δ-catenin promotes Twist1 stabilization in prostate cancer through ubiquitination modification.

Prostate cancer generally has a high long-term survival rate; however, metastatic prostate cancer remains largely incurable despite intensive multimodal therapy. Recent research has identified δ-catenin, a member of the catenin family, as playing a crucial role in the progression of prostate cancer. Nonetheless, the extent to which δ-catenin influences transcription factors associated with epithelial-mesenchymal transition (EMT) has not been thoroughly explored. This study aims to investigate the hypothesis that δ-catenin enhances the stability of Twist1, thereby promoting the migratory and invasive capabilities of prostate cancer cells. Clinical data indicate a strong correlation between δ-catenin and Twist1 expression levels. Western blot analysis confirmed that δ-catenin stabilizes Twist1 and induces ectopic expression. Additionally, δ-catenin was found to reduce Twist1 phosphorylation by inhibiting GSK-3ß activity. Immunoprecipitation analysis suggested that δ-catenin exerts its effect by competing with Twist1 for binding to ubiquitin (Ub). These results highlight the role of δ-catenin in the ubiquitination modification of Twist1, suggesting that the combined presence of δ-catenin and Twist1 could serve as a biomarker for tumor progression in prostate cancer.

Design, synthesis, and biological evaluation of tetrahydropyrimidine analogue as GSK-3ß/Aß aggregation inhibitor and anti-Alzheimer's agent.

The complex nature of Alzheimer's disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-ß (Aß) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3ß is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aß plaques, making GSK-3ß an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3ß, tau phosphorylation, and Aß accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3ß and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3ß inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3ß inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of Aß plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood-brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3ß inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.

Evaluation of the effect of GSK-3ß on liver cancer based on the PI3K/AKT pathway.

The PI3K/AKT/GSK-3ß 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-3ß, 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-3ß significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3ß 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-3ß, 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.

Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model through Improving Insulin Resistance via the IRS-1/PI3K/Akt/GSK-3ß Pathway: A Comparative Study with Metformin.

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3ß insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3ß pathway, reducing GSK-3ß activity, and mitigating Tau hyperphosphorylation and Aß accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

An in-silico approach - molecular docking analysis of flavonoids against GSK-3ß and TNF-α targets in Alzheimer's disease.

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-3ß 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-3ß 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-3ß 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-3ß 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.

Ketamine alleviates PTSD-like effect and improves hippocampal synaptic plasticity via regulation of GSK-3ß/GR signaling of rats.

BACKGROUND: 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 3ß (GSK-3ß)/glucocorticoid receptor (GR) signaling pathway in a single prolonged stress (SPS)-induced PTSD rat model. METHODS: After establishing the model, stress-related behavioral alterations in the rats were assessed following intraperitoneal injections of ketamine (10 mg/kg) and GSK-3ß 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-3ß, and phosphorylated glycogen synthase kinase 3ß (p-GSK-3ß), were assessed. We also measured changes in the mRNA expression levels of GR, BDNF, GSK-3ß, 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. RESULTS: SPS induced anxiety-like and depression-like behaviors in rats and induced morphological changes in synapse, which were accompanied by higher GSK-3ß protein expression and conversely, decreased expression of GR, BDNF, p-GSK-3ß, 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-3ß/GR signaling and synaptic deficits. Furthermore, treatment with a GSK-3ß inhibitor played the same effect as ketamine on behavioral changes of SPS model rats. CONCLUSION: Single doses of ketamine effectively ameliorate SPS-induced anxiety-like symptoms, potentially by improving synaptic plastic in the hippocampus by regulating GSK-3ß/GR signaling.

Design, synthesis and biological evaluation of thieno[3,2-c]pyrazol-urea derivatives as potent glycogen synthase kinase 3ß inhibitors based on the DFG-out conformation.

Glycogen synthase kinase 3ß (GSK-3ß) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3ß inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3ß inhibitor with an IC50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.

Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3ß Pathway in In Vivo and In Silico Experimental Models.

BACKGROUND: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic agent. However, its therapeutic efficacy is often limited by associated adverse effects, with hepatotoxicity being frequently reported with 5-FU therapy. Thymol is a monoterpene found in thyme (Thymus vulgaris L., Lamiaceae) and is known for its antioxidant, anti-apoptotic, and anticancer activities. This study aimed to explore the hepatoprotective activity of thymol against 5-FU-induced liver injury. METHODS: Rats received two intraperitoneal doses of 5-FU (150 mg/kg) either alone or in combination with thymol at doses of 60 mg/kg or 120 mg/kg. Liver enzymes, oxidative stress, and apoptotic markers, in addition to histopathological changes, were assessed. RESULTS: 5-FU induced marked liver injuries as evidenced by elevated liver enzymes and histopathological changes, in addition to abnormalities of oxidative and apoptotic markers. The administration of thymol ameliorated the 5-FU-induced oxidative damage through increasing hepatic antioxidants and lowering lipid peroxidation. Apoptotic response markers such as Bax, Bcl-2, Bax/Bcl-2 ratio, and PARP were also improved. Furthermore, Western blotting analysis showed that thymol modulated the 5-FU-induced changes in the expression of Akt/GSK-3ß and p44/42 MAPK (ERK1/2) signaling pathways. CONCLUSIONS: Our research is the first to shed light on thymol's potential protective effect against 5-FU- induced hepatotoxicity by inhibiting oxidative and apoptotic pathways and modulating the Akt/ GSK-3ß as well as p44/42 MAPK (ERK1/2) signaling pathways.

Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3ß to Combat Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3ß and BuChE are prominent enzymatic targets associated with Alzheimer's disease. Co-targeting GSK3ß 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-3ß 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-3ß 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-3ß 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-3ß and BuChE.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation.

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-3ß 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-3ß 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-3ß activation in primary hippocampal neurons, suggesting that GSK-3ß, 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-3ß as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.

Anti-oxidative stress and cognitive improvement of a semi-synthetic isoorientin-based GSK-3ß inhibitor in rat pheochromocytoma cell PC12 and scopolamine-induced AD model mice via AKT/GSK-3ß/Nrf2 pathway.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive deficits. Although the pathogenesis of AD is unclear, oxidative stress has been implicated to play a dominant role in its development. The flavonoid isoorientin (ISO) and its synthetic derivatives TFGF-18 selectively inhibit glycogen synthase kinase-3ß (GSK-3ß), a potential target of AD treatment. PURPOSE: To investigate the neuroprotective effect of TFGF-18 against oxidative stress via the GSK-3ß pathway in hydrogen peroxide (H2O2)-induced rat pheochromocytoma PC12 cells in vitro and scopolamine (SCOP)-induced AD mice in vivo. METHOD: The oxidative stress of PC12 cells was induced by H2O2 (600 µM) and the effects of TFGF-18 (2 and 8 µM) or ISO (12.5 and 50 µM) were observed. The AD mouse model was induced by SCOP (3 mg/kg), and the effects of TFGF-18 (2 and 8 mg/kg), ISO (50 mg/kg), and donepezil (DNP) (3 mg/kg) were observed. DNP, a currently accepted drug for AD was used as a positive control. The neuronal cell damages were analyzed by flow cytometry, LDH assay, JC-1 assay and Nissl staining. The oxidative stress was evaluated by the detection of MDA, SOD, GPx and ROS. The level of ACh, and the activity of AChE, ChAT were detected by the assay kit. The expressions of Bax, Bcl-2, caspase3, cleaved-caspase3, p-AKT (Thr308), AKT, p-GSK-3ß (Ser9), GSK-3ß, Nrf2, and HO-1, as well as p-CREB (Ser133), CREB, and BDNF were analyzed by western blotting. Morris water maze test was performed to analyze learning and memory ability. RESULTS: TFGF-18 inhibited neuronal damage and the expressions of Bax, caspase3 and cleaved-caspase3, and increased the expression of Bcl-2 in vitro and in vivo. The level of MDA and ROS were decreased while the activities of SOD and GPx were increased by TFGF-18. Moreover, TFGF-18 increased the p-AKT, p-GSK-3ß (Ser9), Nrf2, HO-1, p-CREB, and BDNF expression reduced by H2O2 and SCOP. Meanwhile, MK2206, an AKT inhibitor, reversed the effect of TFGF-18 on the AKT/GSK-3ß pathway. In addition, the cholinergic system (ACh, ChAT, and AChE) disorders were retrained and the learning and memory impairments were prevented by TFGF-18 in SCOP-induced AD mice. CONCLUSIONS: TFGF-18 protects against neuronal cell damage and cognitive impairment by inhibiting oxidative stress via AKT/GSK-3ß/Nrf2 pathway.

Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3ß/ß-catenin driven resistance to doxorubicin.

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 ß-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 ß-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 ß-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 ß-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.

Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling.

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-ß (TGF-ß). 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-ß1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3ß. 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-ß1, 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-ß1/Smad signalling pathway and restoring GSK-3ß phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease.

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-3ß) 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 Aß 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.

Synthetic Benzylic Diselenides and Disulfides: Potential Anticancer Activities via Modulation of the ROS-dependent Akt/ß-Catenin Signaling Pathway.

