Serine-threonine Kinase Akt Research Articles

Network pharmacology analysis revealed novel target genes of Astragaloside IV in breast cancer and breast cancer stem cells

Objective: Breast cancer is one of the most common malignant tumors in women and a leading cause of cancer death in women. Astragaloside IV (AS-IV) has been extensively shown to possess various pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor and immune-regulatory effects. However, the target genes of AS-IV for breast cancer and breast cancer stem cells (BCSCs), and underlying mechanisms remain unknown. Our investigation focused on investigating the potential hub genes of AS-IV in breast cancer and BCSCs, focusing specifically on the underlying signaling pathways. Methods: In this study, we employed the network pharmacology to identify the hub genes targeted by AS-IV in breast cancer and BCSCs. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were conducted to investigate the underlying mechanism of AS-IV treatment. Finally, a comprehensive interaction network was constructed to demonstrate the relationships among AS-IV, BCSCs, breast cancer, KEGG pathways, GO terms, and hub genes. Results: A total of 20 shared genes were identified, from which 10 hub genes were selected: catenin beta 1 (CTNNB1), Jun proto-oncogene (JUN), signal transducer and activator of transcription 3 (STAT3), glycogen synthase kinase 3 beta (GSK3B), AKT serine/threonine kinase 1 (AKT1), phosphatase and tensin homolog (PTEN), epidermal growth factor (EGF), interleukin 6 (IL6), hypoxia inducible factor 1 subunit alpha (HIF1A), tumor necrosis factor (TNF). Enrichment analyses revealed their involvement in key pathways, including PD1 and PDL1 checkpoint pathway in cancer, EGFR tyrosine kinase inhibitor resistance and so on, which regulate cancer cell proliferation, survival, metastasis, and immune evasion. The interaction network highlighted the pivotal roles of these hub genes in oncogenic and immunological processes. Conclusion: AS-IV demonstrated therapeutic potential against breast cancer and BCSCs by targeting critical hub genes and modulating multiple oncogenic signaling pathways. These findings provide novel insights into the molecular mechanisms of AS-IV, offering potential targets for overcoming anti-estrogen therapy resistance and advancing breast cancer treatment.

Integrating Network Pharmacology and in vivo Validation to Explore the Mechanisms of Buyang Huanwu Decoction in Myocardial Ischemia-Reperfusion Injury

ObjectiveBuyang Huanwu Decoction (BYHWD), a traditional Chinese herbal formula, has been widely used to manage cardiovascular disorders. However, its cardioprotective mechanisms in myocardial ischemia/reperfusion injury (MI/RI) remain unclear. This study aims to investigate its pharmacological mechanisms against MI/RI through network pharmacology and experimental validation.Materials and MethodsActive components and targets of BYHWD were identified via Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Encyclopedia of Traditional Chinese Medicine, BATMAN-TCM, and SymMap databases. MI/RI-related targets were retrieved from DisGeNET, GeneCard, Online Mendelian Inheritance in Man, Comparative Toxicogenomics Database, and DrugBank databases. The intersecting targets were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Protein-protein interaction (PPI) networks, compound-target networks, and herb-target-pathway networks were constructed using Cytoscape, and molecular docking was performed via AutoDock Vina. A rat MI/RI model was used to assess infarct size, protein expression, and cytokine levels for in vivo validation.Results95 compounds were identified, with 75 MI/RI-related targets. PPI analyses highlighted ten hub genes, including interleukin-6 (IL6), AKT serine/threonine kinase 1 (AKT1), tumor necrosis factor (TNF), intercellular adhesion molecule 1 (ICAM1), matrix metalloproteinase 9 (MMP9), interleukin-10 (IL10), vascular cell adhesion molecule 1 (VCAM1), nitric oxide synthase 3, albumin, and C-reactive protein. GO and KEGG analyses highlighted TNF signaling, apoptosis, and p53 signaling pathways. Carthami Flos and Radix Astragali emerged as core herbs, with quercetin, kaempferol, baicalein, stigmasterol, baicalin, and beta-sitosterol as key compounds exhibiting strong binding affinities to hub genes. In vivo, BYHWD significantly reduced myocardial infarct size, decreased inflammatory cytokines (IL6 and TNF-α), ICAM1, VCAM1, and MMP9 protein expression, and IL10 and phosphorylated AKT1 expression.ConclusionBYHWD alleviates MI/RI through multicomponent, multitarget, and multipathway mechanisms, primarily modulating TNF and AKT1-mediated inflammatory/apoptotic pathways. These effects collectively support its potential as a complementary treatment for ischemic heart disease.

