Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3Kα subunit. Our cutting-edge study employed a structure-based virtual screening of ∼3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3Kα inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 µM, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3Kα dysregulation, offering promising new possibilities for effective CRC treatment.

Colorectal cancer is a major global health burden, with significant heterogeneity in clinical outcomes among patients. Identifying robust prognostic gene expression signatures can help stratify patients, guide treatment decisions, and improve clinical management. This review provides an overview of current prognostic gene expression profiles in colorectal cancer research. We have synthesized evidence from numerous published studies investigating the association between tumor gene expression patterns and patient survival outcomes. The reviewed literature reveals several promising gene signatures that have demonstrated the ability to predict disease-free survival and overall survival in CRC patients, independent of standard clinicopathological risk factors. These genes are crucial in fundamental biological processes, including cell cycle control, epithelial-mesenchymal transition, and immune regulation. The implementation of prognostic gene expression tests in clinical practice holds great potential for enabling more personalized management strategies for colorectal cancer.

Skeletal muscle is the main site of glucose deposition in the body during meals and the major glucose utilizer during physical activity. Although in both instances the supply of glucose from the circulation to the muscle is of paramount importance, in most conditions the rate-limiting step in glucose uptake, storage, and utilization is the transport of glucose across the muscle cell membrane. This step is dependent upon the translocation of the insulin- and contraction-responsive glucose transporter GLUT4 from intracellular storage sites to the sarcolemma and T tubules. Here, we first analyze how glucose can traverse the capillary wall into the muscle interstitial space. We then review the molecular processes that regulate GLUT4 translocation in response to insulin and muscle contractions and the methodologies utilized to unravel them. We further discuss how physical activity and inactivity, respectively, lead to increased and decreased insulin action in muscle and touch upon sex differences in glucose metabolism. Although many key processes regulating glucose uptake in muscle are known, the advent of newer and bioinformatics tools has revealed further molecular signaling processes reaching a staggering level of complexity. Much of this molecular mapping has emerged from cellular and animal studies and more recently from application of a variety of -omics in human tissues. In the future, it will be imperative to validate the translatability of results drawn from experimental systems to human physiology.

Breast cancer, which arises from the epithelial tissue of the breast, is one of the most common cancers affecting women worldwide. Its incidence and mortality rates have been increasing in both developed and developing countries. As a hormone-dependent cancer, breast cancer is classified into several molecular subtypes based on the expression of key markers: Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER-2), and Ki67. PR loss is associated with endocrine resistance and a poorer prognosis in breast cancer. Despite this, the underlying mechanisms of ER-positive/PR-negative (ER+PR-) breast cancer remain poorly understood. This study aims to review recent advancements in research on ER+PR- breast cancer, analyze its clinical characteristics and molecular mechanisms, and provide recommendations for more targeted therapeutic approaches.

Pampus argenteus, a species distributed throughout the Indo-West Pacific, plays a significant role in the yield of aquaculture species. However, cultured P. argenteus has always been characterised by unbalanced growth synchronisation among individuals, slow growth rate, and lack of excellent germplasm resources. Therefore, we conducted mass selection for fast-growing strain P. argenteus for several consecutive years. Various genetic improvement programs have modified its genome sequence through selective pressure, leaving nucleotide signals that can be detected at the genomic level. In the present study, we combined bulked segregant analysis and transcriptome sequencing to identify candidate single nucleotide polymorphisms (SNPs) and key genes for growth-related traits in P. argenteus. A total of 7,280,936 SNPs and 2,212,379 insertions/deletions were identified in the extreme phenotypes of the fast-growing and slow-growing groups. Based on the examination of SNP frequency differences and sliding-window analysis, 42 SNPs were identified as candidate markers. Moreover, 14 of the 42 SNPs linked to growth-related traits were confirmed to be credible SNPs, and eight growth-related genes were screened, namely myb-binding protein 1 A, insulin A/B chains, α-1B adrenoceptor, engulfment and cell motility protein 3, myosin light chain kinase family member 4, insulin receptor located, unconventional myosin-9b, and matrilin-1. An optimal three-factor model (SNP4&SNP12&SNP14) was constructed using the generalized multifactor dimensionality reduction method, and its accuracy was verified as 67.72 %. These results may benefit genetic studies and accelerate genetic improvement of fast-growing strains of P. argenteus.

