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PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The frequent activation of the PI3K/AKT/mTOR (PAM) pathway makes it an attractive therapeutic target in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. In addition, compensatory pathways can be activated when only the PAM pathway is inhibited. Here, we show that gedatolisib, a PAM inhibitor targeting multiple PAM pathway nodes, exerted greater growth-inhibitory effects relative to single-node PAM inhibitors in gynecologic cancer cell models. In addition, gedatolisib combined with inhibitors of compensatory pathways involved in the estrogen response and cell cycle progression inhibited tumor growth in endometrial and ovarian cancer mouse models. Gedatolisib in combination with other therapies has previously shown promising preliminary clinical efficacy and safety in various solid tumor types. The non-clinical data presented here support the development of gedatolisib in combination with hormonal therapy and/or cell cycle inhibitors for gynecologic cancer treatment. Background/Objectives: The PI3K/AKT/mTOR (PAM) pathway is frequently activated in gynecological cancers. Many PAM inhibitors selectively target single PAM pathway nodes, which can lead to reduced efficacy and increased drug resistance. To address these limitations, multiple PAM pathway nodes may need to be inhibited. Gedatolisib, a well-tolerated panPI3K/mTOR inhibitor targeting all Class I PI3K isoforms, mTORC1 and mTORC2, could represent an effective treatment option for patients with gynecologic cancers. Methods: Gedatolisib and other PAM inhibitors (e.g., alpelisib, capivasertib, and everolimus) were tested in endometrial, ovarian, and cervical cancer cell lines by using cell viability, cell proliferation, and flow cytometry assays. Xenograft studies evaluated gedatolisib in combination with a CDK4/6 inhibitor (palbociclib) or an anti-estrogen (fulvestrant). A pseudo-temporal transcriptomic trajectory of endometrial cancer clinical progression was computationally modeled employing data from 554 patients to correlate non-clinical studies with a potential patient group. Results: Gedatolisib induced a substantial decrease in PAM pathway activity in association with the inhibition of cell cycle progression and the decreased cell viability in vitro. Compared to single-node PAM inhibitors, gedatolisib exhibited greater growth-inhibitory effects in almost all cell lines, regardless of the PAM pathway mutations. Gedatolisib combined with either fulvestrant or palbociclib inhibited tumor growth in endometrial and ovarian cancer xenograft models. Conclusions: Gedatolisib in combination with other therapies has shown an acceptable safety profile and promising preliminary efficacy in clinical studies with various solid tumor types. The non-clinical data presented here support the development of gedatolisib combined with CDK4/6 inhibitors and/or hormonal therapy for gynecologic cancer treatment. [ABSTRACT FROM AUTHOR]

Copyright of Food Research & Development is the property of Food Research & Development Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression. Methods: Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells. Results: Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts. Conclusions: Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is an aggressive cancer with limited treatment options. Parishin A, a natural compound derived from Gastrodia elata, possesses multiple therapeutic properties. However, its effects on OSCC remain unexplored. Purpose: This study explores the anti-cancer potential of Parishin A on OSCC and its mechanisms. Methods: OSCC cell lines YD-10B and Ca9-22 were treated with varying Parishin A concentrations. Cell viability was detected using the CCK-8 assay, and colony formation was evaluated in agarose gel. Migration and invasion ability were assessed through wound healing and Matrigel invasion assays. The protein expression levels involved in the PI3K/AKT/mTOR signaling pathway and epithelial–mesenchymal transition (EMT) markers were examined via Western blotting. Results: Parishin A inhibited OSCC cell viability in both dose- and time-dependent manners, with significant reductions at 20, 40, 60, and 80 μM, without affecting normal human gingival fibroblasts. Colony formation decreased substantially at ≥40 μM higher Parishin A concentrations in a dose-dependent manner. Also, migration and invasion assays showed significant suppression by Parishin A treatment concentration ≥40 μM in a dose-dependent manner, as evidenced by decreased wound closure and invasion. Western blot analyses revealed increased E-cadherin levels and decreased N-cadherin and vimentin levels, suggesting EMT inhibition. Parishin A also decreased the phosphorylation levels of PI3K, AKT, and mTOR. Conclusion: Collectively, these findings support the potential of Parishin A as an anti-OSCC agent. [ABSTRACT FROM AUTHOR]

