Discovery of a potential bladder cancer inhibitor CHNQD-01281 by regulating EGFR and promoting infiltration of cytotoxic T cells.

As one of the common malignancies that threaten human life, bladder cancer occurs frequently with a high mortality rate in the world, due to its invasion, recurrence and drug resistance. Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities, especially in the area of cancer. Brefeldin A (BFA) is a natural Arf-GEFs inhibitor, but due to the low aqueous solubility, strong toxicity, and poor bioavailability, it is urgent to conduct structural optimization research. Herein, a new BFA pyridine acrylate derivative CHNQD-01281 with improved solubility was prepared and found to exert moderate to strong antiproliferative activity on a variety of human cancer cell lines. It was noteworthy that CHNQD-01281 was most sensitive to two bladder cancer cell lines T24 and J82 (IC50 = 0.079 and 0.081 µmol/L) with high selectivity index (SI = 14.68 and 14.32), suggesting a superior safety to BFA. In vivo studies revealed that CHNQD-01281 remarkably suppressed tumor growth in a T24 nude mice xenograft model (TGI = 52.63%) and prolonged the survival time (ILS = 68.16%) in an MB49 allogeneic mouse model via inducing infiltration of cytotoxic T cells. Further mechanism exploration indicated that CHNQD-01281 regulated both EGFR/PI3K/AKT and EGFR/ERK pathways and mediated the chemotactic effect of chemokines on immune effector cells. Overall, CHNQD-01281 may serve as a potential therapeutic agent for bladder cancer through multiple mechanisms. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00246-w.

Exploring therapeutic targets and molecular mechanisms for treating diabetes mellitus-associated heart failure with Qishen Yiqi dropping pills: A network pharmacology and bioinformatics approach.

Diabetes mellitus (DM) and heart failure frequently coexist, presenting significant public health challenges. QiShenYiQi Dropping Pills (QSDP) are widely employed in the treatment of diabetes mellitus concomitant with heart failure (DM-HF). Nevertheless, the precise mechanisms underlying their efficacy have yet to be elucidated. Active ingredients and likely targets of QSDP were retrieved from the TCMSP and UniProt databases. Genes associated with DM-HF were pinpointed through searches in the GeneCards, OMIM, DisGeNET, and TTD databases. Differential genes connected to DM-HF were sourced from the GEO database. Enrichment analyses via gene ontology and Kyoto Encyclopedia of Genes and Genomes pathways, as well as immune infiltration assessments, were conducted using R software. Further analysis involved employing molecular docking strategies to explore the interactions between the identified targets and active substances in QSDP that are pertinent to DM-HF treatment. This investigation effectively discerned 108 active compounds and 257 targets relevant to QSDP. A protein-protein interaction network was constructed, highlighting 6 central targets for DM-HF treatment via QSDP. Gene ontology enrichment analysis predominantly linked these targets with responses to hypoxia, metabolism of reactive oxygen species, and cytokine receptor interactions. Analysis of Kyoto Encyclopedia of Genes and Genomes pathways demonstrated that these targets mainly participate in pathways linked to diabetic complications, such as AGE-RAGE signaling, dyslipidemia, arteriosclerosis, the HIF-1 signaling pathway, and the tumor necrosis factor signaling pathway. Further, immune infiltration analysis implied that QSDP's mechanism in treating DM-HF might involve immune-mediated inflammation and crucial signaling pathways. Additionally, molecular docking studies showed that the active substances in QSDP have strong binding affinities with these identified targets. This research presents a new model for addressing DM-HF through the use of QSDP, providing novel insights into incorporating traditional Chinese medicine (TCM) principles in the clinical treatment of DM-HF. The implications of these findings are substantial for both clinical application and further scientific inquiry.

Exploring the common mechanisms and biomarker ST8SIA4 of atherosclerosis and ankylosing spondylitis through bioinformatics analysis and machine learning.

