FXR1 facilitates axitinib resistance in clear cell renal cell carcinoma via regulating KEAP1/Nrf2 signaling pathway.

Axitinib is emerging as a first-line combination treatment drug for metastatic renal cell carcinoma, but the acquired resistance significantly bothers the treatment efficacy. This article is to investigate the impact of fragile X mental retardation autosomal homolog 1 (FXR1) and its mechanistic involvement with Kelch-like epoxy chloropropan-associated protein 1 (KEAP1)/NF-E2-related factor 2 (Nrf2) pathway on cell resistance to axitinib in clear cell renal cell carcinoma (ccRCC). Establishment of axitinib resistance cells (786-O, Caki-1, 786-O/axitinib, or Caki-1/axitinib) was made, and the cells were then transfected with sh-FXR1, or co-transfected with sh-FXR1 and sh-KEAP1. The quantitative real-time PCR (qRT-PCR) and western blotting assays were employed to measure the expression of FXR1, KEAP1, Nrf2, LC3 II/I, Beclin 1, p62, MDR-1, and MRP-1. In addition, the binding between FXR1 and KEAP1 was verified by RNA-immunoprecipitation and RNA pull-down assays, and FXR1-dependent KEAP1 mRNA degradation was determined. Herein, FXR1 was demonstrated to be overexpressed in ccRCC cells, and showed higher expression in 786-O/axitinib and Caki-1/axitinib cells. Mechanistically, FXR1 enriched KEAP1 mRNA, and pulled downed by biotinylated KEAP1 probes. Results of RNA stability assay reveled that KEAP mRNA stability was suppressed by FXR1. Furthermore, knockdown of FXR1 promoted cell apoptosis and showed a restrained feature on cell resistance to axitinib. Of note, KEAP1 knockdown suppressed cell autophagy, oxidative stress, resistance to axitinib, and promoted apoptosis, despite FXR1 was downregulated in ccRCC cells. In conclusion, FXR1 played an encouraging role in ccRCC cell resistance to axitinib by modulating KEAP/Nrf2 pathway.

Design, synthesis, and analgesia evaluation of novel Transient Receptor Potential Vanilloid 1 (TRPV1) agonists modified from Cannabidiol (CBD).

Pain-relief is a long-term research hotspot with huge demand in clinical treatment. The analgesics currently used have several side effects, such as being addictive and causing gastrointestinal bleeding. Therefore, new drugs and targets in analgesic field are both desirable. Transient Receptor Potential Vanilloid 1 (TRPV1) plays an essential role in pain perception and regulation, providing a new strategy for the development of antinociceptive agents. Here, a series of novel TRPV1 agonists were designed and synthesized based on Cannabidiol (CBD), a widely used pain-relieving agent with weak agonistic activity on TRPV1. According to the results of systematic in vitro and in vivo biological assays, compound 10f was finally identified as a promising TRPV1 agonist, with higher target affinity, stronger analgesic activity, and weak side effect of hyperthermia. Molecular docking simulations revealed a significant hydrogen bond interaction between 10f and Arg557, an amino acid residue key to the activity of TRPV1 protein. Taken together, compound 10f can be used as a lead compound for further optimization.

6-Shogaol as a Novel Thioredoxin Reductase Inhibitor Induces Oxidative-Stress-Mediated Apoptosis in HeLa Cells.

Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs. 6-Shogaol (6-S), a primary bioactive compound in ginger, has high anticancer activity. However, its potential mechanism of action has not been thoroughly investigated. In this study, we demonstrated for the first time that 6-S, a novel TrxR inhibitor, promoted oxidative-stress-mediated apoptosis in HeLa cells. The other two constituents of ginger, 6-gingerol (6-G) and 6-dehydrogingerduone (6-DG), have a similar structure to 6-S but fail to kill HeLa cells at low concentrations. 6-Shogaol specifically inhibits purified TrxR1 activity by targeting selenocysteine residues. It also induced apoptosis and was more cytotoxic to HeLa cells than normal cells. The molecular mechanism of 6-S-mediated apoptosis involves TrxR inhibition, followed by an outburst of reactive oxygen species (ROS) production. Furthermore, TrxR knockdown enhanced the cytotoxic sensitivity of 6-S cells, highlighting the physiological significance of targeting TrxR by 6-S. Our findings show that targeting TrxR by 6-S reveals a new mechanism underlying the biological activity of 6-S and provides meaningful insights into its action in cancer therapeutics.