Objective To investigate the impacts of long non-coding RNA-lung adenocarcinoma metastasis- associated transcripton-1 (lncRNA MALAT1) on apoptosis, autophagy and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian rapasin target protein (mTOR) pathway in granulosa cells of polycystic ovary syndrome (PCOS). Methods The expression levels of lncRNA MALAT1 in PCOS ovarian tissue, normal ovarian tissue, human ovarian granulosa cells (KGN) and normal ovarian epithelial cells IOSE80 were detected by qRT-PCR. KGN cells were cultured in vitro and grouped into the control group, the si-NC group, the si-MALAT1 group, the pc-NC group, the pc-MALAT1 group and the pc-MALAT1+740Y-P (PI3K activator) group. qRT-PCR was applied to detect the expression level of MALAT1 mRNA in cells of each transfection group. CCK-8 was applied to detect cell viability. Flow cytometry was applied to detect cell apoptosis rate. Transmission electron microscopy was applied to observe autophagosomes in KGN cells. Western blot assay was applied to detect expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), microtubule- associated protein Ⅱ light chain 3 (LC3 Ⅱ), microtubule-associated protein Ⅰ light chain 3 (LC3 Ⅰ), Beclin1, p-PI3K, PI3K, p-Akt, Akt, p-mTOR and mTOR proteins in cells. Results The expression level of MALAT1 mRNA in PCOS ovarian tissue was lower than that in normal ovarian tissue, and that in KGN cells was lower than that in normal ovarian epithelial IOSE80 cells. A small number of autophagosomes were observed in KGN cells in the control group. After interfering MALAT1 expression, OD450 values (24, 48 and 72 hours) and the Bcl-2 protein expression of KGN cells were reduced, and the apoptosis rate, the expression of Bax, LC3 Ⅱ/LC3 Ⅰ, Beclin1, p-PI3K/PI3K, p-Akt/Akt and p-mTOR/ mTOR proteins were increased (P＜0.05). The number of autophagosomes increased. Changes of the above indexes were reversed after overexpression of MALAT1 (P＜0.05). Compared with the pc-MALAT1 group, the OD450 values (24, 48, 72 h), and the expression of Bcl-2 protein were obviously reduced in the pc-MALAT1+740Y-P group, while the apoptosis rate, number of autophagosomes, the expression of Bax, LC3 Ⅱ/LC3 Ⅰ, Beclin1, p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR proteins were obviously increased (P＜0.05). The number of autophagosomes increased. Conclusion Overexpression of MALAT1 may inhibit apoptosis and autophagy in PCOS granulosa cells by inhibiting the PI3K/Akt/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Breast cancer is a significant health challenge for women globally, including the Pakistani population. Numerous pathways and small molecules like noncoding ribonucleotides are implicated in breast cancer development and progression. Among these, lncRNAs, have garnered considerable attention due to their role in breast cancer tumorigenesis and metastasis. In the current study involving 52 mammary tumor samples from the Pakistani population, the expression of lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) was studied via RT-PCR (Real-Time polymerase chain reaction). In addition, PI3K/AKT/mTOR pathway expression was also assessed through RT-PCR and immunohistochemistry in breast cancer patient samples. The study also investigated the cross-talk of lncRNA MALAT1 and PI3K pathway genes by inhibiting it with PI3K inhibitor (LY294002) in MDA-MB-231 cell line. Furthermore, lncRNA MALAT1 was silenced in MDA-MB-231 cells using siRNA to determine its impact on breast cancer proliferation and metastasis. The results revealed an upregulated expression of MALAT1 and PI3K/AKT/mTOR pathway genes in grade II and III breast tissue samples before chemotherapy. The proliferation, growth, and invasion of breast cancer cells were significantly reduced upon MALAT1 silencing in MDA-MB-231. Further, its downregulation substantially reduced the PI3K pathway expression levels at mRNA and protein levels. In conclusion, the current study suggests that MALAT1 could serve as a therapeutic target for breast cancer, underscoring its role in breast cancer proliferation and metastasis. Moreover, the study proposes a mechanism of action of MALAT1, demonstrating that its inhibition can reduce the expression of the PI3K/AKT/mTOR axis. These findings emphasize the potential significance of targeting MALAT1 as a therapeutic strategy for breast cancer, and further exploration of this interaction is warranted to gain deeper insight into the molecular mechanism of this lncRNA. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer (NSCLC) is a lethal malignancy. There is mounting evidence indicating that lncRNAs are crucial players with dual roles as both biomarkers and regulators across various cancers. It was reported that LINC00941 plays a cancer‐promoting role in NSCLC. However, its impact on tumour autophagy remains poorly understood. In this study, we developed a risk assessment model and identified an autophagy‐related lncRNA LINC00941, which has independent predictive and early diagnostic potential. Using RT‐qPCR analysis, we confirmed the upregulation of LINC00941 in tumour tissues and cell lines of human lung adenocarcinoma (LUAD). Functional assays, such as CCK8, colony formation and xenograft models, demonstrated the cancer‐promoting activity of LINC00941 both in vitro and in vivo. Further analysis using Western blotting analysis, mRFP‐GFP‐LC3 double fluorescence lentivirus vector and transmission electron microscopy (TEM) confirmed that the knockdown of LINC00941 triggered autophagy. These results indicate that knockdown of LINC00941 induces autophagy and impairs the proliferation of LUAD. Therefore, we propose LINC00941 as an independent biomarker for early diagnosis as well as a therapeutic target in LUAD. [ABSTRACT FROM AUTHOR]

Maternal stress experienced during prenatal development is recognized as a significant risk factor for neurodevelopmental and neuropsychiatric disorders across the offspring's lifespan. The placental barrier serves a crucial function in safeguarding the fetus from detrimental exposures during gestation. However, previous investigations have not yet comprehensively elucidated the extensive connections between prenatal stress and the expression of placental proteins. In this study, we used iTRAQ-based quantitative proteomics to elucidate the placental adaptive mechanisms of pregnant rats in response to fear-induced stress. Our results showed that during pregnancy, exposure to fear-induced stress led to a pathological hypercoagulable state in the mother's body. Placental circulation was also disrupted, significantly reducing placental efficiency and blood oxygen saturation in newborn rats. Proteomic analyses showed that most of the DEPs were annotated to the PI3K-Akt and ECM-receptor interaction signaling pathway. In addition, the expressions of CDC37, HSP90β, AKT, p-AKT and p-mTOR were down-regulated significantly in the placenta. Our results demonstrated that prenatal fear-induced stress led to inhibition of the cellular signal transduction of placental PI3K/AKT/mTOR, which affected biological processes such as rRNA processing, translation, protein folding, protein stability, and oxygen transport in the placenta. These abnormalities in biological functions could potentially damage the barrier function of the placenta and thereby result in abnormal development in the offspring. [ABSTRACT FROM AUTHOR]

Background: Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties. Objectives: This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives. Methods: The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents. Results: nine compounds showed potent antioxidant activities with IC50 values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC50 values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC50 values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates. [ABSTRACT FROM AUTHOR]

The enmein-type diterpenoids are a class of anticancer ent-Kaurane diterpnoids that have received much attention in recent years. Herein, a novel 1,14-epoxy enmein-type diterpenoid 4, was reported in this project for the first time. A series of novel enmein-type diterpenoid derivatives were also synthesized and tested for anticancer activities. Among all the derivatives, compound 7h exhibited the most significant inhibitory effect against A549 cells (IC50 = 2.16 µM), being 11.03-folds better than its parental compound 4. Additionally, 7h exhibited relatively weak anti-proliferative activity (IC50 > 100 µM) against human normal L-02 cells, suggesting that it had excellent anti-proliferative selectivity for cancer cells. Mechanism studies suggested that 7h induced G0/G1 arrest and apoptosis in A549 cells by inhibiting the PI3K/AKT/mTOR pathway. This process was associated with elevated intracellular ROS levels and collapsed MMP. In summary, these data identified 7h as a promising lead compound that warrants further investigation of its anticancer properties. [ABSTRACT FROM AUTHOR]

Copyright of Farmacia is the property of Societatea de Stiinte Farmaceutice Romania and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Titanium dioxide nanoparticles (TiO2 NPs) can result in the reduction of sperm numbers, but the mechanisms have not been well elucidated. The purpose of this study was to investigate the effects of TiO2 NPs on cell cycle and apoptosis in spermatogonia and to explore the role of PI3K/AKT/mTOR signaling pathway in this process. The mouse spermatogonia cell line (GC-1) was treated with TiO2 NPs at different concentrations (0, 25, 50, 75 and 100 μg/mL) for 24 h to detect cell viability, cell cycle, apoptosis, and key proteins related to cell cycle and PI3K/AKT/mTOR signaling pathway. The agonist (IGF-1) and inhibitor (LY294002) of PI3K were used to verify the role of PI3K/AKT/mTOR signaling pathway in cell cycle and apoptosis. TiO2 NPs significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and resulted in apoptosis. TiO2 NPs downregulated the levels of cyclin-dependent kinases (CDKs) and cyclins, including CDK4, CDK2, Cyclin D1 and Cyclin E1, while upregulated the levels of p21 and p53 proteins. Furthermore, TiO2 NPs inhibited the PI3K/AKT/mTOR signaling pathway by decreasing the levels of p-PI3K, p-AKT and p-mTOR. IGF-1 reversed the G0/G1 phase arrest and apoptosis caused by TiO2 NPs. However, LY294002 aggravated the G0/G1 phase arrest and apoptosis resulting from TiO2 NPs. Collectively, TiO2 NPs induced cell cycle arrest at G0/G1 phase and apoptosis through inhibiting the activation of PI3K/AKT/mTOR pathway, which could be the main reason for the reduction in sperm numbers caused by TiO2 NPs. [ABSTRACT FROM AUTHOR]

