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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]

Oxidative stress and inflammation are significant causes of aging. At the same time, citrus flavanones, naringenin (NAR), and hesperetin (HES) are bioactives with proven antioxidant and anti-inflammatory properties. Nevertheless, there are still no data about flavanone's influence and its potential effects on the healthy aging process and improving pituitary functioning. Thus, using qPCR, immunoblot, histological techniques, and biochemical assays, our study aimed to elucidate how citrus flavanones (15 mg/kg b.m. per os) affect antioxidant defense, inflammation, and stress hormone output in the old rat model. Our results showed that HES restores the redox environment in the pituitary by down-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein while increasing kelch-like ECH-associated protein 1 (Keap1), thioredoxin reductase (TrxR1), and superoxide dismutase 2 (SOD2) protein expression. Immunofluorescent analysis confirmed Nrf2 and Keap1 down- and up-regulation, respectively. Supplementation with NAR increased Keap1, Trxr1, glutathione peroxidase (Gpx), and glutathione reductase (Gr) mRNA expression. Decreased oxidative stress aligned with NLRP3 decrement after both flavanones and glycogen synthase kinase-3 (GSK3) only after HES. The signal intensity of adrenocorticotropic hormone (ACTH) cells did not change, while corticosterone levels in serum decreased after both flavanones. HES showed higher potential than NAR in affecting a redox environment without increasing the inflammatory response, while a decrease in corticosterone level has a solid link to longevity. Our findings suggest that HES could improve and facilitate redox and inflammatory dysregulation in the rat's old pituitary. [ABSTRACT FROM AUTHOR]

The biological clock in eukaryotes controls daily rhythms in physiology and behavior. It displays a complex organization that involves the molecular transcriptional clock and the redox oscillator which may coordinately work to control cellular rhythms. The redox oscillator has emerged very early in evolution in adaptation to the environmental changes in O2 levels and has been shown to regulate daily rhythms in glycerolipid (GL) metabolism in different eukaryotic cells. GLs are key components of lipid droplets (LDs), intracellular storage organelles, present in all living organisms, and essential for energy and lipid homeostasis regulation and survival; however, the cell bioenergetics status is not constant across time and depends on energy demands. Thus, the formation and degradation of LDs may reflect a time-dependent process following energy requirements. This work investigated the presence of metabolic rhythms in LD content along evolution by studying prokaryotic and eukaryotic cells and organisms. We found sustained temporal oscillations in LD content in Pseudomonas aeruginosa bacteria and Caenorhabditis elegans synchronized by temperature cycles, in serum-shock synchronized human embryonic kidney cells (HEK 293 cells) and brain tumor cells (T98G and GL26) after a dexamethasone pulse. Moreover, in synchronized T98G cells, LD oscillations were altered by glycogen synthase kinase-3 (GSK-3) inhibition that affects the cytosolic activity of the metabolic oscillator or by knocking down LIPIN-1, a key GL synthesizing enzyme. Overall, our findings reveal the existence of metabolic oscillations in terms of LD content highly conserved across evolutionary scales notwithstanding variations in complexity, regulation, and cell organization. [ABSTRACT FROM AUTHOR]

The article discusses the use of organoids and tissue/organ chips in stem cell research. Organoids and spheroids are 3D cell culture models that mimic specific organs and tissues, while tissue and organ chips recreate human organ complexity by incorporating multiple cell types and physiological cues. Integrating organoids with tissue and organ chips has led to more realistic models for drug discovery, toxicity testing, diagnostics, and personalized medicine. However, challenges such as variability in cell lineage and differentiation, scalability, and functional integration still need to be addressed. The article also highlights specific studies on the development of organoids for studying hematopoietic diseases, vascular complications, kidney development, drug interactions, and bile duct injury. The authors emphasize the need for further research to refine these models, improve reproducibility and functionality, and address ethical and regulatory challenges. [Extracted from the article]

The nucleocapsid protein of severe acute respiratory syndrome coronavirus 2 encapsidates the viral genome and is essential for viral function. The central disordered domain comprises a serine-arginine-rich (SR) region that is hyperphosphorylated in infected cells. This modification regulates function, although mechanistic details remain unknown. We use nuclear magnetic resonance to follow structural changes occurring during hyperphosphorylation by serine arginine protein kinase 1, glycogen synthase kinase 3, and casein kinase 1, that abolishes interaction with RNA. When eight approximately uniformly distributed sites have been phosphorylated, the SR domain binds the same interface as single-stranded RNA, resulting in complete inhibition of RNA binding. Phosphorylation by protein kinase A does not prevent RNA binding, indicating that the pattern resulting from physiologically relevant kinases is specific for inhibition. Long-range contacts between the RNA binding, linker, and dimerization domains are abrogated, phenomena possibly related to genome packaging and unpackaging. This study provides insight into the recruitment of specific host kinases to regulate viral function. [ABSTRACT FROM AUTHOR]

This article explores the potential side effect of osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates, medications used to treat bone diseases. The exact mechanism of how bisphosphonates contribute to ONJ is not fully understood, but it is believed to involve the inhibition of osteoclast differentiation and angiogenesis. The article suggests that local therapies targeting osteoclast differentiation in the jaw, such as inhibiting Glycogen synthase kinase-3 beta (GSK3b), administering geranyl-geraniol (GG), or using magnesium (Mg), may be potential treatments for ONJ. However, further studies are needed to explore these potential treatments. The article also mentions the potential use of teriparatide, a recombinant form of parathyroid hormone, in stimulating bone formation. Further research is needed to investigate these potential treatments for osteonecrosis of the jaw. [Extracted from the article]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Despite advances in understanding the pathophysiological mechanisms of AD, effective treatments remain scarce. Lithium salts, recognized as mood stabilizers in bipolar disorder, have been extensively studied for their neuroprotective effects. Several studies indicate that lithium may be a disease-modifying agent in the treatment of AD. Lithium’s neuroprotective properties in AD by acting on multiple neuropathological targets, such as reducing amyloid deposition and tau phosphorylation, enhancing autophagy, neurogenesis, and synaptic plasticity, regulating cholinergic and glucose metabolism, inhibiting neuroinflammation, oxidative stress, and apoptosis, while preserving mitochondrial function. Clinical trials have demonstrated that lithium therapy can improve cognitive function in patients with AD. In particular, meta-analyses have shown that lithium may be a more effective and safer treatment than the recently FDA-approved aducanumab for improving cognitive function in patients with AD. The affordability and therapeutic efficacy of lithium have prompted a reassessment of its use. However, the use of lithium may lead to potential side effects and safety issues, which may limit its clinical application. Currently, several new lithium formulations are undergoing clinical trials to improve safety and efficacy. This review focuses on lithium’s mechanism of action in treating AD, highlighting the latest advances in preclinical studies and clinical trials. It also explores the side effects of lithium therapy and coping strategies, offering a potential therapeutic strategy for patients with AD. [ABSTRACT FROM AUTHOR]

