PI3K-Akt Signaling Pathway Research Articles

Identifying common pathways for doxorubicin and carfilzomib-induced cardiotoxicities: transcriptomic and epigenetic profiling

Cancer therapy-related cardiovascular toxicity (CTR-CVT) is now recognised as one of the leading causes of long-term morbidity and mortality in cancer patients. To date, potential overlapping cardiotoxicity mechanism(s) across different chemotherapeutic classes have not been elucidated. Doxorubicin, an anthracycline, and Carfilzomib, a proteasome inhibitor, are both known to cause heart failure in some patients. Given this common cardiotoxic effect of these chemotherapies, we aimed to investigate differential and common mechanism(s) associated with Doxorubicin and Carfilzomib-induced cardiac dysfunction. Primary human cardiomyocyte-like cells (HCM-ls) were treated with 1 µM of either Doxorubicin or Carfilzomib for 72 h. Both Doxorubicin and Carfilzomib induced a significant reduction in HCM cell viability and cell damage. DNA methylation analysis performed using MethylationEPIC array showed distinct and common changes induced by Doxorubicin and Carfilzomib (10,270 or approximately 12.9% of the DMPs for either treatment overlapped). RNA-seq analyses identified 5,643 differentially expressed genes (DEGs) that were commonly dysregulated for both treatments. Pathway analysis revealed that the PI3K-Akt signalling pathway was the most significantly enriched pathway with common DEGs, shared between Doxorubicin and Carfilzomib. We identified that there are shared cardiotoxicity mechanisms for Doxorubicin and Carfilzomib pathways that can be potential therapeutic targets for treatments across 2 classes of anti-cancer agents.

Effects of Combined Transcriptome and Metabolome Analysis Training on Athletic Performance of 2-Year-Old Trot-Type Yili Horses

Objectives: Training is essential for enhancing equine athletic performance, but the genetic mechanisms that regulate athletic performance are unknown. Therefore, this paper aims to identify candidate genes and metabolic pathways for the effects of training on equine athletic performance through multi-omics analyses. Methods: The experiment selected 12 untrained trot-type Yili horses, which underwent a 12-week professional training program. Blood samples were collected at rest before training (BT) and after training (AT). Based on their race performance, whole blood and serum samples from 4 horses were chosen for transcriptomic and metabolomic analyses. Results: The race performance of the horses is dramatically improved in the AT period compared to the BT (p < 0.01) period. The transcriptome analysis identified a total of 57 differentially expressed genes, which were significantly enriched in pathways related to circadian entrainment, steroid hormone biosynthesis, chemokine signaling, and cholinergic synapses (p < 0.05). Additionally, metabolomic analysis revealed 121 differentially identified metabolites, primarily enriched in metabolic pathways such as histidine metabolism, purine metabolism, and the PI3K-Akt signaling pathway. The integration of transcriptomic and metabolomic analyses uncovered five shared pathways, and further combined pathway analyses identified eight differentially expressed genes that correlate with 19 differentially identified metabolites. Conclusions: The current findings will contribute to establishing a theoretical framework for investigating the molecular mechanisms of genes associated with the impact of training on equine athletic performance. Additionally, these results will serve as a foundation for enhancing the athletic capabilities of trot-type Yili horses.

Muscle fiber types switched during the development of experimental autoimmune myasthenia gravis via the PI3K/Akt signaling pathway.

As one of the largest organs of our human body, skeletal muscle has good research prospects in myasthenia gravis (MG), the symptoms of which include systemic skeletal muscle weakness. Skeletal muscle is composed of two types of muscle fibers. Different fiber subtypes can be converted into each other; however, the underlying mechanism is not yet clear. In this paper, we firstly established an experimental autoimmune myasthenia gravis (EAMG) rat model and found that the skeletal muscle fibers of the EAMG group were atrophied, with a change in the proportion of fiber subtypes, which switched from type IIa to type I in the EAMG group at the peak stage, as verified by histological and molecular analyses. Second-generation sequencing results predicted that the PI3K-Akt signaling pathway might be involved in the switch, and the mRNA expression levels of the PI3K-Akt pathway-related genesNr4a1, IL2rb, Col1A1 and Ddit4 were significantly different. In conclusion, this study indicates that the switch of muscle fiber subtypes in MG via the PI3K-Akt signaling pathway may be a potential target for the treatment of MG-related skeletal muscle atrophy in the future.