Background: Atherosclerosis (AS) is a major contributor to cerebrovascular and cardiovascular events. There is growing evidence that ankylosing spondylitis is closely linked to AS, often co-occurring with it; however, the shared pathogenic mechanisms between the two conditions are not well understood. This study employs bioinformatics approaches to identify common biomarkers and pathways between AS and ankylosing spondylitis. Methods: Gene expression datasets for AS (GSE100927, GSE28829, GSE155512) and ankylosing spondylitis (GSE73754, GSE25101) were obtained from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) and module genes for AS and ankylosing spondylitis were identified using the Limma R package and weighted gene co-expression network analysis (WGCNA) techniques, respectively. The machine learning algorithm SVM-RFE was applied to pinpoint promising biomarkers, which were then validated in terms of their expression levels and diagnostic efficacy in AS and ankylosing spondylitis, using two separate GEO datasets. Furthermore, the interaction of the key biomarker with the immune microenvironment was investigated via the CIBERSORT algorithm, single-cell analysis was used to identify the locations of common diagnostic markers. Results: The dataset GSE100927 contains 524 DEGs associated with AS, whereas dataset GSE73754 includes 1,384 genes categorized into modules specific to ankylosing spondylitis. Analysis of these datasets revealed an overlap of 71 genes between the DEGs of AS and the modular genes of ankylosing spondylitis. Utilizing the SVM-RFE algorithm, 15 and 24 central diagnostic genes were identified in datasets GSE100927 and GSE73754, respectively. Further validation of six key genes using external datasets confirmed ST8SIA4 as a common diagnostic marker for both conditions. Notably, ST8SIA4 is upregulated in samples from both diseases. Additionally, ROC analysis confirmed the robust diagnostic utility of ST8SIA4. Moreover, analysis through CIBERSORT suggested an association of the ST8SIA4 gene with the immune microenvironment in both disease contexts. Single-cell analysis revealed that ST8SIA4 is primarily expressed in Macrophages, Monocytes, T cells, and CMPs. Conclusion: This study investigates the role of ST8SIA4 as a common diagnostic gene and the involvement of the lysosomal pathway in both AS and ankylosing spondylitis. The findings may yield potential diagnostic biomarkers and offer new insights into the shared pathogenic mechanisms underlying these conditions.

Emodin suppresses mast cell migration via modulating the JAK2/STAT3/JMJD3/CXCR3 signaling to prevent cystitis.

AIMS: This study aimed to determine the preventive effects of emodin on cyclophosphamide (CYP)-induced cystitis and to explore the molecular mechanism. METHODS: In vivo, mice were modeled by CYP. Before a half hour of CYP treatment, Jumonji domain-containing protein-3 (JMJD3) inhibitors (GSK-J4) and emodin were used to treat CYP model mice. Bladder samples were stained for hematoxylin-eosin and toluidine blue. Next, JMJD3 was quantified by immunofluorescence staining, RT-PCR, and Western blot. CXCR3 was quantified by Western blot and ELISA. In vitro, before stimulated by lipopolysaccharide (LPS), human bladder smooth muscle cells (hBSMCs) were transfected with pcDNA3.1-JMJD3 plasmids, shRNA-JMJD3 plasmids or pretreated with emodin. Collected cells to detect JMJD3 and CXCR3 ligands again; collected supernatant of culture for Transwell assay. Finally, as the JAK2 inhibitor, AG490 was used to pretreat LPS-induced hBSMCs. Western blot was performed to quantify proteins. RESULTS: Emodin inhibited mast cell migration and suppressed the expression of JMJD3, CXCR3, and CXCR3 ligands, not only in vivo but also in vitro. The pharmacological effects of emodin were similar to GSK-J4 or JMJD3 inhibition. In addition, emodin significantly downregulated the phosphorylation of JAK2 and STAT3, and inhibited JMJD3/CXCR3 axis transduction like AG490. CONCLUSION: Emodin has a preventive effect on cystitis by inhibiting mast cell migration through inhibition of the JAK2/STAT3/JMJD3/CXCR3 signaling pathway.

