Search Results (348)

Macrophages are undoubtedly one of the most widely studied cells of the immune system, among other reasons, because they are involved in a wide variety of biological processes. Deregulation of their activity is observed in a number of different disorders, including autoimmune diseases. At the same time, mammalian target of rapamycin (mTOR) is attracting increasing research attention because the pathways dependent on this kinase are activated by a variety of signals, including cytokines and proinflammatory mediators, mediate essential processes for cell survival and metabolism, and can be regulated epigenetically via microRNAs. Therefore, our narrative review aimed to summarize and discuss recent advances in the knowledge of the activation of mTOR signaling in macrophages, with a special focus on autoimmune disorders and the possibility of mTOR control by microRNAs. The summarized research observations allowed us to conclude that the effects of activity and/or inhibition of individual mTOR complexes in macrophages are largely context dependent, and therefore, these broad immunological contexts and other specific conditions should always be taken into account when attempting to modulate these pathways for therapeutic purposes. Full article

Miller–Dieker Syndrome (MDS) is a rare neurodevelopmental disorder caused by a heterozygous deletion of approximately 26 genes within the MDS locus of human chromosome 17. MDS, which affects 1 in 100,000 babies, can lead to a range of phenotypes, including lissencephaly, severe neurological defects, distinctive facial abnormalities, cognitive impairments, seizures, growth retardation, and congenital heart and liver abnormalities. One hallmark feature of MDS is an unusually smooth brain surface due to abnormal neuronal migration during early brain development. Several genes located within the MDS locus have been implicated in the pathogenesis of MDS, including PAFAH1B1, YWHAE, CRK, and METTL16. These genes play a role in the molecular and cellular pathways that are vital for neuronal migration, the proper development of the cerebral cortex, and protein translation in MDS. Improved model systems, such as MDS patient-derived organoids and multi-omics analyses indicate that WNT/β-catenin signaling, calcium signaling, S-adenosyl methionine (SAM) homeostasis, mammalian target of rapamycin (mTOR) signaling, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and others are dysfunctional in MDS. This review of MDS integrates details at the clinical level alongside newly emerging details at the molecular and cellular levels, which may inform the development of novel therapeutic strategies for MDS. Full article

Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation. Full article

Childhood obesity is a major global health problem, and its management involves a multidisciplinary approach that includes lifestyle changes, dietary interventions, and the use of dietary supplements. In this review, we summarize current findings on the role of amino acids in pediatric obesity, with a particular focus on their involvement in metabolic pathways and weight regulation. The involvement of branched-chain and aromatic amino acids in the pathophysiology and potential management of pediatric obesity is highlighted in recent studies. Both experimental and clinical studies have shown that obese children often exhibit altered plasma amino acid profiles, including increased levels of leucine, isoleucine, valine, phenylalanine, and tyrosine, as well as decreased levels of glycine and serine. These imbalances are correlated with insulin resistance, inflammation, and early metabolic dysfunction. One of the mechanisms through which branched-chain amino acids can promote insulin resistance is the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Metabolomic profiling has demonstrated the potential of specific amino acid patterns to predict obesity-related complications before they become clinically evident. Early identification of these biomarkers could be of great help for individualized interventions. Although clinical studies indicate that changes in dietary amino acids could lead to modest weight loss, improved metabolic profiles, and increased satiety, further studies are needed to establish standardized recommendations. Full article