The hematopoietic function, histological characteristics, and transcriptome profiling of Wanxi white geese ovary during nesting and late-laying stages.

Despite several factors influencing reproduction in geese, but the precise molecular mechanisms of egg cessation are not fully understood. In the present study, the hematopoietic parameters and serum hormone levels in Wanxi white geese were analyzed. RNA-Seq was utilized to identify the differentially expressed mRNAs (DEGs) and lncRNAs (DE lncRNAs) in the ovarian tissues associated with nesting in geese during the late-laying and nesting periods. Triglyceride (TG) and alkaline phosphatase (ALP) levels were higher in late-laying geese, while white blood cell (WBC), neutrophil (NEU), hemoglobin (HGB), and hematocrit (HCT) levels were significantly lower in late-laying geese. Serum levels of luteinizing hormone (LH), estrogen (E2), and progesterone (P4) increased significantly during the late-laying period, whereas prolactin (PRL) level was lower in the late-laying period than the nesting period. During the late-laying period, geese had a clear follicular hierarchy, with ovaries exhibiting mature and primary follicles. In the nesting period, the ovaries were degenerated and had many primary follicles without follicular development. Analysis of mRNA-lncRNA expression revealed 1,257 DEGs between the nesting and the late-laying stages, of which 841 were up-regulated and 416 were down-regulated DEGs. A total of 340 DE lncRNAs were identified between the nesting and the late-laying periods, with 113 being up-regulated and 227 down-regulated lncRNAs. DEGs, including TMEM, DRD3, IGFBP7, MAPK13, GnRHR2, HECTD3, KCNU1, OPRD1, and VCAM1, along with DE lncRNAs, including XR_001203613.1, XR_001206155.1, XR_001207759.1, XR_001213571.1 and XR_001214368.1 participate in reproduction in geese. Correlation analysis indicated that the cis-regulation of XR_001213096.1-ITPR3, XR_001203613.1-GALNT15, XR_001206155.1-COL6A3, XR_001207759.1-ANKS1B, and XR_001214368.1-VPS45 participate in the molecular mechanisms underlying nesting in geese. Functional enrichment analysis revealed the DEGs and DE lncRNAs associated with focal adhesion, extracellular matrix (ECM)-receptor interaction, cell adhesion molecules (CAMs), and PI3K-Akt signaling pathways, were responsible for the differences in the ovaries between the nesting and late-laying periods. This study offers valuable information on the roles of genes and lncRNAs, and the mechanisms underlying variations in reproductive performance between the late-laying and nesting periods.

Potential molecular mechanisms of tobacco smoke exposure in Alzheimer's disease.

Smoking is detrimental to health, with tobacco use being a critical factor in the development of various neurodegenerative diseases, including Alzheimer's disease (AD), which progressively impairs brain function and poses a significant threat to public health. This study aims to examine the potential genetic alterations induced by smoking that are associated with AD and to investigate the underlying regulatory mechanisms. The research will provide theoretical foundations for targeted prevention and treatment strategies for AD. This study analyzed datasets from the Gene Expression Omnibus (GEO) and the Comparative Toxicogenomics Database (CTD) to identify genes affected by tobacco smoke exposure and those altered in patients with AD relative to normal controls. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using OmicShare tools to screen for key pathways. Key genes were identified by constructing protein-protein interaction networks (PPI) in the STRING database with the aid of CytoHubba. Additionally, the binding activity of the proteins encoded by these key genes to nicotine, the main component of tobacco, was analyzed using molecular docking techniques. Finally, the analytical results were verified using Quantitative Real-Time Polymerase Chain Reaction. The CTD identified 12,164 CE-related genes affected by tobacco smoke exposure. A comparison of these datasets yielded 94 common genes that were both influenced by tobacco and differentially expressed across all brain regions. The GO and KEGG pathway enrichment analyses showed that these common differentially expressed genes (DEGs) were predominantly enriched in the Wnt/β-catenin and PI3K-AKT signaling pathways. The DEGs' PPI network, constructed using the STRING database, highlighted key genes such as HSP90AB1, SOS2, MAGI1, and YWHAZ. Molecular docking studies demonstrated that nicotine binds effectively to the protein structures of these key genes, primarily through amino acid residues such as Ser and Glu. Experimental validation showed that HSP90AB1 and YWHAZ exhibited notable expression discrepancies under varying concentrations of cigarette smoke extract (CSE) treatments, particularly demonstrating a pronounced down-regulation trend at elevated concentrations. The study indicates that tobacco may impact the function of transmembrane transporter proteins and contribute to the development of AD by affecting key genes such as HSP90AB1 and YWHAZ, as well as signaling pathways like PI3K-AKT.

