Involvement Of Pathway Research Articles

Diagnostic potential of NRG1 in benign nerve sheath tumors and its influence on the PI3K-Akt signaling and tumor immunity

ObjectiveBenign nerve sheath tumors (BNSTs) present diagnostic challenges due to their heterogeneous nature. This study aimed to determine the significance of NRG1 as a novel diagnostic biomarker in BNST, emphasizing its involvement in the PI3K-Akt pathway and tumor immune regulation.MethodsDifferential genes related to BNST were identified from the GEO database. Gene co-expression networks, protein-protein interaction networks, and LASSO regression were utilized to pinpoint key genes. The CIBERSORT algorithm assessed immune cell infiltration differences, and functional enrichment analyses explored BNST signaling pathways. Clinical samples helped establish PDX models, and in vitro cell lines to validate NRG1’s role via the PI3K-Akt pathway.ResultsNine hundred eighty-two genes were upregulated, and 375 downregulated in BNST samples. WGCNA revealed the brown module with the most significant difference. Top hub genes included NRG1, which was also determined as a pivotal gene in disease characterization. Immune infiltration showed significant variances in neutrophils and M2 macrophages, with NRG1 playing a central role. Functional analyses confirmed NRG1’s involvement in key pathways. Validation experiments using PDX models and cell lines further solidified NRG1’s role in BNST.ConclusionNRG1 emerges as a potential diagnostic biomarker for BNST, influencing the PI3K-Akt pathway, and shaping the tumor immune microenvironment.

Doxorubicin alters G-protein coupled receptor-mediated vasocontraction in rat coronary arteries.

Doxorubicin (Doxo)-associated cardio-and vasotoxicity has been recognised as a serious complication of cancer chemotherapy. The purpose of this novel paper was to determine the effect of Doxo on G-protein coupled receptor (GPCR)-mediated vasocontraction located on vascular smooth muscle cells. Rat left anterior descending artery segments were incubated for 24h with 0.5 µM Doxo. The vasocontractile responses by activation of endothelin receptor type A (ETA) and type B (ETB), serotonin receptor 1B (5-HT1B) and thromboxane A2 prostanoid receptor (TP) were investigated by a sensitive myography using specific agonists, while the specificity of the GPCR agonists was verified by applying selective antagonists (i.e. ETA and ETB agonist = 10- 14-10- 7.5 M endothelin-1 (ET-1); ETA antagonist = 10 µM BQ123; ETB agonists = 10- 14-10- 7.5 M sarafotoxin 6c (S6c) and ET-1; ETB antagonist = 0.1 µM BQ788; 5-HT1B agonist = 10- 12-10- 5.5 M 5-carboxamidotryptamine (5-CT); 5-HT1B antagonist = 1 µM GR55562; TP agonist = 10- 12-10- 6.5 M U46619; TP antagonist = 1 µM Seratrodast). Our results show that 0.5 µM Doxo incubation of LAD segments leads to an increased VSMC vasocontraction through the ETB, 5-HT1B and TP GPCRs, with a 2.2-fold increase in ETB-mediated vasocontraction at 10- 10.5 M S6c, a 2.0-fold increase in 5-HT1B-mediated vasocontraction at 10- 5.5 M 5-CT, and a 1.3-fold increase in TP-mediated vasocontraction at 10- 6.5 M U46619. Further studies unravelling the involvement of intracellular GPCR signalling pathways will broaden our understanding of the Doxo-induced vasotoxicity, and thus pave the way to mitigate the adverse effects by potential implementation of adjunct therapy options.

Metabolomic biomarkers for (R, S)-ketamine and (S)-ketamine in treatment-resistant depression and healthy controls: A systematic review.

Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Comprehensive analysis of genetic associations and single-cell expression profiles reveals potential links between migraine and multiple diseases: a phenome-wide association study.