Identification of common mechanisms and biomarkers for dermatomyositis and atherosclerosis based on bioinformatics analysis.

BACKGROUND: Dermatomyositis (DM) manifests as an autoimmune and inflammatory condition, clinically characterized by subacute progressive proximal muscle weakness, rashes or both along with extramuscular manifestations. Literature indicates that DM shares common risk factors with atherosclerosis (AS), and they often co-occur, yet the etiology and pathogenesis remain to be fully elucidated. This investigation aims to utilize bioinformatics methods to clarify the crucial genes and pathways that influence the pathophysiology of both DM and AS. METHOD: Microarray datasets for DM (GSE128470, GSE1551, GSE143323) and AS (GSE100927, GSE28829, GSE43292) were retrieved from the Gene Expression Omnibus (GEO) database. The weighted gene co-expression network analysis (WGCNA) was used to reveal their co-expressed modules. Differentially expression genes (DEGs) were identified using the "limma" package in R software, and the functions of common DEGs were determined by functional enrichment analysis. A protein-protein interaction (PPI) network was established using the STRING database, with central genes evaluated by the cytoHubba plugin, and validated through external datasets. Immune infiltration analysis of the hub genes was conducted using the CIBERSORT method, along with Gene Set Enrichment Analysis (GSEA). Finally, the NetworkAnalyst platform was employed to examine the transcription factors (TFs) responsible for regulating pivotal crosstalk genes. RESULTS: Utilizing WGCNA analysis, a total of 271 overlapping genes were pinpointed. Subsequent DEG analysis revealed 34 genes that are commonly found in both DM and AS, including 31 upregulated genes and 3 downregulated genes. The Degree Centrality algorithm was applied separately to the WGCNA and DEG collections to select the 15 genes with the highest connectivity, and crossing the two gene sets yielded 3 hub genes (PTPRC, TYROBP, CXCR4). Validation with external datasets showed their diagnostic value for DM and AS. Analysis of immune infiltration indicates that lymphocytes and macrophages are significantly associated with the pathogenesis of DM and AS. Moreover, GSEA analysis suggested that the shared genes are enriched in various receptor interactions and multiple cytokines and receptor signaling pathways. We coupled the 3 hub genes with their respective predicted genes, identifying a potential key TF, CBFB, which interacts with all 3 hub genes. CONCLUSION: This research utilized comprehensive bioinformatics techniques to explore the shared pathogenesis of DM and AS. The three key genes, including PTPRC, TYROBP, and CXCR4, are related to the pathogenesis of DM and AS. The central genes and their correlations with immune cells may serve as potential diagnostic and therapeutic targets.

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) is among the most difficult malignancies to treat. Type III collagen (COL3A1) can affect the progression and chemoresistance development of NSCLC. We herein explored the mechanism that drives COL3A1 dysregulation in NSCLC. Potential RNA-binding proteins (RBPs) and transcription factors (TFs) that could bind to COL3A1 were searched by bioinformatics. mRNA expression was detected by quantitative PCR. Protein expression was evaluated using immunoblotting and immunohistochemistry. The effects of the variables were assessed by gauging cell growth, invasiveness, migratory capacity, apoptosis, and cisplatin (DDP) sensitivity. The direct YY1/COL3A1 relationship was confirmed by ChIP and luciferase reporter experiments. Xenograft experiments were done to examine COL3A1's function in DDP efficacy. COL3A1 showed enhanced expression in DDP-resistant NSCLC. In H460/DDP and A549/DDP cells, downregulation of COL3A1 exerted inhibitory functions in cell growth, invasiveness, and migration, as well as promoting effects on cell DDP sensitivity and apoptosis. Mechanistically, ELAV-like RNA binding protein 1 (ELAVL1) enhanced the mRNA stability and expression of COL3A1, and Yin Yang 1 (YY1) promoted the transcription and expression of COL3A1. Furthermore, upregulation of COL3A1 reversed ELAVL1 inhibition- or YY1 deficiency-mediated functions in DDP-resistant NSCLC cells. Additionally, COL3A1 downregulation enhanced the anti-tumor efficacy of DDP in vivo. Our investigation demonstrates that COL3A1 upregulation, induced by both RBP ELAVL1 and TF YY1, exerts important functions in phenotypes of NSCLC cells with DDP resistance, offering an innovative opportunity in the treatment of drug-resistant NSCLC.

