Unraveling the signaling mechanisms behind Histoplasma capsulatum-induced neutrophil NETosis.

Laryngeal cancer has one of the highest mortality rates of all head and neck cancers. DACT1 is a cuproptosis-related gene in laryngeal cancer and serves as a risk factor for patient prognosis. This study aimed to investigate the effects of DACT1 on the malignant behavior and cuproptosis of laryngeal squamous cell carcinoma (LSCC) cells. DACT1 expression in LSCC cells was measured using RT-qPCR and western blotting. To establish cuproptosis cell model, TU212 and TU686 cells were incubated with elesclomol (20nM) and CuCl2 (20nM) for 24h. Transfection of shRNA or pcDNA3.1 vectors was performed to interfere DACT1 expression. LY294002 (PI3K inhibitor) and 740Y-P (PI3K agonist) were used to silence and overexpress PI3K signaling in LSCC cells, respectively. A cuproptosis-specific inhibitor, tetrathiomolybdate, was used to suppress cuproptosis in LSCC cells. Cell viability, proliferation, migration, and invasion were assessed using CCK-8 assays, colony formation assays, Transwell migration, and Transwell invasion assays. Copper concentration and reactive oxygen species (ROS) level were also measured. Western blotting was performed to quantify protein levels of cuproptosis-related genes and factors involved in the PI3K/AKT pathway. DACT1 expression was upregulated in LSCC cells. DACT1 knockdown inhibited LSCC cell proliferation, migration, and invasion. DACT1 depletion enhanced cuproptosis, as evidenced by more pronounced decreases in cell viability, increased intracellular copper concentration and ROS levels, upregulation of HSP70, and downregulation of LIAS. Notably, treatment with the cuproptosis inhibitor tetrathiomolybdate reversed the pro-cuproptosis effects induced by DACT1 silencing. Furthermore, the silencing of DACT1 inactivated the PI3K/AKT signaling, as shown by reduced ratios of p-PI3K/PI3K and p-AKT/AKT. Conversely, DACT1 overexpression activated the PI3K/AKT pathway, an effect that was abolished by LY294002. Moreover, LY294002 reversed the promoting effects of DACT1 on LSCC cell malignancy and its inhibitory effects on cuproptosis. In contrast, activation of the PI3K signaling by 740Y-P reversed the enhancement of cuproptosis caused by DACT1 deficiency. DACT1 promotes the malignant behavior of LSCC cells and suppresses cuproptosis by activating the PI3K/AKT signaling.

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAF) promotes antiandrogen resistance through human epidermal growth factor receptor 3 (HER3)-AKT signaling. In this study, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. IHC analysis of radical prostatectomy specimens from patients with prostate cancer treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition, independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment-derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers.

Mycn, a MYC gene family member, is implicated in both carcinogenesis through amplification and Feingold syndrome through its deficiency. Previous studies have indicated that increased Mycn expression enhances vascularization in human neuroblastomas, yet its precise role in vascular development remains elusive. In this study, we utilized single-cell RNA-seq and live imaging analyses to confirm that mycn is expressed during zebrafish vasculogenesis. We investigated vascular development in zebrafish using a genetically engineered mycn mutation. Our findings reveal that mycn-deficient zebrafish exhibit reduced intersegmental vessels and malformed subintestinal vessels, primarily due to decreased cell proliferation in vascular endothelial cells. Importantly, we discovered that activation of PI3K signaling significantly ameliorates these vascular abnormalities. Our study establishes Mycn as a key regulator of vascular development in zebrafish, acting through the PI3K signaling pathway.