1-Azakenpaullone, a selective inhibitor of glycogen synthase kinase-3β, was synthesized by carrying out a two-step protocol featuring an indium-trichloride-mediated intramolecular cyclization and mild reaction conditions. The concise synthesis showed significantly improved synthetic efficiency and reduced discharge of waste. We expect the present study to boost the applications of 1-azakenpaullone and its analogues in cellular regeneration and regenerative medicine. [ABSTRACT FROM AUTHOR]

Ischemia‐reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase‐3β (GSK‐3β) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK‐3β provides protection against IRI, making it a viable target for drug development. Though numerous GSK‐3β inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK‐3β roles in IRI. First, we provide an overview of GSK‐3β's basic background. Subsequently, we briefly review the pathological mechanisms of GSK‐3β in accelerating IRI, and highlight the latest progress of GSK‐3β in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK‐3β inhibitors in various organ IRI, offering a thorough and insightful reference for GSK‐3β as a potential target for future IRI therapy. [ABSTRACT FROM AUTHOR]

This article explores the potential link between consciousness and quantum computations in brain microtubules. The authors discuss the hypothesis proposed by Penrose, which suggests that there is a connection between brain microtubules and consciousness through the entangled stage of delocalized p electrons. They provide information on the dynamics and composition of brain microtubules, as well as the role they play in synaptic vesicle delivery and signal transmission. The article also delves into the concept of consciousness and its potential biological and physical bases. Finally, the authors discuss the entangled stage and the role of delocalized p electrons in this process. The document provides a comprehensive list of sources for library patrons conducting research on topics such as consciousness, Alzheimer's disease, and quantum cognition. [Extracted from the article]

The myocardium is a highly oxidative tissue in which mitochondria are essential to supply the energy required to maintain pump function. When pathological hypertrophy develops, energy consumption augments and jeopardizes mitochondrial capacity. We explored the cardiac consequences of chronic swimming training, focusing on the mitochondrial network, in spontaneously hypertensive rats (SHR). Male adult SHR were randomized to sedentary or trained (T: 8-week swimming protocol). Blood pressure and echocardiograms were recorded, and hearts were removed at the end of the training period to perform molecular, imaging, or isolated mitochondria studies. Swimming improved cardiac midventricular shortening and decreased the pathological hypertrophic marker atrial natriuretic peptide. Oxidative stress was reduced, and even more interesting, mitochondrial spatial distribution, dynamics, function, and ATP were significantly improved in the myocardium of T rats. In the signaling pathway triggered by training, we detected an increase in the phosphorylation level of both AKT and glycogen synthase kinase-3 β, key downstream targets of insulin-like growth factor 1 signaling that are crucially involved in mitochondria biogenesis and integrity. Aerobic exercise training emerges as an effective approach to improve pathological cardiac hypertrophy and bioenergetics in hypertension-induced cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Simple Summary: Alzheimer's disease is a chronic neurodegenerative disorder that causes brain shrinkage and cellular death. The pathological changes like formation of amyloid plaques and aggregation of hyperphosphorylated tau in the brain begin years before the clinical symptoms appear. Moreover, there has been a drastic increment in the number of people affected by this disease. Unfortunately, there is no cure for Alzheimer's. In this scenario, natural compounds with potent neuroprotective properties and minimal side effects hold promise. Therefore, the present study investigated the effects of Huperzine A (an alkaloid isolated from the moss Huperzia serrata) on the amyloid processing and tau conformations under physiological conditions with an aim of developing a preventive rather than curative approach. The outcome of this study shows that Huperzine A can significantly modulate the amyloid-β and tau processing, suggesting that it could protect the nerve cells, slow cognitive decline, and improve memory. We further suggest that advancement of Huperzine A as a general therapeutic agent might alleviate the socio-economic burden related to the progressive debilitating nature of this disease. The beneficial actions of the natural compound Huperzine A (Hup A) against age-associated learning and memory deficits promote this compound as a nootropic agent. Alzheimer's disease (AD) pathophysiology is characterized by the accumulation of amyloid beta (Aβ). Toxic Aβ oligomers account for the cognitive dysfunctions much before the pathological lesions are manifested in the brain. In the present study, we investigated the effects of Hup A on amyloid precursor protein (APP) proteolysis in SH-SY5Y neuroblastoma cells. Hup A downregulated the expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) levels but augmented the levels of A disintegrin and metalloproteinase 10 (ADAM10) with significant decrement in the Aβ levels. We herein report for the first time an in silico molecular docking analysis that revealed that Hup A binds to the functionally active site of BACE1. We further analyzed the effect of Hup A on glycogen synthase kinase-3 β (GSK3β) and phosphorylation status of tau. In this scenario, based on the current observations, we propose that Hup A is a potent regulator of APP processing and capable of modulating tau homeostasis under physiological conditions holding immense potential in preventing and treating AD like disorders. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase‐3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity‐driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD‐associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (n = 17/group) showed a Braak stage‐dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD‐related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass‐spectrometry or RNA‐sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map‐based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin‐like growth factor 1 (IGF‐1), microtubules, and Polo‐like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD‐associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron‐like SH‐SY5Y cells with the EGFR inhibitor AG‐1478 showed a neuroprotective effect against hydrogen peroxide‐induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid‐beta (Aβ)‐induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD. [ABSTRACT FROM AUTHOR]