Arnicolide D, a potent sesquiterpene lactone from Centipeda minima, has emerged as a promising anticancer candidate, demonstrating significant efficacy in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis across various cancer models. This comprehensive study delves into the molecular underpinnings of Arnicolide D's anticancer actions, emphasizing its impact on key signaling pathways such as PI3K/AKT/mTOR and STAT3, and its role in modulating cell cycle and survival mechanisms. Quantitative data from preclinical studies reveal Arnicolide D's dose-dependent cytotoxicity against cancer cell lines, including nasopharyngeal carcinoma, triple-negative breast cancer, and human colon carcinoma, showcasing its broad-spectrum anticancer potential. Given its multifaceted mechanisms and preclinical efficacy, Arnicolide D warrants further investigation in clinical settings to validate its therapeutic utility against cancer. The evidence presented underscores the need for rigorous pharmacokinetic and toxicological studies to establish safe dosing parameters for future clinical trials. [ABSTRACT FROM AUTHOR]

Objective To investigate whether activation of PI3K/AKT/mTOR pathway can reduce inflammation in acute pancreatitis (AP) rats. Methods SD rats were grouped into sham surgery group, model group, Gln group, and Gln+LY294002 group (PI3K/AKT/mTOR pathway inhibitors). Intra-abdominal pressure (IAP), ascites volume(AS), serum amylase (AMY), diamine oxidase (DAO), interleukin(IL-1β, IL-6), Tumor necrosis factor (TNF-α) were measured. The pathological change in pancreatic and small intestinal tissues was evaluated by microscopy; The expression of PI3K, Akt and mTOR genes and cytoplasm compact linking protein (ZO-1), compact linking protein (occludin-1), PI3K, Akt and mTOR in ileum of each group were detected. Results Compared with the sham surgery group, the IAP and AS, IL-1β, IL-6, TNF-α, AMY, DAO, and pathological injury scores of pancreas and small intestine in the model group were obviously increased; The expression of PI3K mRNA,Akt mRNA, mTOR mRNA, ZO-1, occludin-1, p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue significantly reduced (P＜0.05). Compared with the model group, the level of IAP and AS, IL-1β, IL-6, TNF-α, AMY, DAO and pathological injury scores of pancreas and small intestine in the Gln group were significantly reduced; The expression of PI3K mRNA, Akt mRNA, mTOR mRNA, ZO-1, occludin-1, p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue was significantly increased (P＜0.05); LY294002 could specifically reverse the therapeutic effect of Gln on acute pancreatitis in rats. Conclusions Activation of PI3K/AKT/mTOR pathway may reduce inflammation and improve gastrointestinal function in rats with acute pancreatitis.

Abstract Background Solute carrier family 38 member 5 (SLC38A5) is an amino acid transporter that plays a significant role in various cellular biological processes and may be involved in regulating the progression of tumors However, its function and underlying mechanism in osteosarcoma remain unexplored. Methods Utilizing various database analyses and experiments, we have explored the dysregulation of SLC38A5 in osteosarcoma and its prognostic value. A series of in vitro functional experiments, including CCK-8, colony formation, wound healing, and transwell invasion assays, were conducted to evaluate the effects of SLC38A5 on the proliferation, migration, and invasion of osteosarcoma cells. Downstream pathways of SLC38A5 were explored through methods such as western blot and metabolic assays, followed by a series of validations. Finally, we constructed a subcutaneous xenograft tumor model in nude mice to explore SLC38A5 function in vivo. Results SLC38A5 is upregulated in osteosarcoma and is associated with poor prognosis in patients. Upregulation of SLC38A5 promotes proliferation, migration, and invasion of osteosarcoma cells, while the PI3K inhibitor BKM120 can counteract these effects. Additionally, silencing of SLC38A5 inhibits tumor growth in vivo. Mechanistically, SLC38A5 mediates the activation of the PI3K/AKT/mTOR signaling pathway by transporting glutamine, which subsequently enhances the SREBP1/SCD-1 signaling pathway, thereby suppressing ferroptosis in osteosarcoma cells. Conclusion SLC38A5 promotes osteosarcoma cell proliferation, migration, and invasion via the glutamine-mediated PI3K/AKT/mTOR signaling pathway and inhibits ferroptosis. Targeting SLC38A5 and the PI3K/AKT signaling axis may provide a meaningful therapeutic strategy for the future treatment of osteosarcoma. Graphical abstracts

Abstract PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.

Abstract Background The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression. Methods Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells. Results Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts. Conclusions Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

Non-alcoholic fatty liver disease (NAFLD) is one abnormal buildup of fat within the liver, independent of excessive alcohol intake. In type 2 diabetes, the presence of NAFLD can exacerbate chronic kidney diseases and mortality in patients. Hepatocyte nuclear factor 1 homeobox A (HNF1A) predominantly expressed in the liver, owns one crucial role in liver development, function and tumorigenesis. However, the precise regulatory role of HNF1A on the progression of type 2 diabetes combined with NAFLD keep dimness. This investigation uncovered that HNF1A levels, both in protein and mRNA expressions, were elevated in high-fat diet plus hyperglycemia (HFG) mice. Furthermore, liver steatosis was strengthened in the HFG group, which was mitigated following the HNF1A inhibition. Knockdown of HNF1A ameliorated glucose and lipid metabolism disorders in HFG mice. Lastly, the study observed an stimulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in HFG mice, but this change was neutralized uponHNF1A silencing. In conclusion, knockdown of HNF1A improved type 2 diabetes combined with NAFLD, as well as disorders in glucose and lipid metabolism, and retarded the PI3K/AKT/mTOR signaling pathway. These finding demonstrated that HNF1A may be one serviceable target for ameliorating type 2 diabetes combined with NAFLD.