Background and ObjectivesMultiple sclerosis (MS) is more prevalent in women, with a female-to-male ratio of 3:1. The molecular mechanisms driving this sex difference are still mostly unknown. MS results from immune dysfunction, with an imbalance in effector and regulatory T cells. Among the latter, Type I regulatory T cells (Tr1) are dysfunctional in people with MS (pwMS), secreting less IL-10, a potent anti-inflammatory cytokine, than in healthy donors. Our objectives were to explore the effect of biological sex on Tr1 cell differentiation in healthy donors and pwMS.MethodsCD4+ T cells were isolated from peripheral blood mononuclear cells, and Tr1 differentiation was induced by costimulation with the complement regulator CD46 or IL-27. The frequency of Tr1 cells and their production of IL-10 and IFN-γ were examined. The impact of the PI3K/mTOR pathway on male and female Tr1 cells was also studied.ResultsWe found that healthy female Tr1 cells produce less IL-10 than male cells (16 women and 16 men, 18–45 years old, p = 0.0053). This sex difference was only observed when Tr1 cells were differentiated by CD46 costimulation. Mechanistically, this sex difference in IL-10 expression by Tr1 cells was due to the differential activity of a negative feedback loop targeting PI3K signaling in male vs female Tr1 cells. In contrast to findings in healthy donors, no sex difference in IL-10 production was observed when CD4+ T cells from pwMS (12 women and 12 men, 18–48 years old) were differentiated to Tr1 cells via the CD46 pathway, further emphasizing the dysregulation of Tr1 generation in MS. However, PI3Kδ inhibition in MS cells also revealed a sex bias, as it reduced IL-10 production by IL-27–induced Tr1 cells only in men (7 men and 5 women, p = 0.0043), while increasing IL-10 levels in the CD46 pathway in both sexes (8 men and 11 women).DiscussionWe demonstrate that sex influences IL-10 production by Tr1 cells via the PI3K pathway, potentially contributing to the greater susceptibility of women to MS. Furthermore, our data suggest that targeting PI3Kδ may represent a novel therapeutic strategy to boost IL-10 production in female pwMS.

This study aims to investigate the potential risk and possible mechanisms of Raynaud's phenomenon (RP) associated with the use of calcitonin gene-related peptide (CGRP) antagonists through a comprehensive analysis of the FDA Adverse Event Reporting System (FAERS) database combined with drug-gene network analysis methods. In this disproportionality study, we evaluated the adverse event (AE) signal of RP associated with CGRP antagonists from the FAERS covering the quarter 2 of 2018 to quarter 1 of 2025, using four methods. The gene targets of CGRP antagonists and RP targets were predicted using multiple databases and protein-protein interactions (PPI) using the STRING database. Subsequently, Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis was performed using R software to identify the potential mechanisms of CGRP antagonists related to RP. This study retrieved a total of 149 AE reports related to CGRP antagonists and RP reports from the FAERS database, involving 7 CGRP antagonists. Erenumab has the highest number of reports. The data mining results indicate that fremanezumab resulted in the strongest AE signals of the four methods. Protein-protein interaction (PPI) network analysis revealed key nodes of non-peptide small molecule CGRP antagonists in RP, such as the key nodes of rimegepant in RP is AKT1, EGFR, ERBB2, and others. The KEGG pathway enrichment analysis showed that the most possible mechanisms of rimegepant, atogepant, and ubrogepant induce RP is the PI3K signaling pathway.Using a novel approach, we systematically integrated the FAERS database with drug-gene network analysis. Our results not only suggest a potential risk of RP associated with CGRP antagonists but also reveal that the PI3K/AKT pathway is the underlying mechanism for non-peptide small molecules. We recommend that patients receiving these antagonists, particularly those with underlying vascular dysfunction, undergo regular monitoring for RP.

RNA viruses can generate “defective” viral genomes during replication, which can interact with standard viral genomes affecting the course of infections. These non-standard viral genomes are related to milder clinical outcomes and are currently being tested as antivirals. Decades of research in influenza have focused on viral mechanisms affecting the production of deletion-containing viral genomes (DelVGs). Based on adaptations of influenza NS1 protein to manipulate host cell metabolism, we hypothesized host metabolic state could also alter the quantity and pattern of deletion-containing viral genomes and the particles that house them. To test this hypothesis, we manipulated host cell anabolic signaling activity and monitored the production of DelVGs and non-infectious particles by two influenza strains, using single-cell immunofluorescence and third-generation sequencing. We show that: 1) influenza infection activates PI3K signaling, with the A/H1N1 strain having roughly double the pAKT levels in single cells as the A/H3N2; 2) alpelisib, a PI3K receptor inhibitor, subverted the ability of both influenza strains to activate PI3K in a dose dependent manner; 3) DelVGs were increased roughly tenfold in polymerase complex segments and ~ 60% in the hemagglutinin segment of A/H1N1 at 20uM of alpelisib; and 4) the A/H3N2 strain did not show changes in DelVG production, but had a modest, statistically significant maximum increase of 11% in non-infectious particles. We find that host cell metabolism can increase the production of non-infectious particles and DelVGs during single rounds of infection, shifting potential interactions among virions. The differential results according to strain and alpelisib concentration suggest future directions examining strain differences in the NS1::p85β virus-host interaction and the specific metabolic state of the cell. Our study presents a new line of investigation into metabolic states associated with less severe flu infection and opens the possibility for potential induction of these states with metabolic drugs.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12964-025-02598-x.