Abstract During a SARS-CoV-2 infection, macrophages recognize viral components resulting in cytokine production. While this response fuels virus elimination, overexpression of cytokines can lead to severe COVID-19. Previous studies suggest that the spike protein (S) of SARS-CoV-2 can elicit cytokine production via the transcription factor NF-κB and the toll-like receptors (TLRs). In this study, we found that: (i) S and the S2 subunit induce CXCL10, a chemokine implicated in severe COVID-19, gene expression by human macrophage cells (THP-1); (ii) a glycogen synthase kinase-3 inhibitor attenuates this induction; (iii) S and S2 do not activate NF-κB but do activate the transcription factor IRF; (iv) S and S2 do not require TLR2 to elicit CXCL10 production or activate IRF; and (v) S and S2 elicit CXCL10 production by peripheral blood mononuclear cells (PBMCs). We also discovered that the cellular response, or lack thereof, to S and S2 is a function of the recombinant S and S2 used. While such a finding raises the possibility of confounding LPS contamination, we offer evidence that potential contaminating LPS does not underly induced increases in CXCL10. Combined, these results provide insights into the complex immune response to SARS-CoV-2 and suggest possible therapeutic targets for severe COVID-19.

The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12–15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology. [ABSTRACT FROM AUTHOR]

Summary: Seminal roots play a critical role in water and nutrient absorption, particularly in the early developmental stages of wheat. However, the genes responsible for controlling SRN in wheat remain largely unknown.Genetic mapping and functional analyses identified a candidate gene (TraesCS3D01G137200, TaSRN‐3D) encoding a Ser/Thr kinase glycogen synthase kinase 3 (STKc_GSK3) that regulated SRN in wheat. Additionally, experiments involving hormone treatment, nitrate absorption and protein interaction were conducted to explore the regulatory mechanism of TaSRN‐3D.Results showed that the TaSRN‐3D4332 allele inhibited seminal roots initiation and development, while loss‐of‐function mutants showed significantly higher seminal root number (SRN). Exogenous application of epi‐brassinolide could increase the SRN in a HS2‐allelic background. Furthermore, chlorate sensitivity and 15N uptake assays revealed that a higher number of seminal roots promoted nitrate accumulation. TaBSR1 (BIN2‐related SRN Regulator 1, orthologous to OsGRF4/GL2 in rice) acts as an interactor of TaSRN‐3D and promotes TaBSR1 degradation to reduce SRN.This study provides valuable insights into understanding the genetic basis and regulatory network of SRN in wheat, highlighting their roles as potential targets for root‐based improvement in wheat breeding. [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]

Alzheimer's disease (AD) is an extremely popular neurodegenerative condition associated with dementia, responsible for around 70% of the cases. There are presently 50 million people living with dementia in the world, but this number is anticipated to increase to 152 million by 2050, posing a substantial socioeconomic encumbrance. Despite extensive research, the precise mechanisms that cause AD remain unidentified, and currently, no therapy is available. Numerous signalling paths related to AD neuropathology, including glycogen synthase kinase 3-β (GSK-3β), have been investigated as potential targets for the treatment of AD in current years.GSK-3β is a proline-directed serine/threonine kinase that is linked to a variety of biological activities, comprising glycogen metabolism to gene transcription. GSK-3β is also involved in the pathophysiology of sporadic as well as familial types of AD, which has led to the development of the GSK3 theory of AD. GSK-3β is a critical performer in the pathology of AD because dysregulation of this kinase affects all the main symbols of the disease such as amyloid formation, tau phosphorylation, neurogenesis and synaptic and memory function. The current review highlights present-day knowledge of GSK-3β-related neurobiology, focusing on its role in AD pathogenesis signalling pathways. It also explores the possibility of targeting GSK-3β for the management of AD and offers an overview of the present research work in preclinical and clinical studies to produce GSK-3β inhibitors. [ABSTRACT FROM AUTHOR]

For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists. [ABSTRACT FROM AUTHOR]

Morus alba Linn. is a popular medium-sized tree with a potent neuroprotective activity such as anti-Alzheimer. To date, it is not known which phytocompound of M. alba exerts anti-Alzheimer activity. Therefore, the present study was aimed to identify the phytochemicals of M. alba responsible for the anti-Alzheimer activity by targeting proteins such as acetylcholinesterase (AChE) and glycogen synthase kinase-3 beta (GSK-3β) that are associated in the pathogenesis of Alzheimer disease (AD). Molecular docking, molecular dynamics (MD) simulations and MM-GBSA calculations were performed for the study. Phytocompounds with code 32, 41, 67, and 70 showed the best glide gscore against AchE and GSK-3β. All these phytocompounds interacted with multiple crucial amino acids present at the active binding site of the proteins through conventional hydrogen bonds and hydrophobic interactions. MD simulations of 100 ns revealed stable conformation for all protein-ligand complexes. Based on the computational findings, we conclude that M. alba's phytoconstituents (32, 41 67, and 70) exerts anti-Alzheimer potential by inhibiting AChE and GSK-3β. [ABSTRACT FROM AUTHOR]

Wolbachia pipientis is a maternally transmitted symbiotic bacterium that mainly colonizes arthropods, potentially affecting different aspects of the host’s physiology, e.g., reproduction, immunity, and metabolism. It has been shown that Wolbachia modulates glycogen metabolism in mosquito Aedes fluviatilis (Ae. fluviatilis). Glycogen synthesis is controlled by the enzyme GSK3, which is also involved in immune responses in both vertebrate and invertebrate organisms. Here we investigated the mechanisms behind immune changes mediated by glycogen synthase kinase β (GSK3β) in the symbiosis between Ae. fluviatilis and W. pipientis using a GSK3β inhibitor or RNAi-mediated gene silencing. GSK3β inhibition or knockdown increased glycogen content and Wolbachia population, together with a reduction in Relish2 and gambicin transcripts. Furthermore, knockdown of Relish2 or Caspar revealed that the immunodeficiency pathway acts to control Wolbachia numbers in the host. In conclusion, we describe for the first time the involvement of GSK3β in Ae. fluviatilis immune response, acting to control the Wolbachia endosymbiotic population. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser325 situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser325 is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser325 phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser325 phosphorylation on the protein’s properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify angiogenic microRNAs (miRNAs) that could be used in the treatment of hindlimb ischemic tissues. miRNAs contained in extracellular vesicles (EVs) deriving from the plasma were analyzed in C57BL/6 mice, which have ischemia tolerance, and in BALB/c mice without ischemia tolerance as part of a hindlimb ischemia model; as a result 43 angiogenic miRNA candidates were identified. An aortic ring assay was employed by using femoral arteries isolated from BALC/c mice and EVs containing miRNA; as a result, the angiogenic miRNA candidates were limited to 14. The blood flow recovery was assessed after injecting EVs containing miRNA into BALB/c mice with hindlimb ischemia, and miR-709 was identified as a promising angiogenic miRNA. miR-709-encapsulating EVs were found to increase the expression levels of the fibroblast growth factor 2 (FGF2) mRNA in the thigh tissues of hindlimb ischemia model BALB/c mice. miR-709 was also found to bind to the 3′UTR of glycogen synthase kinase 3 beta (GSK3B) in three places. GSK3B-knockdown human artery-derived endothelial cells were found to express high levels of FGF2, and were characterized by increased cell proliferation. These findings indicate that miR-709 induces an upregulation of FGF2 through the downregulation of GSK3B. [ABSTRACT FROM AUTHOR]