Triptolide restrains the growth, invasion, stemness, and glycolysis of non-small cell lung cancer cells by PFKFB2-mediated PI3K/AKT pathway.

Triptolide (TP) has been found to have anti-tumor effects. However, more potential molecular mechanisms of TP in the progression of non-small cell lung cancer (NSCLC) deserve further investigation. Cell proliferation, apoptosis, invasion, and stemness were detected by cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay, and sphere formation assay. Cell glycolysis was evaluated by corresponding assay kits. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) expression was measured by western blot (WB), qRT-PCR and immunohistochemical staining. PI3K/AKT pathway-related markers were determined by WB. Besides, xenograft tumor model was conducted to evaluate the anti-tumor effect of TP in NSCLC. Our results revealed that TP treatment suppressed NSCLC cell proliferation, invasion, stemness, glycolysis, and enhanced apoptosis. PFKFB2 was upregulated in NSCLC tissues and cells, and its expression was decreased by TP. PFKFB2 knockdown restrained NSCLC cell functions, and its overexpression also eliminated TP-mediated NSCLC cell functions inhibition. TP decreased PFKFB2 expression to inactivate PI3K/AKT pathway. Moreover, PI3K/AKT pathway inhibitor LY294002 also could reverse the promoting effect of PFKFB2 on NSCLC cell functions. In addition, TP suppressed NSCLC tumorigenesis by inhibiting PFKFB2/PI3K/AKT pathway. In conclusion, TP exerted anti-tumor role in NSCLC, which was achieved by reducing PFKFB2 expression to inactivate PI3K/AKT pathway.

Emodin inhibits bladder inflammation and fibrosis in mice with interstitial cystitis by regulating JMJD3.

PURPOSE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating urological chronic pelvic pain condition. In search of a potential treatment, we investigated the effect of emodin on IC/BPS inflammation and fibrosis, and explore the potential mechanism. METHODS: An experimental model of interstitial cystitis was induced by cyclophosphamide, and human bladder smooth muscle cells were treated with lipopolysaccharide to establish the cell model in vitro. In both models, inflammation- and fibrosis-related indexes were measured after emodin administration. Furthermore, the specific antagonists were used to dig for the mechanisms underlying the response to emodin treatment. RESULTS: Emodin significantly ameliorated management of cystitis, reduced the amount of inflammatory cytokines (tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, interleukin-8, and interleukin-6) in models, as well as reducing the synthesis of fibrosis marker including collagen1, collagen3, vimentin, fibronectin and α-smooth muscle actin. Further mechanism studies demonstrated that emodin inhibited inflammatory reaction and fibrosis through blocking lysine-specific demethylase 6B (JMJD3) expression via JAK/STAT, NF-κB and TGF-ß/SMAD pathways. CONCLUSIONS: Our study reveals the critical role of emodin-JMJD3 signaling in interstitial cystitis by regulating inflammation, fibrosis, and extracellular matrix deposition in cells and tissues, and these findings provide an avenue for effective treatment of patients with cystitis.

Colchicine efficacy comparison at varying time points in the peri-operative period for coronary artery disease: a systematic review and meta-analysis of randomized controlled trials.

