The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.

Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs.

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer.

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

Change in Healthy Lifestyle and Subsequent Risk of Cognitive Impairment Among Chinese Older Adults: A National Community-Based Cohort Study.

BACKGROUND: The association between change in lifestyle and cognitive impairment remains uncertain. OBJECTIVES: To investigate the association of change in lifestyle with cognitive impairment. METHODS: In this study, 4 938 participants aged 65 or older were involved from the Chinese Longitudinal Healthy Longevity Survey for years 2008-2018. A weighted healthy lifestyle score was derived from 4 lifestyle factors (smoking, alcohol consumption, physical activity, and diet). Multivariable Cox proportional hazards regression models were applied to investigate the associations between 3-year changes in healthy lifestyle (2008-2011) and cognitive impairment (2011-2018). RESULTS: Researchers documented 833 new-onset of cognitive impairments more than 20 097 person-years of follow up. Compared with those in the persistently unhealthy group, those in the improved and persistently healthy groups had a lower risk of cognitive impairment, with the multivariate-adjusted hazard ratios (HRs) of 0.67 (95% confidence interval (CI): 0.55, 0.83) and 0.53 (95% CI: 0.40, 0.71), respectively. Furthermore, a significant interaction was observed between change in lifestyle and sex (p-interaction = .032); the HRs were 0.48 (95% CI, 0.34, 0.69) for the improved group and 0.41 (95% CI: 0.26, 0.64) for persistently healthy group among male vs 0.81 (95% CI, 0.63, 1.04) and 0.64 (95% CI, 0.44, 0.92) among female, respectively. CONCLUSIONS: This study suggests that improving or maintaining a healthy lifestyle can significantly mitigate the risk of cognitive impairment in Chinese older adults. Additionally, researcher's findings emphasize the significance of maintaining a healthy lifestyle and highlights the potential positive impact of improving previous unhealthy habits, especially for older women.

Knowledge mapping and research trends of exosomes in pancreatic cancer: a bibliometric analysis and review (2013-2023).

Objective: This review aims to provide a quantitative and qualitative bibliometric analysis of literature from 2013 to 2023 on the role of exosomes in PC, with the goal of identifying current trends and predicting future hotspots. Methods: We retrieved relevant publications concerning exosomes in PC, published between 2013 and 2023, from the Web of Science Core Collection. Bibliometric analyses were conducted using VOSviewer(1.6.19), CiteSpace(6.2.R4), and Microsoft Excel (2019). Results: A total of 624 papers were analyzed, authored by 4017 researchers from 55 countries/regions and 855 institutions, published in 258 academic journals. China (n=285, 34.42%) and the United States (n=183, 24.87%) were the most frequent contributors and collaborated closely. However, publications from China had a relatively low average number of citations (41.45 times per paper). The output of Shanghai Jiao Tong University ranked first, with 28 papers (accounting for 4.5% of the total publications). Cancers (n=31, 4.9%); published the most papers in this field. Researcher Margot Zoeller published the most papers (n=12) on this topic. Research hotspots mainly focused on the mechanisms of exosomes in PC onset and progression, the role of exosomes in PC early diagnosis and prognosis, exosomes promote the development of PC chemoresistance, and potential applications of exosomes as drug carriers for PC therapies. We observed a shift in research trends, from mechanistic studies toward clinical trials, suggesting that clinical applications will be the focus of future attention. Emerging topics were pancreatic stellate cells, diagnostic biomarkers, mesenchymal stem cells, extracellular vesicles. Conclusion: Our scientometric and visual analysis provides a comprehensive overview of the literature on the role of exosomes in PC published during 2013-2023. This review identifies the frontiers and future directions in this area over the past decade, and is expected to provide a useful reference for researchers in this field.

One-stop detection of anterior cruciate ligament injuries on magnetic resonance imaging using deep learning with multicenter validation.