Adult neurogenesis in the dentate gyrus (DG) is impaired during Alzheimer's disease (AD) progression. Curcumin has been reported to reduce cell apoptosis and stimulate neurogenesis. This study aimed to investigate the influence of curcumin on adult neurogenesis in AD mice and its potential mechanism. Two-month-old male C57BL/6J mice were injected with soluble β-amyloid (Aβ1–42) using lateral ventricle stereolocalization to establish AD models. An immunofluorescence assay, including bromodeoxyuridine (BrdU), doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), was used to detect hippocampal neurogenesis. Western blot and an enzyme-linked immunosorbent assay (ELISA) were used to test the expression of related proteins and the secretion of brain-derived neurotrophic factor (BDNF). A Morris water maze was used to detect the cognitive function of the mice. Our results showed that curcumin administration (100 mg/kg) rescued the impaired neurogenesis of Aβ1–42 mice, shown as enhanced BrdU+/DCX+ and BrdU+/NeuN+ cells in DG. In addition, curcumin regulated the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) -mediated glycogen synthase kinase-3β (GSK3β) /Wingless/Integrated (Wnt)/β-catenin pathway and cyclic adenosine monophosphate response element-binding protein (CREB)/BDNF in Aβ1–42 mice. Inhibiting Wnt/β-catenin and depriving BDNF could reverse both the upregulated neurogenesis and cognitive function of curcumin-treated Aβ1–42 mice. In conclusion, our study indicates that curcumin, through targeting PI3K/Akt, regulates GSK3β/Wnt/β-catenin and CREB/BDNF pathways, improving the adult neurogenesis of AD mice. [ABSTRACT FROM AUTHOR]

CRISPR/Cas9 is a recently discovered genomic editing technique that altered scientist's sight in studying genes function. Cas9 is controlled via guide (g) RNAs, which match the DNA targeted in cleavage to modify the respective gene. The development in prostate cancer (PC) modeling directed not only to novel resources for recognizing the signaling pathways overriding prostate cell carcinoma, but it has also created a vast reservoir for complementary tools to examine therapies counteracting this type of cancer. Various cultured somatic rat models for prostate cancer have been developed that nearly mimic human prostate cancer. Nano-medicine can passively target cancer cells via increasing bioavailability and conjugation via specific legend, contributing to reduced systemic side-effects and increased efficacy. This article highlights liposomal loaded Nano-medicine as a potential treatment for prostate cancer and clarifies the CRISPR/Cas9 variation accompanied with prostate cancer. PC is induced experimentally in western rat model via ethinyl estradiol for 4 weeks and SC. dose of 3, 2'- dimethyl-4-aminobiphenyl estradiol (DAE) (50mg/kg) followed by treatment via targeted liposomal-coated compounds such as liposomal dexamethasone (DXM), liposomal doxorubicin (DOX) and liposomal Turmeric (TUR) (3mg/kg IP) for four weeks in a comparative study to their non-targeted analogue dexamethasone, doxorubicin and Turmeric. 3, 2'- dimethyl-4-aminobiphenylestradiol elicit prostate cancer in western rats within 5 months. Simultaneous supplementations with these liposomal compounds influence on prostate cancer; tumor markers were investigated via prostate-specific antigen (PSA), Nitric oxide (NOX) and CRISPR/Cas9 gene editing. Several long non-coding RNAs were reported to be deregulated in prostate cell carcinoma, including MALAT1. On the other hand, gene expression of apoptotic biomarkers focal adhesion kinase (AKT-1), phosphatidylinistol kinase (PI3K) and glycogen synthase kinase-3 (GSK-3) was also investigated and further confirming these results via histopathological examination. Liposomal loaded dexamethasone; doxorubicin and Turmeric can be considered as promising therapeutic agents for prostate cancer via modulating CRISPR/Cas9 gene editing and long non coding gene MALAT1. [ABSTRACT FROM AUTHOR]