Non-small cell lung cancer (NSCLC) with PIK3CA mutations demonstrates significant challenges in treatment due to enhanced bone metastasis and immune checkpoint resistance. This study investigates the efficacy of tumor-targeting peptide 1-modified cancer stem cell-derived extracellular vesicles (TMTP1-TSRP-EVs) in reshaping the tumor microenvironment and reversing immune checkpoint resistance in NSCLC. By integrating TMTP1-TSRP into EVs, we aim to specifically deliver therapeutic agents to NSCLC cells, focusing on inhibiting the PI3K/Akt/mTOR pathway, a crucial driver of oncogenic activity and immune evasion in PIK3CA-mutated cells. Our comprehensive in vitro and in vivo analyses show that TMTP1-TSRP-EVs significantly inhibit tumor growth, reduce PD-L1 expression, and enhance CD8+ T cell infiltration, effectively reversing the immune-suppressive microenvironment. Moreover, the in vivo models confirm that our approach not only suppresses bone metastases but also overcomes primary resistance to immune checkpoint inhibitors by modulating the expression of key immunological markers. These findings suggest that targeted delivery of TMTP1-TSRP-EVs could provide a novel therapeutic strategy for treating PIK3CA-mutant NSCLC, offering significant improvements over traditional therapies by directly targeting the molecular pathogenesis of tumor resistance and metastasis. Molecular Mechanisms Reshaping the TME to Halt PI3K-Mutant Bone Metastasis of NSCLC and Overcoming Primary ICI Resistance. (Created by BioRender).

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a critical intracellular signaling pathway that is pivotal in various cellular functions. It is in senescence, survival, and growth under normal physiological and pathological conditions, including neoplasms. Additionally, this pathway has been recognized as essential for the regulation of the cell cycle. Several previous studies have indicated that the PI3K/Akt signaling pathway can be influenced by various natural products, with resveratrol (3,4',5-trihydroxy-trans-stilbene) being a particularly important phytoalexin polyphenol in this context. This review explores the impact of the PI3K/Akt signaling pathway on the initiation and advancement of various cancerous conditions and the potential of resveratrol to target this signaling mechanism. The review begins by summarizing the anti-tumor capabilities of resveratrol and then emphasizes the significant role of the PI3K/Akt signaling pathway in the progression of multiple malignancies. Finally, we discuss the therapeutic effects of resveratrol on human neoplasms, from brain cancers to gastrointestinal malignancies, through regulation of this signaling cascade.

Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.

Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.

The incidence of Gastric cancer (GC) has shown a sharp upward trend, and patients with GC complicated by diabetes exhibit significantly worse clinical outcomes and prognosis compared to those without diabetes. Traditional Chinese medicine has played a crucial role in the treatment of both GC and diabetes. Currently, Banzhilian(Scutellaria barbata D. Don) is utilized in the treatment of GC; however, the specific small-molecule monomers it contains and their mechanisms of action have not yet been fully elucidated. This study aims to explore the mechanism of quercetin, a key component of Banzhilian, through network pharmacology, molecular docking, molecular dynamics (MD) simulation, bioinformatics, and in vitro and in vivo experiments. Initially, core targets and key pathways involved in the treatment of diabetes-associated GC (GC-diabetes) were identified using public databases. Subsequently, molecular docking, MD simulation, and survival analysis were performed. Experimental validation included CCK-8 assays, colony formation assays, apoptosis detection, cell cycle analysis, wound healing assays, Transwell migration assays, Western blotting, and mouse subcutaneous tumor formation experiments to evaluate the effects of quercetin, as an active monomer in Banzhilian, on Gastric cancer cells (HGC-27-HG cells) under high-glucose conditions. In this study, quercetin was identified as the key active component, with AKT1, TP53, JUN, MYC, and CCND1 recognized as the target genes, and the PI3K/AKT signaling pathway as the primary regulatory pathway. The results of the study indicate that the proliferation, migration, and invasion capabilities of HGC-27-HG cells are significantly higher than those of HGC-27 cells. However, quercetin inhibited the growth of HGC-27-HG cells, promoted apoptosis, induced cell cycle arrest at the G0/G1 phase, and reduced the cells' migration and invasion abilities. Furthermore, it downregulated the expression of target genes and their phosphorylation levels. The experimental findings confirmed that quercetin, as an active monomer in Banzhilian, suppresses the proliferation of HGC-27-HG cells by inhibiting the PI3K/AKT/MYC pathway, promoting apoptosis, blocking cell cycle progression, and inhibiting cell migration and invasion.

Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.

