As a \"silent threat,\" Alzheimer\'s disease (AD) is quickly rising to the top of the list of costly and troublesome diseases facing humanity. It is growing to be one of the most troublesome and expensive conditions, with annual health care costs higher than those of cancer and comparable to those of cardiovascular disorders. One of the main pathogenic characteristics of AD is the deficiency of the neurotransmitter acetylcholine (ACh) which plays a vital role in memory, learning, and attention. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in hydrolyzing ACh. Consequently, a frequent therapy approach for AD is the suppression of AChE and BChE to improve cholinergic neurotransmission and reduce cognitive symptoms. The accumulation of amyloid plaques (Aβ) is a primary factor contributing to neurodegenerative diseases, particularly AD. Glycogen synthase kinase-3β (GSK3-β) is regarded as a pivotal player in the pathophysiology of AD since dysregulation of this kinase affects all major hallmarks of the disease, such as tau phosphorylation, Aβ aggregation, memory, neurogenesis, and synaptic function. One of the most challenging and risky issues in modern medicinal chemistry is the urgent and ongoing need for the study and development of effective therapeutic candidates for the treatment of AD. A significant class of heterocyclic molecules that can target the complex and multifactorial pathogenesis of AD are fused thiophene derivatives. The goal of the current review is to demonstrate the advancements made in fused thiophene derivatives\' anti-AD activity. It also covers their mechanisms of action and studies of the structure-activity relationships in addition to the compilation of significant synthetic routes for fused thiophene derivatives with anti-AD potential. This review is intended to stimulate new ideas in the search for more rationale designs of derivatives based on fused thiophene, hoping to be more potent in treating AD.

Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium\'s efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium\'s neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.

[Formula: see text]-Escin is an oleanane-type pentacyclic triterpenoid saponin extracted from the seeds of Aesculus hippocastanum (AH), which is more widely distributed. [Formula: see text]-Escin sodium has been approved by the American FDA for clinical usage. This paper is intended to summarize an updated and comprehensive review of the pharmacological activities, pharmacokinetic properties, toxicity, and analytical methods of [Formula: see text]-escin. Studies have shown that [Formula: see text]-escin has significant antitumor, antiviral, anti-inflammatory, and other activities alongside less adverse effects and higher safety than other compounds. The review shows that the pharmacological effects of [Formula: see text]-escin involve mechanisms such as ATM/[Formula: see text]H2AX, RhoA/Rock, GSK-3[Formula: see text]/[Formula: see text]-Catenin, HER2/HER3/Akt, and PI3K/Akt signaling pathways, and Cyclin A, p21[Formula: see text], survivin, Bcl-2, Mcl-1, Caspases, TGF-[Formula: see text], MMPs, and TNF-[Formula: see text] among other inflammatory factors. [Formula: see text]-Escin has significant cytotoxicity; the use of the chitosan/xanthan gum-based polyelectrolyte complexes PA1 and PC-11 to modify it not only to reduces its toxicity, but also improves its drug efficacy. Because of this, these compounds may become a new research hotspot. [Formula: see text]-Escin in vivo metabolism can be converted by the CYP1A2 enzyme in the intestinal flora to produce [Formula: see text]-escin, deacylated, deglycosylated, and 21[Formula: see text]-[Formula: see text]-crotonoyl-protoescin, and the binding rate of the plasma proteins is higher than 90%. These are mainly metabolized by the liver, kidneys, and other organs, and excreted in the form of urine and feces. The number of reports on the specific mediators of the metabolism of [Formula: see text]-escin and their mechanisms and metabolites is relatively small; furthermore, the results are vague. Therefore, a complete and in-depth exploration of the pharmacokinetic characteristics of [Formula: see text]-escin is needed to provide a more complete and effective theoretical reference for the study of its pharmacodynamic activity.