SG06, a Chalcone Derivative Targets PI3K/AKT1 Pathway for Neuroprotection and Cognitive Enhancement in an Alzheimer's Disease-Like Zebrafish Model.

Alzheimer's disease (AD) and Alzheimer's dementia (ADM) are common neurodegenerative disorders marked by progressive cognitive decline, memory impairment, and behavioral deficits, which impose a significant burden on individuals and healthcare systems worldwide. Due to the complex nature of AD pathophysiology, effective treatment strategies may require targeting multiple pathways. This study explored the neuroprotective effects of the chalcone derivative SG06 in a scopolamine-induced AD-like zebrafish model using network pharmacology and molecular docking. SG06 showed strong binding to key targets such as AKT serine/threonine kinase 1 (AKT1), which are involved in processes like tau phosphorylation, amyloid-beta (Aβ) production, and inflammation. Behavioral assays indicated that SG06 improved cognitive function, reduced anxiety-like behavior, and restored social interactions. Additionally, sensory recovery was observed through better light/dark transitions and recovered olfactory function, likely due to improved neuronal communication and reduced oxidative stress. Mechanistically, SG06 appeared to activate the PI3K/AKT1 pathway, inhibiting Glycogen Synthase Kinase 3 beta (GSK3β) activity, which may help reduce tau hyperphosphorylation and amyloid processing. SG06 also restored antioxidant markers (CAT, GSH, GPx) and improved acetylcholinesterase (AChE) activity, reducing oxidative damage and cholinergic dysfunction. Histological analysis revealed improved cellular morphology and decreased Aβ plaque accumulation, while gene expression studies showed downregulation of pro-inflammatory markers and upregulation of neuroprotective genes. Additionally, SG06 helped improving neurotransmitter balance, particularly in Gamma-Aminobutyric Acid (GABA) and Dopamine (DPAN), contributing to improved synaptic plasticity and cognitive function. These findings suggest that SG06 may have potential as a multi-target therapeutic agent in addressing the complex pathology of AD.

Network pharmacology, molecular docking, and molecular dynamics analyses to explore the molecular mechanism of paclitaxel in atherosclerosis therapy

Atherosclerosis is a chronic arterial disease and the leading cause of vascular death. Paclitaxel has long been recognized as an anticancer agent, but recent studies have shown that paclitaxel can also potentially reduce the progression of atherosclerosis. The aim of this study was to explore the molecular mechanism of paclitaxel as an atherosclerosis therapy using in silico study. Pharmacokinetic and pharmacodynamic analyses of paclitaxel were conducted using SwissADME, ProTox v3.0, and SCFbio websites. Cytoscape software was used to construct a network of protein-protein interactions, and the key proteins involved in paclitaxel-related atherosclerosis were identified, including AKT serine/threonine kinase 1 (AKT1), Jun N-terminal kinase (JNK), and Endothelin 1 (ET1). These key proteins were then subjected to molecular docking and molecular dynamic simulation using MOE and Yasara applications. Pharmacokinetic and pharmacodynamic analyses revealed that paclitaxel has good distribution, metabolism, and excretion properties. However, paclitaxel has shortcomings in absorption, toxicity, and water solubility. According to the results of molecular docking, paclitaxel showed consistent results as the most potential inhibitor of AKT1 (-9.59 kcal/mol), ET1 (-9.16 kcal/mol), JNK (-8.72 kcal/mol) when compared to the control ligands. Molecular dynamics simulations also confirmed the interaction stability between paclitaxel with AKT1, ET1, and JNK, with paclitaxel-AKT1 demonstrating the highest conformational stability (Carbon-α Root Mean Square Deviation <3.0 Å). Even though our in-silico results are promising, more experimental studies are required to confirm the efficacy of paclitaxel as an atherosclerosis therapy.

