Urinary bladder cancer (UBC), the tenth most common cancer globally, is primarily categorized into non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) types. NMIBC has a low risk of metastasis but tends to recur frequently after transurethral resection, whereas MIBC is associated with a higher likelihood of metastasis and poorer prognosis. At diagnosis, roughly 75 % of UBC patients have NMIBC, while the remaining 25 % present with tumor invasion into the bladder's muscle layer. The molecular complexity of UBC has driven research toward identifying subtypes for more personalized treatment approaches. Glycogen synthase kinase-3β (GSK-3β) has emerged as a pivotal regulator in UBC through its dual roles across six key pathways: (1) Wnt/β-catenin regulation (tumor suppression vs oncogenic activation), (2) ER stress responses (apoptosis induction vs cytoprotection), (3) Akt/GSK-3β/β-catenin/c-Myc signaling, (4) PI3K/Akt/mTOR interactions, (5) NF-κB-mediated immune modulation, and (6) Snail1/β-catenin-driven epithelial mesenchymal transition (EMT). Our analysis reveals that GSK-3β's context-dependent functions create both therapeutic opportunities and challenges - while inhibition suppresses tumor growth via β-catenin degradation, it may simultaneously activate NF-κB-mediated oncogenic processes. These paradoxical effects are particularly evident in the tumor microenvironment, where GSK-3β modulation differentially regulates CD8+ T cell function and macrophage polarization. Understanding these complex pathway interactions is crucial for developing precision therapies that exploit GSK-3β's tumor-suppressive roles while mitigating its oncogenic potential.

Gastric cancer (GC), one of the most prevalent malignancies worldwide, is distinguished by extensive genetic and phenotypic heterogeneity, posing persistent challenges to conventional diagnostic and therapeutic strategies. The significant global burden of GC highlights an urgent need to unravel its complex underlying mechanisms, discover novel diagnostic and prognostic biomarkers, and develop more effective therapeutic interventions. In this context, this review comprehensively examines the transformative roles of cutting-edge technologies, including radiomics, pathomics, genomics, transcriptomics, epigenomics, proteomics, and metabolomics, in advancing precision diagnosis and treatment for GC. Multiomics data analysis not only deepens our understanding of GC pathogenesis and molecular subtypes but also identifies promising biomarkers, facilitating the creation of tailored therapeutic approaches. Additionally, integrating multiomics approaches holds immense potential for elucidating drug resistance mechanisms, predicting patient outcomes, and uncovering novel therapeutic targets, thereby laying a robust foundation for precision medicine in the comprehensive management of GC.

This study aimed to (i) investigate the relationship between X-ray repair cross-complementing protein 1 gene (XRCC1) and prognosis in patients with adenocarcinoma of the esophagogastric junction (AEG), and (ii) analyze the roles of XRCC1 in human gastric adenocarcinoma (AGS) cells following X-ray radiation.

A total of 46 AEG patients were enrolled and examined for XRCC1 protein by immunohistochemistry. XRCC1 was knocked down in AGS cells by transfection, and AGS cells were subsequently exposed to 6 Gy of X-ray radiation. XRCC1 mRNA and protein expression was examined via quantitative real-time PCR (qRT-PCR) and Western blot analysis. The apoptosis of AGS cells was examined by flow cytometer. RNA-sequencing technology was used to identified differentially expressed genes and alternative splicing events following XRCC1 knockdown and radiation exposure.

XRCC1 positivity was strongly associated with distant metastasis, pathological tumor-node-metastasis (pTNM) classification, and radiotherapy resistance in AEG patients. A significant difference in progression-free survival was observed between AEG patients with low and high XRCC1 protein expression. The knockdown of XRCC1 notably exacerbated the effects of X-ray radiation on apoptosis in AGS cells. Additionally, X-ray radiation modified the expression of genes related to apoptosis and immune response in XRCC1-knockdown AGS cells. Furthermore, the generation of splice variants was influenced by XRCC1 knockdown in AGS cells.

XRCC1 may serve as a key oncogene that elucidates the role of alternative splicing events in the progression of AEG following X-ray treatment.

Gastric cancer (GC) remains a significant health concern with limited therapeutic options. While trastuzumab, a Human Epidermal Growth Factor Receptor 2 (HER2)-targeting antibody, has shown efficacy in HER2-positive GC, its therapeutic response is moderate. Hedgehog (Hh) signalling plays a critical role in the progression of GC.

We evaluated the sensitivity of various GC cell lines to trastuzumab. The HER2-positive HGC-27 cell line was identified as the most sensitive. In addition, the effects of two Hedgehog inhibitors, vismodegib and cyclopamine, were assessed on cell growth by monitoring SMO expression. Both in vitro and in vivo assays were conducted to explore the combination of Hh inhibitors and trastuzumab.

Both vismodegib and cyclopamine exerted anti-proliferative effects, and synergistically enhanced the anti-tumour activity of trastuzumab in HER2-positive GC models. Mechanistically, Hh inhibitors inhibited the AKT/mTOR signalling pathway through Smoothened (SMO) depletion, contributing to their anti-growth effects.

This study highlights the potential of combining Hh inhibitors with trastuzumab as a therapeutic strategy for HER2-positive GC by targeting the AKT/mTOR pathway.

