DDX19A promotes gastric cancer cell proliferation and migration by activating the PI3K/AKT pathway.

BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer. METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation. RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus. CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.

MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression.

BACKGROUND: The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. METHODS: In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. RESULTS: Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79-87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. CONCLUSIONS: Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Conduction and validation of a novel mitotic spindle assembly related signature in hepatocellular carcinoma: prognostic prediction, tumor immune microenvironment and drug susceptibility.

Introduction: We have developed a risk-scoring model using gene expression levels related to mitotic spindle assembly (MSA) to predict the prognosis of liver cancer. Methods and results: Initially, we identified 470 genes related to MSA from public databases. Subsequently, through analysis of sequencing data from liver cancer patient samples in online databases, we identified 7 genes suitable for constructing the risk-scoring model. We validated the predictive accuracy and clinical utility of the model. Through drug sensitivity analysis, we identified SAC3D1 as a gene sensitive to the most common anti-tumor drugs among these 7 genes. We propose SAC3D1 as a significant target for future clinical treatment. Furthermore, we conducted in vivo and in vitro experiments to validate the relevance of SAC3D1 to MSA and found its significant impact on the PI3K/Akt signaling pathway and spindle function. Conclusion: Our research introduces a novel risk-scoring model that accurately predicts liver cancer prognosis. Additionally, our findings suggest SAC3D1 as a promising therapeutic target for hepatocellular carcinoma, potentially revealing new mechanisms underlying liver cancer development.

Diosmin ameliorates inflammation, apoptosis and activates PI3K/AKT pathway in Alzheimer's disease rats.

Alzheimer's disease (AD), a prevalent cognitive disorder among the elderly, is frequently linked to the abnormal accumulation of myloid-ß (Aß), which is mainly as a result of neuronal death and inflammation. Diosmin, a flavonoid, is considered a potential drug for the treatment of AD. Our study aimed to uncover the molecular mechanism of diosmin in AD therapy. Here, rats were randomly divided into three groups: control, Aß25-35, and Aß25-35 + diosmin groups. AD model rats were induced by Aß25-35 intraventricular injection, meanwhile 50 mg/kg diosmin was orally administered for 6-week intervention. Morris water maze test assessed learning and memory abilities. Hippocampal neuronal damage was determined by HE, Nissl, and TUNEL staining. These assays indicate that diosmin improves cognitive dysfunction and reduces hippocampal neuronal loss and apoptosis. Western blot showed that diosmin reduced Bax (1.21 ± 0.12) and cleaved caspase-3 (1.27 ± 0.12) expression, and increased Bcl-2 (0.70 ± 0.06), p-PI3K (0.71 ± 0.08), and p-AKT (0.96 ± 0.10) in the hippocampus. ELISA indicated diosmin reduces IL-1ß, IL-6, and TNF-α levels, suggesting anti-inflammation effect. These results suggest that diosmin inhibits neuronal apoptosis and neuroinflammatory responses to improve cognitive dysfunction in AD rats, possibly related to upregulation of the PI3K/AKT pathway, providing a scientific basis for its use in AD treatment.

Shenfu injection ameliorates endotoxemia-associated endothelial dysfunction and organ injury via inhibiting PI3K/Akt-mediated glycolysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Microcirculatory dysfunction is one of the main characteristics of sepsis. Shenfu Injection (SFI) as a traditional Chinese medicine is widely applied in clinical severe conditions. Recent studies have shown that SFI has the ability to ameliorate sepsis-induced inflammation and to improve microcirculation perfusion. AIM OF THE STUDY: This study aims to investigate the underlying mechanism of SFI for ameliorating sepsis-associated endothelial dysfunction and organ injury. MATERIALS AND METHODS: Side-stream dark-field (SDF) imaging was used to monitor the sublingual microcirculation of septic patients treated with or without SFI. Septic mouse model was used to evaluate the effects of SFI in vivo. Metabolomics and transcriptomics were performed on endothelial cells to identify the underlying mechanism for SFI-related protective effect on endothelial cells. RESULTS: SFI effectively abolished the disturbance and loss of sublingual microcirculation in septic patients. Twenty septic shock patients with or without SFI administration were enrolled and the data showed that SFI significantly improved the levels of total vessel density (TVD), perfused vessel density (PVD), microvascular flow index (MFI), and the proportion of perfused vessels (PPV). The administration of SFI significantly decreased the elevated plasma levels of Angiopoietin-2 (Ang2) and Syndecan-1, which are biomarkers indicative of endothelial damage in sepsis patients. In the mouse septic model in vivo, SFI inhibited the upregulation of endothelial adhesion molecules and Ly6G + neutrophil infiltration while restored the expression of VE-Cadherin in the vasculature of the lung, kidney, and liver tissue. Additionally, SFI reduced the plasma levels of Ang2, Monocyte Chemoattractant Protein-1(MCP1), and Interleukin-6 (IL6), and alleviated liver and kidney injury in septic mice. Moreover, SFI significantly inhibited the inflammatory activation and increased permeability of endothelial cells induced by endotoxins in vitro. By performing metabolomics and transcriptomics, we identified the activation of PI3K/Akt-mediated glycolysis as the underlying mechanism for SFI-related protective effect on endothelial cells. CONCLUSIONS: Our findings revealed that SFI may improve microcirculation perfusion and endothelial function in sepsis via inhibiting PI3K/Akt-mediated glycolysis, providing theoretical evidence for the clinical application of SFI.