Background: Anterior cruciate ligament (ACL) injuries are closely associated with knee osteoarthritis (OA). However, diagnosing ACL injuries based on knee magnetic resonance imaging (MRI) has been subjective and time-consuming for clinical doctors. Therefore, we aimed to devise a deep learning (DL) model leveraging MRI to enable a comprehensive and automated approach for the detection of ACL injuries. Methods: A retrospective study was performed extracting data from the Osteoarthritis Initiative (OAI). A total of 1,589 knees (comprising 1,443 intact, 90 with partial tears, and 56 with full tears) were enrolled to construct the classification model. This one-stop detection pipeline was developed using a tailored YOLOv5m architecture and a ResNet-18 convolutional neural network (CNN) to facilitate tasks based on sagittal 2-dimensional (2D) intermediate-weighted fast spin-echo sequence at 3.0T. To ensure the reliability and robustness of the classification system, it was subjected to external validation across 3 distinct datasets. The accuracy, sensitivity, specificity, and the mean average precision (mAP) were utilized as the evaluation metric for the model performance by employing a 5-fold cross-validation approach. The radiologist's interpretations were employed as the reference for conducting the evaluation. Results: The localization model demonstrated an accuracy of 0.89 and a sensitivity of 0.93, achieving a mAP score of 0.96. The classification model demonstrated strong performance in detecting intact, partial tears, and full tears at the optimal threshold on the internal dataset, with sensitivities of 0.941, 0.833, and 0.929, specificities of 0.925, 0.947, and 0.991, and accuracies of 0.940, 0.941, and 0.989, respectively. In comparison, on a subset consisting of 171 randomly selected knees from the OAI, the radiologists demonstrated a sensitivity ranging between 0.660 and 1.000, specificity ranging between 0.691 and 1.000, and accuracy ranging between 0.689 and 1.000. On a subset consisting of 170 randomly selected knees from the Chinese dataset, the radiologists exhibited a sensitivity ranging between 0.711 and 0.948, specificity ranging between 0.768 and 0.977, and accuracy ranging between 0.683 and 0.917. After retraining, the model achieved sensitivities ranging between 0.630 and 0.961, specificities ranging between 0.860 and 0.961, and accuracies ranging between 0.832 and 0.951, respectively, on the external validation dataset. Conclusions: The proposed model utilizing knee MRI showcases robust performance in the domains of ACL localization and classification.

Investigating the Immunogenic Cell Death-Dependent Subtypes and Prognostic Signature of Triple-Negative Breast Cancer.

Recently, immunotherapy has emerged as a promising and effective method for treating triple-negative breast cancer (TNBC). However, challenges still persist. Immunogenic cell death (ICD) is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells. Nevertheless, the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood. In this study, we observed dysregulation of the ICD process and verified the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To investigate the potential role of the ICD process in TNBC progression, we determined the ICD-dependent subtypes, and two were identified. Analysis of their distinct tumor immune microenvironment (TIME) and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune "cold" and "hot" phenotypes, respectively. In addition, we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability. The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identification of targeted effective agents for individualized clinical strategies. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00133-x.

Still water run deep: Therapeutic TP effect of ucMSC-Ex via regulating mTOR to enhance autophagy.

Our previous study confirmed that umbilical cord mesenchymal stem cells-exosomes (ucMSC-Ex) inhibit apoptosis of pancreatic acinar cells to exert protective effects. However, the relationship between apoptosis and autophagy in traumatic pancreatitis (TP) has rarely been reported. We dissected the transcriptomics after pancreatic trauma and ucMSC-Ex therapy by high-throughput sequencing. Additionally, we used rapamycin and MHY1485 to regulate mTOR. HE, inflammatory factors and pancreatic enzymatic assays were used to comprehensively determine the local versus systemic injury level, fluorescence staining and electron microscopy were used to detect the effect of autophagy, and observe the expression levels of autophagy-related markers at the gene and protein levels. High-throughput sequencing identified that autophagy played a crucial role in the pathophysiological process of TP and ucMSC-Ex therapy. The results of electron microscopy, immunofluorescence staining, polymerase chain reaction and western blot suggested that therapeutic effect of ucMSC-Ex was mediated by activation of autophagy in pancreatic acinar cells through inhibition of mTOR. ucMSC-Ex can attenuate pancreas injury by inhibiting mTOR to regulate acinar cell autophagy after TP. Future studies will build on the comprehensive sequencing of RNA carried by ucMSC-Ex to predict and verify specific non-coding RNA.

Dietary polyphenols regulate appetite mechanism via gut-brain axis and gut homeostasis.

Nowadays, due to the rise of fast-food consumption, the metabolic diseases are increasing as a result of high-sugar and high-fat diets. Therefore, there is an urgent need for natural, healthy and side-effect-free diets in daily life. Whole grain supplementation can enhance satiety and regulate energy metabolism, effects that have been attributed to polyphenol content. Dietary polyphenols interact with gut microbiota to produce intermediate metabolites that can regulate appetite while also enhancing prebiotic effects. This review considers how interactions between gut metabolites and dietary polyphenols might regulate appetite by acting on the gut-brain axis. In addition, further advances in the study of dietary polyphenols and gut microbial metabolites on energy metabolism and gut homeostasis are summarized. This review contributes to a better understanding of how dietary polyphenols regulate appetite via the gut-brain axis, thereby providing nutritional references for citizens' dietary preferences.