Eltrombopag Inhibits Metastasis in Breast Carcinoma by Targeting HuR Protein.

Eltrombopag is a small molecule TPO-R agonist that has been shown in our previous studies to inhibit tumor growth by targeting Human antigen R (HuR) protein. HuR protein not only regulates the mRNA stability of tumor growth-related genes, but it also regulates the mRNA stability of a variety of cancer metastasis-related genes, such as Snail, Cox-2, and Vegf-c. However, the role and mechanisms of eltrombopag in breast cancer metastasis have not been fully investigated. The purpose of this study was to investigate whether eltrombopag can inhibit breast cancer metastasis by targeting HuR. Our study first found that eltrombopag can destroy HuR-AU-rich element (ARE) complexes at the molecular level. Secondly, eltrombopag was found to suppress 4T1 cell migration and invasion and inhibit macrophage-mediated lymphangiogenesis at the cellular level. In addition, eltrombopag exerted inhibitory effects on lung and lymph node metastasis in animal tumor metastasis models. Finally, it was verified that eltrombopag inhibited the expressions of Snail, Cox-2, and Vegf-c in 4T1 cells and Vegf-c in RAW264.7 cells by targeting HuR. In conclusion, eltrombopag displayed antimetastatic activity in breast cancer in an HuR dependent manner, which may provide a novel application for eltrombopag, hinting at the multiple effects of HuR inhibitors in cancer therapy.

Pseudoephedrine and its derivatives antagonize wild and mutated severe acute respiratory syndrome-CoV-2 viruses through blocking virus invasion and antiinflammatory effect.

The coronavirus disease 2019 has infected over 150 million people worldwide and led to over 3 million deaths. Severe acute respiratory syndrome (SARS)-CoV-2 lineages B.1.1.7, B.1.617, B.1.351, and P.1 were reported to have higher infection rates than that of wild one. These mutations were noticed to happen in the receptor-binding domain of spike protein (S-RBD), especially mutations N501Y, E484Q, E484K, K417N, K417T, and L452R. Currently, there is still no specific medicine against the virus; moreover, cytokine storm is also a dangerous factor for severe infected patients. In this study, potential S-RBD-targeted active monomers from traditional Chinese medicine Ephedra sinica Stapf (ephedra) were discovered by virtual screening. NanoBiT assay was performed to confirm blocking activities of the screened compounds against the interaction between SARS-CoV-2 S-RBD and angiotensin-converting enzyme 2 (ACE2). We further analyzed the blocking effect of the active compounds on the interactions of mutated S-RBD and ACE2 by computational studies. Moreover, antiinflammatory activities were evaluated using qRT-PCR, enzyme-linked immune sorbent assay, and Western blot analysis. As a result, pseudoephedrine (MHJ-17) and its derivative (MHJ-11) were found as efficient inhibitors disrupting the interactions between ACE2 and both wild and mutated S-RBDs. In addition, they also have antiinflammatory activities, which can be potential drug candidates or lead compounds for further study.

Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.

RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

Upregulated PPP1R14B is connected to cancer progression and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an oncogenic gene found in a variety of tumors, but its role in the prognosis and development of kidney renal clear cell carcinoma (KIRC) remains unknown. Our study aimed to determine whether PPP1R14B could be a prognostic biomarker for KIRC and its role in the development of KIRC. METHODS: In this work, we used The Cancer Genome Atlas (TCGA) database to explore the expression of PPP1R14B in tumor tissues, its relationship with the prognosis of tumor patients, and its role in tumor occurrence and development. We validated our findings using the International Cancer Genome Consortium (ICGC) cohort, our clinical samples, and in vitro experiments. RESULTS: PPP1R14B was upregulated in KIRC compared to adjacent normal tissue. Moreover, multivariate analysis revealed that upregulated PPP1R14B expression was an independent risk factor for KIRC progression. High-PPP1R14B groups had shorter overall survival (OS) and disease-free survival (DFS) in TCGA and ICGC cohorts. We used Cell Counting Kit-8 (CCK8) and scratch wound healing assay to explore the proliferation and migration of KIRC cells following PPP1R14B knockdown. Our results indicated that PPP1R14B knockdown significantly reduced the proliferation and migration of KIRC cells in vitro. We also explored the possible cellular mechanisms of PPP1R14B through the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO) analysis, and TISIDB analysis. The function enrich analysis revealed that PPP1R14B-related genes were mainly enriched in purine metabolism and the macromolecule catabolic process. PPP1R14B expression was associated with tumor-infiltrating immune cells (TIICs) in the TCGA cohort, and the results of single-cell RNA-seq (scRNA) further demonstrated that PPP1R14B expression was associated with the enhanced infiltration of CD8 + T lymphocytes. CONCLUSION: PPP1R14B may serve as a prognostic biomarker in KIRC, affect purine metabolism, activate immune infiltration, and promote KIRC cell migration.