Glutamine and glutamate metabolism play crucial roles in the development of various tumors, yet their specific involvement in colorectal cancer (CRC) remains poorly understood. This study aimed investigate the roles of glutamine and glutamate metabolism in CRC progression and to elucidate themolecular mechanisms by which their key regulatory enzyme, GLS1, contributes to CRC development. Blood samples from healthy controls and individuals with colorectal polyp (CRP), colorectal adenoma (CRA), early-stage CRC (ECRC), and advanced CRC (ACRC) were analyzed using liquid chromatography‒mass spectrometry and gas chromatography‒mass spectrometry to quantify metabolite levels. Bioinformatic analyses and molecular experiments were performed to examine GLS1 expression and function in CRC. GLS1 expression was manipulated using siRNAs and lentiviral vectors for knockdown and overexpression, respectively. Functional assays, including CCK-8, Transwell, and colony formation assays, were used to assess the effects of GLS1 on CRC cell proliferation, migration, and invasion. Rescue experiments with rapamycin (autophagy activator) and LY294002 (PI3K inhibitor) were conducted to explore underlying mechanisms. An in vivo tumorigenesis model in nude mice was also established. Patients with ACRC exhibited significantly reduced circulating glutamine levels compared with healthy controls, whereas glutamate levels were elevated across all disease stages (CRP, CRA, ECRC, and ACRC). Circulating glutamine was associated with both CRC diagnosis and prognosis. GLS1 was upregulated in CRC tissues and cell lines and correlated with poor clinical outcomes. Glutamine deprivation and GLS1 knockdown suppressed CRC cell proliferation, migration, and invasion, while GLS1 overexpression enhanced these malignant phenotypes. Bioinformatic analysis revealed that GLS1 activates the PI3K signaling pathway in CRC, which was confirmed by Western blotting following GLS1 knockdown and overexpression. Additionally, glutamine deprivation and GLS1 knockdown induced autophagy in CRC cells, whereas GLS1 overexpression inhibited autophagy, as further evidenced by transmission electron microscopy. Rescue experiments demonstrated that LY294002 and rapamycin reversed the effects of GLS1 on CRC cell proliferation, migration, and invasion . In vivo, GLS1 overexpression promoted tumor growth in nude mice, which was attenuated by LY294002 and rapamycin treatment. Glutamine and glutamate show promise as diagnostic and prognostic biomarkers for CRC. GLS1 plays a critical role in CRC progression by activating the PI3K-AKT signaling pathway and modulating autophagy. These findings provide new insights into glutamine metabolism in CRC and highlight GLS1 as a potential therapeutic target.

ABSTRACTZona pellucida (ZP) proteins, essential for oocyte development, undergo posttranslational regulation through furin‐mediated cleavage. Nevertheless, our understanding of the functional significance of furin‐mediated cleavage of ZP proteins in female reproduction remains limited. Here, using mouse models with disrupted furin cleavage sites in ZP1, ZP2, and ZP3, we found that loss of the furin site in ZP2 caused female infertility associated with empty follicle syndrome (EFS), manifested by the failure to retrieve oocytes after ovarian hyperstimulation. In contrast, female mice carrying cleavage‐resistant variants at the furin sites of ZP1 and ZP3 exhibited defective ZP in a subset of oocytes, leading to reduced fecundity. Mechanistically, disruption of the furin cleavage site in ZP2 impaired the transmembrane transport of the non‐cleaved ZP2 protein and subsequently reduced the levels of SNARE proteins, ultimately triggering oocyte apoptosis through activation of the p53 and PI3K signaling pathways. Collectively, we uncovered the essential role of furin‐mediated cleavage of ZP proteins in female fertility and provided new mechanistic insights into the pathogenesis of EFS. These findings open new avenues for investigating the contribution of posttranslational modifications to female reproduction and for developing potential therapeutic strategies to treat female infertility.

