Search Results (1,273)

Cancer progression is primarily driven by disruptions in critical biological pathways, including ErbB signaling, p53-mediated apoptosis, and GSK3 signaling. However, experimental and clinical studies typically identify only limited disease-associated genes, challenging traditional pathway analysis methods that require larger gene sets. To overcome this limitation, reliably expanded gene sets are required to align with cancer-related pathways. Although various propagation methods are available, the key challenge is to select techniques that can effectively propagate signals from limited seed gene sets through protein interaction networks, thereby generating robust, expanded sets capable of revealing pathway disruptions in cancer. In this study, the number of seed genes was systematically varied to evaluate the alignment of pathways obtained from different propagation methods with known pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Among the evaluated propagation methods, normalized Laplacian diffusion (NLD) demonstrated the strongest alignment with reference pathways, with an average area under the ROC curve (AUC) of 95.11% and an area under precision–recall (AUPR) of 71.20%. Focusing specifically on well-established cancer pathways, we summarized the enriched pathways and discussed their biological relevance with limited gene input. Results from multiple runs were aggregated to identify genes consistently prioritized but absent from core pathway annotations, representing potential pathway extensions. Notable examples include RAC2 (ErbB pathway), FOXO3 and ESR1 (GSK3 signaling), and XIAP and BRD4 (p53 pathway), which were significantly associated with patient survival. Literature validation confirmed their biological relevance, underscoring their potential as prognostic markers and therapeutic targets. In summary, NLD-based diffusion proves effective for pathway discovery from limited input, extending beyond annotated members to reveal clinically relevant genes with therapeutic and biomarker potential. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease’s progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024–2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks. Full article

Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer’s disease. Flavonoids such as quercetin derivatives have emerged as promising neuroprotective agents. This study investigates the impact of 3-O-methylquercetin (3OMQ), a methylated quercetin metabolite, on Wnt/β-catenin signaling and its potential relevance in neurodegenerative disease models. Methods: The ability of 3OMQ to modulate Wnt/β-catenin activity was analyzed using a luciferase-based reporter assay in both neural and non-neural cell lines. Cell viability assays evaluated cytotoxicity at various concentrations. We mapped 3OMQ activity within the pathway using targeted cell signaling experiments. Docking and molecular dynamics simulations suggested glycogen synthase kinase 3β (GSK3β) as a putative target of 3OMQ. Finally, we employed a mouse model of acute amyloid-β oligomer (AβO) toxicity to assess the in vivo effects of 3OMQ on spatial memory and Wnt-related gene expression. Results: We compared the flavonoids quercitrin, quercetin, and 3-O-methylquercitrin (3OMQ) with pharmacologically active compounds in a gene reporter assay (TOPFLASH) using Wnt-sensitive RKO cells treated with Wnt3a-conditioned medium. XAV-939 and PNU-74654 showed inhibitory activity, while BIO, CHIR99021, quercitrin, and 3OMQ enhanced the Wnt/β-catenin pathway. Notably, 3OMQ potentiated this pathway at concentrations 5–10 times lower than quercitrin and outperformed 1 μM BIO at 10 μM without cytotoxicity, highlighting its remarkable potency. Mechanistically, 3OMQ acts downstream of initial membrane activation and upstream of the β-catenin destruction complex. Consistently, molecular docking indicates a strong interaction with GSK3, a central regulator of the pathway. In adult mice, 3OMQ administration prevented AβO-induced recognition memory deficits and favored normalization of Wnt-related gene expression. Conclusions: These findings identify 3OMQ as a potent positive modulator of the Wnt/β-catenin pathway, with both in vitro and in vivo neuroprotective effects. Targeting Wnt signaling with compounds such as 3OMQ holds promise for maintaining neuronal health and developing therapeutic strategies for neurodegenerative conditions. Full article

Alzheimer’s disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC₅₀ = 54 pM) and MONO (IC₅₀ = 50 pM), whereas TRI (IC₅₀ = 160 pM) was less potent, and OXI (IC₅₀ = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases. Full article

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the small-molecule inhibitor of GSK3β, tideglusib (TG), reduces DM1 pathology in DM1 cell and mouse models by correcting the GSK3β-CUGBP1 pathway, decreasing the mutant CUG-containing RNA. Respectively, clinical trials using TG showed promising results for patients with congenital DM1 (CDM1). The drug development in DM1 human studies needs specific and noninvasive biomarkers. We examined the blood levels of active GSK3β in different clinical forms of DM1 and found an increase in active GSK3β in the peripheral blood mononuclear cells (PBMCs) in patients with CDM1, juvenile DM1 and adult-onset DM1 vs. unaffected patients. The blood levels of active GSK3β correlate with the length of CTG repeats and severity of muscle weakness. Thrombospondin and TGFβ, linked to the TG-GSK3β pathway in DM1, are also elevated in the DM1 patients’ blood. These findings show that the blood levels of active GSK3β might be developed as a potential noninvasive biomarker of muscle weakness in DM1. Full article