Allosteric regulation is a pivotal mechanism governing a wide array of cellular functions. Essential to this process is a flexible biomolecule allowing distant sites to interact through coordinated or sequential conformational shifts. Phosphoinositide-dependent kinase 1 (PDK1) possesses a conserved allosteric binding site, the PIF-pocket, which regulates the kinase's ATP binding, catalytic activity, and substrate interactions. We elucidated the allosteric mechanisms of PDK1 by comparing conformational ensembles of the kinase bound with different small-molecule allosteric modulators in the PIF-pocket with that of the modulator-free kinase. Analysis of over 48 μs of simulations consistently shows that the allosteric modulators predominantly influence the conformational dynamics of specific distal regions from the PIF-pocket, driving allosteric activation. Furthermore, a recently developed advanced difference contact network community analysis is employed to elucidate allosteric communications. This approach integrates multiple conformational ensembles into a single community network, offering a valuable tool for future studies aimed at identifying function-related dynamics in proteins.

Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.

Background: In addition to its known antioxidant function, the reduced form of vitamin C, ascorbate, also acts as a neuromodulator in the nervous system. Previous work showed a reciprocal interaction of ascorbate with glutamate in chicken embryo retinal cultures. Ascorbate modulates extracellular glutamate levels by inhibiting excitatory amino acid transporter 3 and promoting the activation of NMDA receptors and the consequent activation of intracellular signaling pathways involved in transcription and survival. Objective: In the present work, we investigated the regulation of AKT phosphorylation by ascorbate in chicken embryo retina cultures. Methodology: Cultures of chicken embryo retina cells were tested using Western blot, immunocytochemistry, fluorescent probe transfection, and cellular imaging techniques. Results: Our results show that ascorbate induces a concentration and time-dependent increase in AKT phosphorylation via the accumulation of extracellular glutamate, the activation of glutamate receptors, and the activation of the PI3K pathway. Ascorbate produces an increase in intracellular calcium accumulation and, accordingly, AKT phosphorylation by ascorbate is blocked by the calcium chelator BAPTA-AM. Moreover, AKT phosphorylation is also blocked by the nitric oxide synthase inhibitor 7-nitroindazole, indicating that it is mediated by calcium and nitric oxide-dependent mechanisms. Conclusions: We demonstrate that ascorbate modulates the PI3K/AKT pathway in retinal cultures through the activation of glutamate receptors and NO production in a calcium-dependent manner. Given that previous research has shown that glutamate induces ascorbate release in retinal cultures, our findings emphasize the significance of the reciprocal interactions between ascorbate and glutamate in retinal development. These findings provide further evidence supporting the role of ascorbate as a neuromodulator in retinal development.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME-through inhibition of ECM components, MMPs, or integrin signaling-may enhance immune responses and improve clinical outcomes.

This review delves into the pivotal role and intricate mechanisms of aerobic glycolysis in nasopharyngeal carcinoma (NPC). NPC, a malignancy originating from the nasopharyngeal epithelium, displays distinct geographical and clinical features. The article emphasizes the significance of aerobic glycolysis, a pivotal metabolic alteration in cancer cells, in NPC progression. Key enzymes such as hexokinase 2, lactate dehydrogenase A, phosphofructokinase 1, and pyruvate kinase M2 are discussed for their regulatory functions in NPC glycolysis through signaling pathways like PI3K/Akt and mTOR. Further, the article explores how oncogenic signaling pathways and transcription factors like c-Myc and HIF-1α modulate aerobic glycolysis, thereby affecting NPC's proliferation, invasion, metastasis, angiogenesis, and immune evasion. By elucidating these mechanisms, the review aims to advance research and clinical practice in NPC, informing the development of targeted therapeutic strategies that enhance treatment precision and reduce side effects. Overall, this review offers a broad understanding of the multifaceted role of aerobic glycolysis in NPC and its potential impact on therapeutic outcomes.

Breast cancer (BC) is the leading cancer among women globally, which has the highest incidence and mortality rate in over a hundred countries. This study was intended to discover a new prognostic biomarker, facilitating personalized treatment approaches.

RNA sequencing data from The Cancer Genome Atlas database and Gene Expression Omnibus database were utilized to download to evaluate expression levels and prognostic significance of Keratin 14 (KRT14). Methylation of KRT14 was also assessed. The CIBERSORT and single-sample gene set enrichment analysis algorithms were applied to explore the connection between KRT14 and the tumor microenvironment. Primary drugs' sensitivity and potential small molecule therapeutic compounds were analyzed through the "pRRophetic" R package and the Connectivity Map. The prognostic value of KRT14 was additionally corroborated through a comparison of protein levels in peritumoral and cancerous tissues via immunohistochemistry. Moreover, an immune-related prognostic model based on KRT14 was designed to enhance the prediction accuracy for the prognosis of BC patients.