Identification of Common miRNAs Differentially Expressed in Periodontitis and Pancreatic Cancer

Background/AimPeriodontitis is a prevalent multifactorial, oral infectious disease and is considered a high-risk factor for pancreatic cancer. Nevertheless, there is limited understanding of the underlying epigenetic mechanisms governing this relationship. The aim of this study was to identify dysregulated miRNAs associated with periodontitis and pancreatic cancer, along with their related genes, signaling pathways, and compounds.Materials and MethodsmiRNA expression datasets for tissues affected by periodontitis and pancreatic cancer were obtained from the Gene Expression Omnibus database. miRNAs differentially expressed relative to normal tissues were detected, and those common to both datasets were determined. Further bioinformatics approaches were used to explore the association of common differentially expressed miRNAs with periodontitis and pancreatic cancer.ResultsTwenty shared, differentially expressed miRNAs were identified; 14 exhibited similar expression patterns in both diseases. Among these common differentially expressed miRNAs, 10 were found to be overexpressed. hsa-miR-155, hsa-miR-186, hsa-miR-765, hsa-miR-211 and hsa-miR-375 were the top miRNA nodes in the gene network, with hsa-mir-155 being the sole miRNA node in the transcription factor network. Top candidate miRNA-dysregulated genes included superoxide dismutase 2 (SOD2), nuclear FMR1 interacting protein 2 (NUFIP2), SFT2 domain-containing 2 (SFT2D2), thioredoxin-interacting protein (TXNIP), and cyclin D1 (CCND1), while top dysregulated transcription factors were Argonaute RISC catalytic component 2 (AGO2), AKT serine/threonine kinase 1 (AKT1), BCL6 transcription repressor (BCL6), breakpoint cluster region (BCR), and BRCA1 DNA repair associated (BRCA1). Relevant compounds for targeting these emerged, including 5-fluorouracil, gemcitabine, doxorubicin, ascorbate, diethylstilbestrol, and temozolomide.ConclusionOur study suggests candidate molecular mechanisms linking periodontitis to pancreatic cancer, highlighting potential compounds that may target both diseases. These findings provide a foundation for guiding future fundamental and clinical research.

Actin Gamma Smooth Muscle 2 Promotes Epithelial Ovarian Cancer Cell Proliferation via the AKT1/NF-κB Signaling Pathway.

Epithelial ovarian cancer (EOC) is associated with high mortality rates worldwide and is characterized as the most lethal gynecological cancer. The study aimed to investigate the functional role and underlying molecular mechanism of actin gamma smooth muscle 2 (ACTG2) in the progression of EOC. Data mining from The Cancer Genome Atlas (TCGA) databases showed the expression of ACTG2 was significantly upregulated in EOC and negatively associated with longer overall survival and better prognosis of patients. By using of gain-of-function and loss-of-function experiments in vitro and in vivo, we found that ACTG2 promoted EOC cell proliferation and suppressed cell apoptosis. Mechanistic study revealed that ACTG2 regulates EOC cell proliferation by activating the AKT serine/threonine kinase 1 (AKT1)/nuclear factor-κB (NF-κB) signaling pathway. Importantly, p65 plays a crucial role in this newly identified regulatory mechanism. Our findings demonstrate that ACTG2 may play an oncogenic role in EOC, suggesting its potential as a therapeutic target.