[Compatibility mechanism of Qishen Yiqi Dripping Pills for treatment of myocardial ischemia based on UPLC-Q-Exactive Orbitrap-MS and network pharmacology].

Clinical efficacy and mechanism of Qishen Yiqi Dripping Pills(QSYQ) have been well researched, but the compatibility mechanism underlying its therapeutic effect still requires further analysis. This study aims to explore the compatibility mechanism of QSYQ in treating myocardial ischemia. UPLC-Q-Exactive Orbitrap-MS technique was used to obtain the absorbed blood components of QSYQ. Target proteins of the absorbed components were collected and screened using TCMSP, TCMIP, and SwissTargetPrediction databases. Disease proteins related to myocardial ischemia were obtained through GeneCards, OMIM, and DisGeNET databases. Core targets and core components were obtained using online plotting software Venny 2.1.0, STRING, and Cytoscape 3.9.1 software. David database was used for GO functional annotation and KEGG pathway enrichment of core targets, obtaining the main pathways of QSYQ in treating myocardial ischemia and drawing visualized network diagrams. The compatibility mechanism was analyzed based on "component-target", "drug-pathway", and "PI3K-AKT" characteristic pathways, and molecular docking was used for validation. This study obtained 42 absorbed blood components of QSYQ, 556 component targets, 1 980 disease targets, 69 core targets, and 15 core components. QSYQ can exert therapeutic effects on myocardial ischemia by regulating proteins such as MAPK1, RELA, SRC, JUN, and STAT3, acting on signaling pathways such as HIF-1, PI3K-AKT, Toll-like, MAPK, VEGF, etc. The interaction network diagrams of "component-target" and "drug-pathway" preliminarily elucidated the synergy among the four drugs in this prescription at the level of targets and pathways. The PI3K-AKT characteristic pathway indicated that the sovereign drug Huangqi(Astragali Radix) and minister drug Danshen(Salviae Miltiorrhizae Radix et Rhizoma) could regulate most targets in this pathway, while the assistant drug Sanqi(Notoginseng Radix et Rhizoma) cooperated with Huangqi and Danshen on IL6 and AKT proteins, and the envoy drug Jiangxiang(Dalbergiae Odoriferae Lignum) acted on AKT and RXRA proteins, with all drugs acting synergistically on proteins such as AKT, RXRA, NFKB to regulate cell survival and promote angiogenesis. Molecular docking indicated that hydrogen bonding and hydrophobic interactions might be the main forms of action, also validating the distribution of binding energy of the PI3K-AKT signaling pathway. This study analyzed the compatibility connotation of QSYQ from multiple dimensions including drugs, components, targets, and pathways, providing reference basis for the study of the mechanism of action and compatibility rules of QSYQ.

[Effect of 2-phenylethyl-beta-glucopyranoside isolated from Huaizhong No. 1 Rehmannia glutinosa on hypoxic pulmonary hypertension by regulating PI3K/Akt/m TOR/HIF-1α pathway].

The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.