B cell subsets contribute to myocardial protection by inducing neutrophil apoptosis after ischemia and reperfusion.

A robust, sterile inflammation underlies myocardial ischemia and reperfusion injury (MIRI). Several subsets of B cells possess the immunoregulatory capacity that limits tissue damage, yet the role of B cells in MIRI remains elusive. Here, we sought to elucidate the contribution of B cells to MIRI by transient ligation of the left anterior descending coronary artery in B cell-depleted or -deficient mice. Following ischemia and reperfusion (I/R), regulatory B cells are rapidly recruited to the heart. B cell-depleted or -deficient mice exhibited exacerbated tissue damage, adverse cardiac remodeling, and an augmented inflammatory response after I/R. Rescue and chimeric experiments indicated that the cardioprotective effect of B cells was not solely dependent on IL-10. Coculture experiments demonstrated that B cells induced neutrophil apoptosis through contact-dependent interactions, subsequently promoting reparative macrophage polarization by facilitating the phagocytosis of neutrophils by macrophages. The in vivo cardioprotective effect of B cells was undetectable in the absence of neutrophils after I/R. Mechanistically, ligand-receptor imputation identified FCER2A as a potential mediator of interactions between B cells and neutrophils. Blocking FCER2A on B cells resulted in a reduction in the percentage of apoptotic neutrophils, contributing to the deterioration of cardiac remodeling. Our findings unveil a potential cardioprotective role of B cells in MIRI through mechanisms involving FCER2A, neutrophils, and macrophages.

Dissecting Maillard reaction production in fried foods: Formation mechanisms, sensory characteristic attribution, control strategy, and gut homeostasis regulation.

Foods rich in carbohydrates or fats undergo the Maillard reaction during frying, which promotes the color, flavor and sensory characteristics formation. In the meanwhile, Maillard reaction intermediates and advanced glycation end products (AGEs) have a negative impact on food sensory quality and gut homeostasis. This negative effect can be influenced by food composition and other processing factors. Whole grain products are rich in polyphenols, which can capture carbonyl compounds in Maillard reaction, and reduce the production of AGEs during frying. This review summarizes the Maillard reaction production intermediates and AGEs formation mechanism in fried food and analyzes the factors affecting the sensory formation of food. In the meanwhile, the effects of Maillard reaction intermediates and AGEs on gut homeostasis were summarized. Overall, the innovative processing methods about the Maillard reaction are summarized to optimize the sensory properties of fried foods while minimizing the formation of AGEs.

Recognition of methamphetamine and other amines by trace amine receptor TAAR1.

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous ß-phenylethylamine (ß-PEA)1 as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and ß-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

CircNOLC1 Promotes Colorectal Cancer Liver Metastasis by Interacting with AZGP1 and Sponging miR-212-5p to Regulate Reprogramming of the Oxidative Pentose Phosphate Pathway.

Liver metastasis is a common cause of death in progressive colorectal cancer patients, but the molecular mechanisms remain unclear. Here, it is reported that a conserved and oxidative pentose phosphate pathway-associated circular RNA, circNOLC1, plays a crucial role in colorectal cancer liver metastasis. It is found that circNOLC1 silencing reduces the oxidative pentose phosphate pathway-related intermediate metabolites and elevates NADP+ /NADPH ratio and intracellular ROS levels, thereby attenuating colorectal cancer cell proliferation, migration, and liver metastasis. circNOLC1 interacting with AZGP1 to activate mTOR/SREBP1 signaling, or sponging miR-212-5p to upregulate c-Met expression, both of which can further induce G6PD to activate oxidative pentose phosphate pathway in colorectal cancer liver metastasis. Moreover, circNOLC1 is regulated by the transcription factor YY1 and specifically stabilized HuR induces its parental gene mRNA expression. The associations between circNOLC1 and these signaling molecules are validated in primary CRC and corresponding liver metastasis tissues. These findings reveal that circNOLC1 interacting with AZGP1 and circNOLC1/miR-212-5p/c-Met axis plays a key role in oxidative pentose phosphate pathway-mediated colorectal cancer liver metastasis, which may provide a novel target for precision medicine of colorectal cancer.