Natural marine products possess pharmacological effects and have been a source of novel drugs for centuries. In this study, we explored the anti-tumor activity and underlying mechanism of action of ilimaquinone, a sesquiterpene quinone from marine sponges, in gastric cancer. Three gastric cancer cell lines (KATO III, SCM-1, and AZ521) were cultured. Cell viability, cell cycle, and apoptosis were determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and flow cytometry. The levels of apoptotic proteins, proteins related to autophagy, and signal transducer and activator of transcription 3 (STAT3) were detected using western blotting. Transient transfection experiments were conducted to assess the expression of STAT3 in the gastric cancer cells. Ilimaquinone inhibited cell growth, caused cell cycle arrest in the S phase, and induced apoptosis. In addition, ilimaquinone modulates autophagy, and the viability of gastric cancer cells decreases upon exposure to a combination of the autophagic inhibitor, chloroquine. Notably, ilimaquinone downregulated the expression of p-STAT3 in a concentration- and time-dependent manner in both gastric cancer cell lines. Moreover, the compound-mediated inhibition of gastric cancer cell proliferation was restored by ectopic STAT3 expression. Collectively, these findings demonstrate the value of ilimaquinone in the treatment of gastric cancer.

Gastrointestinal malignancies are a major public health concern worldwide, characterized by high incidence and mortality rates. Despite continuous advancements in existing treatment methods, overall survival rates remain low. Lipid metabolism plays a crucial role in the occurrence, progression, and treatment of gastrointestinal malignancies. Its involvement in the metabolic reprogramming of tumor cells, regulation of the tumor microenvironment, and drug response has become a research hotspot.

This review summarizes current research related to lipid metabolism mechanisms, biomarkers, and therapies in GI cancers, with emphasis on its interaction with the tumor microenvironment.

Gallbladder Cancer (GBC) is a lethal malignancy with limited treatment options and poor prognosis. Recent studies have emphasized the role of ferroptosis, a regulated form of cell death, in various cancers, including GBC. We applied bioinformatics methodologies on four GBC datasets to identify differentially expressed genes (DEGs). An intersection of DEGs from the four datasets with ferroptosis and GBC-associated genes was done to identify key ferroptosis-related genes in GBC. GSVA pathway enrichment analysis and immune cell infiltration assessment were conducted to explore their functional roles and interactions. Seven ferroptosis-related genes, EZH2, MUC1, PVT1, GOT1, CDO1, LIFR, and TFAP2A, were identified to be related to GBC. These genes were associated with vital signaling pathways like the G2/M checkpoint and DNA repair and showed significant correlations with immune cell infiltration in GBC. Receiver Operating Characteristic (ROC) curve analysis revealed their high diagnostic potential, with Area Under the Curve (AUC) values ranging from 0.796 to 0.953. Our findings underscore the pivotal role of ferroptosis in GBC and the potential of ferroptosis-related genes as diagnostic biomarkers. This study lays a foundation for further research into ferroptosis-based therapeutic strategies for GBC.

The phosphatidylinositol-3-kinases (PI3K) signaling pathway is highly complex and well-known to exert oncogenic roles in multiple cancer types. Exploring new factors involved in this pathway may offer the potential for improving the early diagnosis and treatment strategies for cancers. Here we used gastric cancer (GC) as a model to identify co-regulated effectors downstream of three catalytic subunits of PI3K through high-throughput sequencing in PIK3CA, PIK3CB, and PIK3CD knockdown GC cells. C15orf39, a new uncharacterized gene, was selected due to the most significant expression change. qRT-PCR and immunohistochemistry analyses revealed that C15orf39 was frequently upregulated in GC tissues and strongly correlated with poor clinical outcomes in GC patients. Gain- and loss-of-function studies demonstrated that C15orf39 promoted GC cell proliferation, migration, and drug resistance. Mechanistically, C15orf39 promoted GC progression possibly via modulating cell mitosis and cell cycle. FOXK2, a transcription factor activated by PI3K/AKT signaling, could bind to the promoter of C15orf39 and positively regulate C15orf39 expression. These findings unveiled a new PI3K/AKT/FOXK2/C15orf39 signaling axis that promotes GC development and progression. C15orf39 may become a potential biomarker for early diagnosis and personalized treatment to improve the prognosis of GC patients.

Gastric cancer (GC) is a prevalent malignancy with a high incidence rate. Growth factor receptor-bound protein 14 (GRB14) is crucial in cell signal transduction and is associated with tumor growth, invasion, and metastasis. The aim of this study is to investigate the impact of GRB14 on GC growth and metastasis. GRB14 expression and prognosis in GC tissues were analyzed using bioinformatics. The GC cell lines, SGC-7901, MGC-803, BGC-823, and normal gastric epithelial cell line (GES-1) were used in this study. Cell viability, cycle progression, and apoptosis were assessed via CCK-8 and flow cytometry. The colony formation, transwell, and wound-healing assays were conducted to evaluate cell proliferation, invasion, and migration. Protein levels involved in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by Western blot. GRB14 expression was significantly higher in GC tissues than adjacent healthy tissues, correlating with poor prognosis. GRB14 knockdown promoted apoptosis and inhibited cell growth, invasion, and migration, while its overexpression exhibited opposite effects. GRB14 directly interacted with cordon-bleu WH2 repeat protein like 1, facilitating PI3K/AKT signaling in GC cells. This study highlights GRB14's critical role in GC progression and suggests its potential as a therapeutic target.

