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The PI3K/AKT/FOXO signaling pathway. The PI3K/AKT pathway is the canonical pathway regulating transcriptional activity of FOXOs. Upon activation of GFR tyrosine kinases, PI3K becomes activated and generates PIP3 at the plasma membrane. PIP3 facilitates the phosphorylation of AKT by PDK1. Subsequently, phosphorylates nuclear FOXOs, facilitate nuclear export of FOXOs and simultaneously obstruct relocation into the nucleus. Upon accumulation in the nucleus FOXOs can bind various transcription-cofactors and regulate the transcription of genes involved in the cell proliferation, growth, survival, cell cycle, apoptosis and metabolism, etc. Pathway activity is negatively regulated by PTEN feedback loop
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Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway play a central role in multiple cellular functions such as cell proliferation and survival. The forkhead box O (FOXO) transcription factors are negatively regulated by the PI3K/AKT signaling pathway and considered to have inhibitory effect on cell proliferation. Psori...
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Background
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Citations
... Subsequently, Akt, a central mediator of the PI3K pathway, is recruited and phosphorylated. Once activated, Akt phosphorylates a series of downstream targets, ultimately mediating different functions in follicular cells, including glycogen synthesis, cell survival, glycolysis, and glucose transporter 4 (GLUT4)-mediated uptake of glucose [87,88] . ...
The female ovaries are critical for follicle growth and development in the process known as "folliculogenesis". This complex process is regulated by various factors, among which the microenvironment around follicles appears to be crucial. According to previous studies, folliculogenesis is an energy-demanding process. In fact, well-balanced follicular energy metabolism is associated with ovarian function and female fertility. Consequently, glucose metabolism has been widely described as the main source of energy during folliculogenesis. Generally, the follicular glucose metabolism profiles change dynamically during follicular development. Metabolic abnormalities during folliculogenesis are associated with aging, primary ovarian insufficiency, and polycystic ovary syndrome, thereby leading to subfertility and infertility in females. The signaling pathways in follicles appear to form a link between glucose metabolism and folliculogenesis. Therefore, a better understanding of glucose metabolism dynamics at different stages of folliculogenesis and the associated signaling pathways will provide potential implications for follicle developmental competence. This review aimed to describe variations in glucose metabolism at different stages of folliculogenesis, provide new insights into glucose metabolic disorder-related diseases, and specifically discuss two major signaling pathways that regulate glucose metabolism during folliculogenesis: phosphatidylinositol 3-kinase, protein kinase B (PI3K-PKB/AKT), and AMP-activated protein kinase (AMPK) signaling pathways.
... The forkhead box protein O4 (FOXO4) is highly conserved in evolution, has the same domain as the FOX family molecules, and plays a variety of biological functions in organisms. As a downstream target, related studies have reported that FOXO is adversely modulated by the PI3K/AKT signal transduction pathway, and implicated in cell cycle arrest, DNA damage repair, and apoptosis [38]. Additionally, numeric studies have demonstrated that the binding of Bcl-6 to Bcl-XL can inhibit its expression, while the specific binding of FOXO4 to the Bcl-6 promoter can increase the expression of Bcl-6, thereby triggering apoptosis [39]. ...
Background
Accumulating evidence indicates that aberrant non-SMC condensin II complex subunit D3 (NCAPD3) is associated with carcinogenesis of various cancers. Nevertheless, the biological role of NCAPD3 in the pathogenesis of non-small cell lung cancer (NSCLC) remains unclear.
Methods
Immunohistochemistry and Western blot were performed to assess NCAPD3 expression in NSCLC tissues and cell lines. The ability of cell proliferation, invasion, and migration was evaluated by CCK-8 assays, EdU assays, Transwell assays, and scratch wound healing assays. Flow cytometry was performed to verify the cell cycle and apoptosis. RNA-sequence and rescue experiment were performed to reveal the underlying mechanisms.
Results
The results showed that the expression of NCAPD3 was significantly elevated in NSCLC tissues. High NCAPD3 expression in NSCLC patients was substantially associated with a worse prognosis. Functionally, knockdown of NCAPD3 resulted in cell apoptosis and cell cycle arrest in NSCLC cells as well as a significant inhibition of proliferation, invasion, and migration. Furthermore, RNA-sequencing analysis suggested that NCAPD3 contributes to NSCLC carcinogenesis by regulating PI3K/Akt/FOXO4 pathway. Insulin-like growth factors-1 (IGF-1), an activator of PI3K/Akt signaling pathway, could reverse NCAPD3 silence-mediated proliferation inhibition and apoptosis in NSCLC cells.
Conclusion
NCAPD3 suppresses apoptosis and promotes cell proliferation via the PI3K/Akt/FOXO4 signaling pathway, suggesting a potential use for NCAPD3 inhibitors as NSCLC therapeutics.