Migraine is a common neurological disorder that affects more than one billion people worldwide. Recent genome-wide association studies have identified 123 genetic loci associated with migraine risk. However, the biological mechanisms underlying migraine and its relationships with other complex diseases remain unclear. We performed a phenome-wide association study (PheWAS) using UK Biobank data to investigate associations between migraine and 416 phenotypes. Mendelian randomization was employed using the IVW method. For loci associated with multiple diseases, pleiotropy was tested using MR-Egger. Single-cell RNA sequencing data was analyzed to profile the expression of 73 migraine susceptibility genes across brain cell types. qPCR was used to validate the expression of selected genes in microglia. PheWAS identified 15 disorders significantly associated with migraine, with one association detecting potential pleiotropy. Single-cell analysis revealed elevated expression of seven susceptibility genes (including ZEB2, RUNX1, SLC24A3, ANKDD1B, etc.) in brain glial cells. And qPCR confirmed the upregulation of these genes in LPS-treated microglia. This multimodal analysis provides novel insights into the link between migraine and other diseases. The single-cell profiling suggests the involvement of specific brain cells and molecular pathways. Validation of gene expression in microglia supports their potential role in migraine pathology. Overall, this study uncovers pleiotropic relationships and the biological underpinnings of migraine susceptibility.

Genome-wide analysis of PvMADS in common bean and functional characterization of PvMADS31 in Arabidopsis thaliana as a player in abiotic stress responses.

Changing climatic conditions with rising temperatures and altered precipitation patterns pose significant challenges to agricultural productivity, particularly for common bean crops. Transcription factors (TFs) are crucial regulators that can mitigate the impact of biotic and abiotic stresses on crop production. The MADS-box TFs family has been implicated in various plant physiological processes, including stress-responsive mechanisms. However, their role in common bean and their response to stressful conditions remain poorly understood. Here, we identified 35 MADS-box gene family members in common bean, with conserved MADS-box domains and other functional domains. Gene duplication events were observed, suggesting the significance of duplication in the evolutionary development of gene families. The analysis of promoter regions revealed diverse elements, including stress-responsive elements, indicating their potential involvement in stress responses. Notably, PvMADS31, a member of the PvMADS-box gene family, demonstrated rapid upregulation under various abiotic stress conditions, including NaCl, polyethylene glycol, drought, and abscisic acid (ABA) treatments. Transgenic plants overexpressing PvMADS31 displayed enhanced lateral root development, root elongation, and seed germination under stress conditions. Furthermore, PvMADS31 overexpression in Arabidopsis resulted in improved drought tolerance, likely attributed to the enhanced scavenging of ROS and increased proline accumulation. These findings suggest that PvMADS31 might play a crucial role in modulating seed germination, root development, and stress responses, potentially through its involvement in auxin and ABA signaling pathways. Overall, this study provides valuable insights into the potential roles of PvMADS-box genes in abiotic stress responses in common bean, offering prospects for crop improvement strategies to enhance resilience under changing environmental conditions.

Tert‐ Butyl nitrite promoted visible light induced steric‐hindrance‐regulated concurrent cross‐coupling and regioselective nitration of 3‐alkylidene‐2‐ oxindoles

tert‐ butylnitrite (TBN) promoted visible‐light‐induced one‐pot C‐N cross coupling reaction of 3‐alkylidene‐2‐oxindoles with benzene‐1,2‐diamine has been explored. Simultaneously, the indoline motif of 3‐alkylidene‐2‐oxindoles as well as 3‐ylidene oxindoles are regioselectively nitrated at C‐6 position by in‐situ formed NO2 radical. (E)‐3‐(2‐(aryl)‐2‐oxoethylidene)oxindole and (E)‐3‐ylidene oxindole, produce distinct nitrated diastereomeric coupling products, a phenomenon influenced by the steric bulk of the functional group. The experimental findings suggest the potential involvement of a radical pathway in this reaction.

Delving into the Role of Receptor-like Tyrosine Kinase (RYK) in Cancer: In Silico Insights into Its Diagnostic and Prognostic Utility

The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.