Comprehensive analysis of vulnerability status and associated affect factors among prehospital emergency patients: a single-center descriptive cross-sectional study.

Background: Prehospital emergency care is a critical but often understudied aspect of healthcare. Patient vulnerability in this setting can significantly impact outcomes. The aim of this study was to investigate the vulnerability status and to determine associated affect factors among prehospital emergency patients in China. Methods: In this cross-sectional study conducted in China, from April 2023 to July 2023, we assessed the vulnerability of prehospital emergency patients using the Safety in Prehospital Emergency Care Index (SPECI) scale. We conducted a detailed questionnaire-based survey to gather demographic and disease-related information. We employed the SPECI scale, consisting of two subscales, to evaluate patient vulnerability. Statistical analyses, including t-tests, ANOVA, and multiple linear regression, were used to identify factors associated with vulnerability. Results: The study included a total of 973 prehospital emergency patients, with a response rate of 81.9%. These patients exhibited a low-to-moderate level of vulnerability, with an average SPECI score of 14.46 out of 40. Vulnerability was significantly associated with age (particularly those aged 60 and above), disease severity (severe conditions increased vulnerability), disease type (circulatory diseases correlated with higher vulnerability), alterations in consciousness, and chronic diseases. Unexpectedly, digestive system diseases were negatively correlated with vulnerability. Conclusion: Addressing patient vulnerability in prehospital care is essential. Tailored interventions, EMS provider training, and interdisciplinary collaboration can mitigate vulnerability, especially in older patients and those with severe conditions.

Neuroprotective effects of the salidroside derivative SHPL-49 via the BDNF/TrkB/Gap43 pathway in rats with cerebral ischemia.

Ischemic stroke is a common intravascular disease and one of the leading causes of death and disability. The salidroside derivative SHPL-49, which we previously synthesized, significantly attenuates cerebral ischemic injury in a rat model of permanent middle cerebral artery occlusion. To explore the neuroprotective mechanism of SHPL-49, the effects of SHPL-49 on the expression levels of neurotrophic factors in neurons and microglia and the polarization of microglia were investigated in the present study. SHPL-49 activated the brain-derived neurotrophic factor (BDNF) pathway, decreased the number of degenerated neurons, and accelerated neurogenesis in rats with cerebral ischemia. In addition, SHPL-49 promoted the polarization of microglia toward the M2 phenotype to alleviate neuroinflammation. In BV2 cells, SHPL-49 upregulated CD206 mRNA and protein levels and inhibited CD86 mRNA and protein levels. SHPL-49 also increased neurotrophic factor secretion in BV2 cells, which indirectly promoted the survival of primary neurons after oxygen-glucose deprivation (OGD). Proteomics analysis revealed that SHPL-49 promoted growth-associated protein 43 (Gap43) expression. SHPL-49 enhanced synaptic plasticity and increased Gap43 protein levels via activation of the BDNF pathway in the OGD primary neuron model. These results indicate that SHPL-49 prevents cerebral ischemic injury by activating neurotrophic factor pathways and altering microglial polarization. Thus, SHPL-49 is a potential neuroprotective agent.

Prognostic analysis of anoikis-related genes in bladder cancer: An observational study.