High-intensity acute noise exposure causes anxiety in female rats by inducing hippocampal neuron apoptosis.

The increasing prevalence of acute noise exposure poses a significant threat to mental health. Identifying the intensity of noise that impair health is crucial for developing effective interventions. The study aimed to determine the acute noise intensity thresholds that elicit anxiety-like behaviors and brain damage in female rats, and then to elucidate the underlying neurobiological mechanisms. Female rats were subjected to acute noise exposure at levels of 105, 115, 125, and 135 dB to determine the intensity thresholds that elicit anxiety-like behaviors and brain damage were assessed at the 3th day and 1 month post-exposure. We found that acute noise exposure at 135 dB induced significant anxiety-like behaviors and hippocampal neuron apoptosis on the third day, with these effects persisting up to one month after exposure. KEGG enrichment analysis of differentially expressed genes (DEGs) revealed alterations in the PI3K-AKT signaling pathway, as confirmed by Western blot analysis. Our findings indicate that acute noise exposure at 135 dB elicits anxiety-like behaviors in female rats on the third day post-exposure, with these effects persisting up to one month. This sustained anxiety is attributed to the inhibition of the PI3K-AKT signaling pathway and the subsequent activation of the apoptotic Caspase-3/BCL-2/BAX pathway, culminating in hippocampal neuron apoptosis.

Effect of Leonurus japonicus alkaloids on endometrial inflammation and its mechanisms.

The aerial parts of Leonurus japonicus Houtt. (Chinese motherwort) are famous for their efficacy in treating obstetrical and gynecological diseases in traditional Chinese medicine (TCM). Alkaloids are the major bioactive components of motherwort and have gained extensive attention for alleviating several symptoms of obstetrical and gynecological diseases such as postpartum hemorrhage, postpartum rehabilitation, irregular menstruation, and dysmenorrhea. However, the effects of motherwort alkaloids on endometritis remain unclear. The aim of this study was to investigate the effect of motherwort total alkaloids (MTAs) on endometritis and explore the molecular mechanisms using an integrating network analysis and in vitro experimental verification. Ultra-high performance liquid chromatography-tandem quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS) was used to analyze and identify the components in the MTAs. The effects of MTAs were evaluated using bacteria-induced endometritis in rats. Network pharmacology was conducted to predict possible mechanism pathways of MTAs in endometritis. Finally, lipopolysaccharide-stimulated mouse mononuclear macrophage (RAW 264.7) cells and human endometrial epithelial cells were used to identify signaling pathways through which MTAs exert their effects. Thirty-nine alkaloids were identified in MTAs using the UPLC-Q-Orbitrap HRMS analysis. Their corresponding putative targets were then predicted. The MTAs exerted pharmacological effects on endometritis through a multi-ingredient and multi-target pattern. Network pharmacology showed that the MTAs had 152 candidate targets in treating endometritis. According to the KEGG analysis, the MTAs were found to potentially affect the PI3K-AKT and NF-κB signaling pathways. The following experiments showed that the MTAs exhibited significant effects on endometritis in vivo, significantly reduced the overproduction of inflammatory mediators, and promoted endometrial cell repair via the PI3K/AKT/NF-κB signaling pathway. Motherwort alkaloids can be used to treat endometrial inflammation by regulating the PI3K/AKT/NF-κB pathway. This study provides a scientific basis for the use of MTAs for treating endometritis.

Ethacrynic acid inhibits the growth and proliferation of prostate cancer cells by targeting GSTP1 and regulating the PI3K-AKT signaling pathway.