High factor VIII concentrations interfere with glycoprotein VI-mediated platelet activation in vitro

BackgroundThe recruitment of activated factor VIII (FVIII) at the surface of activated platelets is a key step toward the burst of thrombin and fibrin generation during thrombus formation at the site of vascular injury. It involves binding to phosphatidylserine and, possibly, to fibrin-bound αIIbβ3. Seminal work had shown the binding of FVIII to resting platelets, yet without a clear understanding of a putative physiological relevance. ObjectivesTo characterize the effects of FVIII-platelet interaction and its potential modulation of platelet function. MethodsFVIII was incubated with washed platelets. The effects on platelet activation (spontaneously or triggered by collagen and thrombin) were studied by flow cytometry and light transmission aggregometry. We explored the involvement of downstream pathways by studying phosphorylation profiles (Western blot). The FVIII-glycoprotein (GP) VI interaction was investigated by ELISA, confocal microscopy, and proximity ligation assay. ResultsFVIII bound to the surface of resting and activated platelets in a dose-dependent manner. FVIII at supraphysiological concentrations did not induce platelet activation but rather specifically inhibited collagen-induced platelet aggregation and altered glycoprotein VI (GPVI)-dependent phosphorylation. FVIII, freed of its chaperone protein von Willebrand factor (VWF), interacted in close proximity with GPVI at the platelet surface. ConclusionWe showed that VWF-free FVIII binding to, or close to, GPVI modulates platelet activation in vitro. This may represent an uncharacterized negative feedback loop to control overt platelet activation. Whether locally activated FVIII concentrations achieved during platelet accumulation and thrombus formation at the site of vascular injury in vivo are compatible with such a function remains to be determined.

Role of an interdependent Wnt, GSK3-β/β-catenin and HB-EGF/EGFR mechanism in arsenic-induced hippocampal neurotoxicity in adult mice

We previously reported the neurotoxic effects of arsenic in the hippocampus. Here, we explored the involvement of Wnt pathway, which contributes to neuronal functions. Administering environmentally relevant arsenic concentrations to postnatal day-60 (PND60) mice demonstrated a dose-dependent increase in hippocampal Wnt3a and its components, Frizzled, phospho-LRP6, Dishevelled and Axin1 at PND90 and PND120. However, p-GSK3-β(Ser9) and β-catenin levels although elevated at PND90, decreased at PND120. Additionally, treatment with Wnt-inhibitor, rDkk1, reduced p-GSK3-β(Ser9) and β-catenin at PND90, but failed to affect their levels at PND120, indicating a time-dependent link with Wnt. To explore other underlying factors, we assessed epidermal growth factor receptor (EGFR) pathway, which interacts with GSK3-β and appears relevant to neuronal functions. We primarily found that arsenic reduced hippocampal phosphorylated-EGFR and its ligand, Heparin-binding EGF-like growth factor (HB-EGF), at both PND90 and PND120. Moreover, treatment with HB-EGF rescued p-GSK3-β(Ser9) and β-catenin levels at PND120, suggesting their HB-EGF/EGFR-dependent regulation at this time point. Additionally, rDkk1, LiCl (GSK3-β-activity inhibitor), or β-catenin protein treatments induced a time-dependent recovery in HB-EGF, indicating potential inter-dependent mechanism between hippocampal Wnt/β-catenin and HB-EGF/EGFR following arsenic exposure. Fluorescence immunolabeling then validated these findings in hippocampal neurons. Further exploration of hippocampal neuronal survival and apoptosis demonstrated that treatment with rDkk1, LiCl, β-catenin and HB-EGF improved Nissl staining and NeuN levels, and reduced cleaved-caspase-3 levels in arsenic-treated mice. Supportively, we detected improved Y-Maze and Passive Avoidance performances for learning-memory functions in these mice. Overall, our study provides novel insights into Wnt/β-catenin and HB-EGF/EGFR pathway interaction in arsenic-induced hippocampal neurotoxicity.

A therapeutical insight into the correlation between circRNAs and signaling pathways involved in cancer pathogenesis.