Objectives: Over the years, it has been found that colchicine offers substantial benefits in secondary prevention in patients with coronary artery disease (CAD). We studied the effects of colchicine timing because there are no guidelines about when to provide it during the perioperative period for patients with CAD. Methods: Up to January 1, 2023, seven electronic literature databases were screened (including three English databases and four Chinese databases). Randomized controlled trials included only treatment with colchicine in the perioperative period of CAD. The Cochrane Evaluation Tool was used to judge the risk of bias in research. Statistical analysis was performed by Stata 16.0 software. Results: We evaluated twelve studies that found colchicine to be effective in decreasing the occurrence of major adverse cardiac events (MACEs) (p < 0.00001), but it also raised the rate of adverse events (p = 0.001). Subgroup analysis showed the same benefit in lowering the incidence of MACE with continuous administration of a total daily dose of 0.5 mg postoperatively while minimizing drug-related side effects in the patients (p = 0.03). When it comes to preventing surgical stroke occurrences, postoperative administration is more effective (p = 0.006). While the effect of simultaneous preoperative and postoperative administration was marginally greater than other periods in reducing postoperative hs-CRP levels (p = 0.02). Conclusion: Colchicine, a traditional anti-inflammatory drug, also reduces the risk of MACE by reducing inflammation after PCI. Administration at different periods had no significant effect on decreasing the occurrence of MACE, but when administered postoperatively, we advise continuous administration with a total daily dose of 0.5 mg to obtain the same benefit while minimizing the drug's side effects. Postoperative administration is the better measure to prevent postoperative stroke events. Due to the effective anti-inflammatory effect of colchicine, we recommend its use as early as possible in the perioperative period and its continued use at low doses in the postoperative period. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=316751, identifier CRD42022316751.

Association between psychological stress, anxiety and oral health status among college students during the Omicron wave: a cross-sectional study.

BACKGROUND: Within 3 years of the COVID-19 pandemic, increasing interest has been given to its potential influence on health status due to lockdowns caused by the pandemic. However, the impact is inadequately understood, especially for college students. This study aimed to investigate the potential association between psychological stress, anxiety and oral health of college students during the Omicron wave of the COVID-19 pandemic. METHODS: An online survey with measurements of psychological stress, anxiety and oral health was completed by 1770 Chinese college students. The Perceived Stress Scale-14 (PSS-14) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure psychological stress and anxiety, respectively. Oral health status was self-reported including toothache, gingival bleeding, and oral ulcer. Multivariable logistic regressions were performed to determine underlying associations for outcome variables. Structural equation modeling (SEM) was performed to confirm the relationship between mental and oral health status. RESULTS: Of the 1770 subjects, 39.2% presented high psychological stress and only 41.2% expressed no anxiety. A significant association was found between psychological stress, anxiety and oral health status. Anxiety has significant impacts on toothache (OR = 0.36; 95%CI: 0.23-0.55; p < 0.01), gingival bleeding (OR = 0.43; 95%CI: 0.29-0.65; p < 0.01), and oral ulcer (OR = 0.54; 95%CI: 0.36-0.80; p < 0.01). Anxiety significantly mediated the association between psychological stress and self-reported oral symptoms. CONCLUSIONS: Anxiety may be a significant risk indicator for mental health among college students and demonstrates a significant relationship with the occurrence of self-reported oral symptoms. Concerns about academic and life changes caused by the pandemic were the two most significant sources of stress.

Deep Learning Based Traffic Prediction Method for Digital Twin Network.

Network traffic prediction (NTP) can predict future traffic leveraging historical data, which serves as proactive methods for network resource planning, allocation, and management. Besides, NTP can also be applied for load generation in simulated and emulated as well as digital twin networks (DTNs). This paper focuses on accurately predicting background traffic matrix (TM) of typical local area network (LAN) for traffic synchronization in DTN. A survey is firstly conducted on DTN, conventional model, and deep learning based NTP methods. Then, as the major contribution, a linear feature enhanced convolutional long short-term memory (ConvLSTM) model based NTP method is proposed for LAN. An autoregressive unit is integrated into the ConvLSTM model to improve its linear prediction ability. In addition, this paper further optimizes the proposed model from both spatial and channel-wise dimensions. Particularly, a traffic pattern attention (TPA) block and a squeeze & excitation (SE) block are derived and added to the enhanced ConvLSTM (eConvLSTM) model. Comparative experiments demonstrate that the eConvLSTM model outperforms all the baselines. It can improve the prediction accuracy by reducing the mean square error (MSE) up to 10.6% for one-hop prediction and 16.8% for multi-hops prediction, compared to the legacy CovnLSTM model, with still satisfying the efficiency requirements. The further enhancement of the eConvLSTM model can additionally reduce the MSE about 2.1% for one-hop prediction and 4.2% for multi-hops prediction, with slightly degrading efficiency. The proposed eConvLSTM model based NTP method can play a vital role on DTN traffic synchronization.