AbstractContext Polyporus polysaccharide (PPS), the leading bioactive ingredient extracted from Polyporus umbellatus (Pers.) Fr. (Polyporaceae), has been demonstrated to exert anti-bladder cancer and immunomodulatory functions in macrophages.Objective To explore the effects of homogeneous Polyporus polysaccharide (HPP) on the proliferation and autophagy of bladder cancer cells co‐cultured with macrophages.Materials and methods MB49 bladder cancer cells and RAW264.7 macrophages were co-cultured with or without HPP intervention (50, 100, or 200 μg/mL) for 24 h. The cell counting kit-8 (CCK-8) assay and 5-ethynyl-2″-deoxyuridine (EdU) staining evaluated MB49 cell proliferation. Monodansylcadaverine (MDC) staining and transmission electron microscopy (TEM) observed autophagosomes. Western blotting detected the expression levels of autophagy-related proteins and PI3K/Akt/mTOR pathway proteins.Results HPP inhibited the proliferation of MB49 cells co-cultured with RAW264.7 cells but not MB49 cells alone. HPP altered the expression of autophagy-related proteins and promoted the formation of autophagosomes in MB49 cells in the co-culture system. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) not only antagonized HPP-induced autophagy but also attenuated the inhibitory effects of HPP on MB49 cell proliferation in the co-culture system. HPP or RAW264.7 alone was not sufficient to induce autophagy in MB49 cells. In addition, HPP suppressed the protein expression of the PI3K/Akt/mTOR pathway in MB49 cells in the co-culture system.Discussion and conclusions HPP induced bladder cancer cell autophagy by regulating macrophages in the co-culture system, resulting in the inhibition of cancer cell proliferation. The PI3K/Akt/mTOR pathway was involved in HPP-induced autophagy in the co-culture system.

Abstract 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.

Objective To explore the impact of knocking down Sec31A on the malignant phenotype of head and neck squamous cell carcinoma(HNSCC) and its possible mechanisms. Methods Transcriptome sequencing data of HNSCC tissues and adjacent tissues were obtained from the TCGA database, and the expression levels of Sec31A were compared. Immunohistochemical staining was used to analyze the expression of Sec31A in HNSCC tissues. Kaplan-Meier survival analysis was used to compare the relationship between Sec31A and the prognosis of HNSCC patients. Small interfering plasmids si-Sec31A and si-NC were transfected into HNSCC cell lines HN6 and HN4, and the impact of knocking down Sec31A on the biological behavior of HNSCC cells was detected through CCK-8 experiments, plate cloning experiments, scratch healing experiments, and Transwell experiments. Changes in the expression levels of PI3K/AKT/mTOR pathway related proteins in cells were detected after knocking down Sec31A with HN6 and HN4 through Western Blot(WB)experiments. Stable transfected cell lines of HN6 siSec31A and HN6 siNC were constructed and inoculated subcutaneously in nude mice to further verify the tumorigenic effect of Sec31A in vivo. Results TCGA data showed that Sec31A was higher in HNSCC tissues than in adjacent normal tissues(P

Abstract Background Insulin has been known to regulate bone metabolism, yet its specific molecular mechanisms during the proliferation and osteogenic differentiation of dental pulp stem cells (DPSCs) remain poorly understood. This study aimed to explore the effects of insulin on the bone formation capability of human DPSCs and to elucidate the underlying mechanisms. Methods Cell proliferation was assessed using a CCK-8 assay. Cell phenotype was analyzed by flow cytometry. Colony-forming unit-fibroblast ability and multilineage differentiation potential were evaluated using Toluidine blue, Oil red O, Alizarin red, and Alcian blue staining. Gene and protein expressions were quantified by real-time quantitative polymerase chain reaction and Western blotting, respectively. Bone metabolism and biochemical markers were analyzed using electrochemical luminescence and chemical colorimetry. Cell adhesion and growth on nano-hydroxyapatite/collagen (nHAC) were observed with a scanning electron microscope. Bone regeneration was assessed using micro-CT, fluorescent labeling, immunohistochemical and hematoxylin and eosin staining. Results Insulin enhanced the proliferation of human DPSCs as well as promoted mineralized matrix formation in a concentration-dependent manner. 10− 6 M insulin significantly up-regulated osteogenic differentiation-related genes and proteins markedly increased the secretion of bone metabolism and biochemical markers, and obviously stimulated mineralized matrix formation. However, it also significantly inhibited the expression of genes and proteins of receptors and receptor substrates associated with insulin/insulin-like growth factor-1 signaling (IIS) pathway, obviously reduced the expression of the phosphorylated PI3K and the ratios of the phosphorylated PI3K/total PI3K, and notably increased the expression of the total PI3K, phosphorylated AKT, total AKT and mTOR. The inhibitor LY294002 attenuated the responsiveness of 10− 6 M insulin to IIS/PI3K/AKT/mTOR pathway axis, suppressing the promoting effect of insulin on cell proliferation, osteogenic differentiation and bone formation. Implantation of 10− 6 M insulin treated DPSCs into the backs of severe combined immunodeficient mice and the rabbit jawbone defects resulted in enhanced bone formation. Conclusions Insulin induces insulin resistance in human DPSCs and effectively promotes their proliferation, osteogenic differentiation and bone formation capability through gradually inducing the down-regulation of IIS/PI3K/AKT/mTOR pathway axis under insulin resistant states.

Abstract 2′,4′‐Dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC) is a typical and abundant chalcone compound from the buds of Cleistocalyx operculatus, which is well‐known for its edible and medicinal qualities. In this study, DMC showed effective cell cycle arrest at G2/M on MDA‐MB‐231 cells, though dual impacts, including the inhibition of microtubule polymerization through binding to β‐tubulin and the stimulation of reactive oxygen species (ROS) production by inhibiting catalase activity. The increased ROS level inhibited PI3K/Akt/mTOR pathway and further suppressed the expression level of Cdc2, Cdc25C, and Cyclin B1, alongside stimulated the expression level of p21 and p27. Above 29.5% MDA‐MB‐231 cells were arrested at G2/M phase, subsequently undergoing apoptosis due to heightened levels of apoptosis‐related proteins Bax and caspase 3. In summary, this study demonstrated that DMC concomitantly plays dual roles in apoptotic inducing by inhibiting the ROS consumption and microtubules formation in triple‐negative breast cancer cells.

Abstract This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A’s influence on CRC advancement through in vivo tumor experiments and hematoxylin–eosin (HE) staining. Transwell assays gauged ACVR2A’s role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC’s PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A’s influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A’s critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress.

Aberrant PI3K/AKT/mTOR/ pathway have been considered one of the starting points of various types of human cancer, including the oral squamous cell carcinoma (OSCC). The important role played by this signaling pathway in oncogenesis and cancer evolution, oriented the researchers’ attention toward studies of AKT and the PI3K/AKT/mTOR axis in the context of malignant transformation of oral precancerous lesions. Consequently, this article’s aim is an update of the possible key role played by the PI3K /AKT/mTOR axis on the oral lesions’ malignant transformation stage. Oral potentially malignant disorders are defined as lesions that will most probably progress to malignant lesions of the oral cavity. These lesions are mainly represented by leukoplakia, erythroplakia, actinic cheilitis and lichen planus. PI3K/AKT/mTOR signaling cascade should be regarded as a crucial subject for additional research, focusing not only on the early identification of malignant transformations of oral lesions, but also on opening new therapeutic ways in order to prevent malignant transformation and OSCC evolution.