Unique and overlapping mechanisms of valbenazine, deutetrabenazine, and vitamin E for tardive dyskinesia

In 2017, the Food and Drug Administration (FDA) approved valbenazine and deutetrabenazine, two vesicular monoamine transporter 2 (VMAT2) inhibitors, as treatments for tardive dyskinesia (TD). Additionally, some trials have suggested that vitamin E may benefit TD patients. However, the mechanistic basis for these treatments remains unclear. The objective of this study was to analyze and compare the mechanisms of valbenazine, deutetrabenazine, and vitamin E in TD treatment utilizing network pharmacology and molecular docking approaches. Putative target genes associated with valbenazine, deutetrabenazine, and vitamin E were retrieved from the PharmMapper, CTD, GeneCards, SwissTargetPrediction, and DrugBank databases. TD-related targets were identified using the GeneCards, DisGeNET, OMIM, and TTD databases. A protein-protein interaction (PPI) network was created to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via DAVID, and Cytoscape was used to build a drug-pathway-target-disease network. Molecular docking evaluated drug-target interactions. A total of 32, 36, and 62 targets relevant to the treatment of TD were identified for valbenazine, deutetrabenazine, and vitamin E, respectively. PPI and KEGG pathway analyses suggested that valbenazine and deutetrabenazine may influence TD through the dopaminergic synapse signaling pathway via common core targets (e.g., Dopamine Receptor D1 (DRD1), DRD2, Monoamine Oxidase B (MAOB), Solute Carrier Family 6 Member 3 (SLC6A3), SLC18A2) and specific targets (DRD3 for valbenazine, MAOA for deutetrabenazine). Vitamin E may affect TD by targeting the PI3K-Akt pathway through AKT Serine/Threonine Kinase 1 (AKT1), Brain-Derived Neurotrophic Factor (BDNF), Insulin (INS), Nitric Oxide Synthase 3 (NOS3), and Toll-Like Receptor 4 (TLR4). This study provides insights into the common and unique molecular mechanisms by which valbenazine, deutetrabenazine, and vitamin E may treat TD. Pharmacological experiments should be conducted to verify and further explore these results. The findings offer a theoretical basis for further pharmacological investigation and a resource for TD drug screening.

Exploration of the molecular mechanism of modified Danggui Liuhuang Decoction in treating central precocious puberty and its effects on hypothalamic-pituitary-gonadal axis hormones

AimTo evaluate the molecular mechanism of modified Danggui Liuhuang Decoction (MDGLHD) in treating central precocious puberty (CPP).MethodsCPP-related genes were obtained from GEO dataset, MalaCard, DisGeNET and GeneCards databases. MDGLHT ingredients and targets were obtained in TCMSP, HERB, and SwissTargetPrediction databases. Protein-protein interaction (PPI) network was constructed and analyzed using STRING database and Cytoscape 3.9.1. Genetic ontological (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed with DAVID and Metascape databases. Molecular docking was performed with PyMoL and AutoDock-Vina software. The GnRH secretion model was established by E2 induction of GT1-7 cells. CCK-8, ELISA and qRT-PCR were used to detect the effects of MDGLHD on gonadotropin-releasing hormone (GnRH) secretion and endocrine signaling receptor gene expression.Results318 potential targets of MDGLHD in CPP treatment were screened out. Quercetin, kaempferol, and (S)-Canadine were considered to be the most important active ingredients in MDGLHD. Bioinformatics analysis showed that these targets were associated with response to hormone, JAK-STAT signaling pathway and HIF-1 signaling pathway. Quercetin, kaempferol, and (s)-Canadine had good binding affinity with tumor protein p53 (TP53), estrogen receptor 1(ESR1), Jun proto-oncogene (JUN), MYC proto-oncogene (MYC) and AKT serine/threonine kinase 1 (AKT1). In vitro experiments showed that MDGLHD extract can inhibit GnRH secretion and the expression of neuroendocrine signaling receptor protein gene.ConclusionMDGLHD treatment of CPP is achieved through multi-components, multi-targets and multi-pathways, and inhibition of GnRH secretion and neuroendocrine signaling.Graphical

Insights into curcumin's anticancer activity in pancreatic ductal adenocarcinoma: Experimental and computational evidence targeting HRAS, CCND1, EGFR and AKT1.