Tempol is a synthetic antioxidant that shows promise in preclinical cancer studies by inhibiting growth and inducing apoptosis. Given that the Mitogen-Activated Protein Kinase (MAPK) and Protein Kinase B/Mammalian Target of Rapamycin (Akt/mTOR) signaling pathways are frequently dysregulated in gastric and colon cancers and contribute to their progression, we investigated Tempol’s anti-cancer potential in HT29 (colon) and CRL-1739 (gastric) cancer cells. Cells were treated with 2 mM Tempol for 48 h, with untreated cells as controls. We evaluated apoptosis (Bax, cleaved caspase-3, and Bcl-2), key signaling pathway activity (p-ERK, p-JNK, p-AKT, and p-mTOR), and levels of stress- and apoptosis-related proteins (WEE1, GADD153, GRP78, and AIF). Tempol significantly increased pro-apoptotic Bax and cleaved caspase-3 (p < 0.0001) and decreased anti-apoptotic Bcl-2 (p < 0.0001) in both cell lines. Furthermore, Tempol markedly reduced the activity of p-ERK, p-JNK, p-AKT, and p-mTOR (p < 0.0001) and significantly increased the protein levels of WEE1, GADD153, GRP78, and AIF (p < 0.0001). Tempol treatment also led to a significant increase in total oxidant status and a decrease in total antioxidant status. In conclusion, our findings suggest that Tempol exhibits its anti-cancer activity through multiple interconnected mechanisms, primarily inducing apoptosis and oxidative stress, while concurrently suppressing pro-survival signaling pathways. These results highlight Tempol’s potential as a therapeutic agent for gastric and colon cancers. Full article

Background/Objectives: The integration of natural compounds in cancer research marked a crucial shift in the modern medical landscape, through a growing acknowledgment of their potential as efficient, less toxic, and cost-effective alternatives to contemporary chemotherapeutics. Liquiritigenin (LIQ) is a compound obtained from different plants, the most important being the Glycyrrhiza species, commonly known as licorice. Methods: This review compiles findings from previously published preclinical studies and experimental research articles focusing on LIQ’s pharmacological effects, with particular attention to its anticancer potential. The relevant literature was identified using established scientific databases and selected based on relevance to cancer biology and LIQ-associated signaling pathways. Results: LIQ demonstrates anti-oxidant, anti-inflammatory, and anti-proliferative effects. It exerts its potential anticancer activities by inducing apoptosis, preventing cell proliferation, and modulating various signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and so on. Conclusions: LIQ represents a promising natural agent for cancer therapy, with evidence supporting its multifunctional role in targeting tumor growth and survival mechanisms. By providing a detailed analysis of LIQ, this review aims to highlight its therapeutic efficacy across various cancer types and emphasize its importance as a promising compound in cancer research. In addition, this review seeks to bridge the gap between traditional medicine and modern pharmacology and paves the way for LIQ’s clinical application in cancer therapy. Full article

As life expectancy increases, muscle atrophy, characterized by a decline in muscle mass and strength that can impair mobility, has become a growing concern, highlighting the potential of protein supplementation as a promising intervention strategy. A horse meat hydrolysate, with a molecular weight of less than 3 kDa, derived from m. biceps femoris and produced using the food-grade enzyme Alcalase^® (A4 < 3kDa) was evaluated for its efficacy in mitigating dexamethasone-induced muscle atrophy, a widely accepted model for studying catabolic muscle loss. Administered orally to C57BL/6 mice at dosages of 200 mg/kg or 500 mg/kg body weight for 35 days, A4 < 3kDa effectively countered the weight loss induced by dexamethasone in the whole body, quadriceps, tibialis anterior, and gastrocnemius muscles. Moreover, it increased muscle fiber cross-sectional area and grip strength. These effects were attributed to increased protein synthesis via the protein kinase B (AKT)/forkhead box O3 (FoxO3a)/mammalian target of rapamycin (mTOR) signaling pathway. A4 < 3kDa augmented the phosphorylation of key components of the signaling pathways associated with muscle atrophy, resulting in reduced mRNA expression of Atrogin-1 and MuRF-1. These findings demonstrate the potential of A4 < 3kDa as a functional food ingredient for preventing muscle atrophy. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy–lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases. Full article