The study found that KRT14 expression was generally downregulated in BC, correlating strongly with poor prognosis. Compared to normal tissues, the methylation level of KRT14 was higher in BC tissues. Lower expression of KRT14 was linked to decreased anti-tumoral immune cells infiltration and increased immunosuppressive cells infiltration. Sensitivity to various key therapeutic drugs was lower in groups with diminished KRT14 expression. In addition, several potential anti-BC small molecule compounds were identified. The model designed in this study significantly enhanced the predictive capability for BC patients compared to predictions based solely on KRT14 expression levels.

Overall, KRT14 was closely correlated with the prognosis in BC, making it a reliable biomarker.

Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy- a cellular process that helps maintain homeostasis by recycling damaged components-in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious virus that poses a significant threat to the global pig farming industry, resulting in substantial economic losses. However, owing to the high variability of PRRSV and unclear mechanisms of infection, there are currently no effective vaccines or drugs available for its prevention and control. Our previous report revealed that highly pathogenic PRRSV (HP-PRRSV) requires the FAK-PI3K-AKT signaling pathway to facilitate its entry into cells. In this study, we further investigated whether the integrin subunit was involved in the entry process of NADC30-like PRRSV. First, the integrin subunits in Marc-145 cells were characterized by RT-PCR, and 11 of these subunits were identified, nearly all of which interacted with the integrin α V and β1 subunits to form heterodimers. Western blot analysis revealed that the integrin α V subunit was highly expressed in Marc-145 cells, and blocking this subunit with a functional antibody or siRNA significantly attenuated NADC30-like PRRSV entry without affecting virus binding. Moreover, in Marc-145 cells, NADC30-like PRRSV could activate the FAK-PI3K-AKT signaling pathway through the integrin α V subunit. Blocking the α V subunit significantly inhibited signal transduction and virus entry, and treatment of cells with the PI3K activator greatly reversed this inhibitory effect. Furthermore, the α V subunit activator manganese could also enhance NADC30-like PRRSV entry and signal transduction. In conclusion, our results revealed that NADC30-like PRRSV could activate the integrin α V subunit and subsequently transduce signals to the FAK-PI3K-AKT signaling pathway to facilitate entry into Marc-145 cells.

PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the molecular details of its activation remain unknown. Here, we present cryo-EM structures of the PI3Kα/KRas complex embedded in lipid nanodiscs, revealing a rich ensemble of PI3Kα states adopted at the membrane surface. The sequential addition of a lipid bilayer, PIP2 and an activating phosphopeptide leads to the progressive release of key inhibitory domains from the PI3Kα catalytic core, which directly correlates with the reorganization of its active site. While association with POPC/POPS nanodiscs partially relieves PI3Kα autoinhibition, incorporation of PIP2 triggers near-complete displacement of PI3Kα inhibitory domains and significant restructuring of active site regulatory motifs. The addition of the activating phosphopeptide induces dimerization of the PI3Kα/KRas complex through a p110α catalytic subunit-mediated interface that is sterically occluded in autoinhibited PI3Kα. In cells, this dimeric PI3Kα complex amplifies Akt signaling in response to growth factor stimulation. Collectively, our structures map the conformational landscape of PI3Kα activation and reveal previously unexplored interfaces for potential therapeutic targeting.

Liver cancer has a high incidence and mortality worldwide, especially in China. Herein, we investigated the therapeutic effect and mechanism of tetrahydrocurcumin against hepatocellular carcinoma (HCC), with a focus on the of phosphoinositide 3-kinases (PI3K)/AKT signaling pathway.

To investigate the effects and mechanism of tetrahydrocurcumin in HCC cell lines HepG2 and Huh7.

Using Metascape, we analyzed the potential targets of tetrahydrocurcumin in HCC. Molecular docking validation was performed using SYBYL2.0. Cell Counting Kit-8, wound healing, and transwell assays were performed to evaluate the effects of tetrahydrocurcumin on HepG2 and Huh7 cell migration, invasion, and apoptosis. The expression of PI3K/AKT signaling pathway-related proteins was detected by western blotting.

Network pharmacology and molecular docking showed that tetrahydrocurcumin has high binding affinity for phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. In vitro experiments demonstrated that tetrahydrocurcumin suppressed the migration and invasion of liver cancer cells, promoted their apoptosis, and downregulated the expression of p-PI3K, p-AKT, and B cell leukemia/lymphoma 2, while upregulating caspase-3, p53, and B cell leukemia/lymphoma 2 associated X.

In summary, tetrahydrocurcumin suppresses PI3K/AKT signaling, promotes apoptosis, and prevents the migration and invasion of liver cancer cells.