As a diuretic, ethacrynic acid (EA) has been shown to play a suppressive role in cancers, including prostate cancer (PC). However, its molecular regulatory mechanism is still unclear. Therefore, our study is centered on investigating the effect of EA on PC development and its mechanism. To verify the binding relationship between EA and GSTP1, molecular docking and cellular thermal shift assay (CETSA) were conducted. To examine how EA affects PC cell proliferation, cell cycle, and apoptosis, cell function assays were performed. qRT-PCR was used to detect GSTP1 mRNA expression. The expression of GSTP1 protein and PI3K-AKT signaling pathway-related proteins in cells was detected by western blot (WB). To verify how EA and GSTP1 influence cell growth in PC, in vivo experiments were conducted. The binding relationship between GSTP1 and EA was confirmed by molecular docking and CETSA results. Cell experiments showed that EA could hinder PI3K/AKT pathway and PC cell proliferation, arrest the cell cycle in G0/G1 phase, and facilitate apoptosis by binding to GSTP1. In vivo experiments in nude mice verified that the interaction between EA and GSTP1 reduced PI3K and AKT phosphorylation and inhibited the growth of PC cells. EA inhibits PC progression by binding to GSTP1 to downregulate the activity of PI3K/AKT pathway, and this result suggests the potential of EA to be an anticancer agent for PC therapy.

FSTL1 sustains glioma stem cell stemness and promotes immunosuppressive macrophage polarization in glioblastoma.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play a crucial role in glioblastoma (GBM) progression by interacting with glioma stem cells (GSCs). These interactions lead to the polarization of TAMs toward an M2 phenotype, which, in turn, enhances the stem-like traits and malignant progression of GSCs. Our study shows that FSTL1, a protein released by GSCs, is significantly elevated in gliomas and linked to the progression of the disease. By suppressing FSTL1 in a mouse model, we observed reduced tumor growth and a decrease in M2 macrophages. In vitro studies show that FSTL1 from GSCs promotes M2 polarization and infiltration. Importantly, GSCs utilize autocrine FSTL1 to interact with TLR2, which inhibits the endocytosis-lysosomal degradation pathway mediated by EGFR, resulting in the activation of the PI3K-AKT signaling pathway that is critical for maintaining their self-renewal. These findings underscore the importance of FSTL1 in GSC maintenance and M2 macrophage polarization, suggesting that interventions targeting the FSTL1/TLR2 pathway could provide a novel therapeutic approach for GBM patients.

Investigation of Substance Basis and Pharmacodynamics of Qingzao Jiefei Decoction in Lung Cancer based on Serum Pharmacochemistry and Proteomics.

Qingzao Jiufei Decoction(QD)is a renownedprescription for nourishing lung Yin to treat lung related diseases in ancient and modern times. It has been reported that QDcan effectively inhibit the growth of lung cancer, but the material basis and mechanism of its treatment of LC remain to be further studied. In this experiment, we combined serum pharmacochemistry and proteomics to study the pharmacodynamic material basis and mechanism of QDagainst lung cancer.The results showed that In vitro a total of 121 compounds were identified. Atotal of 33 prototype chemical components were identified in vivo, which may be effective active ingredients for QDtreatment of LC.Proteomic experiments have shown that compared with the model group, 113 DEPs in LC tissues were significantly changed after QDtreatment, among which 57 proteins were significantly up-regulated and 56 proteins were significantly down-regulated (p< 0.05),GO and KEGG enrichment analysis was performed on these DEPs. Atotal of 205 pathways were enriched, and the PI3K-Akt signaling pathway was experimentally verified. The results showed that QDcan be used to treat lung cancer by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway.

Sunflower Oil Fortified with Vitamins D and A and Sunflower Lecithin Ameliorated Scopolamine-Induced Cognitive Dysfunction in Mice and Exploration of the Underlying Protective Pathways