Melatonin, the hormone of the pineal gland, possesses a range of physiological functions, and recently, its anticancer effect has become more apparent. A more thorough understanding of molecular alterations in the components of several signaling pathways as new targets for cancer therapy is needed because of current innate restrictions such as drug toxicity, side effects, and acquired or de novo resistance. The PI3K/Akt/mTOR pathway is overactivated in many solid tumors, such as breast and ovarian cancers. This pathway in normal cells is essential for growth, proliferation, and survival. However, it is an undesirable characteristic in malignant cells. We have reviewed multiple studies about the effect of melatonin on breast and ovarian cancer, focusing on the PI3K/Akt/mTOR pathway. Melatonin exerts its inhibitory effects via several mechanisms. A: Downregulation of downstream or upstream components of the signaling pathway such as phosphatase and tensin homolog (PTEN), phosphatidylinositol (3,4,5)‐trisphosphate kinase (PI3K), p‐PI3K, Akt, p‐Akt, mammalian target of rapamycin (mTOR), and mTOR complex1 (mTORC1). B: Apoptosis induction by decreasing MDM2 expression, a downstream target of Akt, and mTOR, which leads to Bad activation in addition to Bcl‐XL and p53 inhibition. C: Induction of autophagy in cancer cells via activating ULK1 after mTOR inhibition, resulting in Beclin‐1 phosphorylation. Beclin‐1 with AMBRA1 and VPS34 promotes PI3K complex I activity and autophagy in cancer cells. The PI3K/Akt/mTOR pathway overlaps with other intracellular signaling pathways and components such as AMP‐activated protein kinase (AMPK), Wnt/β‐catenin, mitogen‐activated protein kinase (MAPK), and other similar pathways. Cancer therapy can benefit from understanding how these pathways interact and how melatonin affects these pathways. [ABSTRACT FROM AUTHOR]

Hesperetin, a citrus flavonoid, has been a widely studied anticancer agent against many types of cancers, but the exact mechanism of efficacy is still unrevealed. Therefore, this study has attempted to delineate the mechanical aspect of hesperetin’s anticancer efficacy against colon cancer using immunoblotting, scanning, and transmission electron microscopic studies. The treatment with hesperetin (25 and 50 µM) has significantly (p < 0.0001) curbed down the proliferation and cell viability of HCT-15 cells in a concentration as well as time dependent manner. Hesperetin was able to achieve this through the induction of caspase-dependent apoptosis. Moreover, hesperetin effectively inhibited phosphorylation of Akt with a parallel increase in PTEN expression thereby inhibiting the PI3K signaling axis, which contributes to the suppression of proliferation. In addition, hesperetin enhanced autophagy through dephosphorylating mTOR, one of the downstream targets of Akt with simultaneous acceleration in Beclin-1 and LC3-II expression levels. Interestingly, hesperetin enhanced the effects of Akt inhibitor LY294002 and mTOR inhibitor rapamycin. This study documented the potential of hesperetin to induce apoptosis through simultaneous acceleration over the autophagic process in colon cancer cells. Thus, hesperetin played a beneficial therapeutic role in preventing colon carcinoma growth by regulating the Akt and mTOR signaling axis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3−kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)−2 and MMP−9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP−2, and MMP−9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC. [ABSTRACT FROM AUTHOR]

Natural compounds such as thymoquinone (TQ) have recently gained increasing attention in treating glioblastoma (GBM). However, the effects of TQ in reversing drug resistance are not completely understood. Therefore, we aimed to examine TQ impacts on GBM cells with doxorubicin (DOX) resistance and the involvement of the PI3K/Akt/mTOR pathway. GBM cancer U87 and U87/DOX (resistant cells) cells were exposed to DOX and TQ, and cell proliferation was assessed by the MTT assay. ELISA was applied to evaluate cell apoptosis. The expression of apoptotic mediators such as Caspase‐3, Bax, Bcl‐2 and PI3K, Akt, mTOR, P‐gp, and PTEN was assessed via qRT‐PCR and western blot. We found that a combination of TQ and DOX suppressed dose‐dependent cell growth capacity in cells and increased the cytotoxic effects of DOX in resistant cells. In addition, TQ treatment increased DOX‐mediated apoptosis in U87/DOX cell lines via modulating the pro‐ and anti‐apoptotic markers. A combination of TQ and DOX upregulated PTEN and downregulated PI3K, Akt, and mTOR, suppressing this signal transduction in resistant cells. In conclusion, we showed TQ potentiated doxorubicin‐mediated antiproliferative and pro apoptotic function DOX‐resistant glioblastoma cells, which is mediated by targeting and suppressing PI3K/Akt/mTOR signal transduction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

RNA‐binding proteins can regulate nucleotide metabolism and gene expression. UPF3B regulator of nonsense mediated mRNA decay (UPF3B) exhibits dysfunction in cancers. However, its role in the progression of hepatocellular carcinoma (HCC) is still insufficiently understood. Here, we found that UPF3B was markedly upregulated in HCC samples and associated with adverse prognosis in patients. UPF3B dramatically promoted HCC growth both in vivo and in vitro. Mechanistically, UPF3B was found to bind to PPP2R2C, a regulatory subunit of PP2A, boosting its mRNA degradation and activating the PI3K/AKT/mTOR pathway. E2F transcription factor 6 (E2F6) directly binds to the UPF3B promoter to facilitate its transcription. Together, the E2F6/UPF3B/PPP2R2C axis promotes HCC growth through the PI3K/AKT/mTOR pathway. Hence, it could be a promising therapeutic target for treating HCC. [ABSTRACT FROM AUTHOR]

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice. [ABSTRACT FROM AUTHOR]