Pre-messenger RNA molecules are back-spliced to create circular RNAs, which are non-coding RNA molecules. After a thorough investigation, it was discovered that these circRNAs have critical biological roles. CircRNAs have a variety of biological functions, including their ability to operate as microRNA sponges, interact with proteins to alter their stabilities and activities, and provide templates for the translation of proteins. Evidence supports a link between the emergence of numerous diseases, including various cancer types, and dysregulated circRNA expression. It is commonly known that a significant contributing element to cancer development is the disruption of numerous molecular pathways essential for preserving cellular and tissue homeostasis. The dysregulation of multiple biological processes is one of the hallmarks of cancer, and the molecular pathways linked to these processes are thought to be promising targets for therapeutic intervention. The biological and carcinogenic effects of circRNAs in the context of cancer are thoroughly reviewed in this article. Specifically, we highlight circRNAs' involvement in signal transduction pathways and their possible use as novel biomarkers for the early identification and prognosis of human cancer.

Examining the molecular mechanisms of topiramate in alleviating insulin resistance: A study on C2C12 myocytes and 3T3L-1 adipocytes.

Migraine, a severely debilitating condition, may be effectively managed with topiramate, known for its migraine prevention and weight loss properties due to changes in body muscle and fat composition and improved insulin sensitivity. However, the mechanism of topiramate in modulating insulin response in adipocytes and myocytes remains elusive. This study aims to elucidate these molecular mechanisms, offering insights into its role in weight management for migraine sufferers and underpinning its clinical application. Insulin resistance improvements were evaluated through glucose uptake measurements in C2C12 muscle cells and 3T3L-1 adipocytes, with Oil red O staining conducted on adipocytes. RNA-seq transcriptome analysis was used to identify the regulatory target genes of topiramate in these cells. The involvement of key genes and pathways was further validated through western blot analysis. Topiramate effectively reduced insulin resistance in C2C12 and 3T3L-1 cells. In C2C12 cells, it significantly lowered SORBS1 gene and protein levels. In 3T3L-1 cells, topiramate upregulated CTGF and downregulated MAPK8 and KPNA1 genes. Changes were notable in nuclear cytoplasmic transport and circadian signaling pathways. Furthermore, it caused downregulation of MKK7, pJNK1/ JNK1, BMAL1, and CLOCK proteins compared to the insulin-resistant model. This study provides preliminary insights into the mechanisms through which topiramate modulates insulin resistance in C2C12 myocytes and 3T3L-1 adipocytes, enhancing our understanding of its therapeutic potential in managing weight and insulin sensitivity in migraine patients.

AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance.

The aryl hydrocarbon receptor (AHR) has been identified as a significant driver of tumorigenesis. However, its clinical significance in acute myeloid leukemia (AML) remains largely unclear. In this study, RNA-Seq data from AML patients (bone marrow samples from 173 newly diagnosed AML patients) obtained from the TCGA database, and normal human RNA-Seq data (bone marrow samples from 70 healthy individuals) obtained from the GTEX database are downloaded for external validation and complementarity. The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes. In vitro experiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance. These findings deepen our understanding of the AHR signaling pathway's involvement in AML.

Systems genetics analysis reveals the common genetic basis for pain sensitivity and cognitive function.