LINC01370 suppresses hepatocellular carcinoma proliferation and metastasis by regulating the PI3K/AKT pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) poses a serious threat to human health worldwide. lncRNA dysregulation is frequently observed in various cancers, including HCC. However, the function of LINC01370 in HCC progression and its underlying mechanisms remain unclear. METHODS: LINC01370 expression in HCC tissues with cells was analyzed by applying the GEO and GEPIA databases and qRT-PCR. CCK-8 and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. The PI3K, AKT, with p-AKT protein expression were analyzed by western blotting. RESULTS: Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) showed that LINC01370 expression was significantly lower in HCC tissues than in normal tissues. LINC01370 overexpression markedly repressed HepG2 SMMC-7721 cells proliferation, migration, and invasion. To understand the downstream mechanism of LINC01370 regulation, we further analyzed the genes co-expressed with LINC01370 in GSE136247 and GSE132037 and then performed KEGG analysis. The PA pathway was found to be a downstream pathway regulated by LINC01370 in GSE136247 and GSE132037 via gene co-expression and KEGG analysis. Furthermore, PI3K and p-AKT protein levels decreased after LINC01370 overexpression. Importantly, rescue experiments showed that activation of the PI3K/AKT pathway disrupted the repressive effect of LINC01370 overexpression on the proliferation, migration, and invasion of HepG2 of SMMC-7721 cells. CONCLUSIONS: This study verified that LINC01370 suppresses HCC proliferation with metastasis by regulating the PI3K/AKT pathway.

Polystyrene nanoplastics induce apoptosis, autophagy, and steroidogenesis disruption in granulosa cells to reduce oocyte quality and fertility by inhibiting the PI3K/AKT pathway in female mice.

BACKGROUND: Nanoplastics (NPs) are emerging pollutants that pose risks to living organisms. Recent findings have unveiled the reproductive harm caused by polystyrene nanoparticles (PS-NPs) in female animals, yet the intricate mechanism remains incompletely understood. Under this research, we investigated whether sustained exposure to PS-NPs at certain concentrations in vivo can enter oocytes through the zona pellucida or through other routes that affect female reproduction. RESULTS: We show that PS-NPs disrupted ovarian functions and decreased oocyte quality, which may be a contributing factor to lower female fertility in mice. RNA sequencing of mouse ovaries illustrated that the PI3K-AKT signaling pathway emerged as the predominant environmental information processing pathway responding to PS-NPs. Western blotting results of ovaries in vivo and cells in vitro showed that PS-NPs deactivated PI3K-AKT signaling pathway by down-regulating the expression of PI3K and reducing AKT phosphorylation at the protein level, PI3K-AKT signaling pathway which was accompanied by the activation of autophagy and apoptosis and the disruption of steroidogenesis in granulosa cells. Since PS-NPs penetrate granulosa cells but not oocytes, we examined whether PS-NPs indirectly affect oocyte quality through granulosa cells using a granulosa cell-oocyte coculture system. Preincubation of granulosa cells with PS-NPs causes granulosa cell dysfunction, resulting in a decrease in the quality of the cocultured oocytes that can be reversed by the addition of 17ß-estradiol. CONCLUSIONS: This study provides findings on how PS-NPs impact ovarian function and include transcriptome sequencing analysis of ovarian tissue. The study demonstrates that PS-NPs impair oocyte quality by altering the functioning of ovarian granulosa cells. Therefore, it is necessary to focus on the research on the effects of PS-NPs on female reproduction and the related methods that may mitigate their toxicity.

SHP-1 mediates cigarette smoke extract-induced epithelial-mesenchymal transformation and inflammation in 16HBE cells.

Src-homology region 2 domain-containing phosphatase 1 (SHP-1) is considered an anti-inflammatory factor, but its role in chronic obstructive pulmonary disease (COPD) remains unknown. Herein, overexpression of SHP-1 was utilized to explore the functions of SHP-1 in COPD models established by stimulating 16HBE cells with cigarette smoke extracts (CSE) in vitro. SHP-1 was downregulated in both COPD patients and CES-treated 16HBE cells. SHP-1 overexpression reinforced cell viability and significantly prevented CSE-induced cell apoptosis in 16HBE cells. Furthermore, SHP-1 overexpression greatly reversed the CSE-induced migration, epithelial-mesenchymal transition (EMT), and pro-inflammatory factor production in 16HBE cells. In addition, CSE activated the P65 and PI3K/AKT pathways in 16HBE cells, which was also reversed by SHP-1 overexpression. Our findings indicated that SHP-1 alleviated CSE-induced EMT and inflammation in 16HBE cells, suggesting that SHP-1 regulated the development of COPD, and these functions may be linked to the inhibition of the PI3K/AKT pathway.

Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy.