... Our prediction results indicated that the bioactive natural products (kaempferol, taxifolin, eriodictyol, luteolin, aloe-emodin, and quercetin) in CT act on the FoxO signaling pathway, endocrine resistance, and estrogen signaling pathways. The PI3K/AKT signaling pathway negatively regulates FoxO transcription factors, and the activation of FoxO transcription factors in the liver triggers hyperglycemia [54,55]; endocrine resistance leads to an imbalance between insulin secretion and sensitivity in target tissues, causing metabolic dysregulation and elevated blood sugar [56]. Estrogen signaling pathways regulate glucose metabolism through downstream pathways, including glucose transporter receptor α and insulin release [57,58]. ...
Coreopsis tinctoria (CT) improves energy metabolism. However, the role of CT in alleviating obesity-induced hyperglycemia by targeting the liver remains unknown. Therefore, this article aims to explore the mechanism by which CT improves energy metabolism and resists hyperglycemia. The water and ethanol extracts of CT were administered to high-fat diet-induced (HFD) obese C57BL/6J mice at a dose of 4 g/kg.bw (low-dose water extract, WL; low-dose ethanol extract, EL) or 10 g/kg.bw (high-dose water extract, WH; high-dose ethanol extract, EH). Mice that consumed a maintenance diet (LFD) were included as blank controls. Network pharmacology, liquid chromatography-mass spectrometry (LC-MS), L02 cell cultivation, and liver transcriptomics were used to examine the mechanism and functional components of CT against obesity-induced hyperglycemia. The results indicated that WL significantly (p < 0.05) alleviated glucose intolerance and insulin resistance in obesity-induced hyperglycemia. Kaempferol is the main active compound of CT, which demonstrated significant (p < 0.05) anti-hyperglycemic effects in obese mice and L02 cells. Finally, kaempferol significantly (p < 0.05; fold change >1.2) shifted the genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the mitogen-activated protein kinase (MAPK) pathways toward the trend of LFD, indicating that it exerts an anti-hyperglycemic effect through these molecular mechanisms. Overall, oral intake of CT lowers blood glucose and improves insulin sensitivity in mice with obesity-induced hyperglycemia. Kaempferol is the primary functional component of CT.
... To investigate the cytotoxicity of DHM, HaCaT cells were treated with various concentrations of DHM (25,50,100,200, and 400 µM). Cell viability was assessed at 24, 48, and 72 h post-treatment using the cell count kit-8 (CCK-8) assay, with untreated cells serving as controls. ...
... For instance, appropriate levels of Akt activation in keratinocytes have been suggested to promote growth arrest and differentiation, which facilitates barrier formation. However, excessive activation of Akt signaling has been reported in relation to excessive proliferation and defective keratinocyte differentiation, which leads to a decrease in the production of barrier proteins [24][25][26]. In our study, we observed that treatment with DHM caused a modest increase in Akt phosphorylation, which seemed to be sufficient, but not excessive, to elevate involucrin expression. ...
... HaCaT cells were cultured in 96-well plates for 24 h. The cells were then exposed to either DHM (25,50,100,200, and 400 µM) or the vehicle control (dimethyl sulfoxide; DMSO; Sigma-Aldrich). After the treatment for 24, 48, and 72 h, the CCK-8 solution was added to each well, and the plates were incubated for 2 h. ...
The epidermis serves as a protective barrier against external threats and is primarily composed of keratinocytes, which ultimately form corneocytes. Involucrin, a protein integral to the cornified envelope, plays a pivotal role in preserving the functional integrity of the skin barrier. Previous studies have shown that Akt plays an important role in keratinocyte differentiation and skin barrier development. This study investigated whether dihydromyrcenol (DHM), a plant-derived terpene, could increase involucrin production in keratinocytes and sought to elucidate the possible underlying mechanisms. To accomplish this objective, we assessed the alterations in involucrin by DHM through quantitative PCR and Western blot on the HaCaT cell line. The changes in the promoter levels were investigated using luciferase assays. Furthermore, upstream mechanisms were explored through the use of siRNA and inhibitors. To strengthen our findings, the results were subsequently validated in primary cells and 3D skin equivalents. DHM significantly increased involucrin mRNA and protein levels in a concentration-dependent manner. In addition, the Fyn-Akt signaling pathway was found to be required for DHM-induced involucrin expression, as inhibition of Fyn or Akt blocked the increase in involucrin mRNA induced by DHM. The transcription factor Sp1, which is recognized as one of the transcription factors for involucrin, was observed to be activated in response to DHM treatment. Moreover, DHM increased epidermal thickness in a 3D human skin model. These findings suggest that the modulation of involucrin expression with DHM could improve skin barrier function and highlight the importance of manipulating the Akt pathway to achieve this improvement.