The incidence of cognitive disorders is increasing globally, with a reported prevalence of over 50 million individuals affected, and current interventions offer limited efficacy. This study investigates the effects of sunflower oil fortified with sunflower lecithin, vitamin D, and vitamin A on scopolamine-induced cognitive dysfunction in mice and explores the underlying mechanisms. The incidence of cognitive disorders, such as Alzheimer’s disease, is increasing yearly, and current interventions offer limited efficacy. Therefore, this research aims to evaluate the cognitive improvement effects of the three added functional factors on mice with learning and memory impairments, along with the associated molecular mechanisms. Behavioral tests, biochemical assays, and real-time quantitative polymerase chain reaction (RT-qPCR) were utilized to examine the intervention effects of these functional factors on scopolamine-induced cognitive impairment in mice. The results revealed that the groups treated with sunflower lecithin and vitamin D significantly enhanced the mice’s exploratory behavior, working memory, and spatial memory, with increases of 1.6 times and 4.5 times, respectively, in the open field and novel object recognition tests (VD group). Additionally, these treatments reduced levels of inflammatory markers and IL-6, increased antioxidant GSH levels, and decreased oxidative stress marker MDA levels, with all effects showing significant differences (p &lt; 0.01). The effects were further enhanced when vitamin A was combined with these treatments. Transcriptomic analysis demonstrated that the intervention groups had markedly improved learning and memory abilities through upregulation of key gene expression levels in the PI3K-AKT signaling pathway, cholinergic pathway, and folate biosynthesis pathway. These findings provide a theoretical basis for the development of nutritionally fortified edible oils with added sunflower lecithin, vitamin D, and vitamin A, which may help prevent and ameliorate cognitive disorders.

Comprehensive analysis of ESCRT transcriptome-associated signatures and identification of the regulatory role of LMO7-AS1 in osteosarcoma

Osteosarcoma (OS) is a commonly observed malignant tumor in orthopedics that has a very poor prognosis. The endosomal sorting complex required for transport (ESCRT) is important for the development and progression of cancer and may be a significant target for cancer therapy. First, we built a prognostic signature using 7 ESCRT-related genes (ERGs) to predict OS patient prognosis. Analysis of internal and external datasets revealed that the ERG signature has good predictive ability and reproducibility. Immune analysis demonstrated a significant correlation between OS patient immune status and ERG signature score. Moreover, ERG signature score was found to be associated with the response of OS patients to immunotherapy and anticancer drugs. Additionally, we constructed a prognostic signature consisting of 10 ESCRT-related long noncoding RNAs (ERLs) that effectively predicted the prognosis of OS patients. Furthermore, two subgroups of OS patients with distinct prognoses (clusters 1 and 2) were identified. Finally, LMO7-AS1 was chosen for functional experimental validation. The knockdown of LMO7-AS1 suppressed the malignant progression of OS cells. Furthermore, transcriptome sequencing was performed on OS cells and revealed a correlation between LMO7-AS1 and the PI3K-Akt signaling pathway. In conclusion, our ESCRT transcriptome-associated signatures can act as prognostic biomarkers for OS, and LMO7-AS1 is a novel therapeutic target for the treatment of OS.

Sex reversal induced by 17β-estradiol may be achieved by regulating the neuroendocrine system of the Pacific white shrimp Penaeus vannamei

BackgroundDue to sexual dimorphism in growth of penaeid shrimp, all-female cultivation is desirable for the aquaculture industry. 17β-estradiol (E2) has the potential to induce the male-to-female sex reversal of decapod species. However, the mechanisms behind it remain poorly understood. This study aimed to investigate the effects of E2 immersion on the neuroendocrine system (the eyestalk ganglia, brain, thoracic ganglia, and ventral nerve cord) of the Pacific white shrimp Penaeus vannamei through comparative transcriptomic analyses of the control males (CM), E2-treated males without sex reversal (EM), and neo-females (NF).ResultsImmersion in E2 at 2 mg/l from post-larvae (PL) 5 to 85 results in a skewed female-to-male ratio of 2.56: 1. The survival rate remains unaffected by E2 exposure, while a notable inhibition in growth is exclusively observed in the EM compared to the CM group. The transcriptome analysis result indicates that the observed retardation in growth of the EM may be attributed to the potential neuronal damage caused by the excessive neurotransmission, which in turn disrupts the PI3K-Akt signaling and cell cycle pathways. In contrast, the negatively regulated pathways of neuroactive ligand-receptor interaction and the dopaminergic synapse in the NF group suggest a potential impact of E2 on neuroplasticity through the modulation of neuroregulator binding and signaling, which affects the establishment of morphological differences and gender identity. Moreover, the activation of steroidogenesis and the inhibition of the insulin signaling may be associated with the success of E2-induced sex reversal. With these findings, a proposed mechanism of neuroendocrine system in decapods in response to E2 exposure is presented.ConclusionsThe present study represents a first step in understanding the effects of E2 on the neuroendocrine system at the molecular level. The observed retardation in growth in the EM group may be attributed to the potential for neuronal damage and disruptions in the cell cycle and PI3K-Akt signaling pathways. Furthermore, the success of E2-induced sex reversal may be associated with the downregulation of neuroactive ligand-receptor interaction, dopaminergic synapse, and insulin signaling pathways, as well as the activation of steroidogenesis. These findings provide new insights into the mode of action of E2, and underscore the potential for large-scale production of all-female stocks in P. vannamei.