Anoikis is proved to play a crucial role in the development of cancers. However, the impact of anoikis on the prognosis of bladder cancer (BLCA) is currently unknown. Thus, this study aimed to find potential effect of anoikis in BLCA. The Cancer Genome Atlas (TCGA)-BLCA and GSE13507 cohorts were downloaded from TCGA and the Gene Expression Omnibus (GEO) databases, respectively. Differentially expressed genes (DEGs) were screened between BLCA and normal groups, which intersected with anoikis-related genes to yield anoikis-related DEGs (AR DEGs). Univariate COX, rbsurv, and multivariate COX analyses were adopted in order to build a prognostic risk model. The differences of risk score in the different clinical subgroups and the relevance between survival rate and clinical characteristics were explored as well. Finally, chemotherapy drug sensitivity in different risk groups was analyzed. In total, 78 AR DEGs were acquired and a prognostic signature was build based on the 6 characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1), where the patients of low-risk group had longer survival time. The survival rate of BLCA patients was significantly differential in different groups of age, stage, smoking history, pathologic-T, and pathologic-N. The IC50 of 56 drugs showed significant differences between 2 risk groups, such as imatinib, docetaxel, and dasatinib. At last, the results of real time quantitative-polymerase chain reaction (RT-qPCR) demonstrated that the expression trend of CALR, HGF, and INHBB was consistent with the result obtained previously based on public databases. Taken together, this study identified 6 anoikis-related characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1) for the prognosis of BLCA patients, providing a scientific reference for further research on BLCA.

Association Between Age at Diabetes Diagnosis and Subsequent Incidence of Cancer: A Longitudinal Population-Based Cohort.

OBJECTIVE: Diabetes presenting at a younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. RESEARCH DESIGN AND METHODS: The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years. The incidence of overall and 14 site-specific cancers was compared with the Shanghai general population including 100,649,346 person-years. RESULTS: A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person-years, and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10), and 0.86 (0.84, 0.89), respectively. Similar trends were observed for site-specific cancers, including respiratory, colorectum, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancer and lymphoma among both males and females. CONCLUSIONS: Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardized cancer risks are greater in earlier compared with later onset T2DM.

Macrophage ß2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis.

HuR is a member of the Drosophila Elav protein family that binds mRNA degradation sequences and prevents RNase-mediated degradation. Such HuR-mediated mRNA stabilization, which is stimulated by integrin engagement and is controlled at the level of HuR nuclear export, is critically involved in T-cell cytokine production. However, HuR's role in macrophage soluble factor production, in particular in response to angiogenic stimuli, has not yet been established. We show that the labile transcripts that encode vascular endothelial growth factor and matrix metalloproteinase-9 are stabilized when murine macrophages adhere to the ß(2) integrin ligand intercellular adhesion molecule-1. This mRNA stabilization response was absent in bone marrow-derived macrophages obtained from conditional macrophage-specific HuR knockout mice. The microvascular angiogenic response to an inflammatory stimulus (ie, subcutaneous polyvinyl alcohol sponge implantation) was markedly diminished in these macrophage HuR knockout mice despite the equal levels of macrophage localization to those observed in littermate wild-type controls. Furthermore, blood flow recovery and ischemic muscle neovascularization after femoral artery ligation were impaired in the conditional macrophage-specific HuR knockout mice. These results demonstrate that dynamic effects on mRNA, mediated by the RNA-binding and RNA-stabilizing protein HuR, are required for macrophage production of angiogenic factors, which play critical roles in the neovascular responses to a variety of stimuli, including tissue ischemia.

Both total testosterone and sex hormone-binding globulin are independent risk factors for metabolic syndrome: results from Fangchenggang Area Male Health and Examination Survey in China.