A Strong Adhesive Biological Hydrogel for Colon Leakage Repair and Abdominal Adhesion Prevention.

Colon leakage is one of the most severe complications in abdominal trauma or surgery cases. It can lead to severe abdominal infection and abdominal adhesions, resulting in prolonged hospital stays and increased mortality. In this study, a photosensitive hydrogel is proposed, which can swiftly form a strong adhesion coating on the damaged colon after UV irradiation, to realize quick cure and suture-free repair of colon leakage. The newly developed biological gel consists of hyaluronic acid methacryloyl (HAMA) and hyaluronic acid o-nitroso benzaldehyde (HANB) in the optimal ratio of 3: 1, which exerts both the rapid photocuring properties of HAMA and the strong tissue adhesion properties of HANB. HAMA/HANB shows excellent adhesion stability on wet surfaces, presenting controllable mechanical properties, ductility, adhesion stability, and chemical stability; it also evades foreign body response, which relieves the degree of abdominal adhesion. The underlying mechanism for HAMA/HANB promoting wound healing in colon leakage involves the reconstruction of the colon barrier, as well as the regulation of the immune reaction and neovascularization. In all, HAMA/HANB is a promising alternative suture-free approach for repairing colon leakage; it has a reliable healing effect and is expected to be extended to clinical application for other organ injuries.

The future of robotic pancreaticoduodenal surgery: a bibliometric analysis.

OBJECTIVES: Robotic pancreaticoduodenectomy (RPD) has garnered significant research attention in the last decade. However, no bibliometric studies have been conducted on this field yet. Therefore, the aim of this study is to provide an up-to-date analysis of the current state of research, as well as future trends and hotspots in RPD, through a bibliometric analysis. MATERIALS AND METHODS: We conducted a thorough search of all literature related to RPD in the Web of Science Core Collection (WoSCC). We then analyzed this literature for a variety of factors, including authorship, country of origin, institutional affiliations, and keywords. To visualize our findings, we utilized Citespace 6.1.R3, which enabled us to create network visualization maps, perform cluster analysis, and extract burst words. RESULTS: A total of 264 articles were retrieved. Zureikat is the author with the largest contribution in this field, and Surgical Endoscopy and Other International Techniques is the journal with the largest number of papers in this field. The United States is the core research country in this field. The University of Pittsburgh is the most productive institution. According to the data, outcome, pancreas fistula, definition, risk factor, stay, survival, learning curve and experience are recognized as research hotspots in this field. CONCLUSIONS: This study is the first bibliometric study in the field of RPD. Our data will help us better understand the development trend of the field, and determine research hotspots and research directions. The research results provide practical information for other scholars to understand key directions and cutting-edge information.

Oncology nursing on the move: a contemporary issue on Chinese oncology nursing in cancer care.

Cancers have become the primary cause of death among Chinese residents, seriously affecting their health and life. Oncology nursing is a specialized nursing practice focusing on cancer education, prevention, screening, early detection, and palliative and hospice care. China has made tremendous progress in developing oncology nursing. However, to ensure more individuals can get cancer care, the country's healthcare system still confronts several problems in oncology nursing that need to be addressed to ensure that more individuals can receive cancer care. This article reviews the current development of oncology nursing in China, especially in pain symptom control, palliative care, end-of-life care, education and training. The challenges faced in oncology nursing in China and the suggestions for developing oncology nursing in China are also discussed and proposed in this review. The growth of research on oncology nursing by Chinese nursing scholars and concerned policymakers is anticipated to ultimately improve oncology nursing and the quality of life of patients with cancer in China.

