phenotype switching remain to be fully elucidated. OBJECTIVES: To illustrate the biological function and mechanism of a VSMC-enriched long noncoding RNA and its encoded peptide in VSMC phenotype switching and vascular remodeling. RESULTS: We identified a VSMC-enriched transcript encoded by a previously uncharacterized gene, which we called phenotype switching regulator (PSR), which was markedly upregulated during vascular remodeling. Although PSR was annotated as a long noncoding RNA, we demonstrated that the lncPSR (PSR transcript) also encoded a protein, which we named arteridin. In VSMCs, both arteridin and lncPSR were necessary and sufficient to induce phenotype switching. Mechanistically, arteridin and lncPSR regulate downstream genes by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by arteridin. More importantly, the loss of PSR gene or arteridin protein significantly attenuated the vascular remodeling induced by carotid arterial injury. In addition, VSMC-specific inhibition of lncPSR using adeno-associated virus attenuated Ang II (angiotensin II)-induced hypertensive vascular remodeling. CONCLUSIONS: PSR is a VSMC-enriched gene, and its transcript IncPSR and encoded protein (arteridin) coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, with lncPSR/arteridin as potential therapeutic targets for the treatment of VSMC phenotype switching-related vascular remodeling.