Cancer remains a leading global health challenge, necessitating the exploration of novel therapeutic strategies. Vitexin (apigenin-8-C-β-D-glucopyranoside), a natural flavonoid glycoside with a molecular weight of 432.38 g/mol, is derived from plants such as mung bean, beetroot, and hawthorn. This compound features a distinctive C-glycosidic bond at the 8-position of its apigenin backbone, contributing to its enhanced metabolic stability compared to O-glycosidic flavonoids. Preclinical studies demonstrate that vitexin modulates critical cellular processes such as cell cycle progression, apoptosis, autophagy, metastasis, angiogenesis, epigenetic modifications, and tumor glycolysis inhibition. It exerts its effects by targeting key signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription 3 (STAT3), and shows potential for combination therapies to enhance efficacy and overcome resistance. Advances in nanotechnology further enhance its bioavailability and delivery potential. This review comprehensively examines the current evidence on vitexin’s anticancer mechanisms, highlighting its multi-target therapeutic potential and future research directions. Full article

Background/Objectives: Primary pulmonary carcinoma (PC) is a malignant neoplasm that occurs in humans, dogs, and other species. In canine PC, palliative care remains the most practical approach for dogs with inoperable PC. Methods: We investigated the effectiveness of mammalian target of rapamycin (mTOR) inhibitors in canine lung cancer upon PI3K/AKT/mTOR activation. Three canine PC cell lines (AZACL1, AZACL2, and cPAC-1) were treated with three mTOR inhibitors (AZD8055, temsirolimus, and everolimus). In vitro, sensitivity assays were conducted to evaluate proliferation and Western blotting was used to examine pathway activation and phosphorylation of mTOR-related protein. Results: AZD8055 had a stronger inhibitory effect on cell proliferation than temsirolimus and everolimus in all three PC cell lines. The IC₅₀ for AZD8055 in the AZACL1, AZACL2, and cPAC-1 cell lines were 23.8 μM, 95.8 nM, and 237 nM, for temsirolimus they were 34.6 μM, 11.5 μM, and 11.2 μM, and for everolims they were 36.6 μM, 33.4 μM, and 33.0 μM, respectively. Western blotting revealed PI3K/AKT/mTOR pathway activation and differential phosphorylation of mTOR signal-related proteins across the three PC cell lines. In xenograft mice injected with the AZACL1 and AZACL2 cell lines we showed that the AZD8055-treated group exhibited a significant reduction in tumor volume via the inhibition of tumor growth compared to the control group. Conclusions: These findings reveal that the PI3K/AKT/mTOR pathway plays a key role in canine PC and that AZD8055 may be a novel therapeutic agent for PC-bearing dogs. Full article

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (MTOR) pathway hyperactivation is seen in a multitude of malignancies. Due to the importance of this pathway in numerous critical cellular functions, preclinical and clinical investigations have aimed to target this pathway as an anti-cancer therapeutic strategy. This has led to the development of PI3K, AKT, and MTOR inhibitors for use in cancer patients, leading to multiple FDA approvals over the past decade. In this review, we outline therapeutic targets in PI3K/AKT/MTOR signaling in solid tumors, the current state of using inhibitors of this pathway to treat patients whose cancers possess activating mutations in PIK3CA, AKT1/2, or MTOR, and exciting new inhibitors that are entering clinical trials. Full article

Polycystic kidney disease (PKD), a ciliopathy caused primarily by mutations in the Pkd1 and Pkd2 genes, disrupts renal structure and function, leading to progressive renal failure. The primary cilium, a sensory organelle essential for cellular signaling, plays a pivotal role in maintaining renal function. Among its signaling components, G-protein-coupled receptors (GPCRs) within the cilium have gained significant attention for their localized functions and their contribution to PKD pathogenesis. Dysfunction of ciliary GPCR signaling alters key downstream pathways, including mammalian target of rapamycin (mTOR), cyclic adenosine monophosphate (cAMP), and calcium homeostasis, exacerbating cyst formation and disease progression. Additionally, interactions between ciliary GPCRs and PKD-associated proteins, such as Polycystin-1 (PC1) and Polycystin-2 (PC2), underline the complexity of PKD mechanisms. Recent advances highlight GPCRs as promising therapeutic targets for ciliopathies, including PKD. Emerging GPCR modulators and drugs in clinical trials show the potential to restore ciliary signaling and attenuate disease progression. This paper explores the physiological functions of ciliary GPCRs, their mechanistic links to PKD, and the therapeutic implications of targeting these receptors, offering insights into future research directions and therapeutic strategies for PKD. Full article