Insights into curcumin's anticancer activity in pancreatic ductal adenocarcinoma: Experimental and computational evidence targeting HRAS, CCND1, EGFR and AKT1.

Identification of a key environment-responsive gene mediating environmental impact on postmenopausal osteoporosis.

Osteoporosis is a multifactorial disease influenced by genetic, environmental, and metabolic factors. AKT serine/threonine kinase 1 (AKT1), a central regulator of cellular survival and metabolism, has been implicated in bone remodeling, yet its precise role in osteoporosis remains unclear. Gene expression analysis and molecular docking simulations were performed to identify key pathways and interactions involving bisphenol A (BPA) and AKT1. Molecular dynamics simulations further assessed the stability of BPA-AKT1 binding. Experimental validation was conducted using bone marrow-derived macrophages (BMMs) treated with BPA. Osteoclastogenesis was evaluated through TRAcP staining, and AKT1 expression was analyzed via real-time PCR. Protein-level validation of AKT1 phosphorylation was performed using Western blot analysis to confirm its activation during osteoclast differentiation. Computational analyses identified AKT1 as a key mediator linking BPA exposure to bone remodeling pathways. Molecular docking revealed strong interactions between BPA and AKT1, supported by molecular dynamics simulations showing stable binding. Experimental assays demonstrated that BPA significantly enhanced RANKL-mediated osteoclastogenesis, upregulated AKT1 mRNA expression, and promoted AKT1 phosphorylation. These findings indicate that BPA promotes bone resorption through AKT1 activation, potentially contributing to osteoporosis pathogenesis. AKT1 emerges as a critical node connecting environmental pollutants like BPA to bone health, highlighting its potential as a therapeutic target. These findings underscore the complexity of osteoporosis pathophysiology and the importance of mitigating environmental pollutant exposure.

Identification of bioactive compounds and molecular targets of Fuke Huahuang formulation to treat vaginitis

BackgroundFuke Huahuang formulation (FHF) is widely used in the treatment of vaginitis, with clinical evidence indicating its promising anti‐inflammatory properties.MethodsWe explored the bioactive components and potential mechanisms of FHF for treating vaginitis, and reveal its pharmacological activities against vaginitis.ResultsA total of 12 anti‐inflammatory components in FHF and 584 pharmacological targets were identified. Furthermore, 1427 vaginitis‐associated targets were identified, and 184 intersection targets between FHF and vaginitis were constructed for network analysis. Gene Ontology and pathway analysis revealed that the therapeutical targets of FHF against vaginitis are involved in modulating inflammatory stress, enhancing immunoregulation, reconstructing the microenvironment, and suppressing cell damage. Molecular docking analysis further suggested the possible direct binding of the bioactive compounds of FHF (fumarine) to the core targets, including AKT Serine/Threonine Kinase 1 (AKT1), Signal Transducer and Activator of Transcription 3 (STAT3), and nuclear factor‐kappaB (NF‐κB). Experimental validation found that FHF‐treated vaginitis rats exhibited reduced intracellular AKT1, STAT3, and NF‐κB protein expressions.ConclusionOverall, we identified the bioactive compounds and pharmacological mechanisms of FHF against vaginitis, thus offering a theoretical fundament for exploring FHF for treating vaginitis in the future.

Silencing NCAPD3 Inhibits Tumor Growth and Metastasis in Hepatocellular Carcinoma by Suppressing PI3K-AKT Signalling Pathway.