Castration-resistant prostate cancer (CRPC) is largely dependent on the androgen receptor (AR) for growth and often exhibits hyperactive PI3K signaling, most frequently due to PTEN loss. Therapeutic pressure from anti-AR therapies can induce trans-differentiation toward an AR-independent phenotype. Recently, different subtypes of AR-independent CRPC have been redefined, with the stem cell-like (SCL) subtype emerging as one of the most prevalent. Elucidation of the epigenetic mechanisms controlling the maintenance of these distinct CRPC cell states could pave the way for effective combinatorial therapies for CRPC. In this study, we identified a key role for the histone methyltransferase KMT2D in establishing the chromatin competence necessary for the recruitment of AR and FOXA1 transcription factors (TFs) that are essential for the AR transcriptional output in AR-dependent CRPC cell lines, patient derived organoids, and patient samples. Unexpectedly, KMT2D maintained the identity of the AR-low CRPC-SCL subtype and controlled activity of AP-1 TFs such as FOSL1, which acts as a master regulator of this subtype. Single cell transcriptomics and chromatin assays underscored the role of KMT2D in sustaining a mixed lineage cell state via AP-1 and FOXA1. The combined suppression of PI3K/AKT and KMT2D reduced cell proliferation in prostate cancer cells and patient-derived organoids in both CRPC-AR and CRPC-SCL subtypes. Altogether, these results unveil KMT2D as a major mediator of the epigenetic landscape in subtype-specific CRPC, contributing to tumor growth and therapeutic response.

Abstract Glycogen synthase kinase-3beta (GSK3β) is a multifunctional serine/threonine kinase seen at the convergence of several signaling cascades. GSK3β plays a central role in PI3K signaling and Wnt/beta-catenin signaling pathways, which are the key regulators of important biological functions like cell growth, survival, metabolism, epithelial–mesenchymal transition (EMT), cell proliferation and differentiation at various stages of embryonic and adult development. Accordingly, dysregulation of GSK3β has been linked to pathogenesis of cancer, diabetes, and several neurodegenerative disorders. Therefore, pharmacological interventions to inhibit GSK3β activity is an important therapeutic strategy to counter these abnormalities. Previously, we identified a highly selective, with a better pharmacokinetic profile pyrimidinylazaindole based small molecule inhibitor of GSK3β that showed potent growth inhibition in cell based and xenograft models of KRas mutant pancreatic cancers. Pertinently, this small molecule inhibitor was seen to induce apoptosis in a β-catenin and c-Myc dependent manner. Moreover, GSK3β inhibition decreased the nuclear activity of the NF-kB p65 in KRas mutated MiaPaCa-2 cells thereby impeding the cell survival and anti-apoptotic processes in these cells as well as in the xenograft model of pancreatic cancer. Since EMT driven chemoresistance remains one of the important factors involved in pancreatic cancer progression. Overcoming drug resistance in pancreatic cancer patients poses a prominent challenge, predominantly in cancers driven by K-RAS mutation. Here in this study, we have shown that small molecule inhibitor imapacts the EMT progresson in KRAS mutant pancreatic caners through mediating significant decreases in EMT markers like N Cadherins, and slug. No detectable levels of E-cadherin were seen, however, vimentin, ZEB and snail remained unchanged. While the recently FDA approved GSK3β inhibitor, elraglusib, inhibits both alpha and beta isoforms equally and shows relatively higher half maximal inhibitory concentration however, small mole identified in our study would prove a clinically-relevant choice for its higher potency, bioavailability, pharmacokinetic and drug like properties however further analysis. This study opens up new avenues for therapeutic treatment of mutant KRas-dependent human cancers through pharmacological inhibition of GSK3β. Citation Format: MIR OWAIS AYAZ, MOHD JAMAL DAR JAMAL. DAR. GSK3β: a therapeutic target in KRAS mutant pancreatic cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C028.

