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.

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-3β/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-3β and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3β/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.

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-3β (GSK-3β), 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-3β 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-3β, 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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Alzheimer\'s disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure-activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 μM), although the potency was increased by 2\' substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC50 = 0.0021 μM), and the electron-withdrawing group and 2\' and 3\' substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14-35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.

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-3β 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-3β 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-3β. Investigating the effect of compounds 5c and 5 g on CDK2 and GSK-3β downstream cascades showed that they reduced the relative cellular content of phosphorylated RB1 and β-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-3β 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.

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.

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.

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer\'s activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman\'s method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3β, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p. Results: 6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3β and CDK5. Conclusion: The target compounds could be considered in developing anti-Alzheimer\'s disease agents.
[Box: see text].

BACKGROUND: Alzheimer\'s disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it.
OBJECTIVE: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and AChE.
METHODS: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger.
RESULTS: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules.
CONCLUSIONS: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.