Ketogenesis and the PI3K/AKT/mTOR pathway are linked to metabolic imbalance and disease progression. While ketone metabolism and mTOR inhibition are mechanistically connected, their functional relationship across disease models remains unclear. Although ketogenesis can be induced by ketone ingestion, ketogenic diet, or fasting, their individual effects on this pathway require further clarification. This study systematically reviews the relationship between ketogenesis and PI3K/AKT/mTOR signaling, following PRISMA guidelines across 3 databases. Eligible studies that met the selection criteria were evaluated using the risk of bias tools. In most studies involving the ketogenic diet or ketone bodies, suppression of the signaling pathway may lead to positive outcomes in terms of survival rate, lifespan, improved metabolic homeostasis, enhanced neurovascular function and suppressed progression of tumors. By contrast, β-hydroxybutyrate supplementation is associated with the up-regulation of AKT and downstream markers. It may exert an anabolic activity by activating the mTOR signaling pathway in muscle atrophy models and is associated with muscle recovery. Although fasting increases p-AKT expression, this may not necessarily indicate activation of the downstream mTOR signaling cascade, as it could result from an insulin response or regulatory feedback mechanisms. Regulation of the mTOR signaling by ketogenesis may be tissue-specific. Inhibition of PI3K/AKT/mTOR in ketogenesis-induced circumstances may justify the importance of a ketogenic-based diet regimen in combating metabolic diseases. However, future studies should consider standardizing factors such as the duration of fasting, timing, composition of the ketogenic diet and target tissues as these factors may affect study outcomes.

Gastric cancer (GC) is one of the most common malignant tumors with poor survival. Although cisplatin is a first-line chemotherapy drug for GC, it still has the potential to develop drug resistance and side effects. Miltirone, extracted from Chinese herb Salvia miltiorrhiza Bunge, has been reported to significantly inhibit some types of cancer. However, its effects on GC have not been studied, the possible anti-tumor effects of miltirone in combination with cisplatin in GC patients have not been explored.

Human GC cell lines AGS, HGC27, MKN45 and MGC803 cells were treated with miltirone and cisplatin individually or combinatorially. Cell proliferation assay, flow cytometric assay, colony formation assay and Western blot were employed to evaluate the cytotoxic effects under these treatments. Wound healing and transwell assays were used to examine the effects of miltirone and/or cisplatin on GC cell migration and invasion. RNA-seq analysis was used to determine miltirone's potential target genes in AGS cells. GO analysis and molecular docking assay were used to determine the pathways affected by miltirone. Next, we examined changes in the selected pathway proteins. The in vivo animal model was verified the results of the in vitro experiments.

Miltirone inhibited cell growth, migration, and invasion, as well as induced apoptosis in GC cells. In combinatorial treatments, miltirone synergistically enhanced cytotoxicity of cisplatin in GC cells. Moreover, the expression levels of 606 genes appeared to be significantly modulated by miltirone via RNA-seq analyses, and PI3K/AKT signaling pathway was found to refer to miltirone activity. Furthermore, miltirone together with cisplatin treatment significantly reduced the expression levels of p-PI3K, p-Akt, p-mTOR, while the total levels of PI3K and Akt remained unchanged. In addition, compared with the control group, the tumors growth was significantly suppressed in groups treated with the two agents alone or in combination, and even more so in the combination group in vivo.

Miltirone inhibited the proliferation of GC cells and significantly potentiates the anticancer activities of cisplatin by downregulating the PI3K/AKT signaling pathway. Combination therapy of miltirone and cisplatin represents a novel potential treatment of gastric cancer.

Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.

We aimed to explore the biological function of CLMP in colorectal cancer (CRC) and to determine the effect of CLMP on 5-fluorouracil (5-FU) sensitivity in CRC.

Sixteen pairs of CRC tissues and paracancerous tissues were collected. Immortalized intestinal epithelial cell lines and human CRC cell lines were purchased, and the cells were treated with DMSO and 5-FU. RTqPCR, western blotting, CCK8, colony formation, scratch, and Transwell assays were performed to determine the molecular mechanism of CLMP in the regulation of autophagy and sensitivity to 5-FU in CRC cells.

CLMP was expressed at low levels in CRC tissues. The upregulation of CLMP expression could inhibit cell proliferation, colony number, migration and invasion and increase the sensitivity of CRC cells to 5-FU. Mechanistic studies revealed that the overexpression of CLMP could block the activation of the PI3K/AKT signaling pathway, inhibit autophagy, and increase the chemosensitivity of CRC cells to 5-FU.

CLMP overexpression can reduce the level of autophagy and increase the sensitivity of CRC to 5-FU, providing a potential target for the treatment of CRC.

Pharmacological interventions targeting the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway are predominantly employed as anticancer therapies, yet they are frequently associated with significant cardiac toxicity. Additionally, the PI3K/Akt/mTOR pathway plays a crucial role in the treatment of cardiovascular diseases, highlighting its dual significance in both oncology and cardiology. Therefore, the PI3K/Akt/mTOR pathway has become an ideal signaling pathway for studying cardioprotection, anticancer effects, and their associated cardiac toxicity. Botanical drugs have emerged as a significant source for developing therapeutic agents with anticancer and cardioprotective effects, often exhibiting bidirectional protective properties. Consequently, this study investigates the bidirectional regulatory influence of botanical drug metabolites in oncology and cardiology via the PI3K/Akt/mTOR pathway. The research indicated that the PI3K/Akt/mTOR signaling pathway plays a critical regulatory role in the pathogenesis of both tumors and cardiovascular diseases. The botanical drug metabolites Ruscogenin, Sulforaphane, Naringenin, Kaempferol, Poncirin, and Puerarin can improve cancer by inhibiting the phosphorylation levels within the PI3K/Akt/mTOR signaling cascade. Moreover, they also provide cardioprotective effects in cardiac injury conditions by activating the phosphorylation levels of the PI3K/Akt/mTOR pathway. Therefore, the phosphorylation dynamics of key components in the PI3K/Akt/mTOR pathway, particularly the phosphorylation of Akt, along with the functional implications of different phosphorylation sites, may offer new therapeutic strategies and insights for cancer treatment and the mitigation of cardiotoxicity associated with cancer therapies.