The vagus nerve (VN) is a major component of the parasympathetic nervous system that regulates glucose and energy homeostasis. However, the specific molecular signaling pathways within the VN that regulates thishomeostasis remain unclear. Here, we show that vagal neuron-specific deletion of phosphatase and tensin homolog (Pten), the endogenous negative regulator of PI3K, led to increased vagal output. Intriguingly, dopaminergic signaling genes were upregulated, correlating with elevated sympathetic nerve density and increased norepinephrine levels in adipose tissue of vagalPten-deficient mice. These mice were also protected against high-fat diet-induced obesity, insulin resistance, and systemic inflammation. To investigate insulin-specific PI3K signaling within the VN, we generated mice with vagal neuron-specific insulin receptor deletion that resulted in exacerbation of metabolic defects, which was rescued by concomitant Pten deletion. In summary, we show that insulin-PI3K-PTEN axis within vagal neurons is essential in optimizing the autonomic output that determines peripheral inflammatory and metabolic homeostasis.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis. More than 90% of PDAC tumors harbor KRAS mutations, and several KRAS inhibitors, such as off-state, on-state, mutation-specific, and pan-RAS inhibitors, are being tested in preclinical and clinical settings. However, the response to these inhibitors as single agents is less than optimal, indicating the need to identify novel combination therapies to improve treatment outcomes. Proliferating cell nuclear antigen (PCNA) is a ring-shaped clamp protein that regulates DNA replication, repair, and resolution of transcription-replication conflict, which are critical processes for pancreatic cancer survival. AOH1996 is a first-in-class, selective PCNA inhibitor in Phase I trials. Here, we found that AOH1996 treatment is efficacious in various PDAC models in vitro. PCNA and KRAS are predicted to be synthetic lethal partners, and RNA sequencing of AOH1996-treated PDAC cells reveals enrichment of MAPK and PI3K signaling pathways. Combination of AOH1996 with KRAS inhibitors demonstrates strong synergy across KRAS G12C and G12D mutant models. Treatment with a combination of AOH1996 and KRAS inhibitors induces cell cycle arrest and apoptosis in PDAC cells. Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo , the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation.

The poor response to current systemic treatments in liver cancer has been associated with the activation of cancer-associated fibroblasts (CAFs). Herein, we aimed to investigate the effects of chemotherapy on hepatic stellate cells (HSCs), the main origin of CAFs in liver cancer, and regulate HSC activation to improve treatment efficacy. CAF subpopulations and alpha-smooth muscle actin (αSMA) expression were analysed using a single-cell RNA sequencing dataset and immunohistochemical staining in patients. αSMA expression was significantly increased as the proportion of CAFs enriched by COL1A1+ and ACTA2+ subpopulations in patients after transarterial chemoembolisation. In vitro experiments demonstrated that cisplatin activated HSCs through a paracrine effect of excessive reactive oxygen species (ROS) generated from tumour cells of hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) origin. RNA sequencing revealed that the PI3K signalling pathway underlined the activation of HSCs in response to excessive ROS. This was further analysed in HCC mouse models on non-fibrotic and fibrotic livers. 12-parameter flow cytometry panel validated a significant increase in activated CAF subsets in tumours following cisplatin treatment. Alpelisib, an α-specific PI3K inhibitor, selectively targeted PI3K p110α and completely inhibited HSC activation induced by cisplatin. A marked decrease in fibrosis areas was achieved along with a significant reduction of tumour burden in murine HCC models. This study demonstrates a role of platinum-based chemotherapy on HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.