Background: Insulin has been known to regulate bone metabolism, yet its specific molecular mechanisms during the proliferation and osteogenic differentiation of dental pulp stem cells (DPSCs) remain poorly understood. This study aimed to explore the effects of insulin on the bone formation capability of human DPSCs and to elucidate the underlying mechanisms. Methods: Cell proliferation was assessed using a CCK-8 assay. Cell phenotype was analyzed by flow cytometry. Colony-forming unit-fibroblast ability and multilineage differentiation potential were evaluated using Toluidine blue, Oil red O, Alizarin red, and Alcian blue staining. Gene and protein expressions were quantified by real-time quantitative polymerase chain reaction and Western blotting, respectively. Bone metabolism and biochemical markers were analyzed using electrochemical luminescence and chemical colorimetry. Cell adhesion and growth on nano-hydroxyapatite/collagen (nHAC) were observed with a scanning electron microscope. Bone regeneration was assessed using micro-CT, fluorescent labeling, immunohistochemical and hematoxylin and eosin staining. Results: Insulin enhanced the proliferation of human DPSCs as well as promoted mineralized matrix formation in a concentration-dependent manner. 10− 6 M insulin significantly up-regulated osteogenic differentiation-related genes and proteins markedly increased the secretion of bone metabolism and biochemical markers, and obviously stimulated mineralized matrix formation. However, it also significantly inhibited the expression of genes and proteins of receptors and receptor substrates associated with insulin/insulin-like growth factor-1 signaling (IIS) pathway, obviously reduced the expression of the phosphorylated PI3K and the ratios of the phosphorylated PI3K/total PI3K, and notably increased the expression of the total PI3K, phosphorylated AKT, total AKT and mTOR. The inhibitor LY294002 attenuated the responsiveness of 10− 6 M insulin to IIS/PI3K/AKT/mTOR pathway axis, suppressing the promoting effect of insulin on cell proliferation, osteogenic differentiation and bone formation. Implantation of 10− 6 M insulin treated DPSCs into the backs of severe combined immunodeficient mice and the rabbit jawbone defects resulted in enhanced bone formation. Conclusions: Insulin induces insulin resistance in human DPSCs and effectively promotes their proliferation, osteogenic differentiation and bone formation capability through gradually inducing the down-regulation of IIS/PI3K/AKT/mTOR pathway axis under insulin resistant states. [ABSTRACT FROM AUTHOR]

Foam dressing (FD) and micropower vacuum dressing (MVD) have been applied in the treatment of diabetic foot ulcer (DFU). However, research about the mode of action on the efficacy of the two dressings is extremely rare. This study proposed to explore the mechanism involved in diabetic wound healing under FD or MVD treatment. Macroscopical study was performed to evaluate the effectiveness of FD and MVD on wound healing in a rat model of DFU. Morphological analysis in the wound skin tissue was conducted by hematoxylin and eosin staining. Meanwhile, inflammatory cytokines in serum were measured by enzyme linked immunosorbent assay. The protein expression of phosphatidylinositol 3 kinase, protein kinase B and mammalian target of rapamycin (PI3K/AKT/mTOR) and their phosphorylation levels were determined by western blotting. We found that wound healing in rats with DFU was enhanced with the application of FD and MVD. The therapeutic efficacy of FD was superior to MVD. Compared with diabetic foot group, the concentrations of inflammatory cytokines, tumor necrosis factor alpha, interleukin-1β and interleukin-6, were significantly down-regulated. Besides, the phosphorylation levels of PI3K, AKT and mTOR were up-regulated under FD or MVD treatment. We demonstrated that the treatment of FD and MVD effectively promoted the wound skin healing through activating the PI3K/AKT/mTOR pathway. Our research may provide a new idea for exploring the mode of action of dressing application in healing of DFU. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA), characterized by high heterogeneity and extreme malignancy, has a poor prognosis. Doublecortin-like kinase 1 (DCLK1) promotes a variety of malignant cancers in their progression. Targeting DCLK1 or its associated regulatory pathways can prevent the generation and deterioration of several malignancies. However, the role of DCLK1 in CCA progression and its molecular mechanisms remain unknown. Therefore, we aimed to investigate whether and how DCLK1 contributes to CCA progression. Methods: The expression of DCLK1 in CCA patients was detected using Immunohistochemistry (IHC). We established DCLK1 knockout and DCLK1 overexpression cell lines for Colony Formation Assay and Transwell experiments to explore the tumor-promoting role of DCLK1. RT-PCR, Western blot and multiple fluorescent staining were used to assess the association between DCLK1 and epithelial–mesenchymal transition (EMT) markers. RNA sequencing and bioinformatics analysis were performed to identify the underlying mechanisms by which DCLK1 regulates CCA progression and the EMT program. Results: DCLK1 was overexpressed in CCA tissues and was associated with poor prognosis. DCLK1 overexpression facilitated CCA cell invasion, migration, and proliferation, whereas DCLK1 knockdown reversed the malignant tendencies of CCA cells, which had been confirmed both in vivo and in vitro. Furthermore, we demonstrated that DCLK1 was substantially linked to the advancement of the EMT program, which included the overexpression of mesenchymal markers and the downregulation of epithelial markers. For the underlying mechanism, we proposed that the PI3K/AKT/mTOR pathway is the key process for the role of DCLK1 in tumor progression and the occurrence of the EMT program. When administered with LY294002, an inhibitor of the PI3K/AKT/mTOR pathway, the tumor’s ability to proliferate, migrate, and invade was greatly suppressed, and the EMT process was generally reversed. Conclusions: DCLK1 facilitates the malignant biological behavior of CCA cells through the PI3K/AKT/mTOR pathway. In individuals with cholangiocarcinoma who express DCLK1 at high levels, inhibitors of the PI3K/AKT/mTOR signaling pathway may be an effective therapeutic approach. [ABSTRACT FROM AUTHOR]

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Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross‐linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti‐inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC. [ABSTRACT FROM AUTHOR]

This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A's influence on CRC advancement through in vivo tumor experiments and hematoxylin–eosin (HE) staining. Transwell assays gauged ACVR2A's role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC's PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A's influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A's critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress. [ABSTRACT FROM AUTHOR]

In this study, we aimed to explore the effect and underlying mechanism of aging in female ovarian function in mice. The mice at the age of 10 months and 7 weeks were used as the aged model and the young control. The estrus cycle and serum peripheral blood and the number of follicles, oocytes and litter size were also calculated for analysis of ovarian function. Ovarian cells were collected for reactive oxygen species (ROS) and Annexin V staining. Antioxidant and apoptotic proteins BAX and Caspase-3 and phosphoinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in ovaries were also detected. The results showed that compared to the young control, the aged mice exhibited ovarian dysfunction with disrupted estrus cycle and hormone production, accompanied by decreases in the numbers of follicles, oocytes and litter size. The oxidative damage in aged ovarian tissues was induced with increased Malondialdehyde content and reduced activities of Catalase and Superoxide Dismutase enzymes, as well as high level of ROS accumulation and apoptosis in ovarian cells. Furthermore, the expression levels of BAX, Caspase-3 and PI3K, Akt, mTOR and their phosphorylated forms were obviously regulated in the aged ovaries. Thus, these results above suggest oxidative damage with high level of ROS is obviously induced in ovarian tissues of aged mice, and this accumulation mediates apoptosis of ovarian cells, involving with improved expression of apoptotic protein BAX and Caspase-3, ultimately leads to ovarian dysfunction through the PI3K/Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