BACKGROUND: Metabolic syndrome is often beneficial from testosterone replacement therapy. Although testosterone and sex hormone-binding globulin (SHBG) are inversely associated with the risk of metabolic syndrome, it is controversial whether the association between testosterone and metabolic syndrome is independent of SHBG. METHODS: Testosterone, SHBG and metabolic syndrome were evaluated in 2361 men aged 20-73 years, who participated in the population-based Fangchenggang Area Male Health and Examination Survey. Total testosterone, SHBG and other biochemical profiles were measured. Free testosterone and bioavailable testosterone were calculated on the basis of Vermeulen's formula. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria for Asian population. The independent associations with metabolic syndrome were determined by multivariate logistic regression analysis. RESULTS: Men with metabolic syndrome had a lower level of total testosterone, bioavailable testosterone, free testosterone, or SHBG than those without metabolic syndrome (all p < 0.001). Both total testosterone and SHBG were inversely correlated with body mass index or homeostasis model assessment of insulin resistance (all age-adjusted p < 0.001). Men within the lowest quartile of total testosterone [odds ratio (OR) = 4.86, 95% confidence interval (CI) = 2.72-8.68], bioavailable testosterone (OR = 3.04, 95% CI = 1.81-5.10), free testosterone (OR = 3.08, 95% CI = 1.81-5.27) or SHBG (OR = 4.28, 95% CI = 2.52-7.27) had a risk of metabolic syndrome after adjusting for age, smoking, homeostasis model assessment of insulin resistance and body mass index. Total testosterone remained inversely associated with metabolic syndrome after further adjusting for SHBG (OR = 0.95, 95% CI = 0.92-0.99), while SHBG remained inversely associated with metabolic syndrome after further adjusting for total testosterone (OR = 0.99, 95% CI = 0.97-1.00). CONCLUSION: Total testosterone and SHBG are independent risk factors of metabolic syndrome. Prospective studies are needed to explore whether the association between sex hormones and metabolic syndrome was mediated by insulin resistance or obesity.

Effect of the Ruan Jian Qing Mai Recipe on Wound Healing in Diabetic Mice and Prediction of its Potential Targets.

BACKGROUND: The "Ruan Jian Qing Mai (RJQM) recipe" is a traditional Chinese medicine (TCM), which has been found to have significant curative effects on diabetic ulcers in the clinic for a long time. Previous research has shown that RJQM can improve diabetic skin wound healing and promote angiogenesis. However, the active ingredients of the RJQM recipe and its pharmacological mechanism of treatment for diabetic skin wound healing still remain unclear.This study aims to investigate the effect of the RJQM recipe on diabetic wound healing, and to identify the possible active ingredients and their mechanism. METHODS: First, a skin injury model was established in diabetic mice, and wound healing was evaluated by hematoxylin-eosin (HE) staining, quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and western blot analysis. Second, the chemical constituents of the RJQM recipe were analyzed and identified by ultra pressure liquid chromatography-mass spectrometry (UPLC-MS). Finally, the possible targets of drug treatment for diabetic skin injury were analyzed by network pharmacology and verified by in vitro experiments using cell culture. RESULTS: (1) In the full-thickness skin injury model, the skin wound healing rate and healing area were significantly increased in mice treated with the RJQM recipe compared with those of the model group. The results of immunofluorescence staining showed that the RJQM recipe could increase the expression of VEGF protein and promote the proliferation of vascular smooth muscle cells and the formation of microvessels, and RT-qPCR results found that the mRNA expression of angiogenesis-related factors in the RJQM recipe group was significantly higher than that in the model group. (2) A total of 25 compounds were identified by UPLC-MS. (3) According to the results of network pharmacology, the therapeutic effect of the RJQM recipe on diabetic skin injury may be related to S6 (quercetin), S1 (typhaneoside), S18 (isoliquiritigenin), protein kinase B-α (Akt1), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), insulin-like growth factor I receptor (IGF1R), vascular endothelial growth factor-a (VEGF-a), signal transducer and activator of transcription-3 (STAT3) and phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathways. Based on the predictions by network pharmacology, we proved that the drug could treat diabetic skin damage by activating the PI3K-Akt-VEGF signaling pathway. CONCLUSION: The RJQM recipe promotes the formation of granulation tissue during the process of wound healing and exerts a good therapeutic effect on diabetic skin wound healing.

Apoptosis related genes mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide immunotherapy in bladder cancer.

Apoptosis has been discovered as a mechanism of cell death. The purpose of this study is to identify the diagnostic signature factors related to bladder cancer (BLCA) through apoptosis related genes (ARGs). Clinicopathological parameters and transcriptomics data of 1,440 BLCA patients were obtained from 7 datasets (GSE13507, GSE31684, GSE32548, GSE32894, GSE48075, TCGA-BLCA, and IMvigor210). We first identified prognosis-related ARGs in BLCA and used them to construct two ARGs molecular subtypes by using consensus clustering algorithm. By using principal component analysis algorithms, a ARGscore was constructed to quantify the index of individualized patient. High ARGscore correlated with progressive malignancy and poor outcomes in BLCA patients. High ARGscore was associated with higher immune cell, higher estimate scores, higher stromal scores, higher immune scores, higher immune checkpoint, and lower tumor purity, which was consistent with the "immunity tidal model theory". Preclinically, BLCA immunotherapy cohorts confirmed patients with low ARGscore demonstrated significant therapeutic advantages and clinical benefits. These findings contribute to our understanding of ARGs and immunotherapy in BLCA. The ARGscore is a potentially useful tool to predict the prognosis and immunotherapy in BLCA.