Abstract Repurposing Aprocitentan, an Anti-Hypertensive Drug, as a Potential Anticancer Agent: Targeting Endothelin Receptors in Pancreatic and Breast Cancer Models Cancer remains a leading cause of global mortality, with pancreatic and breast cancers representing two of the most aggressive forms, often associated with poor prognosis and limited therapeutic options. Drug repurposing provides a cost-effective and time-efficient strategy to identify novel cancer therapies from existing drugs with established safety profiles. The endothelin system, comprising endothelin-1 (ET-1) and its receptors (ETA and ETB), plays a critical role in tumor progression through promoting proliferation, angiogenesis, and resistance to apoptosis. This study proposes to repurpose Aprocitentan, a dual ETA/ETB antagonist currently approved for hypertension, as a potential anticancer agent. The research will employ in vitro models of pancreatic (MiaPaCa-2, BxPC-3) and breast (MCF-7, MDA-MB-231) cancer cell lines, assessing Aprocitentan’s impact on cell proliferation, apoptosis induction, and angiogenesis-related pathways. Additionally, the interplay between Aprocitentan and the PI3K signaling cascade will be explored using the PI3K inhibitor LY294002. Key molecular and functional assays—including MTT viability assays, Western blotting, ELISA, and PCR—will be utilized to validate mechanistic insights. We hypothesize that Aprocitentan will inhibit cancer cell growth, promote apoptosis, and suppress angiogenic signaling, thereby demonstrating its potential as a repurposed anticancer drug. The outcomes of this study are expected to provide preclinical evidence supporting a novel therapeutic strategy, expanding the application of Aprocitentan beyond cardiovascular disease toward oncology. Citation Format: Rahaf Adnan. Al-Zeer. Repurposing aprocitentan, an anti-hypertensive drug, as a potential anticancer agent: Targeting endothelin receptors in pancreatic and breast cancer models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A014.

This study aimed to investigate the role of FAM172A in epithelial ovarian cancer (EOC), a highly lethal gynecological malignancy often diagnosed at late stages with limited treatment options. FAM172A expression was evaluated in EOC and normal ovarian tissues using western blotting and immunohistochemistry, and its association with patient prognosis, treatment response, and CA125 levels was assessed by multivariate regression analysis. Functional assays were performed to examine the effects of FAM172A on EOC cell proliferation, migration, and invasion. In vivo models were used to evaluate the influence of FAM172A on tumor growth, metastasis, and chemosensitivity. The underlying mechanism was explored by modulating the PI3K-Akt pathway with pharmacological inhibitors and activators. FAM172A was significantly upregulated in EOC tissues, and its elevated expression correlated with poor prognosis, chemotherapy resistance, and increased CA125 levels. Multivariate analysis identified FAM172A expression, platinum sensitivity, and CA125 as independent prognostic factors. In vitro, FAM172A promoted malignant behavior and conferred resistance to cisplatin. In vivo, knockdown of FAM172A suppressed tumor progression and enhanced the efficacy of cisplatin. Mechanistically, FAM172A exerted its effects through regulation of the PI3K-Akt pathway, and modulation of PI3K signaling rescued FAM172A-induced phenotypic changes. These findings highlight FAM172A as a critical promoter of EOC progression, associated with aggressive tumor characteristics and treatment failure. By activating the PI3K-Akt pathway, FAM172A represents a promising therapeutic target for EOC, potentially offering new strategies to improve patient outcomes, particularly in overcoming chemoresistance.

Neutrophil extracellular traps promote bone loss in type 1 diabetes via suppression of the FN1-PI3K/Akt signaling axis.