Construction of a rodent neural network-skeletal muscle assembloid that simulate the postnatal development of spinal cord motor neuronal network

Neuromuscular diseases usually manifest as abnormalities involving motor neurons, neuromuscular junctions, and skeletal muscle (SkM) in postnatal stage. Present in vitro models of neuromuscular interactions require a long time and lack neuroglia involvement. Our study aimed to construct rodent bioengineered spinal cord neural network-skeletal muscle (NN-SkM) assembloids to elucidate the interactions between spinal cord neural stem cells (SC-NSCs) and SkM cells and their biological effects on the development and maturation of postnatal spinal cord motor neural circuits. After coculture with SkM cells, SC-NSCs developed into neural networks (NNs) and exhibited a high proportion of glutamatergic and cholinergic neurons, low proportion of neuroglia and gamma-aminobutyric acidergic neurons, and increased expression of synaptic markers. In NN-SkM assembloids, the acetylcholine receptors of SkM cells were upregulated, generating neuromuscular junction-like structures with NNs. The amplitude and frequency of SkM cell contraction in NN-SkM assembloids were increased by optogenetic and glutamate stimulation and blocked by tetrodotoxin and dizocilpine, respectively, confirming the existence of multisynaptic motor NNs. The coculture process involves the secretion of neurotrophin-3 and insulin growth factor-1 by SkM cells, which activate the related ERK-MAPK and PI3K-AKT signaling pathways in NNs. Inhibition of the ERK-MAPK and PI3K-AKT pathways significantly reduces neuronal differentiation and synaptic maturation of neural cells in NN-SkM assembloids, while also decreasing acetylcholine receptor formation on SkM cells. In brief, NN-SkM assembloids simulate the composition of spinal cord motor NNs and respond to motor regulatory signals, providing an in vitro model for studying postnatal development and maturation of spinal cord motor NNs.

The role of CLDN11 in promotion of granulosa cell proliferation in polycystic ovary syndrome via activation of the PI3K-AKT signalling pathway

Polycystic ovary syndrome (PCOS) is a complex gynecological endocrinological condition that significantly impacts women’s fertility during their reproductive lifespan. The causes of PCOS are multifaceted, and its pathogenesis is not yet clear. This study established a rat model of PCOS and, in conjunction with clinical samples and database data, analysed the role of claudin 11 (CLDN11) in follicular granulosa cells (GCs) in regulating the proliferation of GCs. Our findings revealed a notable decrease in the protein expression of CLDN11 within the follicular GCs of individuals with PCOS. In vitro rat cell experiments revealed that interference with CLDN11 significantly inhibited viability and increased the apoptosis of GCs. Additional research has illuminated the mechanism by which CLDN11 regulates the expression levels of CCND1 and PCNA through the PI3K/AKT signalling pathway, significantly influencing the proliferation of rat follicular GCs. Furthermore, overexpression of CLDN11 via an adeno-associated virus (AAV) vector was found to reverse the PCOS-like phenotype induced in rats by letrozole. Our findings suggest that CLDN11 stimulates the proliferation of these cells by activating the PI3K/AKT pathway, thereby increasing the expression of CCND1 and PCNA. These discoveries underscore the critical function of CLDN11 in regulating the functionality of follicular GCs, which offers novel insights into the fundamental mechanisms governing PCOS.