Skeletal muscle atrophy is one of the serious complications of diabetes, which increases the risk of frailty, falls, and mortality. However, interventions for muscle atrophy are limited, and research is needed regarding the treatment of muscle wasting. Recently, the bioconversion of natural products by lactic acid bacteria has been highlighted as a possibility to improve the bioavailability of active ingredients. This process also produces metabolites, which are key signaling mediators for a variety of physiological functions. This study investigated the effect of bioconverted guava leaf (Psidium guajava L., GL) by Lactobacillus plantarum on hyperglycemia-induced skeletal muscle atrophy in type 2 diabetes mellites (T2DM) mice. Diabetes was induced by a high-fat diet with a two-time streptozotocin (STZ) injection (60 mg/kg BW) in male C57BL/6J mice. After diabetes was induced (a fasting blood glucose level (FBG) ≥ 300 mg/dL), the mice were administered with GL (100 mg/kg/day) or bioconverted GL (FGL) (50 mg/kg/day) by oral gavage for 14 weeks. FGL contains different substances such as hydroxyl-isocaproic acid and hydroxyl-isovaleric acid compared to GLE itself, which have potential to prevent muscle degradation in T2DM mice. GL and FGL supplementation reduced the FBG level in T2DM mice. In addition, GL and FGL supplementation enhanced muscle strength, the skeletal muscle cross-sectional area, and ameliorated ubiquitin–proteasome system (UPS)-related pathways in T2DM mice. On the other hand, GLE supplementation ameliorated glucose tolerance demonstrated by oral glucose tolerance test and enhanced insulin signaling pathway. In addition, only FGL supplementation attenuated skeletal muscle inflammation and apoptosis with an improved mammalian target of the rapamycin (mTOR)-autophagy-related pathway. Although administered at a half dose of GLE, FGL demonstrated greater efficacy in regulating the expression of these molecular markers. The result suggests that even GL itself has anti-diabetic effects, and the functionality would be enhanced by the bioconversion of GL with L. Plantarum, which has an additive or/and a synergistic effect. Taken together, FGL could be used as a potential nutraceutical to attenuate muscle degradation by the inhibition of inflammation, the UPS, and the apoptosis pathway. Full article

Background: Chloroquine (CQ) has been extensively validated for its safety as an antimalarial drug. The treatment regimen combining CQ with 5-fluorouracil (5-FU) has demonstrated promising antitumor effects in both in vitro and animal models. However, the clinical application of this combination therapy still faces numerous challenges, primarily due to the unelucidated mechanistic underpinnings. Methods: We validated the synergistic effect of CQ in antitumor therapy using 5-fluorouracil and N-acetylcysteine. Subsequently, we employed lysosomal pH probes and inhibitors (5-BDBD and bafilomycin A1) to verify the mechanism of CQ in synergistic antitumor therapy. Finally, the therapeutic efficacy and underlying mechanisms of CQ were further confirmed through in vivo experiments. Results: Here, we found that CQ can inhibit the ATP-induced activation of mammalian target of rapamycin (mTOR), enhancing the inhibition of 5-FU on the proliferation and survival of tumors. Mechanistically, CQ affects the lysosomal pH value, leading to the inhibition of P2X4 receptor activity. The ATP-P2X4-mTOR axis is consequently disrupted, resulting in the weakened activation of mTOR. Conclusions: Our findings suggest that CQ may inhibit ATP-induced mTOR activation by suppressing P2X4 receptor signaling, thereby altering the apoptosis resistance of tumors. The combination of CQ and 5-FU represents a promising therapeutic strategy, particularly for mTOR-hyperactivated malignancies refractory to conventional chemotherapy. These findings not only advance our understanding of the mechanisms underlying CQ-based combination therapy but also highlight the therapeutic potential of pharmacologically targeting mTOR and its alternative pathways in combination chemotherapy regimens. Full article