Background: Induced pluripotent stem cells (iPSCs)-derived kidney organoids are a promising model for studying disease mechanisms and renal development. Despite several protocols having been developed, further improvements are needed to overcome existing limitations and enable a wider application of this model. One of the approaches to improve the differentiation of renal organoids in vitro is to include in the system cell types important for kidney organogenesis in vivo, such as macrophages. Another approach could be to improve cell survival. Mesodermal lineage differentiation is the common initial step of the reported protocols. The glycogen synthase kinase-3 (GSK-3) activity inhibitor, CHIR99021 (CHIR), is applied to induce mesodermal differentiation. It has been reported that CHIR simultaneously induces iPSCs apoptosis that can compromise cell differentiation. We thought to interfere with CHIR-induced apoptosis of iPSCs using rapamycin. Methods: Differentiation of kidney organoids from human iPSCs was performed. Cell survival and autophagy were analyzed using Cell counting kit 8 (CCK8) kit and Autophagy detection kit. Cells were treated with rapamycin or co-cultured with human monocytes isolated from peripheral blood or iPSCs-macrophages using a transwell co-culture system. Monocyte-derived extracellular vesicles (EVs) were isolated using polyethylene glycol precipitation. Expression of apoptotic markers cleaved Caspase 3, Poly [ADP-ribose] polymerase 1 (PARP-1) and markers of differentiation T-Box Transcription Factor 6 (TBX6), odd-skipped related 1 (OSR1), Nephrin, E-Cadherin, Paired box gene 2 (Pax2) and GATA Binding Protein 3 (Gata3) was assessed by RT-PCR and western blotting. Organoids were imaged by 3D-confocal microscopy. Results: We observed that CHIR induced apoptosis of iPSCs during the initial stage of renal organoid differentiation. Underlying mechanisms implied the accumulation of reactive oxygen species and decreased autophagy. Activation of autophagy by rapamacin and by an indirect co-culture of differentiating iPSCs with iPSCs-macrophages and human peripheral blood monocytes prevented apoptosis induced by CHIR. Furthermore, monocytes (but not rapamycin) strongly promoted expression of renal differentiation markers and organoids development via released extracellular vesicles. Conclusion: Our data suggest that co-culturing of iPSCs with human monocytes strongly improves differentiation of kidney organoids. An underlying mechanism of monocytic action implies, but not limited to, an increased autophagy in CHIR-treated iPSCs. Our findings enhance the utility of kidney organoid models. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM. [ABSTRACT FROM AUTHOR]

The methylazoxymethanol acetate (MAM) rodent model is used to study aspects of schizophrenia. However, numerous studies that have employed this model have used only males, resulting in a dearth of knowledge on sex differences in brain function and behaviour. The purpose of this study was to determine whether differences exist between male and female MAM rats in neuronal oscillatory function within and between the prefrontal cortex (PFC), ventral hippocampus (vHIP) and thalamus, behaviour, and in proteins linked to schizophrenia neuropathology. We showed that female MAM animals exhibited region-specific alterations in theta power, elevated low and high gamma power in all regions, and elevated PFC-thalamus high gamma coherence. Male MAM rats had elevated beta and low gamma power in PFC, and elevated vHIP-thalamus coherence. MAM females displayed impaired reversal learning whereas MAM males showed impairments in spatial memory. Glycogen synthase kinase-3 (GSK-3) was altered in the thalamus, with female MAM rats displaying elevated GSK-3α phosphorylation. Male MAM rats showed higher expression and phosphorylation GSK-3α, and higher expression of GSK-β. Sex-specific changes in phosphorylated Tau levels were observed in a region-specific manner. These findings demonstrate there are notable sex differences in behaviour, oscillatory network function, and GSK-3 signaling in MAM rats, thus highlighting the importance of inclusion of both sexes when using this model to study schizophrenia. [ABSTRACT FROM AUTHOR]

Background. Prostate cancer (PC) prevention is effectively achieved through its inhibition. Oridonin (ORD), an active diterpenoid isolated from Rabdosia rubescens, has been shown to have an inhibitory effect on PC cells, although its impact on PC is unknown. Objectives. The present work investigated the actions and probable mechanisms of ORD on cellular proliferation, apoptosis, PC, and the wingless-type MMTV integration site family member 2 (Wnt)/β-catenin signaling pathway using the androgen-independent PC-3 cell line. Materials and methods. In this study, cell viability was analyzed with MTT assay method, apoptotic morphology determined using DAPI dye method, while protein (CD1333, OCT-4, Nanog, SOX-2 & Aldh1A1) and mRNA expressions were analyzed with western blotting and real time polymerase chain reaction (PCR). Results. We demonstrated a concentration-dependent ORD inhibition of PC-3 cell proliferation and inhibition of induction apoptosis. Furthermore, ORD decreased PC-3 Wnt-2, phosphorylated glycogen synthase kinase-3 (p-GSK3), and β-catenin protein levels and downregulated cyclin-D1 and c-myc messenger ribonucleic acid (mRNA). Conclusions. Oridonin inhibited proliferation and induced apoptosis in PC-3 cells, with the findings suggesting that it acted via the Wnt/β-catenin pathway to exert its effects. This study demonstrates that ORD may impact PC. [ABSTRACT FROM AUTHOR]

Background: Our previous multicenter case-control study showed that aging, up-regulation of platelet glycogen synthase kinase-3b (GSK-3b), impaired olfactory function, and ApoE ∈4 genotype were associated with cognitive decline in type 2 diabetes mellitus (T2DM) patients. However, the causal relationship between these biomarkers and the development of cognitive decline in T2DM patients remains unclear. Methods: To further investigate this potential relationship, we designed a 6-year follow-up study in 273 T2DM patients with normal cognitive in our previous study. Baseline characteristics of the study population were compared between T2DM patients with and without incident mild cognitive impairment (MCI). We utilized Cox proportional hazard regression models to assess the risk of cognitive impairment associated with various baseline biomarkers. Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic accuracy of these biomarkers in predicting cognitive impairment. Results: During a median follow-up time of 6 years (with a range of 4 to 9 years), 40 patients (16.13%) with T2DM developed MCI. Participants who developed incident MCI were more likely to be older, have a lower education level, have more diabetic complications, a higher percentage of ApoE ∈4 allele and a higher level of platelet GSK-3b activity (rGSK-3b) at baseline (P<0.05). In the longitudinal follow-up, individuals with higher levels of rGSK-3b were more likely to develop incident MCI, with an adjusted hazard ratio (HR) of 1.60 (95% confidence interval [CI] 1.05, 2.46), even after controlling for potential confounders. The AUC of the combination of age, rGSK-3b and ApoE∈4 allele predicted for incident MCI was 0.71. Conclusion: Platelet GSK-3b activity could be a useful biomarker to predict cognitive decline, suggesting the feasibility of identifying vulnerable population and implementing early prevention for dementia. [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]