Absent in melanoma 2: a potent suppressor of retinal pigment epithelial-mesenchymal transition and experimental proliferative vitreoretinopathy

Epithelial-to-mesenchymal transition (EMT) is a critical and complex process involved in normal embryonic development, tissue regeneration, and tumor progression. It also contributes to retinal diseases, such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Although absent in melanoma 2 (AIM2) has been linked to inflammatory disorders, autoimmune diseases, and cancers, its role in the EMT of the retinal pigment epithelium (RPE-EMT) and retinal diseases remains unclear. The present study demonstrated that AIM2 functions as a potent suppressor of RPE cell proliferation and EMT to maintain retinal homeostasis. Transcriptome analysis using RNA-sequencing (RNA-Seq) revealed that AIM2 was significantly downregulated in primary human RPE (phRPE) cells undergoing EMT and proliferation. Consequently, Aim2-deficient mice showed morphological changes and increased FN expression in RPE cells under physiological conditions, whereas AIM2 overexpression in phRPE cells inhibited EMT. In a retinal detachment-induced PVR mouse model, AIM2 deficiency promotes RPE-EMT, resulting in severe experimental PVR. Clinical samples further confirmed the downregulation of AIM2 in the PVR membranes from patients. Kyoto Encyclopedia of Genes and Genome analysis revealed that the PI3K-AKT signaling pathway was significantly related to RPE-EMT and that AIM2 inhibited AKT activation in RPE cells by reducing its phosphorylation. Moreover, treatment with eye drops containing an AKT inhibitor alleviated RPE-EMT and the severity of experimental PVR. These findings provide new insights into the complex mechanisms underlying RPE-EMT and PVR pathogenesis, with implications for rational strategies for potential therapeutic applications in PVR by targeting RPE-EMT.

Network Pharmacological Analysis and Experimental Validation of Anti-lung Cancer Effect of Echinacea Purpurea

Background: Echinacea purpurea is a medicinal plant recognized for its rich array of bioactive constituents, making it a valuable resource for drug development. However, the potential antitumor effects and underlying mechanisms of Echinacea remain largely unexplored. Methods: This study aims to elucidate the active ingredients, targets, and pathways mediating the anti-lung cancer effects of Echinacea through the lens of network pharmacology and to further validate the efficacy of the extract of Echinacea purpurea against lung cancer in vitro. Results: An 'Echinacea-lung cancer-target' network was constructed using network pharmacology, identifying quercetin, β-sitosterol, rutin, dibutyl phthalate, ferulic acid, and protocatechuic acid as the primary active components contributing to Echinacea's anti-lung cancer activity. These components may exert antitumor effects by modulating key targets, including TP53, AKT1, HSP90AA1, JUN, and IL6, through the PI3K-Akt, MAPK, IL-17, HIF-1, and TNF signaling pathways. Subsequently, MEPT was administered to human lung cancer PC-9 cells, revealing that the Echinacea extract inhibited cell proliferation, migration, and the expression of cell cycle proteins in a concentration- and time-dependent manner while also inducing early apoptosis in tumor cells. Conclusion: These findings suggest that the anti-lung cancer activity of Echinacea operates through a synergistic mechanism involving multiple components, targets, and pathways, potentially leading to cell cycle arrest and the induction of apoptosis.

Cell signaling communication within papillary craniopharyngioma revealed by an integrated analysis of single-cell RNA sequencing and bulk RNA sequencing

ObjectiveThis study aims to elucidate the primary signaling communication among papillary craniopharyngioma (PCP) tumor cells.MethodsFive samples of PCP were utilized for single-cell RNA sequencing. The most relevant ligand and receptor interactions among different cells were calculated using the CellChat package in R software. Bulk RNA sequencing of 11 tumor samples and five normal controls was used to investigate the pair interactions detected by single-cell RNA sequencing.ResultsFibroblasts were not found in ACP, whereas they were detected in PCP. InferCNV revealed high CNV scores for the clusters of epithelial cells and fibroblasts using immune cells as a reference. Epithelial Mesenchymal Transition, Interferon Gamma Response, p53 Pathway, and Estrogen Response Early are pathways commonly shared by fibroblasts and epithelial cells, ranking high in priority. The Wnt signaling pathway and PI3K-Akt signaling pathway play a crucial role in facilitating communication between epithelial cells and fibroblasts. Neutrophils were recognized as the main receivers of incoming signals, with ANXA1-FPR1 and MIF-(CD74 + CXCR2) being identified as the primary signals transmitted from fibroblasts to neutrophils.ConclusionThrough analyzing the communication of essential signaling pathways, ligands, and receptors among epithelial cells, fibroblasts, and neutrophils in PCP tumor tissues, we have identified certain molecules with promising prognostic and therapeutic potential.