Gastric cancer (GC) is one of the most common gastrointestinal cancers worldwide, with consistently high morbidity and mortality rates and poor prognosis. Most patients are diagnosed at an advanced stage due to the lack of specific presentation in the early stages. Exosomes are a class of extracellular vesicles (EVs) widely found in body fluids and can release genetic material or multiple proteins to facilitate intercellular communication. In recent years, exosomal miRNAs have gained attention for their role in various cancers. These exosomal miRNAs can impact GC development and progression by targeting specific genes or influencing signaling pathways and cytokines involved in Angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and immune regulation. They show great potential in terms of diagnosis, prognosis, and treatment of GC. Notably, the gastrointestinal tract has the largest number of macrophages, which play a significant role in GC progression. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and can influence macrophage programming through various mediators, including macrophage polarization. Macrophage polarization is involved in inflammatory responses and significantly impacts the GC process.

This study aimed to investigate the role and potential mechanism of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in chronic intermittent hypoxia (CIH)-induced mice and pulmonary arterial smooth muscle cells (PASMCs).

CIH mouse model was pre-injected with AAV-shPLOD2 by tail vein, and the pathological changes of lung was evaluated using hematoxylin-eosin (H&E) and α-SMA immunostaining. Enriched KEGG pathway analyses of PLOD2 targeted genes were performed using GSE11341 and GSE131425 datasets. Next, primary PASMCs were exposed to CIH environment, and then measured its proliferation, migration and glycolysis by CCK8, EdU assay, wound healing assay, Transwell and western blotting.

PLOD2 expression was increased in the lungs of CIH-induced mice and in PASMCs under CIH conditions. Moreover, glycolysis and PI3K/AKT pathway were regulated by PLOD2. Silencing of PLOD2 significantly inhibited the increase of RV/(LV + S) and RVSP, alleviated pathological changes of lung in CIH-induced mice and restrained the proliferation, migration, glycolysis and activation of PI3K/AKT in CIH-induced PASMCs. The inhibitory effects of PLOD2 silencing on PASMC proliferation and migration were accelerated by 2-DG (an inhibitor of glycolysis) and were reversed by lactate (the end product of glycolysis). In addition, the inhibitory effects of PLOD2 silencing on PASMC proliferation, migration and glycolysis were accelerated by PI3K/AKT inhibitor LY294002 and were reversed by the agonist 740Y-P.

Silencing of PLOD2 inhibits PI3K/AKT signaling to limit PASMC glycolysis which allows PASMC proliferation and migration in CIH-induced pulmonary arterial hypertension (PAH).

Cancer represents a significant disease that profoundly impacts human health and longevity. Projections indicate a 47% increase in the global cancer burden by 2040 compared to 2020, accompanied by a further rise in the associated economic burden. Consequently, there is an urgent need to discover and develop new alternative drugs to mitigate the global impact of cancer. Natural products (NPs) play a crucial role in the identification and development of anticancer therapeutics. This study identified ustusolate E (UE) and its analog 11α-hydroxy-ustusolate E (HUE) from strain Aspergilluscalidoustus TJ403-EL05, and examined their antitumor activities and mechanisms of action. The findings demonstrate that both compounds significantly inhibited the proliferation and colony formation of AGS (human gastric cancer cells) and 786-O (human renal clear cell carcinoma cells), induced irreversible DNA damage, blocked the cell cycle at the G2/M phase, and further induced apoptosis in tumor cells. To the best of the authors' knowledge, this is the first report on the anticancer effects of UE and HUE and their underlying mechanisms. The present study suggests that HUE and UE could serve as lead compounds for the development of novel anticancer drugs.

Gastric cancer ranks among the most prevalent malignancies globally, characterized by limited treatment efficacy and high recurrence rates. Effective management of this disease requires a comprehensive understanding of its underlying pathogenic mechanisms. Galectins have emerged as promising targets in gastric cancer therapy, with Galectin-9 (LGALS9) receiving considerable attention in recent years. However, Galectin-9B (LGALS9B) remains relatively under-explored in gastric cancer research. Our study investigates the role of LGALS9B in gastric cancer progression, demonstrating that its over-expression enhances cellular proliferation, migration, and invasion, while its knockdown inhibits these processes both in vitro and in vivo. We further elucidate that LGALS9B competes with the E3 ligase HERC5 for binding to eukaryotic translation elongation factor 1 delta (EEF1D), thereby preventing its protein degradation. This interaction results in the enrichment of EEF1D, which activates the PI3K/AKT signaling pathway and ultimately promotes gastric cancer progression. These findings highlight the regulatory role of LGALS9B in the pathogenesis of gastric cancer, offering valuable insights into potential novel therapeutic strategies for managing this challenging disease.