The natural and synthetic organodiselenides have garnered much research attention due to their chemotherapeutic and chemopreventive activities. Herein, we describe the synthesis of a series of benzylic diselenides, which were synthesized by coupling the in situ generated disodium diselenide with the corresponding benzylic halides. The diselenides were evaluated for their anticancer activities in the highly aggressive triple-negative breast cancer cells. Preliminary anti-proliferative activities indicated 4-cyano-substituted diselenide 7 to be most potent with an IC50 value of 1.9 ± 0.3 µM. Detailed mechanistic investigations showed that diselenide 7 induces apoptosis and causes G1 phase arrest of the cell cycle. It exhibits anticancer activity by suppressing the Akt/ß-catenin signaling pathway. Further control experiments with LiCl (inhibitor of GSK-3ß) revealed that down-regulation of ß-catenin was promoted by GSK-3ß-induced phosphorylation of ß-catenin and its subsequent proteasomal degradation. Moreover, the intracellular ROS was found to act as an upstream mediator for the inactivation of the Akt/ß-catenin signaling pathway. The present study describing the efficient anticancer activity of a synthetic benzylic diselenide towards triple-negative breast cancer cells through the modulation of ROS-dependent Akt/ß-catenin signaling pathway would certainly be helpful in the future towards the development of small-molecule organoselenium compounds for the treatment of cancer.

The SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle insulin resistance in old male rat offspring.

Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (∼30%), fasting blood insulin (FBI) (∼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.

Intracellular effects of lithium in aging neurons.

Lithium therapy received approval during the 1970s, and it has been used for its antidepressant, antimanic, and anti-suicidal effects for acute and long-term prophylaxis and treatment of bipolar disorder (BPD). These properties have been well established; however, the molecular and cellular mechanisms remain controversial. In the past few years, many studies demonstrated that at the cellular level, lithium acts as a regulator of neurogenesis, aging, and Ca2+ homeostasis. At the molecular level, lithium modulates aging by inhibiting glycogen synthase kinase-3ß (GSK-3ß), and the phosphatidylinositol (PI) cycle; latter, lithium specifically inhibits inositol production, acting as a non-competitive inhibitor of inositol monophosphatase (IMPase). Mitochondria and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) have been related to lithium activity, and its regulation is mediated by GSK-3ß degradation and inhibition. Lithium also impacts Ca2+ homeostasis in the mitochondria modulating the function of the lithium-permeable mitochondrial Na+-Ca2+exchanger (NCLX), affecting Ca2+ efflux from the mitochondrial matrix to the endoplasmic reticulum (ER). A close relationship between the protease Omi, GSK-3ß, and PGC-1α has also been established. The purpose of this review is to summarize some of the intracellular mechanisms related to lithium activity and how, through them, neuronal aging could be controlled.

Design, synthesis, antineoplastic activity of new pyrazolo[3,4-d]pyrimidine derivatives as dual CDK2/GSK3ß kinase inhibitors; molecular docking study, and ADME prediction.

In the current study, novel pyrazolo[3,4-d]pyrimidine derivatives 5a-h were designed and synthesized as targeted anti-cancer agents through dual CDK2/GSK-3ß inhibition. The designed compounds demonstrated moderate to potent activity on the evaluated cancer cell lines (MCF-7 and T-47D). Compounds 5c and 5 g showed the most promising cytotoxic activity against the tested cell lines surpassing that of the used reference standard; staurosporine. On the other hand, both compounds showed good safety and tolerability on normal fibroblast cell line (MCR5). The final compounds 5c and 5 g showed a promising dual CDK2/GSK-3ß inhibitory activity with IC50 of 0.244 and 0.128 µM, respectively, against CDK2, and IC50 of 0.317 and 0.160 µM, respectively, against GSK-3ß. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3ß downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and ß-catenin compared to that in the untreated MCF-7 cells. Moreover, compounds 5c and 5 g showed a reasonable selective inhibition against the target kinases CDK2/GSK-3ß in comparison to a set of seven off-target kinases. Furthermore, the most potent compound 5 g caused cell cycle arrest at the S phase in MCF-7 cells preventing the cells' progression to G2/M phase inducing cell apoptosis. Molecular docking studies showed that the final pyrazolo[3,4-d]pyrimidine derivatives have analogous binding modes in the target kinases interacting with the hinge region key amino acids. Molecular dynamics simulations confirmed the predicted binding mode by molecular docking. Moreover, in silico predictions indicated their favorable physicochemical and pharmacokinetic properties in addition to their promising cytotoxic activity.

Multi-signal regulation of the GSK-3ß homolog Rim11 controls meiosis entry in budding yeast.

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-3ß 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.

Unlocking hope: GSK-3 inhibitors and Wnt pathway activation in Alzheimer's therapy.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterised by progressive cognitive decline and the accumulation of amyloid-ß 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-3ß), 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-3ß 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-ß production, tau hyperphosphorylation, enhancement of synaptic plasticity, and inhibition of neuroinflammation. These findings suggest that targeting GSK-3ß 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-3ß as a promising therapeutic strategy in AD.