Pediatric cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest is associated with global myocardial ischemia-reperfusion (IR) injury, leukocyte activation, and a systemic inflammatory response that contributes to early postoperative morbidity and mortality. The mechanisms for acute myocardial dysfunction and end-organ injury after pediatric heart surgery are complex and incompletely understood. This study aimed to: (1) investigate the contributions of the toll-like receptor-4 (TLR-4) pro-inflammatory and the pro-survival hypoxia-inducible factor-1α/phosphatidylinositol 3-kinase (HIF-1α/PI3K) pathways to global myocardial IR injury and inflammation, and (2) evaluate the impact of nicorandil, a coronary vasodilator and anti-ischemic agent, on TLR-4 and HIF-1α/PI3K signaling and end-organ dysfunction in a neonatal piglet model of CPB and cardioplegic arrest.Piglets (4-5 weeks old, N = 12) were randomly assigned to IR or IR + nicorandil. After initiation of CPB with cardioplegic arrest, hearts were reperfused on partial CPB, followed by complete separation from CPB. Left ventricular (LV) systolic and diastolic pressures were continuously recorded, and serial blood and terminal tissue samples were collected to measure inflammation, oxidant stress (OS), and apoptosis.CPB with cardioplegic arrest transiently and significantly impaired both LV contractility (p = 0.01) and diastolic relaxation (p = 0.001) associated with a 39-fold increase in cardiac TLR-4 expression (p = 0.034), a 3-fold increase in IL-6 production (p = 0.01), and significant increases in plasma markers for end-organ injury, but without the expected upregulation in the HIF-1α/PI3K pro-survival pathway. Nicorandil pre-treatment significantly augmented LV systolic (p = 0.004) and diastolic (p = 0.002) functional recovery associated with attenuated upregulation of TLR-4 signaling pathways, augmented HIF-1α/PI3K pro-survival signaling, and reduced inflammation, OS, apoptosis, and end-organ injury.Our piglet model of CPB with cardioplegic arrest demonstrates that the TLR-4 pro-inflammatory signaling pathway plays an essential role in myocardial IR-induced cardiac dysfunction, inflammation, OS, apoptosis, and multi-organ injury. Nicorandil pre-treatment attenuates these effects. Nicorandil also upregulates the HIF-1α/PI3K pro-survival signaling pathway. These results suggest that nicorandil should be studied further to assess its potential therapeutic effects after CPB in children.

Diabetes mellitus type 2 (DMT2) is a chronic metabolic disorder caused by a disruption or resistance in insulin secretion. AKT /PI3K, GSK-3β and CREB signaling pathways influence insulin sensitivity and glucose metabolism. This study aimed to compare the therapeutic impact of pectin extracted from different sources (lemon, orange and grapefruit peels) against diabetic rats. Fourier transform infrared spectroscopy (FT-RI) and Proton Nuclear Magnetic Resonance (1H-NMR) analysis of pectin were done. Treatments were administered daily for one month (500 mg/kg) post diabetes induction via a single dose of streptozotocin (STZ) (40 mg/kg) considering Metformin as a reference drug (250 mg/kg). Biochemical, mutagenicity and genotoxicity analyses were assessed. The FT-IR and1H-NMR revealed that lemon pectin had a strong peak at ≈3.7 ppm. Orange pectin showed a moderate peak at ≈3.7 ppm, and grapefruit pectin showed a weak peak at ≈3.7 ppm. Diabetic rats showed alterations in glucose, insulin, liver function enzymes, urea, oxidative stress indices, IL-6, TNF-α, AKT, PI3K levels and GSK-3β and cAMP responsive element binding protein 1(CREB) genes expression. Changes in micronuclei of polychromatic erythrocytes, chromosomal aberrations, sperm abnormalities and the histopathology of liver and pancreas were also observed. Pectin treatments declared a notable amelioration in glucose and insulin levels as well as the other selected parameters. Pectin extracted from lemon, orange and grapefruit peels showed a promising therapeutic impact against DMT2. High degree of esterification in lemon pectin may explore its potent effect via regulating glucose, α-amylase and the metabolic genes expression pathways. Orange pectin exhibits the strongest anti-mutagenic properties. Together, citrus pectin may be considered as a nutraceutical agent against diabetes.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, yet the transcriptional hierarchies linking endocrine signaling to tumor progression remain poorly defined. Here, we integrated gene-expression profiles from two independent cohorts (TCGA-THCA and GSE33630) to identify consensus transcriptional master regulators (TMRs) driving PTC. After normalization and differential expression analysis, we reconstructed regulon networks with ARACNe-AP, inferred TMR activity using VIPER, and integrated evidence across datasets via Fisher’s meta-analysis. This cross-cohort strategy yielded 50 shared TMRs, predominantly from the Zinc Finger, Forkhead, ETS, and nuclear receptor families. Network topology highlighted PBX4, GATAD2A, BHLHE40, HEY2, and TEAD4 as upstream regulators controlling other TMRs. Functional enrichment revealed activation of NOTCH, MAPK, PI3K, and TGF-β signaling and enrichment of early and late estrogen-response programs, uncovering a noncanonical role of SMAD9 in TGF-β signaling. Together, these findings delineate the transcriptional and hormonal circuitry underlying thyroid tumorigenesis, providing a regulatory framework for biomarker-driven therapies based on network activity states.