Antireflective GaN Nanoridge Texturing by Metal-Assisted Chemical Etching via a Thermally Dewetted Pt Catalyst Network for Highly Responsive Ultraviolet Photodiodes.

Antireflective (AR) surface texturing is a feasible way to boost the light absorption of photosensitive materials and devices. As a plasma-free etching method, metal-assisted chemical etching (MacEtch) has been employed for fabricating GaN AR surface texturing. However, the poor etching efficiency of typical MacEtch hinders the demonstration of highly responsive photodetectors on an undoped GaN wafer. In addition, GaN MacEtch requires metal mask patterning by lithography, which leads to a huge processing complexity when the dimension of GaN AR nanostructure scales down to the submicron range. In this work, we have developed a facile texturing method of forming a GaN nanoridge surface on an undoped GaN thin film by a lithography-free submicron mask-patterning process via thermal dewetting of platinum. The nanoridge surface texturing effectively reduces the surface reflection in the ultraviolet (UV) regime, which can be translated to a 6-fold enhancement in responsivity (i.e., 115 A/W) of the photodiode at 365 nm. The results demonstrated in this work show that MacEtch can offer a viable route for enhanced UV light-matter interaction and surface engineering in GaN UV optoelectronic devices.

Emodin inhibits bladder inflammation and fibrosis in mice with interstitial cystitis by regulating JMJD3

Purpose: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating urological chronic pelvic pain condition. In search of a potential treatment, we investigated the effect of emodin on IC/BPS inflammation and fibrosis, and explore the potential mechanism. Methods: An experimental model of interstitial cystitis was induced by cyclophosphamide, and human bladder smooth muscle cells were treated with lipopolysaccharide to establish the cell model in vitro. In both models, inflammation- and fibrosis-related indexes were measured after emodin administration. Furthermore, the specific antagonists were used to dig for the mechanisms underlying the response to emodin treatment. Results: Emodin significantly ameliorated management of cystitis, reduced the amount of inflammatory cytokines (tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, interleukin-8, and interleukin-6) in models, as well as reducing the synthesis of fibrosis marker including collagen1, collagen3, vimentin, fibronectin and α-smooth muscle actin. Further mechanism studies demonstrated that emodin inhibited inflammatory reaction and fibrosis through blocking lysine-specific demethylase 6B (JMJD3) expression via JAK/STAT, NF-κB and TGF-ß/SMAD pathways. Conclusions: Our study reveals the critical role of emodin-JMJD3 signaling in interstitial cystitis by regulating inflammation, fibrosis, and extracellular matrix deposition in cells and tissues, and these findings provide an avenue for effective treatment of patients with cystitis.

High Performance Flexible Visible-Blind Ultraviolet Photodetectors with Two-Dimensional Electron Gas Based on Unconventional Release Strategy.

Interdigitated photodetectors (IPDs) based on the two-dimensional electron gas (2DEG) at the AlGaN/GaN interface have gained prominence as high sensitivity ultraviolet (UV) PDs due to their excellent optoelectronic performance. However, most 2DEG-IPDs have been built on rigid substrates, thus limiting the use of 2DEG-IPDs in flexible and wearable applications. In this paper, we have demonstrated high performance flexible AlGaN/GaN 2DEG-IPDs using AlGaN/GaN 2DEG heterostructure membranes created from 8 in. AlGaN/GaN on insulator (AlGaN/GaNOI) substrates. The interdigitated AlGaN/GaN heterostructure has been engineered to reduce dark current by disconnecting the conductive channel at the heterostructure interface. Photocurrent has been also boosted by the escaped carriers from the 2DEG layer. Therefore, the utilization of a 2DEG layer in transferrable AlGaN/GaN heterostructure membranes offers great promises for high performance flexible 2DEG-IPDs for advanced UV detection systems that are critically important in myriad biomedical and environmental applications.