WNT/β-catenin signaling is essential for intestinal stem cell development and self-renewal, while its dysregulation can drive tumorigenesis. GSK3, a key negative regulator of β-catenin, in intestinal homeostasis remains incompletely understood. In this study, we investigated the role of GSK3 in intestinal development, niche maintenance, and physiological function. Unlike Apc^Min/+ mice that developed intestinal polyps, neither GSK3α nor GSK3β deficiency disrupted intestinal homeostasis. However, complete GSK3 deletion (DKO) resulted in perinatal lethality, characterized by disturbed crypt–villus architecture, Paneth cell redistribution, and villus elongation. GSK3 deficiency disrupted the intestinal niche, leading to expanded and mislocalized stem cells and Paneth cells, along with reduced tuft and enteroendocrine cells. These alterations impaired nutrient absorption and gut motility. Mechanistically, β-catenin-positive cells were significantly increased following GSK3 deletion. Genetic ablation of β-catenin under GSK3-deficient conditions reduced stem and Paneth cell populations while restoring tuft and enteroendocrine cells, thereby ameliorating niche abnormalities and improving absorptive and peristaltic functions. This study indicates the essential role of GSK3/β-catenin signaling in maintaining intestinal niche integrity and digestive physiology, highlighting potential therapeutic targets for intestinal and digestive disorders. Full article

Background/Objectives: Lithium remains the first choice for long-term prophylaxis of mood episodes in bipolar disorder (BD), but only 30% of patients will respond, and there is no reliable method by which to predict treatment response. Ketamine is a rapid antidepressant therapy which ostensibly yields greater results in patients with clinical phenotypes that are classically associated with lithium non-response. This inspired a scoping review to map the overlapping and divergent clinical and mechanistic evidence for acute ketamine response and long-term prophylactic lithium therapy in BD. Methods: We conducted a scoping review of clinical and preclinical studies that examine convergent and divergent predictors and mechanisms of acute response to ketamine and long-term response to lithium. Results: Data from 19 preclinical studies show mechanistic convergence of ketamine and lithium on the GSK-3β/mTOR pathways, and enhancement of synaptic plasticity. Furthermore, lithium appears to consistently limit ketamine-related oxidative stress and hyperlocomotion. However, data from the 23 clinical studies suggest divergence of predictors of response to ketamine and lithium in BD, with ketamine response associated with metabolic risk factors, anxiety/mixed features, and non-melancholic presentations, which are generally predictors of poorer prophylactic lithium response. No study directly tested ketamine response as a predictor of prophylactic lithium response. An important limitation is that clinical studies of ketamine are enriched for lithium-refractory populations and have often included mixed unipolar and bipolar cases. Conclusions: Overall, existing data support mechanistic overlap but clinical divergence between ketamine and lithium responders, though this is confounded by sampling bias. We must therefore undertake longitudinal studies of prophylactic lithium therapy among patients with BD who received ketamine for acute antidepressant treatment in order to investigate if responsiveness to ketamine predicts response to lithium, and establish control over BD earlier in the course of illness. Full article

Background: Epithelial–mesenchymal transition (EMT) is a fundamental process that drives invasion and metastasis in patients with diffuse-type gastric cancer (DGC). The role of SMARCD3, a subunit of the SWI/SNF chromatin remodeling complex, in this process is largely unknown. The aim of this study is to elucidate the molecular mechanism through which SMARCD3 integrates with the PI3K-AKT and WNT/β-catenin signaling pathways to promote EMT and gastric cancer progression. Methods: Stable SMARCD3-overexpressing MKN45 and MKN74 cell lines were established. RNA sequencing (RNA-seq) was performed to investigate signaling alterations. Western blot analysis confirmed the expression of EMT markers (Snail and Slug) and the phosphorylation of AKT (Ser473) and GSK3β (Ser9). PI3K dependency was tested using the inhibitor LY294002. Cooperative effects were examined by activating the WNT pathway with WNT3A. Results: SMARCD3 overexpression upregulated PI3K-AKT and WNT signaling, which correlated with increased Snail/Slug expression and increased AKT/GSK3β phosphorylation. GSK3β inactivation (pSer9) stabilizes Snail, driving EMT. LY294002 treatment suppressed Snail/Slug expression, attenuated AKT activation, and reversed the mesenchymal phenotype. Furthermore, WNT3A treatment synergistically increased nuclear Snail accumulation. Conclusions: SMARCD3 acts as a critical epigenetic regulator that promotes EMT in patients with gastric cancer through the integration of the PI3K-AKT and WNT/β-catenin pathways. Targeting this SMARCD3-mediated mechanism offers a promising therapeutic strategy to inhibit metastasis and improve outcomes for patients with gastric cancer. Full article

We investigated whether the functional involvement of α1-adrenergic receptors (α1-AR) in the effects induced by antidepressant drugs, desipramine, and milnacipran varies depending on the α1-AR subtype. First, using a mouse line with triple knockout (KO) of genes encoding all three α1-AR subtypes (ABD-KO) and autoradiographic analysis, we demonstrated that the inactivation of α1-AR did not affect the density of other types of adrenergic receptors, α2- and β-AR in the mouse brain. Subsequently, we utilized three mouse knockout lines with selective knockout of the gene encoding a single α1-adrenergic receptor subtype (A-KO, B-KO, and D-KO). We analyzed the impact of these mutations on tissue levels of monoaminergic neurotransmitters in the hypothalamus (HY). Next, we assessed how a specific mutation affects the chronic effects of desipramine and milnacipran in the selected brain regions of male and female mice at various molecular levels: mRNA expression of genes encoding for α1-AR subtypes, gene expression profiling, and phosphorylation of selected signaling proteins (ERK1/2, Akt, GSK3β). The main finding is that the deletion of the α1D subtype predominantly reduced the chronic effects of milnacipran at the examined transcriptomic and proteomic levels. The pattern of changes differed by gender. Our study revealed the functional diversity between α1-AR subtypes in the molecular mechanisms of antidepressants’ drug action. Full article

Elevated exposure to manganese (Mn) has been linked to a broad spectrum of neurological disorders, including motor dysfunction. Neuroinflammation with excessively activated astrocytes plays a critical role in the pathogenesis and progression of neurodegenerative diseases. Astrocyte-mediated neuroinflammation plays a dual role due to distinct astrocyte phenotypes, including deleterious A1 and neuroprotective A2. Our previous studies have confirmed that Mn induces activation of astrocytes in the central nervous system, and endoplasmic reticulum (ER) stress has been verified to regulate A1 activation; however, the molecular mechanisms underlying Mn-induced neurotoxicity remain incompletely understood. We establish in vivo and in vitro Mn exposure models and observed that Mn induced A1 activation of astrocytes in both models, with upregulation of A1-specific markers. Sub-cellular morphological analysis showed Mn-induced ER stress in A1-type astrocytes. We found that EIF2α-PERK signaling pathways are activated in astrocytes and drive ER stress and mitochondrial impairment. Suppression of astrocytic PERK, using either ISRIB or GSK2606414, alleviates Mn-induced ER stress and A1 activation, which in turn mitigates the motor deficits induced by Mn exposure. These findings reveal that inhibition of PERK can ameliorate Mn-induced neurotoxicity by suppressing astrocyte activation and preserving organelle homeostasis, offering a potential therapeutic strategy to mitigate the harmful effects of Mn toxicity. Full article

This study focused on the abnormal phosphorylation of tau and its aggregation process, characteristic of Alzheimer’s disease, and aimed to compare the morphology and formation process of phosphorylated tau aggregates produced by four kinases: Cdk5/p25, GSK3β, MARK4, and p38α. Using quantum dots for 2D and 3D structural analysis, tau aggregates were confirmed in non-phosphorylated tau (non p-tau), as well as tau phosphorylated by GSK3β and MARK4. Aggregation initiation times were observed around 72 h for non-p-tau, and around 96 h for GSK3β and MARK4 phosphorylated tau. The thickness of non-p-tau aggregates was approximately 11 μm, while GSK3β aggregates were significantly thicker (13 μm) and exhibited increased density. TEM analysis suggested that tau forming wavy filaments was less prone to forming large aggregates. ThT assays and CD spectra showed an increased β-sheet structure for all kinases. Non-p-tau and GSK3β exhibited an increased right-twisted β-sheet structure, while Cdk5/p25, MARK4, and p38α showed an increased left-twisted β-sheet structure. The direct correlation between kinase activity and tau aggregate morphology revealed in this study provides a potential mechanistic basis for understanding disease heterogeneity and establishing novel therapeutic targets for AD specifically or for other neurodegenerative diseases as well. Full article

Serotonin or 5-hydroxytryptamine (5-HT) has been implicated in promoting cancer cell growth by acting on 5-HT receptors, such as 5-HT1 and 5-HT2 receptors. However, the role of 5-HT3 receptor antagonists in gastric cancer cell lines remains unclear. This study aimed to evaluate the effect of 5-HT3 receptor antagonists (ondansetron, palonosetron, and ramosetron) on cancer cell growth using AGS and MKN-1 cell lines, as well as the xenograft mouse model. All the three antagonists inhibited cell proliferation, migration, and colony formation in AGS cells. Specifically, palonosetron induced G1 cell cycle arrest, autophagy, and phosphorylation of GSK3β, along with increased expression of p27, p53, and LC3B. In vivo studies demonstrated that palonosetron reduced tumor growth and modulated pro-inflammatory cytokines—tumor necrosis factor alpha, interleukin 6, and interleukin 1β. These findings suggest that 5-HT3 receptor antagonists, especially palonosetron, exert anti-tumor effects in gastric cancer through G1 cell cycle regulation and immunomodulation. The results position palonosetron as a promising lead for further preclinical development in gastric cancer. Full article

Bipolar disorder (BD) exhibits a high comorbidity rate with type 2 diabetes (T2D), suggesting shared pathophysiological mechanisms. Although lithium serves as the first-line treatment for BD, its underlying therapeutic mechanism and potential effects on T2D remain incompletely understood. This study identified the PI3K/AKT pathway as a key link between these disorders. Using an ordinary differential equation (ODE) model that integrates the PI3K/AKT pathway with the phosphatidylinositol (PI) cycle, we simulated lithium’s regulatory effects in BD treatment. Our simulations revealed that lithium’s primary inhibitory effect on GSK3β stems from direct binding, which restores insulin sensitivity, suggesting potential benefits for both BD and T2D, particularly in their comorbid state. Additionally, molecular docking studies indicated that curcumin, a potentially safer alternative to lithium, exhibits enhanced anti-inflammatory properties by binding to both GSK3β and p38 MAPK. These findings provide novel insights into the molecular mechanisms connecting BD and T2D and propose new therapeutic strategies for their management. Full article

Influenced by various physical, chemical, and microbial factors, the aging process of Citri Reticulatae ‘Chachiensis’ Pericarpium (CRCP) poses a complex scientific challenge. Drawing inspiration from the perspective of traditional Chinese medicine, volatile oils were extracted from CRCP aged 1, 3, 5, and 7 years by steam distillation and subsequently analyzed by GC-MS. The results revealed that the relative percentage of 4-vinylguaiacol (4-VG) increased progressively with aging. Nineteen volatile oil components were further assessed for their glucose metabolism-enhancing activities, with 4-VG emerging as a key active compound. Notably, 4-VG remarkably enhanced insulin-stimulated glucose uptake in C2C12 myotubes. Moreover, 4-VG demonstrated potent antihyperglycemic effects by upregulating IRS-1/Akt/GSK-3β phosphorylation in the insulin signaling pathway on a high-fat diet and STZ-induced diabetic mouse model. In addition, the metabolic pathway of 4-VG, from ferulic acid and then to vanillin and guaiacol, was verified via HPLC-UV, metabolomics, and microbiome analyses, which confirmed the microbial conversion of 4-VG within CRCP. The metabolic pathway was ultimately validated by isolating and identifying Priestia aryabhattai, Bacillus velezensis, and Aspergillus fumigatus from CRCP, with further in vitro culture and biotransformation experiments confirming its functionality and efficiency. These findings provide new insights and experimental evidence that deepen our understanding of the aging process of CRCP. Full article

Microcirculation in cutaneous tissue is essential to balance oxygen delivery and maintain the health of the skin. Senescence contributes to microcirculatory dysfunction through mechanisms involving chronic inflammation, structural remodeling of microvessels, and disturbances in hemodynamics. In this study we investigated the promoting effect of escin on blood flow through topical application. To elucidate the molecular mechanisms of escin, kinase phosphorylation changes in human umbilical vein endothelial cells (HUVECs) were examined. Escin stimulates the Wnt/β-Catenin and c-Jun N-terminal kinase (JNK) signaling pathway in cultured HUVECs. To clarify the target of escin in the Wnt/β-Catenin signaling pathway, gene expression in response to escin treatment was evaluated, and escin-mediated signaling activation was accompanied by glycogen synthase kinase-3 beta (Gsk3β), according to inhibitor studies performed with IWR1 (tankyrase inhibitor). In addition, the expression level of the Gsk3β were down-regulated by escin treatment in cultured HUEVCs. Escin also enhanced vascular remodeling, and, when applied topically, led to a sustained increase in cutaneous blood flow. Escin-mediated Wnt signaling activation could enhance blood vessel networks via Gsk3β down-regulation. In conclusion, our data demonstrate that escin promotes angiogenic behavior and enhances adenosine-induced perfusion in humans, thereby supporting its potential role in modulating cutaneous microcirculation. Full article