Comprehensive assessment of emergency departments in county-level public hospitals: a multicenter descriptive cross-sectional study in Henan province, China.

Background: Emergency Departments (EDs) play a crucial role in providing immediate medical care, particularly in densely populated countries like China. While previous research has predominantly focused on well-funded urban hospitals, this study offers a comprehensive evaluation of EDs in county-level public hospitals in Henan province, China, aiming to identify disparities and challenges. Methods: A descriptive cross-sectional survey was conducted in 382 public hospitals across Henan province, China, from July 1, 2023, to August 1, 2023. Data were collected using an electronic questionnaire covering hospital information, human resources, infrastructure, clinical capabilities, and operational capacities. The data collection period for this survey spanned from January 1 to December 31, 2022. Results: With a remarkable 94.0% response rate, our study reveals significant disparities in county-level public hospitals compared to their provincial or municipal counterparts in Henan Province, China. County-level hospitals, which constitute 266 of the total 342 surveyed facilities, exhibit notable differences, including fewer doctors (median: 11 vs. 23, p < 0.0001) and nurses (median: 18 vs. 37, p < 0.0001). Additionally, a higher proportion of junior doctors is observed in these hospitals, while senior medical staff are more prevalent in provincial or municipal hospitals (p < 0.001). County-level hospitals also face resource challenges, with fewer beds in the emergency room (median: 4 vs. 7, p = 0.0003) and limited proficiency in advanced clinical procedures such as POCT, fiberoptic bronchoscopy, CRRT, ECMO, ultrasound equipment operation, and intraosseous infusion, with significant differences noted in most of these capabilities (p < 0.05). Operational capabilities show distinctions as well, with county-level hospitals managing a lower patient volume (median: 14,516 vs. 34,703, p < 0.0001) and handling fewer pre-hospital CPR cases (median: 33 vs. 89, p < 0.0001). In-hospital CPR success rates are also lower in county-level hospitals (median ROSC: 25.0% vs. 42.8%, p = 0.0068). Conclusion: While provincial or municipal hospitals enjoy better resources, county-level hospitals, especially crucial in less urbanized regions, face substantial challenges. Addressing these disparities is imperative, necessitating targeted investments, improved infrastructure, enhanced clinical training, and the adoption of innovations like telemedicine to enhance the quality of emergency care.

An inductive knowledge graph embedding via combination of subgraph and type information.

Conventional knowledge graph representation learn the representation of entities and relations by projecting triples in the knowledge graph to a continuous vector space. The vector representation increases the precision of link prediction and the efficiency of downstream tasks. However, these methods cannot process previously unseen entities during the knowledge graph evolution. In other words, the model trained on the source knowledge graph cannot be applied to the target knowledge graph containing new unseen entities. Recently, a few subgraph-based link prediction models obtained the inductive ability, but they all neglect semantic information. In this work, we propose an inductive representation learning model TGraiL which considers not only the topological structure but also semantic information. First, distance in the subgraph is used to encode the node's topological structure. Second, the projection matrix is used to encode the entity type information. Finally, both kinds of information are fused for training to acquire the ultimate vector representation of entities. The experimental results indicate that the model's performance has been significantly improved compared to the existing baseline models, demonstrating the method's effectiveness and superiority.

The ability of long non-coding RNA RP11-284N8.3 to predict the risk, the severity and 28-day mortality of adults with sepsis.