Objective To explore the molecular mechanism of miR-205-5p targeting ERBB3 to regulate PI3K/AKT/mTOR pathway and inhibit angiogenesis in hemorrhoids. Methods The hemorrhoidal nucleus and normal perianal tissues of 12 patients from July 2021 to June 2022 were collected, the expression of miR-205-5p and ERBB3 in the samples was detected by qRT-PCR, and the targeting relationship was verified by dual- luciferase. miR-205-5p mimic, pcDNA-ERBB3, miR-205-5p inhibitor, sh-ERBB3, oe-ERBB3 and negative control plasmids were respectively or co-transfected into hemorrhoidal model rats and HUVEC cells. The pathological changes and apoptosis of perianal tissue in each group were observed by HE and TUNEL staining, and the localization of expression of ERBB3 and VEGFR2 proteins were detected by immunohistochemistry, and the expression levels of ERBB3, VEGFR2, Cyclin D1, cleaved-caspase 3, Bax, Bcl-2 and PI3K/AKT/mTOR pathway related proteins were detected by Western blot. The proliferation, migration, invasion, apoptosis and angiogenesis of HUVEC were detected by MTT, wound healing, transwell, flow cytometry and angiogenesis assay. Results MiR-205-5p was lowly expressed and ERBB3 was highly expressed in clinical samples of hemorrhoids (P < 0.001), and miR-205-5p targeted the 3'UTR of ERBB3 (WT) (P < 0.001) . The expression of ERBB3 in hemorrhoidal rats and HUVEC cells in miR-205-5p mimic group was significantly decreased (P < 0.01, P < 0.001), and the levels of VEGFR2 (P < 0.001), Cyclin D1 (P < 0.01),Bcl-2 (P < 0.001), p-PI3K/PI3K, p-AKT/AKT, pmTOR/mTOR ( P < 0.001) were significantly down-regulated, the levels of Cleaved-caspase 3 and Bax were significantly up-regulated (P < 0.01), the perianal histopathology of rats was improved, the proliferation, migration and invasion activities of HUVEC cells were reduced (P < 0.001), the apoptosis rate was increased (P < 0.001), and the number and branches of angiogenesis were reduced (P < 0.001), and these effects were eventually reversed by pcDNA-ERBB3 ( P < 0.001). Conclusion MiR-205-5p can reduce angiogenesis and relieve hemorrhoids by targeting the inhibition of ERBB3 expression, down-regulating the activity of PI3K/AKT/mTOR pathway, inhibiting cell proliferation, migration and invasion, and promoting apoptosis. [ABSTRACT FROM AUTHOR]

Recent research has explored the potential use of serum-derived biomarkers in cancer screening, and mounting evidence has illustrated the pivotal roles of long noncoding RNAs (lncRNAs) in regulating laryngeal squamous cell carcinoma (LSCC) progression. LINC02191 is a newly identified lncRNA and no studies have investigated its role in malignant tumors. This study aims to explore the functions and mechanisms of lncRNA LINC02191 in LSCC. LINC02191 was knocked down in LSCC cells using shRNAs for loss-of-function experiments. RT-qPCR revealed that LINC02191 was upregulated in LSCC patients' serum exosomes, tissues and cells. Western blotting and RT-qPCR were implemented for detecting molecular protein and RNA levels. Colony formation, CCK-8, wound healing and Transwell assays were employed for examining LSCC cell malignant behaviors in vitro. A tumor-bearing mouse model (n = 4/group) was established for examining LINC02191 role in vivo. The results showed that LINC02191 silencing hindered LSCC cell proliferation, invasiveness, migration as well as EMT in vitro and impeded tumorigenesis in xenograft mouse model. Luciferase reporter assay was utilized for verifying the interaction between LINC02191, miR-204-5p and RAB22A. Pearson correlation analysis was employed to evaluate their expression correlation in LSCC tissue specimens (N = 30). Mechanistically, LINC02191 upregulated RAB22A by binding to miR-204-5p, and knocking down LINC02191 inhibited PI3K/Akt/mTOR signaling transduction in LSCC cells and tumor-bearing mice. Moreover, RAB22A overexpression reversed LINC02191 depletion-triggered suppression of LSCC cell aggressiveness and inactivation of PI3K/Akt/mTOR signaling. In conclusion, LINC02191 aggravates LSCC by targeting miR-204-5p/RAB22A/PI3K/Akt/mTOR signaling pathway, which indicates that LINC02191 may serve as a promising target for LSCC treatment. [ABSTRACT FROM AUTHOR]

Background: Hippocampal neuron damage and impaired regeneration are critical in depression's pathogenesis. An Enriched Environment (EE) has been shown to ameliorate depressive-like behaviors in animals, suggesting its potential as a daily rehabilitation analog for reducing depression incidence in chronic stress conditions through hippocampal neuron protection. This study aims to investigate the effects and underlying mechanisms of EE training on depression induced by chronic unpredictable mild stress (CUMS) in mice. Method: Forty mice were randomized into four groups: Control, CUMS, Fluoxetine + CUMS, and EE + CUMS. Depression was induced using singlecage isolation and CUMS for 42 days, with intraperitoneal drug administration during this period. EE training commenced on Day 22, continuing through the modeling phase. Depression behavior was assessed using weight monitoring, the Sucrose Preference Test (SPT), Open Field Test (OFT), and Forced Swimming Test (FST). Hematoxylin-Eosin (HE) staining evaluated hippocampal histopathology. Levels of interleukin 1β (IL-1β), interleukin 6 (IL- 6), phosphorylated phosphatidylinositol kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin protein (p-mTOR) were analyzed. Results: By Day 21, chronic stress elicited depressive behaviors, with more pronounced effects by Day 42 in the CUMS group, validating the model's stability and success. Interventions post-Day 22, Resembling early clinical depression detection, demonstrated that three weeks of fluoxetine and EE training effectively reduced depressive behaviors. Both interventions notably mitigated hippocampal histopathological damage, decreased inflammatory factors, and significantly increased expression of mTOR pathway-related proteins. Conclusion: EE training effectively mitigates depressive behavior in chronically stressed mice, primarily through anti-inflammatory actions and modulation of the PI3K/Akt/mTOR signaling pathway. These findings underscore the therapeutic potential of integrating physical fitness and mental health strategies into depression management, emphasizing the importance of environmental and lifestyle factors in neuropsychiatric disorder intervention. [ABSTRACT FROM AUTHOR]