There is growing evidence of a strong correlation between pain sensitivity and cognitive function under both physiological and pathological conditions. However, the detailed mechanisms remain largely unknown. In the current study, we sought to explore candidate genes and common molecular mechanisms underlying pain sensitivity and cognitive function with a transcriptome-wide association study using recombinant inbred mice from the BXD family. The pain sensitivity determined by Hargreaves' paw withdrawal test and cognition-related phenotypes were systematically analyzed in 60 strains of BXD mice and correlated with hippocampus transcriptomes, followed by quantitative trait locus (QTL) mapping and systems genetics analysis. The pain sensitivity showed significant variability across the BXD strains and co-varies with cognitive traits. Pain sensitivity correlated hippocampual genes showed a significant involvement in cognition-related pathways, including glutamatergic synapse, and PI3K-Akt signaling pathway. Moreover, QTL mapping identified a genomic region on chromosome 4, potentially regulating the variation of pain sensitivity. Integrative analysis of expression QTL mapping, correlation analysis, and Bayesian network modeling identified Ring finger protein 20 (Rnf20) as the best candidate. Further pathway analysis indicated that Rnf20 may regulate the expression of pain sensitivity and cognitive function through the PI3K-Akt signaling pathway, particularly through interactions with genes Ppp2r2b, Ppp2r5c, Col9a3, Met, Rps6, Tnc, and Kras. Our study demonstrated that pain sensitivity is associated with genetic background and Rnf20-mediated PI3K-Akt signaling may involve in the regulation of pain sensitivity and cognitive functions.

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives.

Hepatocellular carcinoma (HCC), presently the second leading cause of global cancer-related mortality, continues to pose significant challenges in the realm of medical oncology, impacting both clinical drug selection and mechanistic research. Recent investigations have unveiled autophagy-related signaling as a promising avenue for HCC treatment. A growing body of research has highlighted the pivotal role of autophagy-modulating natural products in inhibiting HCC progression. In this context, we provide a concise overview of the fundamental autophagy mechanism and delineate the involvement of autophagic signaling pathways in HCC development. Additionally, we review pertinent studies demonstrating how natural products regulate autophagy to mitigate HCC. Our findings indicate that natural products exhibit cytotoxic effects through the induction of excessive autophagy, simultaneously impeding HCC cell proliferation by autophagy inhibition, thereby depriving HCC cells of essential energy. These effects have been associated with various signaling pathways, including PI3K/AKT, MAPK, AMPK, Wnt/β-catenin, Beclin-1, and ferroautophagy. These results underscore the considerable therapeutic potential of natural products in HCC treatment. However, it is important to note that the present study did not establish definitive thresholds for autophagy induction or inhibition by natural products. Further research in this domain is imperative to gain comprehensive insights into the dual role of autophagy, equipping us with a better understanding of this double-edged sword in HCC management.

Cancer-associated fibroblasts (CAFs) based model reveals potential for predicting bladder cancer patients’ prognoses and immunotherapy responses

Aim: The purpose of this study is to enhance the understanding of bladder cancer and the role of cancer-associated fibroblasts (CAFs) in its progression. We aim to identify CAF-specific biomarkers and develop a prognostic prediction model based on CAFs, thereby contributing to the advancement of treatment strategies and the identification of prognostic and predictive biomarkers for bladder cancer. Method: We employed single-cell RNA sequencing to detect biomarkers for CAFs in bladder cancer cells. Bladder cancer cohorts were categorized into low- and high-CAF groups using the ssGSEA algorithm. The study also explored the association between CAF-related scores, immune-related cells, and immune checkpoint-related genes. Furthermore, we performed GSVA analysis to understand the biological features of CAFs and their link to various cancer-related pathways. Result: Ten genes were identified as CAF markers in bladder cancer cells. A significant difference was found with 2712 differentially expressed genes between low-CAF and high-CAF tissues. The CAFs-based prognostic prediction model included nine genes (ALDH1L2, AL450384.2, EMP1, LINC02362, WFIKKN1, GOLGA8A, POU5F1, AL354919.2, PTPRR), which are potentially crucial in predicting bladder cancer prognosis. The GSVA analysis revealed the involvement of several cancer-related pathways, such as WNT, toll-like receptor, TGF-beta, MAPK, and MTOR signaling pathways, in the CAFs-based prognostic model. Conclusion: This study highlights the significant role of CAFs in the progression and prognosis of bladder cancer. The identified CAF biomarkers and the constructed prognostic model provide valuable insights for future research and potential therapeutic targets. CAF-dependent pathways are promising for the development of new treatments and improving the prognosis of bladder cancer patients.

Genome-Wide Characterization and Phylogenetic and Stress Response Expression Analysis of the MADS-Box Gene Family in Litchi (Litchi chinensis Sonn.).