Maintenance of hepatocyte homeostasis plays an important role in mediating the pathogenesis of many diseases. A growing body of literature has established a critical role played by tumor necrosis factor-a (TNFa) in maintaining hepatocyte homeostasis; however, the transcriptional mechanisms underlying constitutive Tnf expression are unknown. Whole liver fractions and primary hepatocytes from adult control C57BL/6 mice and the murine hepatocyte cell line AML12 were assessed for constitutive Tnf expression. Impacts of glycogen synthase kinase-3 β (GSK3β) and nuclear factor κB (NF-κB) inhibition on constitutive Tnf expression were assessed in AML12 cells. Finally, AML12 cell proliferation following GSK3β and NF-κB inhibition was evaluated. Constitutive Tnf gene expression is present in whole liver, primary hepatocytes, and cultured AML12 hepatocytes. Cytokineinduced Tnf gene expression is regulated by NF-κB activation. Pharmacological inhibition of GSK3b resulted in a time- and dose-dependent inhibition of Tnf gene expression. GSK3β inhibition decreased nuclear levels of the NF-κB subunits p65 and p50. We determined that NF-κB transcription factor subunit p65 binds to consensus sequence elements present in the murine TNFa promoter and inhibition of GSK3b decreases binding and subsequent Tnf expression. Finally, AML12 cell growth was significantly reduced following GSK3b and NF-κB inhibition. These results demonstrate that GSK3β and NF-κB are essential for mediating Tnf expression and constitutive hepatocyte cell growth. These findings add to a growing body of literature on TNFα mediated hepatocyte homeostasis and identify novel molecular mechanisms involved in mediating response to various disease states in the liver. [ABSTRACT FROM AUTHOR]

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)–induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3β/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598–615. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3β (GSK3B) acts as a signalling and metabolic enzyme and plays a variety of roles in cellular processes such as cell proliferation, DNA repair, cell cycle, signaling, and metabolic processes. GSK3B has been implicated in numerous diseases, including inflammation, neurodegenerative disease, diabetes, and cancer. Yeasts are suitable models for the investigation of various cellular processes because they include homologous genes to human genes. In this study, we transferred the human GSK3B gene to Schizosaccharomyces pombe (Lindner) cells (gsk3Δ) which include a deletion for this gene. Cells with gsk3 gene deletion and transformant cells with the human GSK3B gene that was reversed by genetic complementation were comparatively examined at the level of gene expression for changes in cellular respiration under varying glucose concentration conditions. For this purpose, the expression of fbp1, pka1 and gsk3 genes were analyzed in cells grown under conditions with different glucose concentrations. We revealed that the GSK3B gene was expressed more in glucose starvation conditions than in other conditions. We also observed a decrease in the level of gene expression in mitochondrial respiration when the human GSK3B gene was transferred in cells that preferred mitochondrial respiration in the absence of the gsk3 gene, regardless of ambient conditions. [ABSTRACT FROM AUTHOR]

A new series of cis-dihydroxy-indeno[1,2-d]imidazolone compounds with distinct structures were synthesized to investigate their potential as inhibitors of the Glycogen synthase kinase 3 (GSK-3). The synthesized compounds were thoroughly characterized using IR, Mass, 1H, and 13C NMR, and in silico screening, including molecular docking, DFT studies using the B3LYP/6-31++G(d,p) basis set in the gas phase drug likeness scores, and molecular dynamic simulation studies, was performed to evaluate protein–ligand interactions and determine the stability of the top-ranked conformation. Our results suggested that compound 4 g, among these compounds, has the potential to be a novel GSK-3 inhibitor as an anticancer agent.

Bone healing remains a major challenge in the treatment of osteoporosis. Effective strategies that simultaneously promote bone formation and inhibit bone resorption are crucial for the treatment of osteoporosis and associated bone defects. MicroRNA (miRNA)‐based approaches aim at simultaneously promoting bone formation and suppressing bone resorption and have therapeutic potential. However, the toxicity of cationic carriers and off‐target effects are two major challenges associated with miRNA delivery. This study establishes a bone‐targeting miRNA delivery system (CH6‐SNA‐26a) that integrates aggregation‐induced emission (AIE), a CH6 aptamer, and miRNAs into a single nanoplatform without any cationic carrier. In this system, an AIE molecule is coupled to miR‐26a to form a core–shell spherical nucleic acid (SNA‐26a). The CH6 aptamer is co‐assembled with the SNA to achieve specific miR‐26a delivery to the bone surface. This aptamer‐functionalized, non‐cationic miR‐26a delivery strategy (CH6‐SNA‐26a) enables both bone‐targeted delivery and high transfection efficiency, ultimately optimizing bone remodeling and calvarial bone healing in an osteoporosis mouse model while limiting adverse effects in non‐skeletal tissues. Mechanistically, the overexpression of CH6‐SNA‐26a in skeletal tissues promotes bone anabolic action by functionally targeting glycogen synthase kinase 3 beta in bone marrow mesenchymal stem cells and cellular communication network 2 in osteoclasts. [ABSTRACT FROM AUTHOR]

Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials. [ABSTRACT FROM AUTHOR]

The trace element lithium exerts a versatile bioactivity in humans, to some extend overlapping with in vivo findings in the model organism Drosophila melanogaster. A potentially essential function of lithium in reproduction has been suggested since the 1980s and multiple studies have since been published postulating a regulatory role of lithium in female gametogenesis. However, the impact of lithium on fruit fly egg production has not been at the center of attention to date. In the present study, we report that dietary lithium (0.1–5.0 mM LiCl) substantially improved life time egg production in D. melanogaster w1118 females, with a maximum increase of plus 45% when supplementing 1.0 mM LiCl. This phenomenon was not observed in the insulin receptor mutant InRE19, indicating a potential involvement of insulin‐like signaling in the lithium‐mediated fecundity boost. Analysis of the whole‐body and ovarian transcriptome revealed that dietary lithium affects the mRNA levels of genes encoding proteins related to processes of follicular maturation. To the best of our knowledge, this is the first report on dietary lithium acting as an in vivo fecundity stimulant in D. melanogaster, further supporting the suggested benefit of the trace element in female reproduction. [ABSTRACT FROM AUTHOR]

Aim: The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3β (GSK3β), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. Methods: The protein expression levels of phosphatidylinositol 4‐phosphate 5‐kinase type‐1 gamma (PIP5K1C), phosphatidylinositol 4‐kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3β were measured using enzyme‐linked immunosorbent assays and multiplex fluorescent bead‐based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3β, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. Results: PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3β were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. Conclusion: Our results suggest that the expression levels of Akt1/GSK3β and its upstream regulator PTEN are considerably altered. [ABSTRACT FROM AUTHOR]