2′,4′‐Dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC) is a typical and abundant chalcone compound from the buds of Cleistocalyx operculatus, which is well‐known for its edible and medicinal qualities. In this study, DMC showed effective cell cycle arrest at G2/M on MDA‐MB‐231 cells, though dual impacts, including the inhibition of microtubule polymerization through binding to β‐tubulin and the stimulation of reactive oxygen species (ROS) production by inhibiting catalase activity. The increased ROS level inhibited PI3K/Akt/mTOR pathway and further suppressed the expression level of Cdc2, Cdc25C, and Cyclin B1, alongside stimulated the expression level of p21 and p27. Above 29.5% MDA‐MB‐231 cells were arrested at G2/M phase, subsequently undergoing apoptosis due to heightened levels of apoptosis‐related proteins Bax and caspase 3. In summary, this study demonstrated that DMC concomitantly plays dual roles in apoptotic inducing by inhibiting the ROS consumption and microtubules formation in triple‐negative breast cancer cells. [ABSTRACT FROM AUTHOR]

Idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome present a variety of symptoms thought to be caused by excessive inflammatory cytokines and chemokines, but the underlying mechanisms are unknown. iMCD is broadly classified into two types: iMCD-NOS and iMCD-TAFRO, which have distinct laboratory findings, pathological features, and responses to treatments. It is thought that iMCD-NOS, particularly the IPL type, responds favorably to IL-6 inhibitors due to its IL-6-centric profile. iMCD-TAFRO frequently progresses acutely and seriously, similar to TAFRO syndrome. Elevated levels of cytokines, including IL-1β, TNF-α, IL-10, and IL-23, as well as chemokines like CXCL13 and CXCL-10 (especially in iMCD-TAFRO), SAA, and VEGF, have been linked to the disease's pathology. Recent research has identified key signaling pathways including PI3K/Akt/mTOR and JAK-STAT3, as well as those regulated by type I IFN, as crucial in iMCD-TAFRO. These results suggest that dominant pathways may vary between subtypes. Further research into the peripheral blood and lymph nodes is required to determine the disease spectrum of iMCD-NOS/iMCD-TAFRO/TAFRO syndrome. [ABSTRACT FROM AUTHOR]

Objectives: The purposes of this study were to (i) verify the role of CXCR2 in tacrolimus-induced nephrotoxicity, (ii) explore the specific mechanism of CXCR2-mediated tacrolimus nephrotoxicity, and (iii) target the antagonism of CXCR2 and provide a potential target for the treatment of tacrolimus-induced nephrotoxicity in children. Methods: CXCR2 knockout (CXCR2-KO) mice were used to evaluate the role of CXCR2 in tacrolimus-induced nephrotoxicity. Wistar rats were used to explore the underlying mechanism. Results: In the knockout mice, compared with N-WT group, the renal function index was deteriorative (P < 0.01), the degree of renal fibrosis was aggravated (P < 0.01), the pathological expression of E-cadherin (P < 0.01) and α-SMA (P < 0.01) were occurred in T-WT group. Inversely, compared with T-WT group, the above indicators were improved in T-KO group (P < 0.01). In wistar rats, compared with N group, the renal function index was deteriorative (P < 0.05 or P < 0.01), fibrosis and calcium overload occurred (P < 0.01), CXCL2-CXCR2 was activated (P < 0.05), and meanwhile PI3K/AKT/mTOR pathway was activated (P < 0.05 or P < 0.01) in T group. Inversely, compared with T group, the above indicators were reversed in C group (P < 0.05 or P < 0.01). Conclusion: The present study was firstly to report that CXCL2-CXCR2 activated PI3K/AKT/mTOR pathway and calcium overload in tacrolimus-induced nephrotoxicity, and targeting CXCR2 could inhibit the progression of tacrolimus-induced nephrotoxicity.

Gastric precancerous lesion (GPL) is a crucial stage in the development of gastric cancer, characterized by incomplete intestinal epithelial chemotaxis and heterogeneous hyperplasia with high malignant potential. Early intervention in GPL is vital for preventing gastric cancer. Additionally, there are shared risk factors and pathogenesis between tumors and coronary heart disease (CHD), with an increasing number of tumor patients GPL complicated with CHD due to improved survival rates. Reperfusion therapy in CHD can result in myocardial ischemia-reperfusion injury (MIRI). Traditional Chinese medicine (TCM) has demonstrated unique advantages in treating GPL and MIRI by promoting blood circulation and removing blood stasis. Panax ginseng total saponin (PNS), a component of TCM known for its blood circulation benefits, has shown positive effects in inhibiting tumor growth and improving myocardial ischemia. This study utilized a GPL-MIRI mouse model to investigate the effects of PNS in treatment. Results indicated that PNS significantly improved typical GPL lesions in mice, such as incomplete intestinal epithelialization and heteroplasia, and also reduced myocardial infarction. At the molecular level, PNS exhibited a bidirectional regulatory role in the GPL-MIRI model. It enhanced the autophagic process in gastric mucosal cells by inhibiting the PI3K/Akt/mTOR signaling pathway, while suppressed excessive autophagy in cardiomyocytes. These findings offer new insights and treatment strategies for managing GPL and MIRI using the TCM compound PNS.

Abstract Background Carbazole-based molecules containing thiosemicarbazide functional groups are recognized for their diverse biological activities, particularly in enhancing therapeutic anticancer effects through inhibiting crucial pathways. These derivatives also exhibit noteworthy antioxidant properties. Objectives This study aims to synthesize, characterize, and evaluate the antioxidant and anticancer activities of 18 novel carbazole derivatives. Methods The radical scavenging capabilities of the compounds were assessed using the 2,2-diphenyl-1-picrylhydrazyl assay. Antiproliferative activities were evaluated on MCF-7 cancer cell lines through viability assays. Additionally, the modulation of the PI3K/Akt/mTOR pathway, apoptosis/necrosis induction, and cell cycle analysis were conducted for the most promising anticancer agents. Results nine compounds showed potent antioxidant activities with IC50 values lower than the positive control acarbose, with compounds 4 h and 4y exhibiting the highest potency (IC50 values of 0.73 and 0.38 µM, respectively). Furthermore, compounds 4o and 4r displayed significant anticancer effects, with IC50 values of 2.02 and 4.99 µM, respectively. Compound 4o, in particular, exhibited promising activity by targeting the PI3K/Akt/mTOR signaling pathway, inhibiting tumor survival, inducing apoptosis, and causing cell cycle arrest in MCF-7 cell lines. Furthermore, compound 4o was showed significant antimicrobial activities against S. aureus and E. coli, and antifungal effect against C. albicans. Its potential to overcome drug resistance through this pathway inhibition highlights its promise as an anticancer agent. Molecular docking simulations supported these findings, revealing favorable binding profiles and interactions within the active sites of the enzymes PI3K, AKT1, and mTOR. Moreover, assessing the druggability of the newly synthesized thiosemicarbazide derivatives demonstrated optimal physicochemical properties, further endorsing their potential as drug candidates.