Adiponectin (ADN) regulates DNA synthesis, cell apoptosis and cell cycle to participate in the pathology and progression of glioblastoma. The present study aimed to further explore the effect of ADN on temozolomide (TMZ) resistance in glioblastoma and the underlying mechanism of action. Glioblastoma cell lines (U251 and U87-MG cells) were treated with ADN and TMZ at different concentrations; subsequently, 3.0 µg/ml ADN and 1.0 mM TMZ were selected as the optimal concentrations for the experimental conditions. LY294002 (a PI3K inhibitor) was added to ADN or ADN + TMZ-treated glioblastoma cell lines. Cell growth rate was determined using the Cell Counting Kit-8 assay, the apoptotic rate and cell cycle were evaluated using Annexin V/propidium iodide and cell cycle assays, and p-Akt (Thr308), p-Akt (Ser473), Akt, p-mTOR, c-caspase 3, caspase 3, Bax, cyclin B1 and cyclin D1 expression was determined by western blotting. Adiponectin receptor (ADIPOR) 1 and ADIPOR2 were expressed in glioblastoma cell lines. The glioblastoma cell line growth rate was increased by ADN in a concentration- and time-dependent manner. ADN inhibited glioblastoma cell line apoptosis and facilitated cell cycle. Of note, ADN activated the Akt/mTOR pathway and the addition of LY294002 reversed the effect of ADN, indicating that ADN activated the Akt/mTOR pathway to suppress apoptosis and promote cell cycle in glioblastoma cell lines. Notably, TMZ inhibited glioblastoma cell line growth, promoted apoptosis and increased G2 phase cell cycle arrest. However, the addition of ADN reversed the effect of TMZ in glioblastoma cell lines, disclosing that ADN induced TMZ resistance. Markedly, ADN-mediated TMZ resistance was further attenuated by LY294002, suggesting that ADN activated the Akt/mTOR pathway to induce TMZ resistance in glioblastoma cell lines. In conclusion, ADN activated the Akt/mTOR pathway to facilitate cell cycle, inhibit cell apoptosis and induce TMZ resistance in glioblastoma.

To investigate the role of long non-coding RNAs (lncRNAs) in the metabolic reprogramming of gastric cancer through their regulation of mesenchymal stem cells (MSCs) and HERPUD1 protein targets, aiming to elucidate mechanisms that could lead to novel therapeutic strategies.

The RNA-seq was performed on BGC and hMSC-BGC cells to perform LncRNA screening. And we employed cell culture techniques using hMSC-BM and BGC823 cells, treated with various genetic interventions including siRNA and overexpression vectors. Techniques such as cell viability assays, quantitative PCR (qPCR), Western blotting, RNA pull-down and RNA-FISH were utilized to validate the interaction between lncRNA AC012181.2 and HERPUD1 protein. Flow cytometry were utilized to analyze the impacts of lncRNA AC012181.2 on gene and protein expression related to cancer metabolism. Additionally, a tumorigenic model in nude mice was used to observe the in vivo effects.

Modulation of AC012181.2 in MSCs significantly affected the proliferation, migration, and invasion capabilities of BGC823 gastric cancer cells. Knockdown of AC012181.2 resulted in reduced tumor growth in mouse models, along with changes in key gene and protein expression levels associated with cancer metabolism. Overexpression of AC012181.2 showed the opposite effect, enhancing tumor growth and altering cellular behaviors and molecular expressions in favor of cancer progression.

The lncRNA AC012181.2 is crucial for gastric cancer metabolic reprogramming by regulating HERPUD1 Protein. Targeting it offers a promising avenue to impact the tumor microenvironment and develop novel gastric cancer therapies.

Esophageal cancer (EC) is a leading cause of cancer-related mortality worldwide. Methyltransferase-like 3 (METTL3), a key enzyme involved in m6A methylation, has been implicated in the development and progression of various cancers, including EC. However, its potential mechanism of action in EC progression remains unclear. METTL3 expression was found to be upregulated in EC tissues and cells. Knockdown of METTL3 suppressed EC cell proliferation, invasion, migration, and angiogenesis, while promoting apoptosis. Mechanistically, METTL3 maintained PIK3CA mRNA expression and stability in an m6A-dependent and IGF2BP2-dependent manner, respectively. METTL3 silencing inactivated the AKT pathway by regulating PIK3CA expression. Furthermore, overexpression of PIK3CA mitigated the effects of METTL3 silencing on the malignant growth of KYSE180 and TE1 cells in vivo and in vitro. METTL3/IGF2BP2 promoted the malignant progression of EC by activating the PIK3CA/AKT pathway. Targeting the METTL3-PIK3CA axis may offer a novel therapeutic approach for EC treatment.

Radiation therapy is an important method to treat liver cancer, but because of the strong DNA repair ability of liver cancer cells, even after receiving high doses of radiation still can not get satisfactory results. Atorvastatin (ATO) is a lipophilic and tissue-selective inhibitor of HMG-CoA reductase whose anticancer effects have been validated in various cells, but its effect on the radiation sensitivity of hepatocellular carcinoma cells remains unclear. Therefore, Therefore, this study explored the radiosensitivity of ATO and its possible mechanism by pretreating HepG2 with ATO and collecting HepG2 cells after irradiation. It was found that atorvastatin can not only affect the survival of liver cancer cells when used alone, but also enhance the radiation sensitivity of HepG2 cells. The study found that ATO significantly exacerbated the inhibitory effects of IR on the growth, proliferation, and migration of HepG2 cells. Measurement of ROS, SOD, GPx, and MDA levels indicated that ATO enhanced IR-induced oxidative stress, further promoted the decrease of Mitochondrial Membrane Potential, increased the rate of apoptosis in HepG2, upregulating pro-apoptotic proteins Bax and Cleaved-Caspase 3, and downregulating anti-apoptotic proteins Bcl-2. Western blot analysis showed that the PI3K-Akt-mTOR pathway was inhibited, leading to the activation of cytotoxic autophagy in HepG2 and an increase in the expression of the LC-3II protein. In summary, ATO, in combination with IR, enhances the oxidative stress response of HepG2 induced by IR, promotes autophagy by inhibiting the PI3K-Akt-mTOR pathway, and thereby potentially enhances the radiosensitivity of HepG2 as a pharmacological intervention.