Background Alcohol is a major abused drug worldwide that contributes substantially to health and social problems. These problems result from acute alcohol overuse as well as chronic use, leading to alcohol use disorder (AUD). A major goal of this field is to establish a treatment for alcohol abuse and dependence in patients with AUD. The central molecular mechanisms of acute alcohol actions have been extensively investigated in rodent models. Aims One of the central mechanisms that may be involved is glycogen synthase kinase-3β (GSK-3β) activity, a key enzyme involved in glycogen metabolism but which has crucial roles in numerous cellular processes. Although the exact mechanisms leading from acute alcohol actions to these chronic changes in GSK-3β function are not yet clear, GSK-3β nonetheless constitutes a potential therapeutic target for AUD by reducing its function using GSK-3β inhibitors. This review is focused on the correlation between GSK-3β activity and the degree of alcohol consumption. Methods Research articles regarding investigation of effect of GSK-3β on alcohol consumption in rodents were searched on PubMed, Embase, and Scopus databases using keywords "glycogen synthase kinase," "alcohol (or ethanol)," "intake (or consumption)," and evaluated by changes in ratios of pGSK-3βSer9/pGSK-3β. Results In animal experiments, GSK-3β activity decreases in the brain under forced and voluntary alcohol consumption while GSK-3β activity increases under alcohol-seeking behavior. Conclusions Several pieces of evidence suggest that alterations in GSK-3β function are important mediators of chronic ethanol actions, including those related to alcohol dependence and the adverse effects of chronic ethanol exposure. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) is a pathological state closely associated with various diseases, with hepatic insulin resistance playing a pivotal role. Insulin resistance can be improved by Ginsenoside Rg1 (GRg1), which is known as one of the most biologically active compounds found in ginseng. Nevertheless, the precise role and mechanisms of GRg1 in ameliorating hepatic insulin resistance are still unknown. Objectives: We wanted to demonstrate the impact of GRg1 on hepatic insulin resistance and explore the underlying mechanisms in our work. Materials and Methods: We mimicked insulin resistance conditions by culturing HepG2 cells in 30 mM glucose for 24 h. The effects of GRg1 on cellular glucose consumption and the key kinases of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β) pathway were evaluated. To assess if the PI3K/AKT/GSK-3β pathway is crucial for GRg1's protective effect against insulin resistance, the compound LY294002, which inhibits PI3K, was employed. Results: In HepG2 cells, GRg1 markedly increased glucose uptake while exhibiting no cytotoxicity. Additionally, GRg1 activated the PI3K/AKT/GSK-3β pathway, as indicated by the increased phosphorylation of insulin receptor substrates-1 (IRS-1), AKT, and GSK-3β. Treatment with LY294002 significantly reversed the promotive effects of GRg1 on cellular glucose consumption and PI3K/AKT/GSK-3β pathway activation. Conclusion: Taken together, our present study revealed GRg1 exerted a protective effect against hepatic insulin resistance induced by high glucose through PI3K/AKT/GSK-3β pathway, suggesting its potential as a beneficial therapeutic medication. [ABSTRACT FROM AUTHOR]

Introduction: Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues inmodulating immune responses. Despite this, the precisemechanism through which SST regulates T cells has remained largely unknown. Methods: To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells. Results: We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3. Discussion: Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions. [ABSTRACT FROM AUTHOR]

Background and purpose: Alzheimer's disease (AD) is a common neurodegenerative disease and the fifth leading cause of death among the elderly. The development of drugs for AD treatment is based on inhibiting cholinesterase (ChE) activity and inhibiting amyloid-beta peptide and tau protein aggregations. Many in vitro findings have demonstrated that thiazole- and thiazolidine-based compounds have a good inhibitory effect on ChE and other elements involved in the AD pathogenicity cascade. Experimental approach: In the present review, we collected available documents to verify whether these synthetic compounds can be a step forward in developing new medications for AD. A systematic literature search was performed in major electronic databases in April 2021. Twenty-eight relevant in vitro and in vivo studies were found and used for data extraction. Findings/Results: Findings demonstrated that thiazole- and thiazolidine-based compounds could ameliorate AD's pathologic condition by affecting various targets, including inhibition of ChE activity, amyloid-beta, and tau aggregation in addition to cyclin-dependent kinase 5/p25, beta-secretase-1, cyclooxygenase, and glycogen synthase kinase-3β. Conclusion and implications: Due to multitarget effects at micromolar concentration, this review demonstrated that these synthetic compounds could be considered promising candidates for developing anti-Alzheimer drugs. [ABSTRACT FROM AUTHOR]

Human naïve pluripotent stem cells (hnPSCs) can generate integrated models of blastocysts termed blastoids upon switch to inductive medium. However, the underlying mechanisms remain obscure. Here we report that self-renewing hnPSCs spontaneously and efficiently give rise to blastoids upon three dimensional (3D) suspension culture. The spontaneous blastoids mimic early stage human blastocysts in terms of structure, size, and transcriptome characteristics and are capable of progressing to post-implantation stages. This property is conferred by the glycogen synthase kinase-3 (GSK3) signalling inhibitor IM-12 present in 5iLAF self-renewing medium. IM-12 upregulates oxidative phosphorylation-associated genes that underly the capacity of hnPSCs to generate blastoids spontaneously. Starting from day one of self-organization, hnPSCs at the boundary of all 3D aggregates dedifferentiate into E5 embryo-like intermediates. Intermediates co-express SOX2/OCT4 and GATA6 and by day 3 specify trophoblast fate, which coincides with cavity and blastoid formation. In summary, spontaneous blastoid formation results from 3D culture triggering dedifferentiation of hnPSCs into earlier embryo-like intermediates which are then competent to segregate blastocyst fates. Blastoids are emerging models for early embryo development exploration in vitro. Here, authors found self-renewing human naïve PSCs spontaneously and efficiently give rise to blastoids upon three-dimensional suspension culture. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that currently lacks effective clinical treatments. Evidence highlights the potential role of glycogen synthase kinase-3 (GSK-3) inhibition in mitigating severe inflammation. The inhibition of GSK-3α/β by CHIR99021 promoted fetal lung progenitor proliferation and maturation of alveolar epithelial cells (AECs). The precise impact of CHIR99021 in lung repair and regeneration during acute lung injury (ALI) remains unexplored. This study intends to elucidate the influence of CHIR99021 on AEC behaviour during the peak of the inflammatory phase of ALI and, after its attenuation, during the repair and regeneration stage. Furthermore, a long-term evaluation was conducted post CHIR99021 treatment at a late phase of the disease. Our results disclosed the role of GSK-3α/β inhibition in promoting AECI and AECII proliferation. Later administration of CHIR99021 during ALI progression contributed to the transdifferentiation of AECII into AECI and an AECI/AECII increase, suggesting its contribution to the renewal of the alveolar epithelial population and lung regeneration. This effect was confirmed to be maintained histologically in the long term. These findings underscore the potential of targeted therapies that modulate GSK-3α/β inhibition, offering innovative approaches for managing acute lung diseases, mostly in later stages where no treatment is available. [ABSTRACT FROM AUTHOR]