The intricate molecular pathways governing cancer development and progression have spurred intensive investigations into novel therapeutic targets. Glycogen Synthase Kinase-3 (GSK3), a complex serine/threonine kinase, has emerged as a key player with intricate roles in various cellular processes, including cell proliferation, differentiation, apoptosis, and metabolism. Harnessing GSK3 inhibitors as potential candidates for cancer therapy has garnered significant interest due to their ability to modulate key signalling pathways that drive oncogenesis. The review encompasses a thorough examination of the molecular mechanisms underlying GSK3\'s involvement in cancer progression, shedding light on its interaction with critical pathways such as Wnt/β-catenin, PI3K/AKT, and NF-κB. Through these interactions, GSK3 exerts influence over tumour growth, invasion, angiogenesis, and metastasis, rendering it an attractive target for therapeutic intervention. The discussion includes preclinical and clinical studies, showcasing the inhibitors efficacy across a spectrum of cancer types, including pancreatic, ovarian, lung, and other malignancies. Insights from recent studies highlight the potential synergistic effects of combining GSK3 inhibitors with conventional chemotherapeutic agents or targeted therapies, opening avenues for innovative combinatorial approaches. This review provides a comprehensive overview of the current state of research surrounding GSK3 inhibitors as promising agents for cancer treatment.

Diabetes mellitus (DM) is a non-communicable disease throughout the world in which there is persistently high blood glucose level from the normal range. The diabetes and insulin resistance are mainly responsible for the morbidities and mortalities of humans in the world. This disease is mainly regulated by various enzymes and hormones among which Glycogen synthase kinase-3 (GSK-3) is a principle enzyme and insulin is the key hormone regulating it. The GSK-3, that is the key enzyme is normally showing its actions by various mechanisms that include its phosphorylation, formation of protein complexes, and other cellular distribution and thus it control and directly affects cellular morphology, its growth, mobility and apoptosis of the cell. Disturbances in the action of GSK-3 enzyme may leads to various disease conditions that include insulin resistance leading to diabetes, neurological disease like Alzheimer\'s disease and cancer. Fluoroquinolones are the most common class of drugs that shows dysglycemic effects via interacting with GSK-3 enzyme. Therefore, it is the need of the day to properly understand functions and mechanisms of GSK-3, especially its role in glucose homeostasis via effects on glycogen synthase.

Despite the unavailability of essential anti-dementia drugs, lithium may inhibit glycogen synthase kinase-3 (GSK-3) and decrease beta-amyloid and hyper-phosphorylated tau. In this review, we hypothesized that trace to standard levels of lithium (i.e., corresponding to the therapeutic levels for bipolar disorder) may be effective for dementia prevention. Excluding three insufficient level studies, we obtained two and one excellent clinical studies on standard and trace lithium levels, respectively, all of which supported the effects of lithium for dementia prevention. In addition, we identified good clinical and epidemiological studies (four each) on standard lithium levels, of which six studies supported the effects of lithium. Moreover, of three good epidemiological studies on trace lithium levels, two supported the aforementioned effects of lithium. The number of studies were substantially small, particularly those on trace lithium levels. Moreover, studies on standard lithium levels were insufficient to establish the efficacy of lithium for dementia prevention. This necessitates accumulating good or excellent clinical evidence for the effects of trace to standard lithium levels on dementia prevention.

Glycogen synthase kinase 3 (GSK3) is a monomeric serine-threonine kinase discovered in 1980 in a rat skeletal muscle. It has been involved in various cellular processes including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. GSK3 exists in two different isoforms, GSK3α and GSK3β, both containing seven antiparallel beta-plates, a short linking part and an alpha helix, but coded by different genes and variously expressed in human tissues. In the current review, we comprehensively appraise the current literature on the role of GSK3 in various cancers with emphasis on ovarian carcinoma. Our findings indicate that the role of GSK3 in ovarian cancer development cannot be decisively determined as the currently available data support both prooncogenic and tumor-suppressive effects. Likewise, the clinical impact of GSK3 expression on ovarian cancer patients and its potential therapeutic implications are also limited. Further studies are needed to fully elucidate the pathophysiological and clinical implications of GSK3 activity in ovarian cancer.

BACKGROUND: Preclinical studies, clinical trials, and reviews suggest increasing 3\',5\'-cyclic adenosine monophosphate (cAMP) and 3\',5\'-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer\'s disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1α. PGC1α induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFκB and tau-phosphorylating GSK3β.
OBJECTIVE: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD.
RESULTS: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition.
CONCLUSIONS: Phosphodiesterase inhibitors may prevent and treat AD.

The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer\'s disease (AD) is unknown.
A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients.
We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure.
Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = -0.25, p = 0.11, I2 = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = -0.41, p = 0.04; tideglusib subgroup: SMD = -0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, -0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments.
Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed.

Introduction: Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3\'s functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition.Methods: We conducted a systematic review of literature on GSK3\'s expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers.Results: A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3\'s regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues.Conclusions: Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3\'s role in reproductive tissues makes this molecule\'s function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.