With the development of newer biomarkers in the diagnosis of gastric cancer (GC), therapeutic targets are emerging and molecular-targeted therapy is in progress RNA interference has emerged as a promising method of gene targeting therapy. However, naked small interfering RNA (siRNA) is unstable and susceptible to degradation, so employing vectors for siRNA delivery is the focus of our research. Therefore, we developed LMWP modified PEG-SS-PEI to deliver siRNA targeting BRD4 (L-NPs/siBRD4) for GC therapy. L-NPs/siBRD4 were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The release characteristics, cellular uptake and intracellular localization were also investigated. The in vitro anticancer activity of the prepared nanoparticles was analysed by MTT, Transwell invasion and wound healing assay. Quantitative real time-polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of gene silencing. The results showed that the optimal N/P was 30 and the prepared L-NPs/siBRD4 uniformly distributed in the system with a spherical and regular shape. L-NPs/siBRD4 exhibited an accelerated release in GSH-containing media from 12h to 24h. The uptake of L-NPs/siBRD4 was enhanced and mainly co-localized in the lysosomes. After 6h incubation, LMWP modified PEG-SS-PEI helped siRNA escape from the lysosomes and diffused into the cytoplasm. L-NPs/siBRD4 significantly inhibited the proliferation, migration and invasion of cells. This might be related with the silence of BRD4, then inhibition of PI3K/Akt and c-Myc. Our results demonstrate that L-NPs/siBRD4 are a novel delivery system with anticancer, which may provide a more effective strategy for GC treatment.

Cancer, a highly deadly disease, necessitates safe, cost-effective, and readily accessible treatments to mitigate its impact. Theabrownin (THBR), a polyphenolic pigment found in Pu-erh tea, has garnered attention for its potential benefits in memory, liver health, and inflammation control. By observing different biological activities of THBR, recently researchers have unveiled THBR's promising anticancer properties across various human cancer types. By examining existing studies, it is evident that THBR demonstrates substantial potential in inhibiting cell proliferation and reducing tumour size with minimal harm to normal cells. These effects are achieved through the modulation of key molecular markers such as Bcl-2, Bax, various Caspases, Poly (ADP-ribose) polymerase cleavage (Cl-PARP), and zinc finger E box binding homeobox 1 (ZEB 1). This review aims to provide in-depth insights into THBR's role in cancer research. This review also elucidates the underlying anticancer mechanisms of THBR, offering promise as a novel anticancer drug to alleviate the global cancer burden.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

Background/Objectives:Procambarus clarkii is an important freshwater aquaculture species in China which has the characteristics of rich nutrition and delicious taste. However, the expansion of aquaculture scale, germplasm degradation, and other problems that have become increasingly prominent seriously restrict the sustainable development of the crayfish industry. Genetic improvement is an urgent need for the crayfish aquaculture industry, and selective breeding is an important way to improve the crayfish varieties. Methods: We established full-sibling family populations of the red swamp crayfish and performed whole-genome resequencing of the F3 family-selected red swamp crayfish population and wild red swamp crayfish populations from four regions of Hunan Province (Nanx, Mil, Caish, and Wangc). Results: The results showed that there was a clear separation between the wild population and the family population, and the decline rate was slightly faster in the wild population than that of the family breeding population. There was local gene flow between family populations, as well as gene flow between Mil, Caish, and families. In addition, 52 SNP loci related to body weight traits were identified by genome-wide association analysis, and the candidate gene WIPF1 related to growth was screened out. Conclusions: We established a line selection population of red swamp crayfish and obtained more stable candidate lines. In addition, this study identified Wiskott-Aldrich syndrome protein-interacting protein family member 1 (WIPF1) as a candidate gene related to body weight for the first time. The results provide a theoretical basis for exploring the growth mechanism of P. clarkii and carrying out in-depth genetic improvement.

The molecular non-genetic changes of resistance to sotorasib are currently uncertain. The aim of this study was to generate a sotorasib-resistant cell line via selective pressure and systematically examine the molecular and phenotypic alterations caused by resistance.

Mutant NCI-H358 (KRASG12C) were exposed to incremental doses (2-512 nM) of sotorasib. Then, resistant clones were separated by single-cell sorting. Proliferation was analyzed in real-time by xCELLigence; protein profiles were quantified by protein arrays; and mRNA expression profile was measured using the PanCancer Pathways panel by NanoString. In silico analyses were conducted from a database comprising patient-derived xenograft (PDX) models and cell lines resistant to sotorasib. AKT and p38. The synergistic effect of combining AKT, p38, and EGFR inhibitors was assessed using the SynergyFinder platform. Additionally, AKT and p38 genes were silenced using esiRNA.

Sotorasib-resistant H358-R cell line displayed markers of the mesenchymal-epithelial transition and loss of cell adhesion. Were identified 30 overexpressed genes in the resistance model, implicating in signaling pathways that leads to AKT activation and heightened protein expression levels of phosphorylated AKT and p38. To identify potential therapeutic strategies for overcoming sotorasib resistance, we investigated the combination of AKT and p38 inhibitors. Notably, combined inhibition of AKT (MK2206) and p38 (adezmapimod) restored sensitivity to sotorasib in resistant cell lines, as did silencing AKT expression.

These findings underscore the importance of adaptive mechanisms in sotorasib resistance in NSCLC cells contributing by EMT activation and demonstrates synergic combination with AKT and p38 inhibitors to restore sotorasib sensitivity in KRASG12C cells.