Poly-ADP-ribosylation (PARylation) is a post-translational modification in which ADP-ribose is added to substrate proteins. PARylation is mediated by a superfamily of ADP-ribosyl transferases known as PARPs and influences a wide range of cellular functions, including genome integrity maintenance, and the regulation of proliferation and differentiation. We and others have recently reported that PARylation of SH3 domain-binding protein 2 (3BP2) plays a role in bone metabolism, immune system regulation, and cytokine production. Additionally, PARylation has recently gained attention as a target for cancer treatment. In this review, we provide an overview of PARylation, its involvement in several signaling pathways related to cancer immunity, and the potential of combination therapies with PARP inhibitors and immune checkpoint inhibitors.

Osteoarthritis (OA) is a debilitating disease that predominantly impacts the hip, hand, and knee joints. Its pathology is defined by the progressive degradation of articular cartilage, formation of bone spurs, and synovial inflammation, resulting in pain, joint function limitations, and substantial societal and familial burdens. Current treatment strategies primarily target pain alleviation, yet improved interventions addressing the underlying disease pathology are scarce. Recently, exosomes have emerged as a subject of growing interest in OA therapy. Numerous studies have investigated exosomes to offer promising therapeutic approaches for OA through diverse in vivo and in vitro models, elucidating the mechanisms by which exosomes from various cell sources modulate the cartilage microenvironment and promote cartilage repair. Preclinical investigations have demonstrated the regulatory effects of exosomes originating from human cells, including mesenchymal stem cells (MSC), synovial fibroblasts, chondrocytes, macrophages, and exosomes derived from Chinese herbal medicines, on the modulation of the cartilage microenvironment and cartilage repair through diverse signaling pathways. Additionally, therapeutic mechanisms encompass cartilage inflammation, degradation of the cartilage matrix, proliferation and migration of chondrocytes, autophagy, apoptosis, and mitigation of oxidative stress. An increasing number of exosome carrier scaffolds are under development. Our review adopts a multidimensional approach to enhance comprehension of the pivotal therapeutic functions exerted by exosomes sourced from diverse cell types in OA. Ultimately, our aim is to pinpoint therapeutic targets capable of regulating the cartilage microenvironment and facilitating cartilage repair in OA.

A common urological disorder, calcium oxalate (CaOx) stones are the most common form of kidney stones. Deposition of CaOx crystals leads to tubular damage, interstitial fibrosis, and chronic kidney disease. Understanding the intrinsic mechanisms of kidney stone formation is essential for the prevention of kidney stones and the development of new therapeutic agents. The Golgi apparatus is a key organelle in the secretory pathway of eukaryotic cells, which plays an important role in the sorting, modification, and transport of proteins within the cell, and has been reported to be involved in several diseases, including prostate tumors, gastrointestinal tumors, sepsis, and so on. GOLPH3 is also known as GPP34, GMx33, or MIDAS. It is a glycoprotein that regulates traffic between the trans-Golgi network and the cell membrane. However, its role in renal injury caused by CaOx crystal deposition is still unclear. Results from immunohistochemistry, qRT-PCR, western blot, and public database single nucleotide RNA-seq showed that GOLPH3 was significantly upregulated in kidney stone patients and animal kidneys. Significant inhibition of Golgi stress, apoptosis, and renal fibrosis by GOLPH3 inhibition with siRNA in CaOx-stimulated HK-2 cells. The PI3K\AKT\mTOR signaling pathway was inhibited by GOLPH3 knockdown, which may be associated with reduced inflammatory response and apoptosis, as well as restoration of Golgi morphology and function. In conclusion, GOLPH3 plays a critical role in CaOx-induced kidney injury by promoting Golgi stress and increasing inflammatory responses, apoptosis, and renal fibrosis, suggesting that GOLPH3 is a potential therapeutic target for kidney stones.

Virus-host protein interaction is critical for successful completion of viral replication cycles. As the largest nonstructural protein (NSP) of porcine reproductive and respiratory syndrome virus (PRRSV), NSP2 plays multiple and critical roles in viral replication, antiviral immunity, cellular tropism and virulence. An interactome of this protein with host proteins would be instrumental in full understanding of these multifunctional roles. In this study, we report the identification of 120 NSP2-interacting host proteins by co-immunoprecipitation coupled liquid chromatography mass spectrometry, via rescuing and utilizing a recombinant PRRSV expressing an HA-tagged NSP2. By comparing and subtracting with cells infected with parental virus, a comprehensive interactome was constructed. Bioinformatics analysis revealed that these host factors are mainly involved in translation regulation, metabolism, signal transduction and innate immunity signaling pathways. Selection of five host proteins (CtBP1, CtBP2, HSPA2, PPP1CA, SH3KBP1) for further verification and characterization confirmed their interactions with NSP2 and differential effects on PRRSV replication. Intriguingly, interaction of NSP2 and SH3KBP1 led to specific cleavage of SH3KBP1, antagonizing its pro-apoptotic activity. Taken together, this study provides overarching views on the NSP2-host interactome, paving a solid foundation for functional studies of host proteins in PRRSV biology and their potential as targets for novel therapeutics development.

