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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
Moreover, insulin-induced AKT activation is crucial to modulate gene regulation via blocking the activity of FOXO transcription factors. There are four members of the FOXO family which include FOXO1, FOXO3, FOXO4, and FOXO6, where FOXO1 and FOXO3 are expressed in almost all tissues. AKT phosphorylates FOXO proteins at several serine residues (50) which facilitates the binding of FOXOs to proteins of the 14-3-3 family. This interaction leads to the nuclear exclusion of FOXO proteins and inhibition of their transcriptional activity (50). It has been suggested that the FOXO1 function is an important regulator of food intake and energy balance (51). While insulin inhibits FOXO1 activity and reduces food intake, active FOXO1 enhances food intake. FOXO6 is primarily expressed in the hippocampus of the brain and liver. It has been observed that upon whole-body deletion of FOXO6, although the mice exhibited normal learning behavior, they displayed impaired memory consolidation. In addition, through the process of stereotactic injection of viruses into the hippocampus of wild-type adult mice, it was revealed that FOXO6 activity in the hippocampus was important to promote memory consolidation (52, 53), indicating that insulin action can affect memory via FOXO6 regulation.
Mechanism of Action of Isotretinoin
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
FoxO1 also binds directly to the POMC promoter and negatively regulates its transcription. In addition, FoxO3a interacts with STAT3 and inhibits POMC promoter activity (52,53). Isotretinoin-induced upregulation of FoxO1 and FoxO3a may thus explain isotretinoin-mediated suppression of POMC-dependent pituitary gene expression, the precursor of ACTH. Isotretinoin-mediated upregulation of p53 attenuates androgen receptor (AR) gene expression (54). p53 and FoxO1 suppress AR expression and transactivation, respectively (55,56). This has been demonstrated in the skin of isotretinoin-treated acne patients, where isotretinoin has reduced AR expression as well as 5α-reductase activity in the skin, which has lost 80% of their ability to form 5α-dihydrotestosterone (57,58). In contrast, p53 deletion has activated AR signaling and restored c-MYC-induced differentiation in sebaceous glands (59). p53 is a negative regulator of thyroid hormone receptor-signaling pathways (60).
Dermatology
Published in Hilary McClafferty, Integrative Pediatrics, 2017
Emerging research supports the hypothesis that increased insulin-like growth factor-1 (IGF-1) correlates with acne. Elevated IGF-1 has been associated with hyperproliferative activity of the sebaceous follicle leading to clinical manifestation of acne. A simplified overview suggests that involvement of the metabolic transcription factor FoxO1, which is negatively regulated by IGF-1, effects gene expression that effects androgen signaling and subsequent proliferation of sebum production associated with clinical disease. FoxO1 is a negative regulator of the kinase mTORC1 which has been shown to have an important role in acne related to diet. It has been widely reported that a high glycemic load diet worsens acne, and modulates the activity of both free IGF-1 and free serum androgens whereas a low glycemic diet results in improvement of acne (Melnik 2015b). Milk aggravates acne by increasing both serum growth hormone and IGF-1 via the hepatic production of IGF-1 driven by amino acids in cow’s milk, not by simple transfer of the factors in the milk. The primary amino acid used in synthesis of IGF-1 is tryptophan, a primary component of the whey protein alpha lactoalbumin (Melnik, John, and Schmitz 2013).
Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention
Published in Renal Failure, 2023
Xiaoju Ma, Jingru Ma, Tian Leng, Zhongzhu Yuan, Tingting Hu, Qiuyan Liu, Tao Shen
FoxO1 is a class of highly conserved, ubiquitously expressed transcription factors that has implications for processes such as oxidative stress, inflammation, autophagy and apoptosis upon high glucose stimulation. PI3K/Akt signaling phosphorylates FoxO1 and deactivates it via inducing its nuclear translocation, the process of which is significant for the pathogenesis of diabetic kidney injury [30]. FoxO1 in renal tissue can alleviate the impaired glomerular filtration barrier and apoptosis resulted from the detachment of renal podocytes from the basement membrane because of abnormal glucose metabolism [31]. Early elevation of glucose can stimulate the TGF-β/Smad pathway to prevent the occurrence of kidney fibrosis in DKD [32]. The study of Ma et al. [33] also found that increased phosphorylation of FoxO1 decreased FoxO1 activity and autophagy in DKD animal models, resulting in exacerbation of kidney injury.
Identification of Potential Therapeutic Genes and Pathways in Phytoestrogen Emodin Treated Breast Cancer Cell Lines via Network Biology Approaches
Published in Nutrition and Cancer, 2022
Elif Sakalli-Tecim, Pembegul Uyar-Arpaci, N. Tulin Guray
Previously in MCF-7 cells, it was shown that, RNA interference mediated PI3K inhibition decreased phosphorylated AKT1, increased nuclear FOXO, suppressed CyclinD1 (CCND1) proteins and consequently resulted in cell cycle arrest at G1 phase where apoptosis was induced. FOXO1 suppression reversed apoptosis. It was also stated that CyclinD1 suppression was consistent with FOXO1 induction (39). In addition, Emodin decreased ERα protein levels and further decreased the protein expression of ER regulated CyclinD1 causing proliferation suppression in MCF-7 cells (3). Similarly, in another study, upon Emodin treatment MCF-7 cell growth was inhibited through decreasing AKT, BCL-2, CyclinD1 and protein expressions and cell cycle was inhibited in G0/G1 phase and further apoptosis was induced. It was stated that, suppressions of BCL-2 and CyclinD1 expressions was through ERα genomic pathway inhibition and suppression of AKT expression was through ERα nongenomic pathway inhibition (11).
Dysregulation of lncRNA-H19 in cardiometabolic diseases and the molecular mechanism involved : a systematic review
Published in Expert Review of Molecular Diagnostics, 2021
Ana Iris Hernández-Aguilar, Carlos Aldair Luciano-Villa, Vianet Argelia Tello-Flores, Fredy Omar Beltrán-Anaya, Ma Isabel Zubillaga-Guerrero, Eugenia Flores-Alfaro
Goyal et al. [79] reported that the downregulation of H19 expression promotes an increase in the expression of gluconeogenic genes via forkhead box O1 (FoxO1) and increased hepatic gluconeogenesis, contributing to increased glucose output. Later, in 2019, the same group of researchers reported similar results, noting that a decrease in H19 increases the levels of FoxO1, which is key in the regulation of hepatic gluconeogenesis. They also identified that during H19 inhibition, there is an elevated occupancy of p53 on the FoxO1 promoter that drives the transcriptional activation of FoxO1, which subsequently regulates gluconeogenesis. p53 has been implicated in the deregulated metabolic physiology during diabetes (Figure 3) [80]. These results oppose those obtained by Zhang et al. [81], who identified that liver-specific H19 overexpression promotes hepatic glucose production, hyperglycemia, and IR, while H19 depletion enhances insulin-dependent suppression of hepatic glucose production. The contradictory results may be due to the experimental model and the exposure conditions used in the different investigations. It is important to note that lncRNAs participate in different signaling pathways. Future research should clarify the role of H19 expression in insulin-resistant hepatocytes. However, recent research has indicated that H19 is associated with hepatic glucose production. Different levels of H19 expression involved in glucose metabolism have been described, as well as how they interact in the liver (Table 1).