The human sirtuin 2 gene (SIRT2) encodes a full-length Sirt2 protein (i.e., the Sirt2 isoform 1), which primarily functions as a cytoplasmic α-tubulin deacetylase, and which promotes the growth of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) replication itself, or HBV X (HBx) protein-mediated transcriptional transactivation, enhances Sirt2.1 expression; therefore, Sirt2.1 itself is capable of positively increasing HBV transcription and replication. Sirt2.1 is linked to liver fibrosis and epithelial-to-mesenchymal transition and, consequently, augments the risk of HCC. The Sirt2.1 protein enhances the HBV replication cycle by activating the AKT/glycogen synthase kinase 3 beta (GSK3β)/β-catenin pathway. It also activates the transcription of the viral enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The Sirt2 isoform 2 (Sirt2.2) is mainly localized in the cytoplasm, and the N-terminus is shorter by 37 amino acids than that of Sirt2.1. Despite the truncation of the N-terminal region, Sirt2.2 is still capable of enhancing HBV replication and activating the AKT/GSK3β/β-catenin signaling pathway. The Sirt2 isoform 5 (Sirt2.5) is primarily localized to the nucleus, it lacks a nuclear export signal (NES), and the catalytic domain (CD) is truncated. Upon HBV replication, expression of the Sirt2 isoforms is also enhanced, which further upregulates the HBV replication, and, therefore, supports the vicious cycle of viral replication and progression of the disease. Sirt2 diversely affects HBV replication such that its isoform 1 intensely augments HBV replication and isoform 2 (despite of the truncated N-terminal region) moderately enhances HBV replication. Isoform 5, on the other hand, tends to protect the cell (for smooth long-term continued viral replication) from HBV-induced extreme damage or death via a discrete set of regulatory mechanisms impeding viral mRNAs, the hepatitis B core/capsid protein (HBc), core particles, replicative intermediate (RI) DNAs, and covalently closed circular DNA (cccDNA) levels, and, consequently, limiting HBV replication. In contrast to Sirt2.1 and Sirt 2.2, the Sirt2.5-mediated HBV replication is independent of the AKT/GSK3β/β-catenin signaling cascade. Sirt2.5 is recruited more at cccDNA than the recruitment of Sirt2.1 onto the cccDNA. This recruitment causes the deposition of more histone lysine methyltransferases (HKMTs), including SETDB1, SUV39H1, EZH2, and PR-Set7, along with the respective corresponding transcriptional repressive markers such as H3K9me3, H3K27me3, and H4K20me1 onto the HBV cccDNA. In HBV-replicating cells, Sirt2.5 can also make complexes with PR-Set7 and SETDB1. In addition, Sirt2.5 has the ability to turn off transcription from cccDNA through epigenetic modification via either direct or indirect interaction with HKMTs. [ABSTRACT FROM AUTHOR]

Panicum antidotale has traditionally been used as a poultice to alleviate local inflammation and painful diseases. This study aimed to evaluate the antiinflammatory, wound-healing, analgesic, and antipyretic potential of its ethanol extract (PAAPEE) in vivo for the first time. In vitro antioxidant assays of Panicum antidotale using a 2,2-diphenyl-1-picrylhydrazyl assay revealed that it showed IC50 of 62.50 ± 6.85 μg/mL in contrast to standard, ascorbic acid, that showed IC50 of 85.51 ± 0.38 μg/mL. Administration of PAAPEE at a dose of 500 mg/kg (PAAPEE- 500) displayed 78.44% and 75.13% inhibition of paw edema in carrageenen and histamine-induced edema models. respectively, 6 h post-treatment compared to that of the untreated group. Furthermore, it showed 68.78% inhibition of Freund's complete adjuvant-induced edema 21 days after treatment. It reduced the animal's rectal temperature in the yeast-induced fever model to 99.45 during the fourth h post-treatment. It significantly inhibited abnormal writhing by 44% in the acetic acid-induced pain model. PAE-500 also showed enhancement in wound closure by 72.52% with respect to that of the untreated group on the 10th day post-treatment using the excision healing of wound model. Histopathological examination of skin samples confirmed this improvement, showing enhanced tissue architecture with minimal infiltration of inflammatory cells. High-performance liquid chromatography (HPLC) of PAAPEE revealed the presence of quercetin, gallic, p-coumaric, benzoic, chlorogenic, syringic, ferulic, cinnamic, and sinapic acids. Molecular docking of 5-lipoxygenase and glycogen synthase kinase-3 β protein indicated their potential interaction within the active sites of both enzymes. Thus, P. antidotale serves as an effective natural woundhealing, anti-inflammatory, analgesic, and antipyretic agent. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3-beta (GSK3-β) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer's disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four naturally occurring compounds—apigenin, luteolin, rosmarinic acid, and salvianolic acid—from the Laminaceae family against GSK3-β. The orientation of the ligands within the ATP-binding pocket of GSK3-β and their binding energy were determined through molecular docking. Additionally, molecular dynamics simulations was conducted to study the conformational changes induced by the ligands in the protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potentially ATP-competitive role. Our results suggest these compounds as lead candidates for the design of GSK3-β inhibitors. [ABSTRACT FROM AUTHOR]