Gastric cancer (GC) ranks fourth in global mortality rates and fifth in prevalence, making it one of the most common cancers worldwide. Recent clinical studies have highlighted the potential of immunotherapies as a promising approach to treating GC. This study aims to shed light on the most impactful therapeutic strategies in the context of GC immunotherapy, highlighting both established and emerging approaches.

This review examines over 160 clinical studies conducted globally, focusing on the effectiveness of various immunotherapy modalities, including cancer vaccines, adoptive cell therapy, immune checkpoint inhibitors (ICIs), and monoclonal antibodies (mAbs). A comprehensive search of peer-reviewed literature was performed using databases such as Web of Science, PubMed, and Scopus. The selection criteria included peer-reviewed articles published primarily within the last 10 years, with a focus on studies that provided insights into targeted therapies and their mechanisms of action, clinical efficacy, and safety profiles. The findings indicate that these immunotherapy strategies can enhance treatment outcomes for GC, aligning with current treatment guidelines. ICIs like pembrolizumab and nivolumab have shown significant survival benefits in specific GC subgroups. Cancer vaccines and CAR-T cell therapies demonstrate potential, while mAbs targeting HER2 and VEGFR pathways enhance outcomes in combination regimens. We discuss the latest advancements and challenges in targeted therapy and immunotherapy for GC. Given the evolving nature of this field, this research emphasizes significant evidence-based therapies and those currently under evaluation rather than providing an exhaustive overview. Challenges include resistance mechanisms, immunosuppressive tumor environments, and inconsistent results from combination therapies. Biomarker-driven approaches and further research into emerging modalities like CAR-T cells and cancer vaccines are critical for optimizing treatments.

Immunotherapy is reshaping GC management by improving survival and quality of life. Ongoing research and clinical evaluations are crucial for refining personalized and effective therapies.

Gastric cancer (GC) is a malignant tumor with high morbidity and mortality rates worldwide. This study aimed to investigate the effects and mechanisms of action of didymin, a dietary flavonoid glycoside, on GC treatment. Human GC cell lines Hs-746T and AGS were used to assess the effects of didymin on cell viability, cell proliferation, and cell cycle. The results showed that didymin decreased the proliferative capacity of GC cells and blocked cell cycle. Didymin decreased wound healing, invasion, and migration capacities of GC cells. Mitochondrial reactive oxygen species (ROS) levels and mitochondrial membrane potentials were reduced in cells treated with didymin. Network pharmacology analysis revealed that the therapeutic effects of didymin on AGS cells were related to the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In vivo mouse xenograft studies confirmed that didymin treatment decreased tumor cell proliferation, cell cycle protein levels, and Akt phosphorylation. The present study demonstrated that didymin regulates mitochondrial function and the PI3K/Akt pathway to inhibit cell proliferation and induce apoptosis in GC cells in vitro and in vivo. Therefore, didymin is a promising drug for the treatment of GC.

Despite the progress made in the development of targeted therapies, breast cancer (BC) continues to pose a significant threat to the health of women. Transcriptomics has emerged due to the advancements in high-throughput sequencing technology. This provides crucial information about the role of non-coding RNAs (ncRNAs) in human cells, particularly long ncRNAs (lncRNAs), in disease development and function. When the control of these ncRNAs is disrupted, various illnesses emerge, including cancer. Numerous studies have produced empirical data on the function of lncRNAs in tumorigenesis and disease development. However, the roles and mechanisms of numerous lncRNAs remain unidentified at the molecular level because their regulatory role and the functional implications of abnormalities in cancer biology have yet to be thoroughly defined. The review gives an itemized summary of the most current developments in the role of lncRNA in BC, focusing on three main pathways, PI3K, MAPK, NF-kB, and hypoxia, and their resistance mechanisms.

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5' uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.

Several members of the NIMA-related kinase (NEK) family have been implicated in tumor progression; however, the role and underlying mechanisms of NEK8 in gastric cancer (GC) remain unclear. This study revealed a significant upregulation of NEK8 in GC, identifying it as an independent prognostic marker in patients with GC. Consistent with these findings, NEK8 silencing substantially impeded GC aggressiveness both in vitro and in vivo, while its overexpression produced the opposite effect. Gene Ontology enrichment analysis and metabolic profiling indicated that the impact of NEK8 on GC is primarily associated with reprogramming asparagine metabolism and modulating the mTORC1 pathway. Specifically, NEK8 knockdown suppressed asparagine synthesis by downregulating asparagine synthetase (ASNS) expression in GC cells. A strong correlation was observed between NEK8 levels and ASNS expression in human GC cells and tissue samples. Mechanistically, NEK8 directly interacts with ASNS, phosphorylating it at the S349 site, which inhibits its ubiquitination and subsequent degradation. Moreover, substituting the ASNS-S349 site with alanine abrogated the pro-tumorigenic effects of ASNS-WT overexpression. Additionally, asparagine was identified as an activator of the mTORC1 pathway, with reintroducing asparagine after NEK8 silencing restoring mTORC1 activity. Collectively, these findings demonstrate that NEK8-mediated asparagine synthesis and activation of the mTORC1 pathway play a critical role in promoting GC progression.

Diabetic wounds are notoriously difficult to heal due to impaired cell repair mechanisms, reduced angiogenesis, and a heightened risk of infection. Fibroblasts play a vital role in wound healing by producing extracellular matrix (ECM) components and various growth factors, but their function is inhibited in diabetic wounds. Chitooligosaccharides (COS), intermediate products of chitosan degradation, have shown efficacy in promoting tissue repair, yet their role in diabetic wound healing remains underexplored. In a mouse model of diabetic wounds, COS treatment demonstrated substantial bioactivity in accelerating wound healing by enhancing fibroblast proliferation and migration. Additionally, COS increased collagen III deposition and angiogenesis at the wound sites. The COS also mitigated inflammatory responses by controlling leukocyte infiltration and bacterial infection. Mechanistically, COS regulated fibroblast activity via the PI3K/Akt signaling pathway, providing a novel bioactive material for chronic wound healing.