... It is a key molecule in the signal network of cell kinases and regulates a variety of cell life activities, such as glucose metabolism, apoptosis, cell proliferation and differentiation, cell migration and so on 18, 19,38 . Akt is the central node of many signal pathways, which transmits the signals of upstream regulatory proteins to downstream effector molecules including mTOR, FOXO1, GSK3β and so on [39][40][41] . However, it has not been reported whether SLIT3 can regulate the activity of Akt in SCAP. ...
The odontogenic differentiation of Stem cells from apical papilla (SCAP) is regulated by many extracellular matrix proteins, which plays a crucial role in dentin formation and regeneration. Extracellular matrix protein SLIT3, a classical axon guidance molecule, can link bone resorption to formation as clastokine. However, there is little information about SLIT3 in odontogenesis. Therefore, our study is aimed to explore the effects and possible mechanism of SLIT3 on the proliferation and differentiation of SCAP. Through Immunohistochemical staining and re-analysis of single-cell RNA sequencing and microarray datasets, we found that SLIT3 was expressed in the dental papilla and odontoblast layer of the developing molar tooth of mice. Real time polymerase chain reaction (RT-PCR) and Western blot assays also revealed an increased expression of SLIT3 during the odontogenic differentiation of SCAP. Afterwards, SLIT3 siRNA was used to knockdown SLIT3 and recombinant human SLIT3 (rhSLIT3) protein was used to treat SCAP. Cell Counting Kit-8 assays (CCK8) assays showed SLIT3 promoted proliferation of SCAP. Alkaline phosphatase (ALP) staining and Alizarin red staining were decreased/increased accordingly. Odontogenic markers DMP-1 and DSPP were also down-regulated/up-regulated. In addition, p-Akt and p-GSK3β levels were increased in rhSLIT3-treated SCAP and the movement into cell nucleus of β-catenin was promoted. The effect of SLIT3 was canceled after treatment with the inhibitor of Akt/Wnt/β-catenin signaling pathway. Taken together, our data show that SLIT3 could promote the proliferation and odontogenic differentiation of SCAP by activating Akt/Wnt/β-catenin signaling pathway.
... Several pathways in which FoxO might be involved were also identified based on DEG analysis, including the mTOR signaling pathway, MAPK signaling pathway, Wnt signaling pathway, Toll and Imd signaling pathways, insect hormone biosynthesis, autophagy, and apoptosis ( Figure 5). These aforementioned pathways all have been suggested to play important roles in insect growth and development (Zeng et al., 2017;Zhang and Zhang, 2019;Hughson et al., 2021). For example, alphaketoglutarate (AKG) would extend Drosophila lifespan by inhibiting the mTOR pathway (Su et al., 2019), whereas the development of Drosophila larvae was altered through the MAPK signaling pathway at the condition of ancestral dietary change (Towarnicki et al., 2022). ...
Forkhead box O (FoxO), a key transcription factor in many species, participates in numerous physiological and pathological processes of organisms through a variety of signaling pathways. In the present study, we established DsFoxO knockout ( DsFoxO -KO) strain using CRISPR/Cas9, and the influence on development and fecundity of mutant strain were evaluated. To clarify the corresponding mechanism, a transcriptome analysis was conducted subsequently. The results showed that the survival rates of the DsFoxO -KO strainin larval, pupal, and adult stages were all significantly lower than those of control. The duration of the pupal stage was similar between the two strains; however, durations of egg, larva, adult preoviposition period (APOP), and total APOP (TPOP) in the DsFoxO -KO strain were all significantly longer compared to those of the control strain. The fecundity of the DsFoxO -KO strain was 20.31 eggs/female, which was significantly lower than that of the control strain (430.47 eggs/female). With the transcrip tome analysis, 612 differentially expressed genes (DEGs) were identified. Following COG and GO analyses, we found that most of the DEGs were associated with the metabolic process. According to the KEGG database, the mTOR signaling, MAPK signaling, Wnt sign aling, and Toll and Imd signaling pathways; insect hormone biosynthesis; autophagy; and apoptosis were altered in the DsFoxO -KO strain. These results demonstrated that knockout of DsFoxO in D. suzukii significantly influenced its development and fecundity, while transcriptome analysis provided insights to explore the corresponding molecular mechanism. These findings highlighted the critical role of FoxO in D. suzukii and might contribute to the development of novel management strategies for these flies in the future.