ß-Adrenoceptor regulates contraction and inflammatory cytokine expression of human bladder smooth muscle cells via autophagy under pathological hydrostatic pressure.

AIMS: Abnormal intravesical pressure created by partial bladder outlet obstruction (PBOO) triggered the progression from chronic inflammation to fibrosis, initiating structural and functional alterations of bladder. To elucidate the underlying mechanisms of contraction and inflammatory response, we investigated the isolated human bladder smooth muscle cells (hBSMC) under pathological hydrostatic pressure (HP) mimicking the in vivo PBOO condition. METHODS: hBSMCs were subjected to HP of 200 cm H2 O to explore the contraction and inflammatory cytokine expression of hBSMC treated with ß-adrenoceptors (ADRBs) and/or autophagy signaling pathway agonists and/or antagonists. RESULTS: We showed that pathological HP induced the release of the proinflammatory cytokines, including monocyte chemotactic protein-1, regulated upon activation normal T cell expressed and secreted factor, and interleukin-6. HP downregulated ADRB2 and ADRB3 expression, which was consistent with the results of the PBOO rat model. ADRB2 or autophagy activation repressed pathological HP-induced proinflammatory cytokine production. ADRB2, ADRB3 or autophagy activation ameliorated the HP-enhanced contraction. The increased contraction and autophagy activity by ADRB2 agonist under HP conditions were reversed by pretreatment with antagonists of adenosine monophosphate-activated protein kinase (AMPK). CONCLUSION: The present study provides evidence that the ADRB3 agonist suppresses hBSMC contraction under pathological HP conditions. Moreover, the ADRB2 agonist negatively regulates the contraction and inflammatory response of hBSMCs through AMPK/mTOR-mediated autophagy under pathological HP. These findings provide a theoretical basis for potential therapeutic strategies for patients with PBOO.

Can baseline C-reactive protein level predict functional outcome in acute ischaemic stroke? A meta-analysis.

BACKGROUND: The association between elevated C-reactive protein (CRP) level and poor functional outcome is conflicting in acute ischaemic stroke (AIS) patients. This meta-analysis sought to investigate the value of elevated CRP level in predicting poor functional outcome in AIS patients. MATERIAL AND METHODS: A systematically literature search was performed in PubMed and Embase databases up to 31 October 2019. Prospective and retrospective studies evaluating the association between elevated CRP level and poor functional outcome (defined by the modified Rankin scale ≥3) beyond 3 months after AIS were included. RESULTS: Ten studies with a total of 8087 AIS patients were identified in this meta-analysis. When compared with reference low CRP level, the highest CRP level was associated with an increased risk of poor functional outcome (multivariate-adjusted hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.63-2.44) in a random effect model. Sensitivity analysis further confirmed the significance of CRP elevation for predicting poor functional outcome after AIS. CONCLUSIONS: Elevated CRP level is significantly associated with poor functional outcome in patients with AIS. Baseline CRP level has potential to improve risk stratification of function outcome in AIS patients.

Low-grade fever during COVID-19 convalescence: A report of 3 cases.

BACKGROUND: Low-grade fever during convalescence is an atypical symptom of coronavirus disease 2019 (COVID-19). Reports of such cases are rare, and the mechanism and outcome of low-grade fever during COVID-19 convalescence are not completely clear. We report 3 cases with low-grade fever during COVID-19 convalescence and highlight the main clinical, radiographic, and laboratory characteristics, thereby increasing the level of expertise in the clinical management of COVID-19 during convalescence and facilitating individualized decision-making. CASE SUMMARY: We describe 3 patients with COVID-19, two females aged 62 and 66 years and a male 55 years, who had low-grade fever during COVID-19 convalescence. All 3 patients had no other discomfort or comorbidities during low-grade process. Lesions on computed tomography in all 3 patients had resolved during this period. Two patients tested negative on two consecutive severe acute respiratory syndrome coronavirus 2 tests with an interval of at least 24 h between tests. Body temperature in all 3 patients returned to normal after several days without treatment, and fever recurrence was not observed. CONCLUSION: Enhancing the knowledge of low-grade fever during COVID-19 convalescence may increase the expertise in the delivery of optimal healthcare services.