In a prior study, we identified a novel sepsis specific long noncoding RNAs (lncRNA) RP11-284N8.3, which may primarily participate in T cell activation and immune response during sepsis. However, the clinical significance of lncRNA RP11-284N8.3 in sepsis remains entirely unknown. This single-center prospective cohort study enrolled 147 adults with sepsis and 74 healthy controls (HCs) with matched age and sex between January 2021 and November 2022 at our hospital. Blood samples and clinical data were collected from HCs at enrollment and from adults with sepsis within 24 hours after admission. lncRNA RP11-284N8.3 expression was detected by RT-qPCR. The relative expression of lncRNA RP11-284N8.3 was significantly decreased in adults with sepsis compared to HCs (P < .0001), in adults with septic shock compared to adults without shock (P = .0012), and in 28-day deaths compared to 28-day survivors (P = .0006). receiver operating characteristic curves of lncRNA RP11-284N8.3 in predicting sepsis severity and 28-day mortality showed an area under the curve of 0.6570 (95% confidence interval [CI]: 0.5701-0.7440) and an area under the curve of 0.6765 (95% CI: 0.5809-0.7721), respectively. Multivariate logistic regression analysis revealed that lncRNA RP11-284N8.3 was an independent risk factor for 28-day mortality in adults with sepsis (odds ratio: 0.1057, 95% CI: 0.0115-0.7746, P = .0328). Low expression of lncRNA RP11-284N8.3 is correlated with increased risk, severity and 28-day mortality in adults with sepsis, and it may function as a potential biomarker to facilitate the diagnosis and management of sepsis.

The antinociceptive activity and mechanism of action of cannabigerol.

Cannabis has been used for centuries to treat pain. The antinociceptive activity of tetrahydrocannabinol (THC) or cannabidiol (CBD) has been widely studied. However, the antinociceptive effects of other cannabis components, such as cannabichromene (CBC) and cannabigerol (CBG), have rarely been revealed. The antinociceptive mechanism of CBG is not yet clear, so we investigated the antinociceptive effect of CBG on different pain models, and explored the mechanism of action of CBG to exert antinociceptive effects. In the current study, we compared the antinociceptive effects of CBC, CBD, and CBG on the carrageenan-induced inflammatory pain model in mice, and the results showed that CBG had a better antinociceptive effects through intraplantar administration. On this basis, we further investigated the antinociceptive effect of CBG on CIA-induced arthritis pain model and nerve pain model in mice, and found that CBG also relieved on both types of pain. Then, we explored the antinociceptive mechanism of CBG, which revealed that CBG can activate TRPV1 and desensitize it to block the transmission of pain signals. In addition, CBG can further activate CB2R, but not CB1R, to stimulate the release of ß-endorphin, which greatly promotes the antinociceptive effect. Finally, the safety test results showed that CBG had no irritating effect on the rabbits' skin, and it did not induce significant biochemical and hematological changes in mice. Transdermal delivery results also indicated that CBG has certain transdermal properties. Overall, this study indicates that CBG is promising for developing a transdermal dosage for pain management.

Pro­angiogenic activity of salvianolate and its potential therapeutic effect against acute cerebral ischemia.

Salvianolate (Sal) is a medicinal composition that is widely used in China for the treatment of coronary heart disease and angina pectoris. The aim of the present study was to investigate the potential macrophage-mediated pro-angiogenic effects of Sal in vitro. In addition, another aim was to explore the effects of Sal in a rat model of transient middle cerebral artery occlusion (tMCAO) along with the potential mechanism by which it promotes angiogenesis. In this study, human umbilical vein endothelial cells (HUVECs) and Raw264.7 macrophages in vitro, and a rat tMCAO model in vivo were used to detect the pro-angiogenic effect and mechanism of Sal. The results of in vitro experiments showed that the viability, migration and tube formation of HUVECs were promoted by the supernatant of Sal-treated Raw264.7 macrophages (s-Sal) but not by Sal alone. s-Sal also increased the levels of phosphorylated (p-)VEGFR-2, p-AKT and p-p38 MAPK in HUVECs while Sal alone did not. In vivo, treatment with Sal significantly reduced the cerebral infarction volume and neurological deficit scores in the rat tMCAO model. Similar to the mechanism observed in the in vitro experiments, Sal treatment upregulated the protein expression of VEGF and VEGFR-2, in addition to the phosphorylation of VEGFR-2, AKT and p38, in the brain tissues of the tMCAO model rats. In summary, the results of the present study suggest that the mechanism of Sal-mediated angiogenesis is associated with stimulation of the VEGF/VEGFR-2 signaling pathway by macrophages. This suggests the potential of Sal as a therapeutic option for the treatment of acute cerebral ischemic injury, which may act via the promotion of angiogenesis.