p85β is a regulatory subunit of the phosphoinositide 3-kinase (PI3K). Emerging evidence suggests that p85β goes beyond its role in the PI3K and is functional in the nucleus. In this study, we discover that nuclear p85β is enriched at gene loci and regulates gene transcription and that this regulatory role contributes to the oncogenic potential of nuclear p85β. A multi-omics approach reveals the physical interaction and functional cooperativity between nuclear p85β and a transcription factor BCLAF1. We observe genome-wide co-occupancy of p85β and BCLAF1 at gene targets associated with transcriptional responses. Intriguingly, the targetome includes BCLAF1 of which transcription is activated by p85β and BCLAF1, indicating a positive autoregulation. While BCLAF1 recruits p85β to BCLAF1 loci, p85β facilitates the assembly of BCLAF1, the scaffold protein TRIM28 and the zinc finger transcription factor ZNF263, which together act in concert to activate BCLAF1 transcription. Collectively, this study provides functional evidence and mechanistic basis to support a role of nuclear p85β in modulating gene transcription.

PI3K and AKT signaling pathway has been linked to the pathophysiology of various diseases. This pathway has emerged as a crucial therapeutic strategy for cancer and other diseases. To better understand recent development of PI3K and AKT, a patent-based landscape study was performed. The results shows that both PI3K and AKT targets have shown prolific patent filings over the past 20 years. This study is the first to depict the therapeutic applications of both PI3K and AKT targets based on a patent big data analysis. Ten key therapeutic applications were identified, with over 77% of patents related to anti-cancer therapy for both PI3K and AKT targets. Additionally, our findings show that combination therapy is a distinguishing feature for drugs targeting both PI3K and AKT. The average time from patent application to drug approval for PI3K target drugs is 8.8 years. PI3K target drugs obtain market approval faster compared to AKT drugs. Approximately, 2 years of patent term extension could be obtained if the time from the patent application date to the drug approval date is less than 10 years.

Phosphoinositide 3-kinase (PI3K), Phosphatase and tensin homolog (PTEN) and connexin50 (Cx50) have individually been shown to play critical roles in the growth, development and maintenance of the lens and to functionally interact in vitro. To elucidate how gap junctional coupling mediated by Cx50 and intracellular signaling mediated by PI3K and PTEN synergistically interact to regulate lens homeostasis in vivo, we generated and characterized double knockout animal models lacking the p110α subunit of PI3K and Cx50, or PTEN and Cx50.

We interbred lens specific p110α and PTEN conditional knockout animals with Cx50 deficient mice to generate double knockouts. Animals and eyes were weighed, lenses were dissected, photographed, measured, fixed and sectioned for histological analysis. Lens epithelial cell proliferation was determined using 5-ethynyl-2'-deoxyuridine (EdU) labeling.

Double knockout of p110α and Cx50 led to a significant reduction in lens and eye size, and a high rate of lens rupture. The individual cell proliferation defects of the Cx50 and p110α single knockout lenses both persisted in the double KO. Double deletion of Cx50 and PTEN produced severe lens defects, including cataract, aberrant cell migration, altered cell proliferation, vacuole formation and lens rupture.

The severe phenotypes in p110α/Cx50 and PTEN/Cx50 double deficient lenses suggest that PI3K, PTEN and Cx50 participate in both distinct and common regulatory pathways that are necessary to maintain normal lens growth and homeostasis.

Owing to its high mortality rate, lung cancer (LC) remains the most common cancer worldwide, with the highest malignancy diagnosis rate. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling (PAM) pathway is a critical intracellular pathway involved in various cellular functions and regulates numerous cellular processes, including growth, survival, proliferation, metabolism, apoptosis, invasion, and angiogenesis. This review aims to highlight preclinical and clinical studies focusing on the PAM signaling pathway in LC and underscore the potential of natural products targeting it. Additionally, this review synthesizes the existing literature and discusses combination therapy and future directions for LC treatment while acknowledging the ongoing challenges in the field. Continuous development of novel therapeutic agents, technologies, and precision medicine offers an increasingly optimistic outlook for the treatment of LC.