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

ß-Adrenoceptor signaling regulates proliferation and contraction of human bladder smooth muscle cells under pathological hydrostatic pressure.

BACKGROUND: Partial bladder outlet obstruction (PBOO) promotes bladder detrusor hyperplasia, increases bladder pressure, and decreases bladder compliance. To extensively explore its underlying mechanism, our study aimed to investigate the effect of pathological hydrostatic pressure on human bladder smooth muscle cell (hBSMC) proliferation and contraction through ß-adrenoceptor (ADRB) signaling in vitro. METHODS: hBSMCs were subjected to pathological hydrostatic pressure (100 cm H2 O) to investigate the effect of ADRBs on the proliferation and contraction of hBSMCs treated with its agonists and/or antagonists. RESULTS: Firstly, exposure to 100 cm H2 O hydrostatic pressure significantly upregulated the expression of α-smooth muscle actin (α-SMA) in hBSMCs at 6 hours, and promoted cell proliferation at 24 hours. When subjected to hydrostatic pressure alone, hBSMCs treated with ADRB2 and ADRB3 agonists for 6 hours inhibited α-SMA expression compared with untreated cells. By contrast, hBSMCs treated with ADRB2 agonists for 24 hours suppressed cell proliferation compared with untreated cells. The two classical pathways of ADRB, protein kinase A (PKA), and exchange factor directly activated by cAMP (EPAC) inhibited the contraction of hBSMCs under hydrostatic pressure via regulating mothers against decapentaplegic homolog 2 (SMAD2) activity. The proliferation of hBSMCs was mainly regulated by the EPAC pathway through extracellular signal-regulated kinase 1/2 (ERK1/2) activity. CONCLUSION: The contraction of hBSMCs under hydrostatic pressure was regulated by ADRB2 and ADRB3 via the PKA/EPAC-SMAD2 pathway, and the proliferation of hBSMCs was regulated by ADRB2 via the EPAC-ERK1/2 pathway. Compared with ADRB3, ADRB2 played a predominant role under pathological hydrostatic pressure. These findings markedly uncovered the underlying mechanism of ADRBs in PBOO and provided new insights into the efficient treatment of patients with PBOO.

An Effective Meta-analysis of Magnetic Stimulation Therapy for Urinary Incontinence.

Magnetic stimulation (MS) is a novel approach for treating urinary incontinence (UI), but its applicability remains unclear. This systematic review and meta-analysis were conducted to evaluate the effects of MS treatment on UI. A literature search was performed in EMBASE, PubMed and Cochrane Library (from May 2018 to August 2018), and all randomized control trials (RCTs) published in English were screened to determine whether they met the inclusion criteria. A manual search of the reference lists of the retrieved studies was also performed. Eleven studies involving 612 patients were included in this review. According to the results of the meta-analysis, MS therapy relieved UI symptoms evaluated using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score (mean difference [MD] -3.03, 95% CI -3.27 to -2.79). In addition, the frequency of UI in the MS treatment group was also alleviated compared with sham group (MD -1.42, 95% CI -2.15 to -0.69). Finally, MS treatment improved the quality of life of patients with UI (standardized mean difference [SMD] -1.00, 95% CI -1.24 to -0.76). Our meta-analysis preliminarily indicates that MS treatment is an effective therapeutic modality for patients with UI. Nevertheless, additional large, high quality RCTs with a longer follow-up period that use consistent stimulation methods and analyse comparable outcomes are required to validate the efficacy.