Osteoarthritis (OA) is a chronic degenerative disease characterized by overall joint tissue damage. Metformin (Met) has been shown to inhibit inflammatory reactions, though its potential protective mechanism on cartilage remains unclear. This study investigated Met's potential to protect cartilage in an OA rat model. Various morphological experiments were conducted to assess changes in cartilage tissue morphology before and after Met treatment. Protein and mRNA levels of cartilage-specific genes were measured using western blot, immunohistochemical staining, and RT-qPCR. Additionally, protein levels of autophagy-related and mTOR pathway-related proteins were measured. The results indicate an imbalance in the synthesis and degradation metabolism of chondrocytes, downregulation of cellular autophagy, and activation of the PI3K/Akt/mTOR pathway after surgery. However, treatment with Met could upregulate the expression of synthetic metabolic factors, indicating its contribution to cartilage repair. Furthermore, analysis of autophagy and pathway protein levels indicated that Met effectively attenuated autophagic damage to osteoarthritic cartilage cells and abnormal activation of the PI3K/Akt/mTOR pathway. In conclusion, Met can inhibit the abnormal activation of the PI3K/AKT/mTOR signaling pathway in cartilage tissue, promote the restoration of cartilage cell autophagic function, improve the balance of cartilage cell synthesis and degradation metabolism, and thus exert a protective effect on rat joint cartilage.

Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway.

Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

Unlocking the potential of edible Ulva sp. seaweeds: Metabolomic profiling, neuroprotective mechanisms, and implications for Parkinson's disease management.

Green seaweed (Ulva sp.) is frequently used as a food component and nutraceutical agent because of its high polysaccharide and natural fiber content in Asian countries. This study investigates both metabolomic profiling of Ulva sp. and the neuroprotective efficacy of its ethanol extract and its underlying mechanisms in a rotenone-induced rat model of neurodegeneration, mimicking Parkinson's disease (PD) in humans. Metabolomic profiling of Ulva sp. extract was done using liquid chromatography high resolution electrospray ionization mass spectrometry and led to the identification of 22 compounds belonging to different chemical classes.Catenin Beta Additionally, this study demonstrated the neuroprotective properties against rotenone-induced PD, which was achieved through the suppression of elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 together with the inhibition of reactive oxygen species (ROS) generation, apoptosis, inflammatory mediators, and the phosphoinositide 3-kinases/serine/threonine protein kinase (PI3K/AKT) pathway. Using a protein-protein interaction network, AKT1, GAPDH, TNF-α, IL-6, caspase 3, signal transducer and activator of transcription 3, Catenin Beta 1, epidermal growth factor receptor, B-cell lymphoma -2, and HSP90AA1 were identified as the top 10 most significant genes. Finally, molecular docking results showed that compounds 1, 3, and 7 might possess a promising anti-parkinsonism effect by binding to active sites of selected hub genes. Therefore, it is hypothesized that the Ulva sp. extract has the potential to be further developed as a potential therapeutic agent for the treatment of PD.

Auriculasin induces mitochondrial oxidative stress and drives ferroptosis by inhibiting PI3K/Akt pathway in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for the majority of cases of lung cancer with poor outcomes. Auriculasin is a prenylated isoflavone abundant in the root of F. philippinensis with multiple pharmacological effects, including anticancer role. However, its roles in NSCLC remain largely unknown. NSCLC A549 cells were treated with auriculasin in vitro, and used to induce xenograft models. Cell viability was detected via CCK-8 assay. Mitochondrial oxidative stress was analyzed by JC-1 staining, ROS staining, and levels of MDA, SOD and GSH. Ferroptosis was assessed via iron content, and levels of ACSL4, PTGS2, FSP1 and GPX4. The phosphorylation levels of PI3K and Akt were measured by western blot. Auriculasin reduced NSCLC cell viability. Auriculasin promoted mitochondrial oxidative stress by reducing mitochondrial membrane potential, SOD and GSH levels, and enhancing ROS and MDA contents. In addition, auriculasin induced ferroptosis via increasing iron, ACSL4 and PTGS3 levels, and decreasing FSP1 and GPX4 levels. Furthermore, the potential targets of auriculasin in NSCLC were enriched in PI3K/Akt signaling. Auriculasin blunted PI3K/Akt pathway activation by blocking the phosphorylation. Activated PI3K/Akt signaling by activator 740Y-P reversed the effects of auriculasin on mitochondrial oxidative stress and ferroptosis. Finally, auriculasin reduced NSCLC cell growth in xenograft models. Auriculasin facilitates mitochondrial oxidative stress and induces ferroptosis through inhibiting PI3K/Akt pathway in NSCLC.

miR-144-3p Targets GABRB2 to Suppress Thyroid Cancer Progression In Vitro.