The MADS-box protein is an important transcription factor in plants and plays an important role in regulating the plant abiotic stress response. In this study, a total of 94 MADS-box genes were predicted in the litchi genome, and these genes were widely distributed on all the chromosomes. The LcMADS-box gene family was divided into six subgroups (Mα, Mβ, Mγ, Mδ, MIKC, and UN) based on their phylogenetical relationships with Arabidopsis, and the closely linked subgroups exhibited more similarity in terms of motif distribution and intron/exon numbers. Transcriptome analysis indicated that LcMADS-box gene expression varied in different tissues, which can be divided into universal expression and specific expression. Furthermore, we further validated that LcMADS-box genes can exhibit different responses to various stresses using quantitative real-time PCR (qRT-PCR). Moreover, physicochemical properties, subcellular localization, collinearity, and cis-acting elements were also analyzed. The findings of this study provide valuable insights into the MADS-box gene family in litchi, specifically in relation to stress response. The identification of hormone-related and stress-responsive cis-acting elements in the MADS-box gene promoters suggests their involvement in stress signaling pathways. This study contributes to the understanding of stress tolerance mechanisms in litchi and highlights potential regulatory mechanisms underlying stress responses.

Meta-analysis of microarray data to determine gene indicators involved in cisplatin resistance in non-small cell lung cancer.

Lung cancer is a major cause of cancer-related mortality worldwide, with a 5-year survival rate of approximately 22%. Cisplatin is one of the standard first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC), but its efficacy is often limited by the development of resistance. Despite extensive research on the molecular mechanisms of chemoresistance, the underlying causes remain elusive and complex. We analyzed three microarray datasets to find the gene signature and key pathways related to cisplatin resistance in NSCLC. We compared the gene expression of sensitive and resistant NSCLC cell lines treated with cisplatin. We found 274 DEGs, including 111 upregulated and 163 downregulated genes, in the resistant group. Gene set enrichment analysis showed the potential roles of several DEGs, such as TUBB2B, MAPK7, TUBAL3, MAP2K5, SMUG1, NTHL1, PARP3, NTRK1, G6PD, PDK1, HEY1, YTHDF2, CD274, and MAGEA1, in cisplatin resistance. Functional analysis revealed the involvement of pathways, such as gap junction, base excision repair, central carbon metabolism, and Notch signaling in the resistant cell lines. We identified several molecular factors that contribute to cisplatin resistance in NSCLC cell lines, involving genes and pathways that regulate gap junction communication, DNA damage repair, ROS balance, EMT induction, and stemness maintenance. These genes and pathways could be targets for future studies to overcome cisplatin resistance in NSCLC.

Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus

Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Identification and validation of a novel 9-gene signature of non-specific classification to predict prognosis in glioma patients.

This study aimed to identify and validate a 9-gene signature for predicting overall survival (OS) in glioma patients. Analysis of multiple gene expression datasets led to the identification of 135 candidate genes associated with OS in glioma patients. Further analysis revealed that IGFBP2, PBK, NRXN3, TGIF1, DNAJA4, and LGALS3BP were identified as risk factors for OS, while ENAH, PPP2R2C, and SPHKAP were found to be protective factors. Multifaceted validation using different databases confirmed their differential expression patterns in glioma tissues compared to normal brain tissue. By utilizing LASSO regression and multivariate Cox regression analysis, a risk score was developed based on the expression levels of the 9 crucial genes. The risk score showed a significant correlation with OS in both training and validation cohorts and yielded superior predictive accuracy compared to individual gene expression. Moreover, a predictive nomogram incorporating the risk score, WHO grade, age, IDH mutation, and 1p/19q co-deletion was constructed and validated, which exhibited high predictive capabilities for survival rates at different time points. Enrichment analysis revealed the involvement of extracellular matrix-related pathways and immune system signaling in glioma prognosis. Furthermore, the risk score showed a strong correlation with immune cell infiltration and immune checkpoint expression, suggesting its potential role in the tumor immune microenvironment. In conclusion, our study provides a robust 9-gene signature and a predictive nomogram for evaluating the prognosis of glioma patients, offering valuable insights into personalized treatment strategies.