Multi-level integrative analysis of the roles of lncRNAs and differential mRNAs in the progression of chronic pancreatitis to pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and approximately 5% of patients with chronic pancreatitis (CP) inevitably develop PDAC. This study aims explore the key gene regulation involved in the progression of CP to PDAC, with a particular emphasis on the function of lncRNAs. RESULTS: A total of 103 pancreatic tissue samples collected from 11 to 92 patients with CP and PDAC, respectively, were included in this study. After normalizing and logarithmically converting the original data, differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEGs) in each dataset were selected. To determine the main functional pathways of differential mRNAs, we further annotated DEGs using gene ontology (GO) and analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. In addition, the interaction between lncRNA-miRNA-mRNA was clarified and the protein-protein interaction (PPI) network was constructed to screen for key modules and determine hub genes. Finally, quantitative real-time polymerase chain reaction (qPCR) was used to detect the changes in non-coding RNAs and key mRNAs in the pancreatic tissues of patients with CP and PDAC. In this study, 230 lncRNAs and 17,668 mRNAs were included. There were nine upregulated lncRNAs and 188 downregulated lncRNAs. Furthermore, 2334 upregulated differential mRNAs and 10,341 downregulated differential mRNAs were included in the enrichment analysis. From the KEGG enrichment analysis, cytokine-cytokine receptor interaction, calcium signaling pathway, cAMP signaling pathway, and nicotine addiction exhibited significant differences. Additionally, a total of 52 lncRNAs, 104 miRNAs, and 312 mRNAs were included in the construction of a potential lncRNA-miRNA-mRNA regulatory network. PPI network was established and two of the five central DEGs were created in this module, suggesting that lysophosphatidic acid receptor 1 (LPAR1) and regulator of calcineurin 2 (RCAN2) may play significant roles in the progression from CP to PDAC. Finally, the PCR results suggested that LINC01547/hsa-miR-4694-3p/LPAR1 and LINC00482/hsa-miR-6756-3p/RCAN2 play important roles in the carcinogenesis process of CP. CONCLUSION: Two signaling axes critical in the progression of CP to PDAC were screened out. Our findings will be useful for novel insights into the molecular mechanism and potential diagnostic or therapeutic biomarkers for CP and PDAC.

Translation and validation of the international consultation on incontinence questionnaire-vaginal symptoms: the simplified Chinese version.

INTRODUCTION AND HYPOTHESIS: International Consultation on Incontinence Questionnaire-Vaginal Symptoms (ICIQ-VS) is a simple and effective questionnaire for evaluating vaginal symptoms, sexual problems and the quality of life (QOL) in patients. This study was aimed at validating the simplified Chinese version of the ICIQ-VS. METHODS: A total of 120 women with pelvic organ prolapse (POP) stage <2, 124 with stage ≥ 2, and 51 patients who underwent POP surgery (POP stage ≥2) were included. Cronbach's alpha coefficient and intraclass correlation coefficient (ICC) were used for reliability analysis. We used the content validity index, Kruskal-Wallis H test, and Mann-Whitney U test to study validity. Paired sample t test, Wilcoxon signed-rank test, effect size and standardized response mean were used to assess sensitivity. RESULTS: The Cronbach's alpha coefficients of the vaginal symptoms score (VSS) and sexual matters score (SMS) were 0.787 and 0.861 respectively. The test-retest reliabilities of the VSS, SMS, and QOL score were 0.830, 0.894, and 0.948 respectively. The test-retest reliability was from good to excellent (ICC 0.669-0.948). The item-level content validity index was 0.60 to 1.00. The scale-level content validity index/universal agreement was 0.95, and the scale-level content validity index/average was 0.96. Significant score differences existed between the symptomatic and asymptomatic groups (p < 0.001). Criterion validity was significant (p < 0.001). VSS and QOL score had high sensitivity (p < 0.001, effect size and standardized response mean >0.8). CONCLUSIONS: The simplified Chinese version of the ICIQ-VS can objectively and reliably access vaginal symptoms, sexual matters, and QOL in Chinese women.

Investigating the mechanism of Xian-ling-lian-xia-fang for inhibiting vasculogenic mimicry in triple negative breast cancer via blocking VEGF/MMPs pathway.

BACKGROUND: Xian-ling-lian-xia-fang (XLLXF), a Chinese medicine decoction, is widely used in the treatment of triple negative breast cancer (TNBC). However, the underlying mechanism of XLLXF in TNBC treatment has not been totally elucidated. METHODS: Here, network pharmacology and molecular docking were used to explore the mechanism of Traditional Chinese medicine in the treatment of TNBC. Then, biological experiments were integrated to verify the results of network pharmacology. RESULTS: Network pharmacology showed that the candidate active ingredients mainly included quercetin, kaempferol, stigmasterol, and ß-sitosterol through the "XLLXF-active ingredients-targets" network. Vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase (MMP) 2 were the potential therapeutic targets obtained through the protein-protein interaction (PPI) network. Molecular docking confirmed that quercetin, kaempferol, stigmasterol, and ß-sitosterol could stably combine with VEGFA and MMP2. Experimental verification showed that XLLXF could inhibit proliferation, colony ability, and vasculogenic mimicry (VM) formation and promote cell apoptosis in TNBC. Laser confocal microscopy found that XLLXF impaired F-actin cytoskeleton organization and inhibited epithelial mesenchymal transition. Animal experiments also found that XLLXF could inhibit tumor growth and VM formation in TNBC xenograft model. Western blot analysis and immunohistochemical staining showed that XLLXF inhibited the protein expression of VEGFA, MMP2, MMP9, Vimentin, VE-cadherin, and Twist1 and increased that of E-cadherin, tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-3 in vitro and in vivo. CONCLUSIONS: Integrating the analysis of network pharmacology and experimental validation revealed that XLLXF could inhibit VM formation via downregulating the VEGF/MMPs signaling pathway.