Thyroid cancer, as one of the most common cancers in many countries, has attracted increasing attention, but its pathogenesis is still unclear. This research explored the effects of miR-144-3p and GABRB2 on thyroid cancer cells and the underlying mechanism. Gene expression data was obtained from the GEO database to analyze differential expression of mRNAs and miRNAs in patients with thyroid cancer. CCK-8, transwell, scratch, and flow cytometry assays were performed to detect cell proliferation, invasion, migration, and apoptosis, respectively. Dual-luciferase reporters were used to detect the binding of miR-144-3p to GABRB2. GABRB2 was highly expressed and miR-144-3p was underexpressed in thyroid cancer. In thyroid cancer cells, inhibiting GABRB2 or upregulating miR-144-3p reduced proliferation, invasion, and migration and increased apoptotic rates; GABRB2 overexpression or miR-144-3p inhibition brought about the opposite results. miR-144-3p targeted GABRB2 and negatively regulated its expression. PI3K/AKT activation was reduced in thyroid cancer cells overexpressing miR-144-3p. GABRB2 overexpression partially mitigated the tumor-suppressive effect of miR-144-3p overexpression. In conclusion, miR-144-3p targets GABRB2 to inhibit PI3K/AKT activation, thereby inhibiting the progression of thyroid cancer in vitro.

Multiple omics integration analysis reveals the regulatory effect of chitosan oligosaccharide on testicular development.

Infertility is a global health problem affecting millions of people of reproductive age worldwide, with approximately half caused by males. Chitosan oligosaccharide (COS) has strong antioxidant capacity, but its impact on the male reproductive system has not been effectively evaluated. To address this, we integrated RNA-seq, serum metabolomics and intestinal 16 S rDNA analysis to conduct a comprehensive investigation on the male reproductive system. The results showed that COS has potential targets for the treatment of oligospermia, which can promote the expression of meiotic proteins DDX4, DAZL and SYCP1, benefit germ cell proliferation and testicular development, enhance antioxidant capacity, and increase the expression of testicular steroid proteins STAR and CYP11A1. At the same time, COS can activate PI3K-Akt signaling pathway in testis and TM3 cells. Microbiome and metabolomics analysis suggested that COS alters gut microbial community composition and cooperates with serum metabolites to regulate spermatogenesis. Therefore, COS promotes male reproduction by regulating intestinal microorganisms and serum metabolism, activating PI3K-Akt signaling pathway, improving testicular antioxidant capacity and steroid regulation.

Theaflavins mitigate diabetic symptoms in GK rats by modulating the INSR/PI3K-Akt/GSK-3 pathway and intestinal microbiota.

Dietary management and interventions are crucial in the clinical management of diabetes. Numerous active dietary components in black tea have demonstrated positive effects on blood glucose levels and metabolic functions. However, limited research has explored the potential of theaflavins (TF), polyphenols in black tea, for diabetes management. In this study, high-purity TF was administered to Goto-Kakizaki (GK) diabetic model rats for four weeks to investigate its impact on diabetic pathology and analyze the underlying mechanisms through liver transcriptomics, hepatocyte metabolomics, and gut microbiome analysis. The findings indicated that continuous administration of TF (100 mg/kg) significantly suppressed blood glucose levels, reduced insulin resistance, and decreased the expression of oxidative stress indicators and inflammatory factors in GK rats. Further analysis revealed that TF might alleviate insulin resistance by improving hepatic glycogen conversion and reducing hepatic lipid deposition through modulation of key pathways, such as peroxisome proliferator-activated receptors and PI3K/AKT/GSK-3 pathways within the liver, thereby ameliorating diabetic symptoms. Additionally, TF intake facilitated the restoration of the intestinal microbial community structure by reducing the abundance of harmful bacteria and increasing the abundance of beneficial bacteria. It also reduced endotoxin lipopolysaccharide production, thereby lowering the chances of insulin resistance development and enhancing its efficacy in regulating blood glucose levels. These findings offer a novel perspective on the potential of black tea and its active constituents to prevent and treat diabetes and other metabolic disorders, providing valuable references for identifying and applying active dietary components from tea.

PLCL/SF/NGF nerve conduit loaded with RGD-TA-PPY hydrogel promotes regeneration of sciatic nerve defects in rats through PI3K/AKT signalling pathways.