Bioactive triterpenoid compounds of Poria cocos (Schw.) Wolf in the treatment of diabetic ulcers via regulating the PI3K-AKT signaling pathway

Ethnopharmacological relevanceDiabetic ulcers represent a chronic condition characterized by prolonged hyperglycemia and delayed wound healing, accompanied by endocrine disorders, inflammatory responses, and microvascular damage in the epidermal tissue, demanding effective clinical treatment approaches. For thousands of years, ancient Chinese ethnopharmacological studies have documented the use of Poria cocos (Schw.) Wolf in treating diabetic ulcers. Recent research has substantiated the diverse pharmacological effects of Poria cocos (Schw.) Wolf, including its potential to alleviate hyperglycemia and exhibit anti-inflammatory, antioxidant, and immune regulatory properties, which could effectively mitigate diabetic ulcer symptoms. Furthermore, being a natural medicine, Poria cocos (Schw.) Wolf has demonstrated promising therapeutic effects and safety in the management of diabetic ulcers, holding significant clinical value. Despite its potential clinical efficacy and applications in diabetic ulcer treatment, the primary active components and underlying pharmacological mechanisms of Poria cocos (Schw.) Wolf remains unclear. Further investigations are imperative to establish a solid foundation for drug development in this domain. Aim of the study and Materials and methodsIn this study, we aimed to identify the active compounds and potential targets of Poria cocos (Schw.) Wolf using UHPLC-Q-TOF-MS and TCMSP databases. Additionally, we attempt to identify targets related to diabetic ulcers. Following enrichment analysis, a network of protein-protein interactions was constructed to identify hub genes based on the common elements between the two datasets. To gain insights into the binding activities of the hub genes and active ingredients, molecular docking analysis was employed. Furthermore, to further validate the therapeutic effect of Poria cocos (Schw.) Wolf, we exerted in vitro experiments using human umbilical vein vascular endothelial cells and human myeloid leukemia monocytes (THP-1). The active ingredient of Poria cocos (Schw.) Wolf was applied in these experiments. Our investigations included various assays, such as CCK-8, scratch test, immunofluorescence, western blotting, RT-PCR, and flow cytometry, to explore the potential of Poria cocos (Schw.) Wolf triterpenoid extract (PTE) in treating diabetic ulcers. ResultsThe findings here highlighted PTE as the primary active ingredient in Poria cocos (Schw.) Wolf. Utilizing network pharmacology, we identified 74 potential targets associated with diabetic ulcer treatment for Poria cocos (Schw.) Wolf, with five hub genes (JUN, MAPK1, STAT3, AKT1, and CTNNB1). Enrichment analysis revealed the involvement of multiple pathways in the therapeutic process, with the PI3K-AKT signaling pathway showing significant enrichment. Through molecular docking, we discovered that relevant targets within this pathway exhibited strong binding with the active components of Poria cocos (Schw.) Wolf. In vitro experiments unveiled that PTE (10 mg/L) facilitated the migration of human umbilical vein vascular endothelial cells (P < 0.05). PTE also increased the expression of CD31 and VEGF mRNA (P < 0.05) while activating the expressions of p-PI3K and p-AKT (P < 0.05). Moreover, PTE demonstrated its potential by reducing the expression of IL-1β, IL-6, TNF-α, and NF-κB mRNA in THP-1 (P < 0.05) and fostering M2 macrophage polarization. These results signify the potential therapeutic effects of PTE in treating diabetic ulcers, with its beneficial actions mediated through the PI3K-AKT signaling pathway. ConclusionsPTE is the main active ingredient in Poria cocos (Schw.) Wolf that exerts therapeutic effects. Through PI3K-AKT signaling pathway activation and inflammatory response reduction, PTE promotes angiogenesis, thereby healing diabetic ulcers.