Dysregulated activation of the PI3K/AKT/mTOR pathway is crucial in the development of cancer, and disrupting it could potentially lead to cancer suppression, making it a viable strategy for cancer treatment. Here, as a consecutive work of our team, we described the identification and optimization of PI3K/mTOR inhibitors based on triazine scaffold, which exhibited potent PI3K/mTOR inhibitor activity. The systematically structure-activity relationship (SAR) results demonstrated that compound 5nh displayed high efficacy against PI3Kα and mTOR, with the IC50 values of 0.45 nM and 2.9 nM, respectively. Importantly, compared to the lead compound PKI-587, 5nh demonstrated significant inhibitory activity against non-small-cell lung cancer (NSCLC) cell lines, particularly HCC-827, with a 43-fold increase (3.5 nM vs 150 nM). Additionally, the compound showed effective inhibition against the EGFR-resistant variant HCC-827(GR) cell line. Mechanism validation demonstrated that 5nh significantly interfered with the PI3K/AKT/mTOR signaling pathway in HCC-827 cells. Furthermore, the oral pharmacokinetic properties of 5nh had been observably improved, with AUC0-t and Cmax increasing by 13-16 times at a dose of 10 mg/kg in mice. Importantly, the in vivo efficacy study demonstrated that orally treatment of 5nh led to significant tumor growth suppression, with a TGI value of 84.4 %. Collectively, our systematically medicinal chemistry campaigns suggested that 5nh, a novel oral available triazine derivative, held promise as a candidate for therapy of NSCLC by targeting the PI3K/AKT/mTOR cascade.

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by synovial inflammation and fibrosis. Gentiopicroside (GPS), one of the main active ingredients of Gentiana macrophylla, is widely used in anti-inflammatory and anti-fibrotic therapies. However, the exact mechanism by which GPS treats synovial inflammation and fibrosis in KOA remains unclear.

Fibroblast-like synoviocytes (FLSs) were stimulated with lipopolysaccharide (LPS) to induce inflammation and fibrosis, and CCK-8 was performed to determine the viability of GPS-treated FLSs, using immunofluorescence to examine the expression of P-PI3K and P-AKT, confocal microscopy was used to identify intracellular HMGB1 translocation. The KOA rat model was established by anterior cruciate ligament transection (ACLT) and subsequently subjected to GPS intervention. Inflammatory cytokines (TNF-α, IL-1β, and IL-6), fibrosis-related indicators (TGF-β, collagen I, TIMP1, and α-SMA), and HMGB1/PI3K/AKT signaling axis-related proteins and gene expression of fibroblast-like synoviocytes and synovial tissues were detected by Western blotting and real-time PCR. The histopathology of the synovium of the rats was assessed using Hematoxylin-eosin (HE), Sirius Red, and Masson staining. Immunohistochemistry was performed to detect the expression of HMGB1, P-PI3K, and P-AKT.

The present study revealed that GPS intervention significantly ameliorated inflammation and fibrosis in LPS-stimulated FLSs and KOA rat synovium. Immunofluorescence demonstrated that GPS inhibited the release of HMGB1 from the nucleus. Furthermore, GPS intervention down-regulates the levels of proteins and gene associated with the HMGB1/PI3K/AKT signaling pathway.

GPS ameliorated synovial inflammation and fibrosis in KOA rats, which may involve HMGB1-mediated activation of the PI3K/AKT signaling axis.

As one of the most promising means to repair diseased tissues, stem cell therapy with immense potential to differentiate into mature specialized cells has been rapidly developed. However, the clinical application of stem-cell-dominated regenerative medicine was heavily hindered by the loss of pluripotency during the long-term in vitro expansion. Here, a composite three-dimensional (3D) graphene-based biomaterial, denoted as GO-Por-CMP@CaP, with hierarchical pore structure (micro- to macropore), was developed to guide the directional differentiation of human umbilical cord MSCs (hucMSCs) into osteoblasts. GO-Por-CMP@CaP could act as a high-efficiency living composite material without a "dead space", effectively regulating the cellular response. The 3D topological structure generated via the two-step modification on two-dimensional graphene could effectively mimic the natural 3D microenvironment of cells, enhancing the stem cell attachment, which is not only conducive for the proliferation of stem cells but also beneficial for the osteogenic differentiation. Meanwhile, the wide existence of interconnected macropores was favorable for bone ingrowth, capillary formation, as well as the nutrients transportation. Furthermore, the concurrent existence of micro- and mesopores significantly promoted the extracellular matrix (ECM) adsorption, which ensured cellular attachment, leading to multiscale osteointegration. Both in vitro and in vivo assay demonstrated the above three factors collaborated mutually with nanosized calcium phosphate (CaP, with chemical similarities to the inorganic components of bone), which provided abundant adhesive sites to adequately induce osteogenic differentiation in the absence of any soluble growth factors. Proteomic analysis experiments confirmed that GO-Por-CMP@CaP promoted the differentiation of hucMSCs cells into osteoblasts by affecting the PI3K-Akt signaling pathway through the up-regulation of SPP1 protein. Our study offers a pure material-based stem cell differentiation regulating behavior via engineering the dimension and porosity of material, which provides insights into the design and development of substitutes to bone repair materials.