Laryngeal cancer remains a significant global health concern, with poor prognosis for advanced-stage disease highlighting the need for novel diagnostic, prognostic, and therapeutic approaches. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs, have emerged as important regulators of gene expression and cellular processes in various cancers, including laryngeal cancer. This review summarizes the current understanding of circRNAs in laryngeal cancer, covering their biogenesis, regulatory mechanisms, and potential clinical applications. We explore the diverse functions of circRNAs, including their roles as miRNA sponges, protein interactors, and direct mRNA regulators, and their influence on key cellular processes such as proliferation, invasion, and metastasis. The review highlights promising circRNAs as diagnostic and prognostic biomarkers, as well as potential therapeutic targets. We also outline current strategies for circRNA modulation, including suppression techniques like RNA interference and CRISPR/Cas systems, and overexpression methods using vectors and synthetic circRNAs.

Long non‑coding RNA (lncRNA) is a class of non‑coding RNA molecules located in the cytoplasm or nucleus, which can regulate chromosome structure and function by interacting with DNA, RNA, proteins and other molecules; binding to mRNA bases in a complementary manner, affecting the splicing, stabilization, translation and degradation of mRNA; acting as competing endogenous RNA competitively binds to microRNAs to regulate gene expression and participate in the regulation of various vital activities of the body. The PI3K/AKT signalling pathway plays a key role in numerous biological and cellular processes, such as cell proliferation, invasion, migration and angiogenesis. It has been found that the lncRNA/PI3K/AKT axis regulates the expression of cancer‑related genes and thus tumour progression. The abnormal regulation of lncRNA expression in the lncRNA/PI3K/AKT axis is clearly associated with clinicopathological features and plays an important role in regulating biological functions. In the present review, the expression and biological functions of PI3K/AKT‑related lncRNAs both in vitro and in vivo over recent years, were comprehensively summarized and analyzed. Their correlation with clinicopathological features was also evaluated, with the objective of furnishing a solid theoretical foundation for clinical diagnosis and the monitoring of efficacy in digestive system neoplasms. The present review aimed to provide a comprehensive overview of the expression and biological functions of PI3K/AKT‑related lncRNAs in digestive system neoplasms and to assess their correlation with clinicopathological features. This endeavor seeks to establish a solid theoretical foundation for the clinical diagnosis and efficacy monitoring of digestive system tumors.

Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.

Gastric cancer is associated with high morbidity and mortality rates and seriously threatens human life. Our research aimed to explore the effects of poly (A) binding protein cytoplasmic 1 (PABPC1) on gastric cancer cells and elucidate the underlying mechanisms.

PABPC1 levels in gastric cancer cell lines were assessed by western blotting and RT-qPCR. Cell viability, apoptosis, invasion, and migration were analyzed using MTT assay, flow cytometry, wound healing assay, and transwell assay, respectively. The levels of apoptosis-related proteins (caspase 3 and cleaved-caspase 3) were determined using the caspase 3 vitality test kit and western blotting. The levels of epithelial-to-mesenchymal transition-related genes (E-cadherin and N-cadherin) in AGS and MGC803 cells were analyzed using western blotting and RT-qPCR. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway was examined using western blot analysis.

PABPC1 expression was enhanced in gastric cancer cells, especially in AGS and MGC803 cells. Our findings indicate that PABPC1 knockdown by siRNA inhibited PABPC1 expression, repressed gastric cancer cell growth, promoted apoptosis, and enhanced cleaved-caspase 3 expression. Functional assays revealed that PABPC1-siRNA blocked the migration and invasion of gastric cancer cells, dramatically promoted E-cadherin expression, and reduced N-cadherin levels. We also found decreased p-PI3K and p-AKT expression, along with decreased p-PI3K/PI3K and p-AKT/AKT in PABPC1-siRNA-treated gastric cancer cells.

PABPC1 silencing in gastric cancer cells inhibited cell proliferation, metastasis, and epithelial-to-mesenchymal transition, partly by repressing the PI3K/AKT signaling pathway activation. This may provide a theoretical basis for gastric cancer therapeutics.

Gastric Cancer (GC) was the third highest mortality rate among malignant tumors. Currently, no specific treatment is utilized to prevent the progression of GC. The detailed mechanism of GC was still elusive and this study aimed to clarify the mechanism of GC occurrence and development.

This study was performed to clarify the molecular mechanisms of CST1 promoting GC development through activating AKT. The normal gastric tissue cells and GC cell was obtained, followed by transfection with oe-CST1 or sh-CST1, and their apoptosis and viability were evaluated. Finally, Western blot, Flow cytometry assay, Transwell assay, and Scratch assay were used to elucidate the molecular mechanisms of CST1 promoting GC development through activating the AKT pathway.

Research outcomes show a significant elevation in CST1 and AKT protein as well as mRNA quantities in both the model and CST1-activator cohorts in relation to the control. Conversely, these proteins and mRNA concentrations were notably decreased in the presence of the CST1 inhibitor when compared to the model group, a difference that was statistically significant as evidenced by the p-value.

CST1 can promote the gastric cancer process by targeting the AKT pathway.

Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).

Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.

Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin.

This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy.