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Despite the therapeutic advances in treating malignancies, the efficient radiotherapeutic approaches with deprived adverse reactions still represent a potential clinical inquiry. The current study aims to elucidate the role of gallic acid (GA) in modifying the hazardous renal cytotoxicity induced by acute exposure to radiation. The MTT test was used to evaluate the viability of Vero cells exposed to 2 Gy gamma radiation with or without incubation of GA. In an in vivo model, male Wistar rats were divided into four experimental groups (n = 6): Control, Irradiated (IRR, 5 Gy), GA (100 mg/kg, i.p.) + IRR, and Glycogen synthase kinase inhibitor (GSKI, 3 mg/kg, i.p.) + IRR. Based on the MTT toxicity assay, from 0 and up to 5 μM dosages of GA did not demonstrate any cytotoxicity to Vero cells. The optimal GA dose that could protect the cells from radiation was 5 μM. Furthermore, GA exerted a protective effect from gamma radiation on renal tissue as indicated by corrected renal functions, decreased LDH level in serum, and balanced oxidative status, which is indicated by decreased tissue contents of NOx and TBARS with a significant increase of reduced GSH. These outcomes were inferred by the upregulation of nuclear factor erythroid 2‐related factor 2 (Nrf2) expression. The overall molecular impact of radiation in damaging the renal tissue may be explained by modifying the upstream AKT activity and its downstream targets GSK‐3β/Notch‐1. Here, we concluded that the anticipated adverse reaction in the course of radiation exposure could be protected by daily administration of GA. [ABSTRACT FROM AUTHOR]

Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD‐related bone loss. In this study, APP/PS1 mice (4‐ and 8‐month‐old) and age‐matched wild‐type mice were used to assess the bone vascular alteration and its role in AD‐related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi‐1) and GSK‐3β inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta‐amyloid (Aβ) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aβ‐induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK‐3β was identified as a key regulatory target of Aβ‐induced excessive mitochondrial fission and bone loss. The findings delineated that Aβ‐induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK‐3β inhibitor emerges as a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Celastrus orbiculatus Thunb. is a vine used as a traditional Chinese medicinal herb. In this study, we focused on the anticancer cytotoxicity and underlying mechanism of previously unreported 3‐oxygen–substituted isoflavone analogue (3‐benzyloxychromone, 3‐Boc) from the herb. Initially, we established cell line–derived xenograft mouse model using H1299 non–small cell lung cancer (NSCLC) cells and found that the ethanol crude extracts of the stem part of C. orbiculatus (200 mg/kg) could substantially suppress the growth of xenograft tumors in athymic nu/nu mice. We compared 3‐Boc with three other flavonoid analogues isolated from the stem part of C. orbiculatus. Among these, 3‐Boc showed the most potent cytotoxicity against H1299 and H1975 NSCLC cells. Colony formation, EdU incorporation and Annexin V‐FITC/PI apoptosis assays demonstrated that 3‐Boc induced growth inhibition primarily by inhibiting DNA replication and inducing apoptotic death of NSCLC cells. Structure‐based target prediction and MD simulation suggested that 3‐Boc potentially suppressed the activity of glycogen synthase kinase‐3β (GSK‐3β) by interacting with the ATP–binding site. Western blot analysis indicated that 3‐Boc triggered the phosphorylation of Serine 21 of GSK‐3α or Serine 9 of GSK‐3β in a time‐ and dose‐dependent manner. To investigate the dependency of GSK‐3β, we established GSK‐3β knockout in H1299 cells. Depletion of GSK‐3β enhanced 3‐Boc–induced cytotoxicity compared with wild‐type counterparts through activated c‐Jun/ATF2 signaling pathway. Altogether, our study highlights the anticancer potential of C. orbiculatus and the discovery of novel 3‐oxygen–substituted chromone from the herb, which may have important implications for screening promising modulators of GSK‐3β and related signaling pathways in the treatment of cancer. Summary: A novel compound featured by 3‐Benzyloxychromone (3‐Boc), which was isolated from the stem of Celastrus orbiculatus Thunb, exhibited significant anticancer activity in NSCLC cells.3‐Boc was more likely to act as a potential ATP‐competitive inhibitor rather than an allosteric inhibitor of GSK‐3β.Depletion of GSK‐3β enhanced the sensitivity of NSCLC cells to 3‐Boc by activating the c‐Jun/ATF2 pathway. Significance Statement Natural products serve as good sources of lead molecules for anticancer drugs. We here characterized the anticancer effect of Celastrus orbiculatus Thunb. and reported a novel class of natural product featured by 3‐benzyloxychromone (3‐Boc). By targeting prediction and validation, we found that GSK‐3β was a potential target of 3‐Boc. Moreover, GSK‐3β ablation enhanced the sensitivity of NSCLC to 3‐Boc, which was dependent on the activation of the c‐Jun/ATF2 pathway. Our data further provided an experimental basis for the utilization and development of anticancer precursor from 3‐Boc found in the Celastrus species. [ABSTRACT FROM AUTHOR]

Amyloid β protein (Aβ) deposition has been implicated as the molecular driver of Alzheimer's disease (AD) progression. The modulation of the formation of abnormal aggregates and their post-translational modification is strongly suggested as the most effective approach to anti-AD. Beta-site APP-cleaving enzyme 1 (BACE1) acts upstream in amyloidogenic processing to generate Aβ, which rapidly aggregates alone or in combination with acetylcholinesterase (AChE) to form fibrils. Accumulated Aβ promotes BACE1 activation via glycogen synthase kinase-3β (GSK-3β) and is post-translationally modified by glutaminyl cyclase (QC), resulting in increased neurotoxicity. A novel multi-target inhibitor as a potential AD agent was identified using an in silico approach and experimental validation. Magnolia officinalis, which showed the best anti-AD activity in our preliminary study, was subjected to analysis, and 82 compounds were studied. Among 23 compounds with drug-likeness, blood–brain barrier penetration, and safety, honokiol emerged as a lead structure for the inhibition of BACE1, AChE, QC, and GSK-3β in docking and molecular dynamics (MD) simulations. Furthermore, honokiol was found to be an excellent multi-target inhibitor of these enzymes with an IC50 of 6–90 μM, even when compared to other natural single-target inhibitors. Taken together, the present study is the first to demonstrate that honokiol acts as a multiple enzyme inhibitor with an excellent pharmacokinetic and safety profile which may provide inhibitory effects in broad-range areas including the overproduction, aggregation, and post-translational modification of Aβ. It also provides insight into novel structural features for the design and discovery of multi-target inhibitors for anti-AD. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-3β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50 = 2.26 μM) vs. GSK-3β (IC50 = 4.23 μM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50 = 2.24 μM) than GSK-3α (IC50 = 5.14 μM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers. Schematic diagram shows the molecular docking to simulate how natural compounds might bind to the crystal structure of GSK-3 enzymes. This was followed by additional in silico analyses, including assessments of druglikeness, potential toxicity, bioactivity scores, and pharmacokinetic properties. Through this multi-step screening process, Psoralidin and Rosmarinic acid emerged as potential inhibitors of GSK-3α and GSK-3β isoforms, respectively. Finally, based on their predicted high binding energy with both GSK-3α and GSK-3β, Psoralidin and Rosmarinic acid were selected for further testing using a kinase assay. This assay confirmed their inhibitory potential, demonstrating higher potency against GSK-3α and GSK-3β, respectively. [Display omitted] • Current GSK-3 inhibitors lack specificity and cause side effects. • This study identifies potential GSK-3 isoform-specific natural compounds. • Psoralidin is likely a better inhibitor for GSK-3α while Rosmarinic for GSK-3β. • These natural compounds may be promising future treatments. [ABSTRACT FROM AUTHOR]

Each year, 3–4% of the global population experiences post-traumatic stress disorder (PTSD), a chronic mental disorder with significant social and economic repercussions. Although it has been shown that ketamine can effectively alleviate PTSD symptoms in individuals, the specific mechanism of action underlying its anti-PTSD effects remains unclear. In this study, we investigated how a single, low dose of ketamine affected the glycogen synthase kinase 3β (GSK-3β)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model. After establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3β antagonist SB216763 (5 mg/kg). In the hippocampus, alterations in the expression of specific proteins implicated in PTSD development, such as GR, brain-derived neurotrophic factor (BDNF), GSK-3β, and phosphorylated glycogen synthase kinase 3β (p-GSK-3β), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3β, FK501 binding protein 51 (FKBP5), and corticotropin-releasing hormone (CRH), as well as synaptic ultrastructure, in the hippocampus, and measured changes in corticosterone levels in the blood. SPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3β protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3β, FKBP5 and CRH. Intraperitoneal administration of ketamine (10 mg/kg) after SPS prevented SPS-induced anxiety-like behaviors. Most importantly, ketamine attenuated SPS-induced dysfunctions in GSK-3β/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3β inhibitor played the same effect as ketamine on behavioral changes of SPS model rats. Single doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3β/GR signaling. • Amelioration of hippocampal synaptic plasticity improved anxiety-like behavior in PTSD rats. • The GSK-3β/GR signaling pathway plays a crucial role in regulating PTSD. • Ketamine improved PTSD symptoms by modulating GSK-3β/GR signaling pathway. [ABSTRACT FROM AUTHOR]

The prognosis of patients with high-risk neuroblastoma remains poor, partly due to inadequate immune recognition of the tumor. Neuroblastomas display extremely low surface MHC-I, preventing recognition by cytotoxic T lymphocytes (CTLs) and contributing to an immunosuppressive tumor microenvironment. Glycogen synthase kinase-3 beta (GSK-3β) is involved in pathways that may affect the MHC-I antigen processing and presentation pathway. We proposed that therapeutic inhibition of GSK-3β might improve the surface display of MHC-I molecules on neuroblastoma cells, and therefore tested if targeting of GSK-3β using the inhibitor 9-ING-41 (Elraglusib) improves MHC-I-mediated CTL recognition. We analyzed mRNA expression data of neuroblastoma tumor datasets and found that non-MYCN-amplified neuroblastomas express higher GSK-3β levels than MYCN-amplified tumors. In non-MYCN-amplified cells SH-SY5Y, SK-N-AS and SK-N-SH 9-ING-41 treatment enhanced MHC-I surface display and the expression levels of a subset of genes involved in MHC-I antigen processing and presentation. Further, 9-ING-41 treatment triggered increased STAT1 pathway activation, upstream of antigen presentation pathways in two of the three non-MYCN-amplified cell lines. Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the accumulation of abnormally folded amyloid β‐protein (Aβ) in the brain parenchyma and phosphorylated tau in neurons. Presenilin (PS, PSEN) 1 and PS2 are essential components of γ‐secretase, which is responsible for the cleavage of amyloid precursor protein (APP) to generate Aβ. PSEN mutations are associated with tau aggregation in frontotemporal dementia, regardless of the presence or absence of Aβ pathology. However, the mechanism by which PS regulates tau aggregation is still unknown. Here, we found that tau phosphorylation and secretion were significantly increased in PS double–knock‐out (PS1/2−/−) fibroblasts compared with wild‐type fibroblasts. Tau‐positive vesicles in the cytoplasm were significantly increased in PS1/2−/− fibroblasts. Active GSK‐3β was increased in PS1/2−/− fibroblasts, and inhibiting GSK3β activity in PS1/2−/− fibroblasts resulted in decreased tau phosphorylation and secretion. Transfection of WT human PS1 and PS2 reduced the secretion of phosphorylated tau and active GSK‐3β in PS1/2−/− fibroblasts. However, PS1D257A without γ‐secretase activity did not decrease the secretion of phosphorylated tau. Furthermore, nicastrin deficiency also increased tau phosphorylation and secretion. These results suggest that deficient PS complex maturation may increase tau phosphorylation and secretion. Thus, our studies discover a new pathway by which PS regulates tau phosphorylation/secretion and pathology independent of Aβ and suggest that PS serves as a potential therapeutic target for treating neurodegenerative diseases involving tau aggregation. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterised by progressive cognitive decline and the accumulation of amyloid-β plaques and tau tangles. The Wnt signalling pathway known for its crucial role in neurodevelopment and adult neurogenesis has emerged as a potential target for therapeutic intervention in AD. Glycogen synthase kinase-3 beta (GSK-3β), a key regulator of the Wnt pathway, plays a pivotal role in AD pathogenesis by promoting tau hyperphosphorylation and neuroinflammation. Several preclinical studies have demonstrated that inhibiting GSK-3β leads to the activation of Wnt pathway thereby promoting neuroprotective effects, and mitigating cognitive deficits in AD animal models. The modulation of Wnt signalling appears to have multifaceted benefits including the reduction of amyloid-β production, tau hyperphosphorylation, enhancement of synaptic plasticity, and inhibition of neuroinflammation. These findings suggest that targeting GSK-3β to activate Wnt pathway may represent a novel approach for slowing or halting the progression of AD. This hypothesis reviews the current state of research exploring the activation of Wnt pathway through the inhibition of GSK-3β as a promising therapeutic strategy in AD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3β) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3β in PD neuropathology, and how GSK-3β inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3β is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3β in PD neuropathology is not fully clarified. Over-expression of GSK-3β induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3β in PD leading to progressive neuronal injury. Higher expression of GSK-3β in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3β inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN. [ABSTRACT FROM AUTHOR]

GSK-3β plays a critical role in regulating the Wnt/β-catenin signaling pathway, and manipulating GSK-3β in dendritic cells (DCs) has been shown to improve the antitumor efficacy of DC vaccines. Since the inhibition of GSK-3β leads to the activation of β-catenin, we hypothesize that blocking GSK-3β in DCs negatively regulates DC-mediated CD8 T cell immunity and antitumor immunity. Using CD11c-GSK-3β−/− conditional knockout mice in which GSK-3β is genetically deleted in CD11c-expressing DCs, we surprisingly found that the deletion of GSK-3β in DCs resulted in increased antitumor immunity, which contradicted our initial expectation of reduced antitumor immunity due to the presumed upregulation of β-catenin in DCs. Indeed, we found by both Western blot and flow cytometry that the deletion of GSK-3β in DCs did not lead to augmented expression of β-catenin protein, suggesting that GSK-3β exerts its function independent of β-catenin. Supporting this notion, our single-cell RNA sequencing (scRNA-seq) analysis revealed that GSK-3β-deficient DCs exhibited distinct gene expression patterns with minimally overlapping differentially expressed genes (DEGs) compared to DCs with activated β-catenin. This suggests that the deletion of GSK-3β in DCs is unlikely to lead to upregulation of β-catenin at the transcriptional level. Consistent with enhanced antitumor immunity, we also found that CD11c-GSK-3β−/− mice exhibited significantly augmented cross-priming of antigen-specific CD8 T cells following DC-targeted vaccines. We further found that the deletion of GSK-3β in DCs completely abrogated memory CD8 T cell responses, suggesting that GSK-3β in DCs also plays a negative role in regulating the differentiation and/or maintenance of memory CD8 T cells. scRNA-seq analysis further revealed that although the deletion of GSK-3β in DCs positively regulated transcriptional programs for effector differentiation and function of primed antigen-specific CD8 T cells in CD11c-GSK-3β−/− mice during the priming phase, it resulted in significantly reduced antigen-specific memory CD8 T cells, consistent with diminished memory responses. Taken together, our data demonstrate that GSK-3β in DCs has opposite functions in regulating cross-priming and memory CD8 T cell responses, and GSK-3β exerts its functions independent of its regulation of β-catenin. These novel insights suggest that targeting GSK-3β in cancer immunotherapies must consider its dual role in CD8 T cell responses. [ABSTRACT FROM AUTHOR]

Abstract The prognosis of patients with high-risk neuroblastoma remains poor, partly due to inadequate immune recognition of the tumor. Neuroblastomas display extremely low surface MHC-I, preventing recognition by cytotoxic T lymphocytes (CTLs) and contributing to an immunosuppressive tumor microenvironment. Glycogen synthase kinase-3 beta (GSK-3β) is involved in pathways that may affect the MHC-I antigen processing and presentation pathway. We proposed that therapeutic inhibition of GSK-3β might improve the surface display of MHC-I molecules on neuroblastoma cells, and therefore tested if targeting of GSK-3β using the inhibitor 9-ING-41 (Elraglusib) improves MHC-I-mediated CTL recognition. We analyzed mRNA expression data of neuroblastoma tumor datasets and found that non-MYCN-amplified neuroblastomas express higher GSK-3β levels than MYCN-amplified tumors. In non-MYCN-amplified cells SH-SY5Y, SK-N-AS and SK-N-SH 9-ING-41 treatment enhanced MHC-I surface display and the expression levels of a subset of genes involved in MHC-I antigen processing and presentation. Further, 9-ING-41 treatment triggered increased STAT1 pathway activation, upstream of antigen presentation pathways in two of the three non-MYCN-amplified cell lines. Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.

Protection against blood-brain barrier (BBB) dysfunction is key to reduce the cerebral ischemia injury as its breakdown causes edema formation and extravasation of blood components and immune cells. The maintenance of BBB integrity requires the GSK-3β/β-catenin pathway activity. Naringenin (NAR), an effective monomer from Chinese herbal medicine, had potent protective effect on brain inflammatory and oxidative injury. However, whether NAR could protect the integrity of BBB during cerebral ischemia injury and the involvement of GSK-3β/β-catenin pathway in the beneficial effect of NAR was unknown. Therefore, mouse middle cerebral artery occlusion/reperfusion (IR) model was employed to answer these questions. NAR was intraperitoneally administrated once daily for 6 days immediately after IR with the dose of 10 mg/kg. BBB damage was evaluated with Evans blue. Protein levels of GSK-3β and β-catenin in vascular endothelial cells at penumbra were assessed with western blotting and immunofluorescence. The experimental data suggested that NAR improved neurological deficits, decreased the percentage of infarct volumes and neuronal apoptosis at 7d after IR. NAR improved BBB damage as evidenced by a lower permeability of Evans blue dye and upregulation of tight junction proteins such as zonula occludens-1(ZO-1), Occludin and Claudin-5. Importantly, GSK-3β/β-catenin pathway activity was related to the improvement of BBB integrity rendered by NAR. Our findings demonstrated that NAR might become a potential therapeutic drug for IR. [ABSTRACT FROM AUTHOR]

The PI3K/AKT/GSK-3β signaling pathway plays a pivotal role in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and metabolic regulation. Aberrant activation of the PI3K/AKT pathway is intricately linked to development of tumor. GSK-3β, belonging to the serine/threonine protein kinase family, is crucial in the pathogenesis of liver cancer. As a key rate-limiting enzyme in the glucose metabolism pathway, GSK-3β significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3β diminishes the sensitivity of liver cancer cells to chemotherapeutic agents, thereby playing a substantial role in the development of drug resistance. Consequently, targeting of GSK-3β, particularly within the PI3K/AKT signaling pathway, is regarded as a promising therapeutic strategy for liver cancer. The precise identification and subsequent modulation of this pathway represent a substantial potential for innovative clinical interventions in the management of liver cancer. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer's disease. Co-targeting GSK3β and BChE in Alzheimer's disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer's disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer's disease, capable of simultaneously inhibiting both GSK-3β and BuChE. [ABSTRACT FROM AUTHOR]

Starvation in diploid budding yeast cells triggers a cell-fate program culminating in meiosis and spore formation. Transcriptional activation of early meiotic genes (EMGs) hinges on the master regulator Ime1, its DNA-binding partner Ume6, and GSK-3β kinase Rim11. Phosphorylation of Ume6 by Rim11 is required for EMG activation. We report here that Rim11 functions as the central signal integrator for controlling Ume6 phosphorylation and EMG transcription. In nutrient-rich conditions, PKA suppresses Rim11 levels, while TORC1 retains Rim11 in the cytoplasm. Inhibition of PKA and TORC1 induces Rim11 expression and nuclear localization. Remarkably, nuclear Rim11 is required, but not sufficient, for Rim11-dependent Ume6 phosphorylation. In addition, Ime1 is an anchor protein enabling Ume6 phosphorylation by Rim11. Subsequently, Ume6-Ime1 coactivator complexes form and induce EMG transcription. Our results demonstrate how various signaling inputs (PKA/TORC1/Ime1) converge through Rim11 to regulate EMG expression and meiosis initiation. We posit that the signaling-regulatory network elucidated here generates robustness in cell-fate control. Synopsis: Transcriptional activation of early meiotic genes is triggered by various signaling inputs. This study unveils how the yeast GSK-3β kinase Rim11 acts as a central signal integrator, orchestrating Ume6 phosphorylation and transcriptional activation of early meiotic genes. Starvation-induced nuclear localization of GSK-3β kinase Rim11 is required for Ume6 phosphorylation. TORC1 and PKA control Rim11 localization and expression. Rim11-dependent phosphorylation of Ume6 also requires Ime1. Signal integration by Rim11 and Ime1 controls the decision to enter meiosis. Starvation induces nuclear accumulation of Rim11 that integrates signals from PKA, TORC1 and Ime1 to promote cell entry into meiosis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: β-amyloid (Aβ) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aβ plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aβ, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aβ-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3β and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions. [ABSTRACT FROM AUTHOR]

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and β-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and β-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and β-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the β-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is the most prevalent form of age-related dementia. Even though a century has passed since the discovery of AD, the exact cause of the disease still remains unknown. As a result, this poses a major hindrance in developing effective therapies for treating AD. Glycogen synthase kinase-3 (GSK-3) is one of the kinases that has been investigated recently as a potential therapeutic target for the treatment of AD. It is also known as human tau protein kinase and is a proline-directed serine-threonine kinase. Since dysregulation of this kinase affects all the major characteristic features of the disease, such as tau phosphorylation, amyloid formation, memory, and synaptic function, it is thought to be a major player in the pathogenesis of AD. In this review, we present the most recent information on the role of this kinase in the onset and progression of AD, as well as significant findings that identify GSK-3 as one of the most important targets for AD therapy. We further discuss the potential of treating AD by targeting GSK-3 and give an overview of the ongoing studies aimed at developing GSK-3 inhibitors in preclinical and clinical investigations. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer’s disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3β activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the “SD microbiota” replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3-/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3β activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3β activation in primary hippocampal neurons, suggesting that GSK-3β, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3β as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation. [ABSTRACT FROM AUTHOR]

Introduction: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3β (GSK-3β). Since ketamine activates GSK-3β, we examined the impact of ketamine on DISC1 and GSK-3β expression. Methods: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3β antagonist, lithium. Cleaved-caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium. Results: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3β and axonal length. Conclusion: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration. [ABSTRACT FROM AUTHOR]

GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid β (Aβ) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3β plays the most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive GSK-3β inhibitor (IC50 = 8 nM, Ki = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC50 = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound 62 effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility. [ABSTRACT FROM AUTHOR]

Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti‐cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK‐3β and the effects of apigenin in DOX‐induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX‐induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis‐related factors. Furthermore, the phosphorylation of GSK‐3β was enhanced while the phosphorylation of nuclear factor‐kB (NF‐κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA‐GSK‐3β‐transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK‐3β. Therefore, our study confirmed that the inhibition of GSK‐3β and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX‐stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK‐3β expression and subsequent reduction in NF‐κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK‐3β may offer a promising therapeutic approach for alleviating DOX‐induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Drug development for Alzheimer's disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer's disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer's disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α. Methods: The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1. Results: The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate −10.93 kcal/mol, Fisetin −9.44 kcal/mol and Eriodictyol −8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin −11.52 kcal/mol, Sterubin −10.87 kcal/mol, Biochainin A −10.69 kcal/mol were compared with standard drug donepezil. Conclusion: Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer's agents. However, more invitro and invivo analyses are required to finally confirm the outcomes of this research. [ABSTRACT FROM AUTHOR]

Background: Gynostemma pentaphyllum (Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of G. pentaphyllum. Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation. Methods: The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes. Results: A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment. Conclusion: Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3β/Mcl-1 signaling is potentially involved in this process. [ABSTRACT FROM AUTHOR]

Abstract Purpose Pancreatic cancer is a lethal malignancy with a grim prognosis. Previous studies have proven that Leucine Rich Repeat of Flightless-1 Interacting Protein 1 (LRRFIP1) plays a pivotal role in cell biological processes, while its clinical significance and function in pancreatic cancer remain to be elucidated. Hence, we aimed to explore the roles and mechanisms of LRRFIP1 in pancreatic cancer. Methods The expression of LRRFIP1 in pancreatic cancer tissues and its clinical significance for pancreatic cancer were analyzed by immunohistochemistry assay and bioinformatic analysis. The influences of LRRFIP1 on the proliferation and migration of pancreatic cancer cells were assessed in vitro. The underlying mechanisms of LRRFIP1 in pancreatic cancer progression were explored using gene set enrichment analysis (GSEA) and molecular experiments. Results The results showed that LRRFIP1 expression was significantly upregulated in pancreatic cancer tissues compared to the normal tissues, and such upregulation was associated with poor prognosis of patients with pancreatic cancer. GSEA revealed that LRRFIP1 upregulation was significantly associated with various cancer-associated signaling pathways, including PI3K/AKT signaling pathway and Wnt pathway. Furthermore, LRRFIP1 was found to be associated with the infiltration of various immune cells. Functionally, LRRFIP1 silencing suppressed cell proliferation somewhat and inhibited migration substantially. Further molecular experiments indicated that LRRFIP1 silencing inactivated the AKT/GSK-3β/β-catenin signaling axis. Conclusion Taken together, LRRFIP1 is associated with tumorigenesis, immune cell infiltration, and prognosis in pancreatic cancer, which suggests that LRRFIP1 may be a potential biomarker and therapeutic target for pancreatic cancer.

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Introduction: Alzheimer's disease (AD) accounts for the majority of dementia cases, characterized by a gradual decline in memory and cognitive functions. Traditional Chinese medicine (TCM) has a long history of treating AD and has proposed a series of causes, pathogenesis and treatment methods, and has extremely rich experience in the treatment of AD. TCM believes that deficiency of the spleen, which is the main organ for the body to absorb nutrients, is one of the important causes of AD. Which coincides with the theory that AD is type 3 diabetes in recent years. Therefore, effectively regulating the common targets of AD and diabetes is a potential strategy for treating spleen deficiency type AD. Method: By conducting an in-depth search in PubMed and China National Knowledge Infrastructure (CNKI), using the keywords '' Traditional Chinese Medicine'', ''Alzheimer's Disease'', ''GSK-3β'', ''Tau Protein'' and ''Tau Hyperphosphorylation''. Ultimately, 92 papers were included for review. Result: Glycogen synthase kinase 3 beta (GSK-3β) plays a significant role in the pathogenesis of AD, and numerous in vitro and in vivo experiments have demonstrated that Chinese medicine monomers and compounds can inhibit its activity, reducing the hyperphosphorylation of Tau. Discussion: TCM can affect the activity of GSK-3β through various pathways, thereby reducing the hyperphosphorylation of Tau protein and improving the cognitive function of AD. These studies highlight the potential of TCM in treating AD, but further basic and clinical research is still required to validate their safety and efficacy. It is expected that our review will yield novel insights and a scientific foundation for investigating the underlying mechanisms of AD and developing novel anti-AD therapeutics.

The American Diabetes Association guidelines (2021) confirmed the importance of raising public awareness of diabetes-induced cognitive impairment, highlighting the links between poor glycemic control and cognitive impairment. The characteristic brain lesions of cognitive dysfunction are neurofibrillary tangles (NFT) and senile plaques formed of amyloid-β deposition, glycogen synthase kinase 3 beta (GSK3β), and highly homologous kinase tau tubulin kinase 1 (TTBK1) can phosphorylate Tau proteins at different sites, overexpression of these enzymes produces extensive phosphorylation of Tau proteins making them insoluble and enhance NFT formation, which impairs cognitive functions. The current study aimed to investigate the potential contribution of liraglutide and pramlintide in the prevention of diabetes-induced cognitive dysfunction and their effect on the PI3K/AKT/GSK-3β/TTBK1 pathway in type 2 diabetic (T2D) rat model. T2D was induced by administration of a high-fat diet for 10 weeks, then injection of a single dose of streptozotocin (STZ); treatment was started with either pramlintide (200 μg/kg/day sc) or liraglutide (0.6 mg/kg/day sc) for 6 weeks in addition to the HFD. At the end of the study, cognitive functions were assessed by novel object recognition and T-maze tests. Then, rats were sacrificed for biochemical and histological assessment of the hippocampal tissue. Both pramlintide and liraglutide treatment revealed equally adequate control of diabetes, prevented the decline in memory function, and increased PI3K/AKT expression while decreasing GSK-3β/TTBK1 expression; however, liraglutide significantly decreased the number of Tau positive cells better than pramlintide did. This study confirmed that pramlintide and liraglutide are promising antidiabetic medications that could prevent associated cognitive disorders in different mechanisms. [ABSTRACT FROM AUTHOR]

Background: Jitai tablet, a traditional Chinese medicine, has a neuroprotective effect on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mice. As one of the main active ingredients in the Jitai tablet, corydaline (Cory) has analgesic and anti-allergic effects, but it has not been studied in PD. Here, we investigated the role and mechanism of Cory in PD. Methods: The PD model was induced by MPTP. Cell viability was measured by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide assay. The Pole test and traction test were performed to detect the behaviors of mice. The expression of tyrosine hydroxylase (Th) was detected by immunohistochemistry and Western blot. Immunofluorescence staining, monodansylcadaverine staining, and Western blot were conducted to assess autophagy. A lactic dehydrogenase release assay was used to detect cytotoxicity. Network pharmacology was used to screen the targets. Results: There existed cytotoxicity when the concentration of Cory reached 40 μg/mL. Cory (not exceeding 20 μg/mL) could alleviate MPTP-induced cell damage. In vivo experiments indicated that Cory could improve the motor coordination of mice with PD. Besides, Cory could increase LC3-II/LC3-I levels both in vivo and in vitro. In addition, the Th levels reduced in the striatum and middle brain tissues of Parkinson's mice were recovered by Cory injection. We also found that Cory decreased the phosphorylation of glucogen synthase kinase-3 beta (GSK-3β) at Tyr216 and increased the phosphorylation of GSK-3β at Ser9 not only in primary neurons and SH-SY5Y cells but also in the striatum and middle brain tissues. Furthermore, Cory increased LC3-II/LC3-I levels and decreased p62 levels by regulating GSK-3β. Conclusion: Cory enhanced autophagy, attenuated MPTP-induced cytotoxicity, and alleviated PD partly through the regulation of GSK-3β phosphorylation. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase‐3β (GSK‐3β) plays pivotal role in regulating diverse range of cellular functions. It plays negative role in cellular signaling pathways and believed to involved in the pathologies of various diseases like neurological disorders, type II diabetes, inflammation, cardiac hypertrophy, cancer and bipolar disorders. GSK‐3β is proposed as a promising target for drug discovery in treating these disease conditions. A number of structurally different chemical scaffolds including pyrimidinone derivatives have been identified as potential GSK‐3β inhibitors. In the current study, PHASE module of Schrödinger 3D QSAR was used on about 157 pyrimidinone derivatives for the development of statistically significant PLS model. Consecutively, the best pharmacophore hypothesis with features like three hydrogen bond acceptors (A1‐3), two hydrophobic regions (H1 and H2), and one aromatic ring (R1), was selected to screen ZINC and PUBCHEM databases. Molecules with matching pharmacophoric features and ROF were subjected to structure‐based virtual screening (HTVS→SP→XP) and MMGBSA. Two hits from each library were selected for MD simulation studies that showed good pharmacokinetic properties, binding score (−6.8–−8.8 kcal/mol) and ▵GMMGBSA (−55.80–−58.1 kcal/mol) as compared to the reference molecule, NP‐12. Similarly, MD simulation, and MMPBSA identified three compounds i. e. ZINC67743231, ZINC01582756, and PUBCHEM11553018 displaying stability in the binding pocket and demonstrated better binding affinity of −22.07, −27.33, and −30.61 kcal/mol, respectively, within the active site of GSK‐3β. DFT studies also demonstrated the stability of these three lead compounds with a high energy gap between HOMO and LUMO ranging between 0.14546 and 0.1718 eV. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic cancer is a lethal malignancy with a grim prognosis. Previous studies have proven that Leucine Rich Repeat of Flightless-1 Interacting Protein 1 (LRRFIP1) plays a pivotal role in cell biological processes, while its clinical significance and function in pancreatic cancer remain to be elucidated. Hence, we aimed to explore the roles and mechanisms of LRRFIP1 in pancreatic cancer. Methods: The expression of LRRFIP1 in pancreatic cancer tissues and its clinical significance for pancreatic cancer were analyzed by immunohistochemistry assay and bioinformatic analysis. The influences of LRRFIP1 on the proliferation and migration of pancreatic cancer cells were assessed in vitro. The underlying mechanisms of LRRFIP1 in pancreatic cancer progression were explored using gene set enrichment analysis (GSEA) and molecular experiments. Results: The results showed that LRRFIP1 expression was significantly upregulated in pancreatic cancer tissues compared to the normal tissues, and such upregulation was associated with poor prognosis of patients with pancreatic cancer. GSEA revealed that LRRFIP1 upregulation was significantly associated with various cancer-associated signaling pathways, including PI3K/AKT signaling pathway and Wnt pathway. Furthermore, LRRFIP1 was found to be associated with the infiltration of various immune cells. Functionally, LRRFIP1 silencing suppressed cell proliferation somewhat and inhibited migration substantially. Further molecular experiments indicated that LRRFIP1 silencing inactivated the AKT/GSK-3β/β-catenin signaling axis. Conclusion: Taken together, LRRFIP1 is associated with tumorigenesis, immune cell infiltration, and prognosis in pancreatic cancer, which suggests that LRRFIP1 may be a potential biomarker and therapeutic target for pancreatic cancer. [ABSTRACT FROM AUTHOR]

The human fetal thyroid gland is not capable of producing thyroid hormones independently until 20 weeks of gestation, and if maternal thyroid hormone synthesis is inadequate in early pregnancy, fetal brain and nerve development may be affected by maternal hypothyroidism. Curcumin, which is isolated from turmeric (Curcuma longa), has been shown to be effective in repairing neurological disorders and is effective in relieving nerve damage when consumed over a long period of time. In this experiment, we investigated the effect of curcumin supplementation on synaptic development of rat hippocampal neurons. A cell model of oxidative damage and a young rat model of hypothyroidism were constructed, and model cells and rats were treated with triiodothyronine (T3), tetraiodothyronine (T4), and curcumin, respectively. Damage of nerve cells and animal brain tissues was examined, and the effect of curcumin in alleviating the blocked neurodevelopment was investigated. Further modulation of GSK-3β/β-catenin was performed to investigate the mechanism of action of curcumin. Ultimately, we found that T3-, T4-, and curcumin-treated model cells and young rats had increased numbers of synapses and good neurodevelopment. At the same time, we found that curcumin inhibited the production of GSK-3β and Axin to activate β-catenin. The inhibition of β-catenin weakened the therapeutic effect of curcumin, and the differences between the indicators and the model group disappeared. Both cellular and animal experiments supported that curcumin effectively alleviated the oxidative cell damage caused by thyroxine deficiency and activated the synaptogenic ability of nerve synapses by inhibiting GSK-3β and protecting β-catenin activity. [ABSTRACT FROM AUTHOR]

Current treatments for Alzheimer's disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3β (GSK-3β), a well-documented kinase with increased activity in tau hyperphosphorylation and neurofibrillary tangles—hallmarks of AD pathology. Leveraging quantitative structure–activity relationship (QSAR) data from the PubChem and ChEMBL databases, we employed seven machine learning models: logistic regression (LogR), k-nearest neighbors (KNN), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGB), neural networks (NNs), and ensemble majority voting. Our goal was to correctly predict active and inactive compounds that inhibit GSK-3β activity and identify their key properties. Among the six individual models, the NN demonstrated the highest performance with a 79% AUC-ROC on unbalanced external validation data, while the SVM model was superior in accurately classifying the compounds. The SVM and RF models surpassed NN in terms of Kappa values, and the ensemble majority voting model demonstrated slightly better accuracy to the NN on the external validation data. Feature importance analysis revealed that hydrogen bonds, phenol groups, and specific electronic characteristics are important features of molecular descriptors that positively correlate with active GSK-3β inhibition. Conversely, structural features like imidazole rings, sulfides, and methoxy groups showed a negative correlation. Our study highlights the significance of structural, electronic, and physicochemical descriptors in screening active candidates against GSK-3β. These predictive features could prove useful in therapeutic strategies to understand the important properties of GSK-3β candidate inhibitors that may potentially benefit non-amyloid-based AD treatments targeting neurofibrillary tangles. [ABSTRACT FROM AUTHOR]

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

Background The discovery of an ideal and effective therapy is urgently required for the treatment of Alzheimer’s disease. The main pathological hallmarks of Alzheimer’s disease that appear before the clinical symptoms are neurofibrillary tangles, amyloid plaques, brain inflammation, and neuronal atrophy throughout the cerebral cortex and hippocampus. GSK-3β (Glycogen Synthase Kinase-3β) is regarded as the most important and promising target for therapeutic use because GSK-3β expression levels increase with age and are the most abundant and hyperactive in the brains of patients with Alzheimer’s disease. Methods We used Maestro, which is Schrodinger, for our computational simulation studies. In the present work, we have used different modules that were used in previous studies with a little modification, the modules such as Protein Preparation with the help of Protein Preparation Wizard, Ligand Preparation with the help of LigPrep, for ADME (Absorption, Distribution, Metabolism and Excretion) prediction we used Qikprop, Docking studies we used Glide module, Binding energy prediction we used Prime and Molecular dynamic simulation studies by Desmond Results Our focus is mainly on an in-silico approach, focusing on library generation; we first drew an imidazo [1,5-a]pyridine-3-carboxamide (IMID 2) scaffold structure at Enamine and subjected it to a substructure search to target the receptor grid region (ATP-competitive site) of 6Y9R. They were then subjected to various screening processes. Finally, we selected nine compounds and subjected them to molecular dynamic simulation studies. Conclusions Nine compounds showed good results with the most stable interactions. Further experiments and studies are required to confirm these results.

As a dietary strategy, methionine restriction has been reported to promote longevity and regulate metabolic disorders. However, the role and possible regulatory mechanisms underlying methionine in neurodegenerative diseases such as Alzheimer's disease (AD), remain unexplored. This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3β) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of Aβ and phosphorylated Tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-β (TGF-β). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-β1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3β. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase‐MB (CK‐MB) significantly increased by 40 %, troponin‐I levels significantly increased by 25.4 %, and lactate dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-β1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-β1/Smad signalling pathway and restoring GSK-3β phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

Background Gynostemma pentaphyllum (Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of G. pentaphyllum. Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation. Methods The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes. Results A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment. Conclusion Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3β/Mcl-1 signaling is potentially involved in this process.

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and β-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and β-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and β-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the β-catenin pathway. It also highlights novel insights into CAR’s capacity in reversing DOX chemoresistance in TNBC.

This study aimed to decipher the encoded information within the molecular structure of a dataset of GSK-3β inhibitors through a comprehensive quantity structural-activity relationship (QSAR) investigation employing traditional physicochemical descriptors. Various statistical techniques were applied, encompassing linear methods such as Multiple Linear Regression (MLR) and Partial Least Squares (PLS), along with non-linear approaches such as Artificial Neural Networks (ANN). Rigorous validation using diverse statistical tools confirmed the models’ precision and predictability. The model exhibited exceptional statistical relevance, as evidenced by standard parameters: S-value (0.37), F-value (37.17), r (0.93), r2 (0.855), and r2CV (0.78). They assessed predictive power and robustness by involving specific statistical parameters. Key descriptors analyzed, including Verloop L (subs 2), Lipole Z component (whole molecule), and VAMP Dipole Z component, offered crucial insights into their respective contributions. This analysis implies that targeted modifications in the substitution pattern potentially enhance GSK-3β inhibitory activity significantly. The established model clarified how bioactivity depends on structure and offered valuable recommendations for creating new compounds with better inhibitory activity profiles against the GSK-3β enzyme.

GSK-3β plays a critical role in regulating the Wnt/β-catenin signaling pathway, and manipulating GSK-3β in dendritic cells (DCs) has been shown to improve the antitumor efficacy of DC vaccines. Since the inhibition of GSK-3β leads to the activation of β-catenin, we hypothesize that blocking GSK-3β in DCs negatively regulates DC-mediated CD8 T cell immunity and antitumor immunity. Using CD11c-GSK-3β−/− conditional knockout mice in which GSK-3β is genetically deleted in CD11c-expressing DCs, we surprisingly found that the deletion of GSK-3β in DCs resulted in increased antitumor immunity, which contradicted our initial expectation of reduced antitumor immunity due to the presumed upregulation of β-catenin in DCs. Indeed, we found by both Western blot and flow cytometry that the deletion of GSK-3β in DCs did not lead to augmented expression of β-catenin protein, suggesting that GSK-3β exerts its function independent of β-catenin. Supporting this notion, our single-cell RNA sequencing (scRNA-seq) analysis revealed that GSK-3β-deficient DCs exhibited distinct gene expression patterns with minimally overlapping differentially expressed genes (DEGs) compared to DCs with activated β-catenin. This suggests that the deletion of GSK-3β in DCs is unlikely to lead to upregulation of β-catenin at the transcriptional level. Consistent with enhanced antitumor immunity, we also found that CD11c-GSK-3β−/− mice exhibited significantly augmented cross-priming of antigen-specific CD8 T cells following DC-targeted vaccines. We further found that the deletion of GSK-3β in DCs completely abrogated memory CD8 T cell responses, suggesting that GSK-3β in DCs also plays a negative role in regulating the differentiation and/or maintenance of memory CD8 T cells. scRNA-seq analysis further revealed that although the deletion of GSK-3β in DCs positively regulated transcriptional programs for effector differentiation and function of primed antigen-specific CD8 T cells in CD11c-GSK-3β−/− mice during the priming phase, it resulted in significantly reduced antigen-specific memory CD8 T cells, consistent with diminished memory responses. Taken together, our data demonstrate that GSK-3β in DCs has opposite functions in regulating cross-priming and memory CD8 T cell responses, and GSK-3β exerts its functions independent of its regulation of β-catenin. These novel insights suggest that targeting GSK-3β in cancer immunotherapies must consider its dual role in CD8 T cell responses.

Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in different organs like the kidney, liver, heart, brain, etc., and may not only involve the ischemic organ but also cause systemic damage to distant organs. Oxygen-glucose deprivation in cells causes oxidative stress, calcium overloading, inflammation, and apoptosis. CREB is an essential integrator of the body's various physiological systems, and it is widely accepted that dysfunction of CREB signaling is involved in many diseases, including ischemia-reperfusion injury. The activation of CREB can provide life to a cell and increase the cell's survival after ischemia. Hence, GSK/CREB signaling pathway can provide significant protection to cells of different organs after ischemia and emerges as a futuristic strategy for managing ischemia-reperfusion injury. Different signaling pathways such as MAPK/ERK, TLR4/MyD88, RISK, Nrf2, and NF-κB, get altered during IR injury by the modulation of GSK-3 and CREB (cyclic AMP response element (CRE)–binding protein). GSK-3 (protein kinase B) and CREB are the downstream targets for fulfilling the roles of various signaling pathways. Calcium overloading during ischemia increases the expression of calcium-calmodulin-dependent protein kinase (CaMK), which subsequently activates CREB-mediated transcription, thus promoting the survival of cells. Furthermore, this review highlights the crosstalk between GSK-3 and CREB, promoting survival and rendering the cells resistant to subsequent severe ischemia. [ABSTRACT FROM AUTHOR]

AbstractAluminum (Al) is a known neurotoxic trace element linked to Alzheimer’s disease (AD). Naltrexone, an opioid antagonist, has shown promising effects in reducing neuroinflammation at lower doses than those prescribed for addiction. This study aimed to determine the neuroprotective effects of naltrexone on Al-induced neurotoxicity in an in vitro AD model. The SH-SY5Y cells were first cultivated in a standard growth medium. Subsequently, the cells were induced to differentiate by decreasing the concentration of fetal bovine serum and introducing retinoic acid (RA) into the culture media. Subsequently, the inclusion of brain-derived neurotrophic factor (BDNF) was implemented in conjunction with RA. The process of differentiation was concluded on the seventh day. Study groups (n = 3) were designed as the control group, naltrexone group, Al group, Al-Nal group, Alzheimer’ model (AD) group, Alzheimer model + Al-exposed group (AD-Al), Alzheimer model + Nal applied group (AD-Nal) and Alzheimer model + Al-exposed + Nal applied group (AD-Al-Nal). Hyperphosphorylated Tau protein as the specific marker of AD was measured in all groups. Glycogen synthase kinase-3 (GSK-3)β, Protein phosphatase 2A (PP2A), Akt and Wnt signaling pathways were analyzed comparatively. In addition, oxidative stress parameters (total antioxidant capacity, lipid peroxidase, protein carbonyl and reactive oxygen species) were measured comparatively in the study groups. The results showed that naltrexone reduced hyperphosphorylated tau protein levels by regulating GSK-3β, PP2A, Akt and Wnt signaling. Also, exposure to naltrexone decreased oxidative stress parameters. Based on these results, naltrexone shows promise as a potential therapy for AD, subject to additional clinical assessments. [ABSTRACT FROM AUTHOR]

Metformin has been suggested to have protective effects on the central nervous system, but the mechanism is unknown. The similarity between the effects of metformin and the inhibition of glycogen synthase kinase (GSK)-3β suggests that metformin may inhibit GSK-3β. In addition, zinc is an important element that inhibits GSK-3β by phosphorylation. In this study, we investigated whether the effects of metformin on neuroprotection and neuronal survival were mediated by zinc-dependent inhibition of GSK-3β in rats with glutamate-induced neurotoxicity. Forty adult male rats were divided into 5 groups: control, glutamate, metformin + glutamate, zinc deficiency + glutamate, and zinc deficiency + metformin + glutamate. Zinc deficiency was induced with a zinc-poor pellet. Metformin was orally administered for 35 days. D-glutamic acid was intraperitoneally administered on the 35th day. On the 38th day, neurodegeneration was examined histopathologically, and the effects on neuronal protection and survival were evaluated via intracellular S-100β immunohistochemical staining. The findings were examined in relation to nonphosphorylated (active) GSK-3β levels and oxidative stress parameters in brain tissue and blood. Neurodegeneration was increased (p < 0.05) in rats fed a zinc-deficient diet. Active GSK-3β levels were increased in groups with neurodegeneration (p < 0.01). Decreased neurodegeneration, increased neuronal survival (p < 0.01), decreased active GSK-3β (p < 0.01) levels and oxidative stress parameters, and increased antioxidant parameters were observed in groups treated with metformin (p < 0.01). Metformin had fewer protective effects on rats fed a zinc-deficient diet. Metformin may exert neuroprotective effects and increase S-100β-mediated neuronal survival by zinc-dependent inhibition of GSK-3β during glutamate neurotoxicity. [ABSTRACT FROM AUTHOR]

We explored the role and mechanism of cordycepin (COR) in inhibiting kidney injury. A mouse model of kidney injury was established using cisplatin (CDDP), and the kidney function, histopathology, and ferroptosis indices in mice were detected after intervening with COR. The targets of COR‐ferroptosis‐kidney injury were analyzed by network pharmacology, based on which the association between glycogen synthase kinase‐3 beta (GSK‐3β) and COR was determined. HK‐2 cells were cultured in vitro and treated separately with ferroptosis inducers erastin and CDDP. After the COR intervention, the level of ferroptosis was monitored. In vitro experiments found that COR could inhibit ferroptosis and CDDP‐induced kidney injury. Network pharmacological analysis revealed that GSK‐3β was the target of COR. After inhibiting GSK‐3β expression, COR could not further inhibit the occurrence of ferroptosis. In vitro results also indicated that COR could inhibit ferroptosis in HK‐2 cells. According to our findings, COR can ameliorate CDDP‐induced kidney injury through GSK‐3β‐mediated ferroptosis signaling. We identify new pharmacological effect and target for COR, the major component of Cordyceps sinensis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on the target genes in animals. Gastrodia elata (G. elata) is a valuable traditional Chinese medicine that has significant pharmacological activity against diseases of the central nervous system (CNS). Our previous studies have indicated that G. elata-specific miRNA plays a cross-kingdom regulatory role for the NF-κB signaling pathway in mice. In this study, further bioinformatics analysis suggested that Gas-miR36-5p targets GSK-3β. Through western blot, RT-qPCR, and assessments of T-AOC, SOD, and MDA levels, Gas-miR36-5p demonstrated its neuroprotective effects in an AD cell model. Furthermore, Gas-miR36-5p was detected in the murine brain tissues. The results of the Morris water maze test and western blot analysis provided positive evidence for reversing the learning deficits and hyperphosphorylation of Tau in AD mice, elucidating significant neuroprotective effects in an AD model following G. elata RNA administration. Our research emphasizes Gas-miR36-5p as a novel G. elata-specific miRNA with neuroprotective properties in Alzheimer's disease by targeting GSK-3β. Consequently, our findings provide valuable insights into the cross-kingdom regulatory mechanisms underlying G. elata-specific miRNA, presenting a novel perspective for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Recent studies on biphenyl-containing compounds, a type of PD-1/PD-L1 blocker which binds to PD-L1 and induces dimerisation, have focussed on its immune function. Herein, 10 novel biphenyl derivatives were designed and synthesised. The results of the CCK-8 showed that compounds have different anti-tumour activities for tumour cells in the absence of T cells. Particularly, 12j–4 can significantly induce the apoptosis of MDA-MB-231 cells (IC50 = 2.68 ± 0.27 μM). In further studies, 12j–4 has been shown to prevent the phosphorylation of AKT by binding to cytoplasmic PD-L1, which induces apoptosis in MDA-MB-231 cells through non-immune pathways. The inhibition of AKT phosphorylation restores the activity of GSK-3β, ultimately resulting in the degradation of PD-L1. Besides, in vivo study indicated that 12j–4 repressed tumour growth in nude mice. As these biphenyls exert their anti-tumour effects mainly through non-immune pathways, they are worthy of further study as PD-L1 inhibitors. 10 novel biphenyl derivatives were designed and synthesised. 12j–4 can cause the apoptosis of MDA-MB-231 cells with an IC50 value of 2.68 ± 0.27 μM in the absence of immune cells. 12j–4 prevents the phosphorylation of AKT by binding to cytoplasmic PD-L1 to induce apoptosis through non-immune pathways. [ABSTRACT FROM AUTHOR]