Lung cancer, a leading cause of cancer-related deaths worldwide, is primarily linked to smoking, tobacco use, air pollution, and exposure to hazardous chemicals. Genetic alterations, particularly in oncogenes like RAS, EGFR, MYC, BRAF, HER, and P13K, can lead to metabolic changes in cancer cells. These cells often rely on glycolysis for energy production, even in the presence of oxygen, a phenomenon known as aerobic glycolysis. This metabolic shift, along with other alterations, contributes to cancer cell growth and survival. To develop effective therapies, it's crucial to understand the genetic and metabolic changes that drive lung cancer. This review aims to identify specific genes associated with these metabolic alterations and screen phytochemicals for their potential to target these genes. By targeting both genetic and metabolic pathways, we hope to develop innovative therapeutic approaches to combat lung cancer.

Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.

Carbohydrate kinases (CKs) are pivotal in various biological processes, including energy consumption, cell signaling, and biosynthesis. They are a group of enzymes that facilitate the phosphorylation of carbohydrates, playing a crucial role in cellular metabolism. These enzymes facilitate the transfer of a phosphate group from a high-energy donor like ATP to a specified location on a carbohydrate substrate. Dysregulated kinase activity drives tumor growth and progression. Inhibitors targeting these enzymes have been developed and used in cancer therapy. The CK family encompasses three major types: hexokinases, ribokinases, and phosphatidylinositol kinases, with inhibitors of paramount importance in cancer treatment. This review explores the role of CKs in cancer and its inhibitors, providing insights into improving existing inhibitors and designing new ones.

Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial.

Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of PTEN mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the PTEN gene and retained expression of PTEN were included in subprotocol Z1H. Copanlisib was given intravenously over 1 hour at a dose of 60 mg on days 1, 8, and 15 in a 21-day-on and 7-day-off schedule in 28-day cycles. Patients continued treatment until disease progression or unacceptable toxicity.

Overall, 49 patients (20 patients in Z1G and 29 in Z1H) were included in the primary efficacy analyses. The objective response rates in both cohorts were 0% (Z1G; 90% CI, 0 to 13.9) and 3.4% (Z1H; 90% CI, 0.2 to 15.3), respectively. The median progression-free and overall survival durations were 1.8 months (90% CI, 1.4 to 3.9 months) and 13.7 months (90% CI, 6.8 to 18.3 months) for the Z1G cohort and 1.8 months (90% CI, 1.8 to 2.1 months) and 9.0 months (90% CI, 5.4 to 13.3 months) for the Z1H cohort, respectively.

Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.

Renal fibrosis is the most important feature of the progression of chronic kidney disease (CKD), and epithelial-mesenchymal transition (EMT) plays an important role in renal fibrosis. Dedicator of cytokinesis protein 2 (Dock2) is involved in the immune system and the development of a variety of fibrotic diseases. However, its specific role in renal fibrosis remains unclear. Therefore, in this study, we investigated the role and mechanism of Dock2 in renal fibrosis. We constructed an in vivo mouse model of unilateral ureteral obstruction (UUO) and an in vitro model of recombinant human transforming growth factor-β1 (TGF-β1)-induced HK-2 cells. The function and regulatory mechanism of Dock2 were studied via Western blotting, qRT-PCR, immunohistochemistry and immunofluorescence. First, Dock2 was more highly expressed in the kidneys of UUO mice than in those of sham-operated mice. A reduction in Dock2 can improve pathological changes in the kidney tissue of UUO mice, reduce the deposition of the extracellular matrix (ECM), and alleviate EMT. Silencing Dock2 reduced the activation of both the Rac1 pathway and the PI3K/AKT pathway. TGF-β1 promoted Dock2 expression in HK-2 cells in vitro. A decrease in Dock2 can inhibit the expression of Fibronectin, Collagen I, α-SMA and Vimentin and increase the level of E-cadherin. Treatment of HK-2 cells with the Rac1 activator 8-CPT or the PI3K/AKT pathway activator YS-49 inhibited the above changes induced by siDock2, indicating that Dock2 activates EMT in renal fibrosis through the Rac1/PI3K/AKT pathway. Our data suggest that Dock2 may be a potential target for renal fibrosis treatment.

Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.