... SX phytoconstituents may have a role in controlling these CCs, thereby reducing the severity of PSO. Moreover, PSO is directly associated with tyrosine kinase, protein serine/threonine kinase, and histone kinase activities that are mainly enriched in MFs (Nibbering et al., 1997;Zhang and Zhang, 2019). SX phytoconstituents might play a possible role by targeting these MFs and treating PSO. ...
Solanum xanthocarpum (SX) has been used to treat a variety of diseases, including skin disorders like psoriasis (PSO). SX possesses many pharmacological activities of anti-inflammatory, anti-cancer, immunosuppressive, and healing qualities. However, the multi-target mechanism of SX on PSO still needs clarity. Materials and methods: The Indian Medicinal Plants, Phytochemicals and Therapeutics (IMPPAT) database and the Swiss Target Prediction online tool were used to find the active phytochemical components and their associated target proteins. OMIM and GeneCards databases were used to extract PSO-related targets. A Venn diagram analysis determined the common targets of SX against PSO. Subsequently, the protein–protein interaction (PPI) network and core PPI target analysis were carried out using the STRING network and Cytoscape software. Also, utilising the online Metascape and bioinformatics platform tool, a pathway enrichment analysis of common targets using the Kyoto Encyclopaedia of Genes and Genome (KEGG) and Gene Ontology (GO) databases was conducted to verify the role of targets in biological processes, cellular components and molecular functions with respect to KEGG pathways. Lastly, molecular docking simulations were performed to validate the strong affinity between components of SX and key target receptors. Results: According to the IMPPAT Database information, 8 active SX against PSO components were active. According to the PPI network and core targets study, the main targets against PSO were EGFR, SRC, STAT3, ERBB2, PTK2, SYK, EP300, CBL, TP53, and AR. Moreover, molecular docking simulations verified the binding interaction of phytochemical SX components with their PSO targets. Last but not least, enrichment analysis showed that SX is involved in several biological processes, including peptidyl-tyrosine phosphorylation, peptidyl-tyrosine modification, and peptidyl-serine modification. The relevant KEGG signalling pathways are the PI3K-AKT signalling pathway, the EGFR tyrosine kinase inhibitor resistance pathway, and the MAPK signalling pathway. Conclusion: The network pharmacology technique, which is based on data interpretation and molecular docking simulation techniques, has proven the multi-target function of SX phytoconstituents.
... 9-11 Furthermore, some reports attempted to introduce system biology into the efficacy prediction and mechanism analysis of complex plant extracts, and broadened their applications in psoriasis treatment, UV protection and other dermatological fields. 12,13 Multiple biological processes related to melanin are involved in skin pigmentation, such as synthesis, transport, and metabolism of melanin. Each stage may involve the transduction of external signals, regulation of melanin synthesis limiting enzymes, and initiation of melanin signaling cascade. ...
... It is also connected with upstream regulators such as chemokine receptor-9, TLRs, and IL-6 and plays crucial roles in cell growth, proliferation, survival, migration, and differentiation. Therefore, it has emerged as a central regulator of tissue and organ homeostasis and a key driver of immune-mediated dermatoses [62]. ...
... PI3Ks are characterized as a family of lipid kinases capable of phosphorylating the inositol ring 3 -OH group in inositol phospholipids. The PI3K consists of three distinct classes of regulatory, functional, and structural molecules, with class I PI3K being the most extensively studied [62][63][64][65]. ...
... Furthermore, Akt indirectly induces several anti-apoptotic genes by affecting NF-κB [6]. Akt also negatively regulates the tuberous sclerosis complex (TSC) activity [62]. The TSC1/2 complex acts as a GTPase-activating protein (GAP) for Rheb (Ras homolog enriched in the brain) small GTPase [5] GTP-bound Rheb directly binds to and activates mTORC1 [5]. ...
The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.
... Metabolic and nutrient sensing pathways can coordinate immune cells' and keratinocytes' activation and differentiation in psoriatic skin (Cibrian et al., 2020a). The phosphoinositide 3-kinase (PI3K)/Akt/ mTOR cascade acts as a critical mediator of inflammation and master sensor of the metabolic status at the intracellular level (Zhang and Zhang, 2019;Pålsson-McDermott and O'Neill, 2020). MTOR, the master sensor of nutrients and growth factors, plays a central role between the extracellular nutrient status triggers and the promotion of cell differentiation and proliferation. ...
... Moreover, overexpression of the PI3K/Akt pathway leads to the translocation of the phosphorylated FOXO to the cytoplasm, thereby preventing it from exerting its role as a cell cycle regulator (Buerger, 2018). In addition, beyond its role in T cell proliferation and function, mTOR is upregulated in keratinocytes in response to the pro-inflammatory cytokines and growth factors, promoting cell proliferation and defective differentiation (Zhang and Zhang, 2019). ...
Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn’s disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.