Peripheral nerve defect are common clinical problem caused by trauma or other diseases, often leading to the loss of sensory and motor function in patients. Autologous nerve transplantation has been the gold standard for repairing peripheral nerve defects, but its clinical application is limited due to insufficient donor tissue. In recent years, the application of tissue engineering methods to synthesize nerve conduits for treating peripheral nerve defect has become a current research focus. This study introduces a novel approach for treating peripheral nerve defects using a tissue-engineered PLCL/SF/NGF@TA-PPy-RGD conduit. The conduit was fabricated by combining electrospun PLCL/SF with an NGF-loaded conductive TA-PPy-RGD gel. The gel, synthesized from RGD-modified tannic acid (TA) and polypyrrole (PPy), provides growth anchor points for nerve cells. In vitro results showed that this hybrid conduit could enhance PC12 cell proliferation, migration, and reduce apoptosis under oxidative stress. Furthermore, the conduit activated the PI3K/AKT signalling pathway in PC12 cells. In a rat model of sciatic nerve defect, the PLCL/SF/NGF@TA-PPy-RGD conduit significantly improved motor function, gastrocnemius muscle function, and myelin sheath axon thickness, comparable to autologous nerve transplantation. It also promoted angiogenesis around the nerve defect. This study suggests that PLCL/SF/NGF@TA-PPy-RGD conduits provide a conducive environment for nerve regeneration, offering a new strategy for peripheral nerve defect treatment, this study provided theoretical basis and new strategies for the research and treatment of peripheral nerve defect.

AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells.

Multiple myeloma (MM) is an incurable malignancy of plasma cells that is sensitive to T-5224, an AP-1 inhibitor. Previous study indicated that T-5224 inhibits proliferation and induces apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated ferroptosis induced by T-5224 in MM. Therefore, we further investigated the mechanism by which T-5224 kills MM cells. We observed that T-5224 exhibits antimyeloma properties both in vitro and in vivo. T-5224-induced MM cell death was reversed by the ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels of the key ferroptosis regulators GPX4 and SLC7A11 were decreased by T-5224 in MM cells. Furthermore, T-5224 reduced the phosphorylation of PI3K and AKT signaling pathway components, ultimately causing MM cell death. Using 740 Y-P, a PI3K activator, and Fer-1, a ferroptosis inhibitor, we discovered that T-5224 induces ferroptosis through the PI3K/AKT pathway. Bortezomib (BTZ), an FDA-approved drug for MM treatment, can be administered in combination with other agents. We evaluated the synergistic effect of BTZ combined with AP-1 inhibitors on MM in vivo. Our findings provide a better theoretical basis for the potential mechanism of T-5224 and a new perspective on MM treatment.

Integrating rapamycin with novel PI3K/Akt/mTOR inhibitor microRNAs on NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL).

Introduction: The PI3K/AKT/mTOR signaling pathway plays a significant role in the development of T-cell acute lymphoblastic leukemia (T-ALL). Rapamycin is a potential therapeutic strategy for hematological malignancies due to its ability to suppress mTOR activity. Additionally, microRNAs (miRNAs) have emerged as key regulators in T-ALL pathophysiology and treatment. This study aimed to investigate the combined effects of rapamycin and miRNAs in inhibiting the PI3K/AKT/mTOR pathway in T-ALL cells. Methods: Bioinformatic algorithms were used to find miRNAs that inhibit the PI3K/AKT/mTOR pathway. Twenty-five bone marrow samples were collected from T-ALL patients, alongside five control bone marrow samples from non-leukemia patients. The Jurkat cell line was chosen as a representative model for T-ALL. Gene and miRNA expression levels were assessed using quantitative real-time PCR (qRT-PCR). Two miRNAs exhibiting down-regulation in both clinical samples and Jurkat cells were transfected to the Jurkat cell line to investigate their impact on target gene expression. Furthermore, in order to evaluate the potential of combination therapy involving miRNAs and rapamycin, apoptosis and cell cycle assays were carried out. Results: Six miRNAs (miR-3143, miR-3182, miR-99a/100, miR-155, miR-576-5p, and miR-501- 3p) were predicted as inhibitors of PI3K/AKT/mTOR pathway. The expression analysis of both clinical samples and the Jurkat cell line revealed a simultaneous downregulation of miR-3143 and miR-3182. Transfection investigation demonstrated that the exogenous overexpression of miR-3143 and miR-3182 can effectively inhibit PI3K/AKT/mTOR signaling in the Jurkat cell line. Moreover, when used as a dual inhibitor along with rapamycin, miR-3143 and miR-3182 significantly increased apoptosis and caused cell cycle arrest in the Jurkat cell line. Conclusion: These preliminary results highlight the potential for improving T-ALL treatment through multi-targeted therapeutic strategies involving rapamycin and miR-3143/miR-3182.