The function and effect on prognosis of ANXA2 in gastric cancer peritoneal metastasis patients in cold region

Abstract Objective Heilongjiang Province is part of the northern cold areas of China, where gastric cancer is one of the most common gastrointestinal malignancies. Peritoneal metastases (PM) are the leading cause of mortality among patients. This study conducted bioinformatics and basic research on the gene ANXA2 (Annexin A2), which may influence the prognosis of patients. Methods Genome sequencing was performed on patients from Heilongjiang to identify potential genes impacting survival time. The function of ANXA2 in gastric cancer was analyzed using multiple bioinformatics databases, focusing on its pathways and mechanisms. ANXA2-knockout gastric cancer cell lines were constructed, and in vitro assays, including CCK-8, flow cytometry, scratch, and Transwell experiments, were conducted. A nude mouse tumorigenesis model was also developed to analyze in vivo effects. Results ANXA2 was found to be expressed at higher levels in gastric cancer tissue than in normal gastric tissue, and its mRNA levels were associated with short overall survival (OS). Enrichment analysis indicated that ANXA2 is primarily localized on the cell membrane and primarily influences the PI3K-AKT signaling pathway. Cytological experiments demonstrated that knockdown of ANXA2 suppresses the growth and migration of gastric carcinoma cells, an effect that was also observed in vivo. Conclusions ANXA2 is essential for gastric cancer growth and may represent a potential risk factor affecting the survival probability of patients in cold regions.

Whole-transcriptome analysis reveals the profiles and roles of coding and non-coding RNAs during hair follicle cycling in Rex rabbits

BackgroundRex rabbit is famous for its silky and soft fur coat, a characteristic predominantly attributed to its hair follicles. Numerous studies have confirmed the crucial roles of mRNAs and non-coding RNAs (ncRNAs) in regulating key cellular processes such as cell proliferation, differentiation, apoptosis and immunity. However, their involvement in the regulation of the hair cycle in Rex rabbits remains unknown.ResultsIn this study, we identified the hair follicle stages of Rex rabbits aged 3 to 5.5 months. Skin samples collected at 4, 5 and 5.5 months, representing the morphological features of the anagen, catagen and telogen stage separately, were finally selected for whole-transcriptome analysis. 25,736 mRNA, 8280 lncRNA, 24,885 circRNA and 1138 miRNA transcripts were identified. 6027 differently expressed mRNAs (DEGs), 2381 differently expressed lncRNAs (DELs), 438 differently expressed circRNAs (DECs) and 167 differently expressed miRNAs (DEMs) were detected in the anagen vs. catagen (AvC) comparison. 4092 DEGs, 1540 DELs, 356 DECs and 141 DEMs were detected in the anagen vs. telogen (AvT) comparison. 2290 DEGs, 779 DELs, 249 DECs and 92 DEMs were detected in the catagen vs. telogen (CvT) comparison. DEGs were primarily enriched in GO items including plasma membrane, integral component of plasma membrane and extracellular space. KEGG enrichment analysis revealed that DEGs were mainly enriched in PI3K-Akt signaling pathway, cell cycle and Wnt signaling pathway (p < 0.05). KEGG analysis showed trans-acting genes of DELs were significantly enriched in Hippo signaling pathway, PI3K-Akt signaling pathway and Melanogenesis. Target genes of DEMs were mainly enriched in MAPK signaling pathway, Wnt signaling pathway, ECM-receptor interaction and Signaling pathways regulating pluripotency of stem cells. Based on the ceRNA mechanism, lncRNA/circRNA-miRNA-mRNA networks were constructed involving 9 DECs, 437 DELs, 50 DEMs and 416 DEGs.ConclusionsTotally, this study provides comprehensive insights into the expression patterns of protein-coding genes and non-coding transcripts throughout the HF cycle, and enhancing the understanding of the regulatory mechanisms underlying mammalian hair fiber development.