To evaluate the expression pattern of non-SMC condensin II complex subunit D3 (NCAPD3) in hepatocellular carcinoma (HCC) tissues, assess its association with clinical characteristics, and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms. NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR. Patients were divided into high- and low-expression groups on the basis of NCAPD3 levels, and associations with clinical parameters were assessed. The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase (PI3K) agonist Y-P 740 on cell functions were examined via cell proliferation, Transwell migration, and invasion assays. Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing. Western blotting was performed to measure NCAPD3, AKT serine/threonine kinase 1 (AKT1), and phosphorylated AKT1 levels. NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues. A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC. NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells. mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes. Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown. Elevated NCAPD3 expression was strongly correlated with HCC metastasis. NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K-AKT signalling pathway.

Elucidating Molecule-Crosstalk of Neutrophil Extracellular Traps Between Cardiovascular Disease and Psoriasis: Insights Into Mendelian Randomization, Single-Cell RNA Analysis, Shared Targets and the Role of Resveratrol.

Left ventricular hypertrophy (LVH) associated with hypertension and psoriasis (PSO) are linked by poor prognosis. Neutrophil extracellular traps (NETs) are implicated in both conditions, but the mechanisms remain unclear. We integrated bulk and single-cell RNA sequencing, mendelian randomization, immune microenvironment analysis, and molecular docking to explore the molecular interactions between LVH and PSO, focusing on NET-related pathways. Prediction models were also developed, and gene function was validated through in vivo and in vitro experiments. Our findings identified NETs-associated genes, AKT serine/threonine kinase 1 (AKT1), and receptor-interacting protein kinase 1 (RIPK1), regulating inflammation, fibroblast activation, and apoptosis in LVH and PSO. Functional enrichment analysis revealed mitochondrial metabolic disorders and extensive inflammation as the most prominent shared features of LVH and PSO diseases. Additionally, resveratrol exhibited a high binding affinity to the AKT1 and RIPK1 proteins. Functional validation showed that knockdown of AKT1 reduced LVH cell hypertrophy and PSO cell apoptosis. This study highlights molecular pathways linking LVH and PSO, suggesting novel targets for treating cardiac involvement in PSO patients with LVH.

Indole-3-propionic acid promotes hepatic stellate cells inactivation

Background & aimsWe have previously reported that the serum levels of gut-derived tryptophan metabolite indole-3-propionic acid (IPA) are lower in individuals with liver fibrosis. Now, we explored the transcriptome and DNA methylome associated with serum IPA levels in human liver from obese individuals together with IPA effects on shifting the hepatic stellate cell (HSC) phenotype to inactivation in vitro.MethodsA total of 116 obese individuals without type 2 diabetes (T2D) (age 46.8 ± 9.3 years; BMI: 42.7 ± 5.0 kg/m2) from the Kuopio OBesity Surgery (KOBS) study undergoing bariatric surgery were included. Circulating IPA levels were measured using LC–MS, liver transcriptomics with total RNA-sequencing and DNA methylation with Infinium HumanMethylation450 BeadChip. Human hepatic stellate cells (LX-2) where used for in vitro experiments.ResultsSerum IPA levels were associated with the expression of liver genes enriched for apoptosis, mitophagy and longevity pathways in the liver. AKT serine/threonine kinase 1 (AKT1) was the shared and topmost interactive gene from the liver transcript and DNA methylation profile. IPA treatment induced apoptosis, reduced mitochondrial respiration as well as modified cell morphology, and mitochondrial dynamics by modulating the expression of genes known to regulate fibrosis, apoptosis, and survival in LX-2 cells.ConclusionIn conclusion, these data support that IPA has a plausible therapeutic effect and may induce apoptosis and the HSC phenotype towards the inactivation state, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC activation and mitochondrial metabolism.Graphical

The Multi-Target Action Mechanism for the Anti-Periodontitis Effect of Astragali radix Based on Bioinformatics Analysis and In Vitro Verification.