Discovery of New Estrogen-Related Receptor α Agonists via a Combination Strategy Based on Shape Screening and Ensemble Docking.

Estrogen-related receptor α (ERRα), a member of nuclear receptors (NRs), plays a role in the regulation of cellular energy metabolism and is reported to be a novel potential target for type 2 diabetes therapy. To date, only a few agonists of ERRα have been identified to improve insulin sensitivity and decrease blood glucose levels. Herein, the discovery of novel potent agonists of ERRα determined using a combined virtual screening approach is described. Molecular dynamics (MD) simulations were used to obtain structural ensembles that can consider receptor flexibility. Then, an efficient virtual screening strategy with a combination of similarity search and ensemble docking was performed against the Enamine, SPECS, and Drugbank databases to identify potent ERRα agonists. Finally, a total of 66 compounds were purchased for experimental testing. Biological investigation of promising candidates identified seven compounds that have activity against ERRα with EC50 values ranging from 1.11 to 21.70 µM, with novel scaffolds different from known ERRα agonists until now. Additionally, the molecule GX66 showed micromolar inverse activity against ERRα with an IC50 of 0.82 µM. The predicted binding modes showed that these compounds were anchored in ERRα-LBP via interactions with several residues of ERRα. Overall, this study not only identified the novel potent ERRα agonists or an inverse agonist that would be the promising starting point for further exploration but also demonstrated a successful molecular dynamics-guided approach applicable in virtual screening for ERRα agonists.

microRNA-20b-5p overexpression combing Pembrolizumab potentiates cancer cells to radiation therapy via repressing programmed death-ligand 1.

Radiation therapy (RT) is widely applied in cancer treatment. The sensitivity of tumor cells to RT is the key to the treatment. This study probes the role and mechanism of miR-20b-5p in Pembrolizumab's affecting the radiosensitivity of tumor cells. After Pembrolizumab treatment or cell transfection (miR-20b-5p mimics and miR-20b-5p inhibitors), tumor cells (NCI-H460 and ZR-75-30) were exposed to RT. The sensitivity of NCI-H460 and ZR-75-30 to RT was evaluated by monitoring cell proliferation and apoptosis. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were adopted to evaluate the binding relationship between miR-20b-5p and CD274 (PD-L1). The xenograft model was established in nude mice to examine the mechanism of action of Pembrolizumab in vivo. Our outcomes exhibited that either Pembrolizumab treatment or miR-20b-5p overexpression potentiated radiosensitivity of tumor cells. Overexpressing miR-20b-5p enhanced radiosensitization of Pembrolizumab in vivo and in vitro by targeting PD-L1 and inactivating PD-L1/PD1. Overall, miR-20b-5p overexpression combined with Pembrolizumab potentiated cancer cells' sensitivity to RT by repressing PD-L1/PD1.Abbreviations Akt: serine/threonine kinase 1; cDNA: complementary DNA; CO2: carbon dioxide; EDTA: Ethylene Diamine Tetraacetic Acid; ENCORI: The Encyclopedia of RNA Interactomes; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IGF2BP2: insulin like growth factor 2 mRNA binding protein 2; IHC: Immunohistochemistry; LncRNA MALAT1: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1; miRNAs: MicroRNAs; Mt: Mutant type; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; NC: negative control; NR2F2: nuclear receptor subfamily 2 group F member 2; NSCLC: non-small cell lung cancer; OD: optical density; PBS: phosphate-buffered saline; PD-L1: Programmed death-ligand 1; PD-1: programmed death 1; PI3K: phosphatidylinositol 3-kinase; qRT-PCR: Quantitative reverse transcription-polymerase chain reaction; RIP: RNA immunoprecipitation; RIPA: Radio Immunoprecipitation Assay; RRM2: ribonucleotide reductase regulatory subunit M2; RT: Radiation therapy; U6: U6 small nuclear RNA; V: volume; WB: Western blot; Wt: wild type; x ± sd: mean ± standard deviation.