Background:Astragali radix is a traditional Chinese medicine with potential therapeutic effects on periodontitis; however, its underlying mechanisms require further investigation. Methods: We employed network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experiments to explore the potential actions and mechanisms of Astragali radix in treating periodontitis. Results: A total of 17 compounds (including the most prevalent one, Kaempferol) from Astragali radix and 464 corresponding targets were identified, from which five major active ingredients were selected based on the drug-active ingredient and periodontitis gene network. Protein-protein interaction (PPI) network analysis identified the top ten core potential targets, seven of which possess suitable crystal structures for molecular docking. These include interleukin-6 (IL6), tumor necrosis factor (TNF), AKT serine/threonine kinase 1 (AKT1), interleukin-1β (IL1β), prostaglandin G/H synthase-2 (PTGS2), matrix metalloproteinase-9 (MMP9), and caspase-3 (CASP3). Additionally, 58 Gene Ontology (GO) terms and 146 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified. The five major active ingredients and seven core targets mentioned above were subjected to molecular docking analysis using Discovery Studio 2019 software. Molecular dynamic simulations confirmed a stable interaction between the CASP3 and the Kaempferol ligand system. In vitro experiments indicated that Kaempferol significantly inhibited lipopolysaccharide (LPS)-induced apoptosis in human periodontal ligament stem cells and reduced the expression levels of IL6, CASP3 and MMP9. Conclusions: This study systematically elucidates that the primary active ingredients derived from Astragali radix exert their pharmacological effects (including anti-inflammation and anti-apoptosis) primarily by interacting with multiple targets. These findings establish a promising foundation for the targeted application of Astragali radix in the treatment of periodontitis.

Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis.

Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential alternative to statins. Twenty-three key genes in cholesterol biosynthesis are screened, and FDFT1 is identified via public databases (The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus). Clinical samples reveal that FDFT1 is highly expressed in HCC tissues, and this phenotype is strongly associated with a poor prognosis. Functionally, FDFT1 knockdown inhibits the proliferation and metastasis of HCC cells and suppresses hepatocarcinogenesis in vitro and in vivo, whereas FDFT1 overexpression promotes HCC cell proliferation and metastasis. Mechanistically, FDFT1 downregulation decreases cholesterol and bile acid levels and then increases hepatocyte nuclear factor 4 alpha (HNF4A) transcriptional activity. Experiments indicate that HNF4A combines with the promoter of aldolase B (ALDOB)and promotes the ALDOB transcription and that ALDOB combines with AKT serine/threonine kinase 1 (AKT1) and inhibits AKT1 phosphorylation. Moreover, FDFT1 knockdown combined with AKT inhibitor (AZD5363) treatment shows remarkable therapeutic potential. FDFT1 inhibition reduces cholesterol and bile acid levels to delay HCC progression through the HNF4A/ALDOB/AKT1 axis. Thus, targeting FDFT1 may be a novel potential strategy for treating HCC.

Computational Exploration of a Diverse Flavonoid Library for Targeted Allosteric Inhibition of AKT1 in Cancer Therapy.

AKT serine/threonine kinase 1 (AKT1) is an established therapeutic target in cancer therapy due to its role in promoting cell survival and proliferation. This study aimed to identify potential allosteric inhibitors of AKT1 from a large flavonoid library using computational methods. A computational screening of a comprehensive flavonoid library to identify novel allosteric inhibitors targeting the AKT1 allosteric site was performed. Molecular docking identified compounds with favorable binding interactions and the top 10 were selected for binding pose analysis. Molecular dynamics simulations for 200 ns were further employed to assess the stability of the highest-ranked compound. The study proposed 10 flavonoids as potential allosteric AKT1 inhibitors. The docking analysis highlighted critical interactions between the 10 flavonoids and AKT1, with residues such as Trp-80, Ile-84, Tyr-272, Arg-273 and Asp-292 playing significant roles in binding stability. Trp-80 emerged as a pivotal residue, consistently forming the highest number of non-bonding contacts across most compounds, corresponding with prior studies that identified it as essential for allosteric inhibition. The highest-ranked flavonoid, CID 108790283, demonstrated the strongest binding affinity, with a binding energy of -10.64 kcal/mol, 56 non-bonding contacts, and a hydrogen bond. Molecular dynamics simulations further confirmed the stability of this flavonoid within the allosteric site, exhibiting minimal conformational fluctuation throughout the 200-ns simulation. This computational investigation identified 10 flavonoids with strong interaction profiles and stable binding within the allosteric site of AKT1, suggesting their potential as novel AKT1 inhibitors. These findings provide a basis for further experimental studies to validate their efficacy in cancer treatment.

Exploring the key mechanism of puerarin in treating stomach tumors based on network pharmacology

Objective: Gastric cancer (GC), the fourth most common cancer worldwide and the second leading cause of cancer-related mortality, pose a significant public health threat due to major risk factors such as Helicobacter pylori infection, unhealthy dietary habits, smoking, and genetic predisposition, compounded by the asymptomatic nature of early-stage disease and the limited efficacy of late-stage treatments. Methods: Key active components and potential molecular targets of puerarin were identified through systematic database analysis. The biotransformation of puerarin and its complex interaction pathways within the human body were elucidated. A drug-gene-protein interaction network model was constructed to examine the intricate relationships between puerarin and gastric tumor-associated biomolecules. Results: Ten key molecular targets were identified, including AKT serine/threonine kinase 1 (AKT1), interleukin 6 (IL6), and caspase 3 (CASP3). Experimental findings revealed that puerarin inhibits gastric tumor cell proliferation and invasion, induces apoptosis, modulates immune responses, and suppresses tumor angiogenesis through multiple pathways. These findings underscore puerarin’s potential as a therapeutic agent for gastric tumors. Conclusions: This study highlights puerarin’s potential in gastric tumor treatment by targeting multiple pathways, including tumor suppression, immune regulation, and angiogenesis inhibition. The findings provide theoretical insights and practical guidance for developing novel therapeutic strategies while demonstrating the efficacy of network pharmacology in drug discovery and treatment development. Keywords: Gastric tumors; puerarin; network pharmacology

Antidiabetic potency of glimepiride and naringin: an in silico and in vitro investigation

Glimepiride (GLM) is one of the potential antidiabetic drugs used in clinics for a long time. It is currently used in combination with metformin along with other drugs, but has shown various complications in patients from long-term use. Thus, the hypothesis is to use a lower dose of GLM with a non-toxic class of flavonoid, naringin (NARN), for better therapy with minimal side-effects. Initially, we assessed the binding efficacy of GLM and NARN against nine putative target enzymes using AutoDock 4.2 software. We also analysed the drug chemistry, drug-ability, and cytotoxicity, as well as performed molecular dynamic (MD) simulation at 100 ns with individual and combination states using GROMACS-2022 software. Both candidates showed higher binding efficacy, especially against the AKT-serine/threonine kinase-1 (AKT1) target enzyme (−11.85 kcal/mol), and demonstrated higher stability and compatibility with AKT1 from MD-simulation (based on RMSD, Rg, RMSF, and H-bond plots) in combination than individual form. The in vitro cytotoxicity with human embryonic kidney (HEK-293) cells suggested 100 µg/mL (observed 80% of the cell viability) as a non-toxic dose for further study. Alpha-amylase, alpha-glucosidase, and DPP-IV inhibition assays revealed that both GLM and NARN inhibited up to 60% at 100 µg/mL in a concentration-dependent manner. At the end, selecting a lower dose of GLM and a higher dose of NARN (2:8 v/v ratio) showed up to 87% inhibition at 100 µg/mL. Both in silico and in vitro studies suggest that the investigated formulation could be a potential and non-toxic dose for diabetics.

US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test. Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region. A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3). Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.