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(A) Nuclear exclusion of FoxO proteins into the cytoplasm by growth factor signaling due to Akt kinase-mediated phosphorylation of nuclear FoxO proteins. (B) isotretinoin-mediated upregulation of FoxO expression as a secondary response of proapoptotic rAr-signaling. FoxOregulated genes are switched on. iGF-1, insulin-like growth factor-1; FGFs, fibroblast growth factors; Pi3K, phosphoinositol-3 kinase; Akt, Akt kinase (protein kinase B); FoxO, forkhead box class O transcription factor; ATrA, all-trans-retinoic acid; CrABP2, cellular retinoic acid binding protein-2; rAr, retinoic acid receptor.
Source publication
Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastom...
Contexts in source publication
Context 1
... DNA binding sequence TTG TTT AC. 14,19 Furthermore, FoxO proteins can interact with several other transcription factors like androgen receptor (AR) or β-catenin, therby modifying gene regulation. Central to the regulation of FoxO transcription factors is a shuttling system, which confines FoxO factors to either the nucleus or the cyto- sol ( Fig. 1). 14,15 Among other involved and less important kinases, shuttling of FoxOs requires protein phosphorylation of nuclear FoxOs by phosphoinositol-3-kinase (PI3K)-mediated activation of the serine/threonine kinase Akt (also known as protein kinase B, PKB). 11-14 Activated (phosphorylated) Akt translocates into the nucleus for FoxO ...
Context 2
... requires protein phosphorylation of nuclear FoxOs by phosphoinositol-3-kinase (PI3K)-mediated activation of the serine/threonine kinase Akt (also known as protein kinase B, PKB). 11-14 Activated (phosphorylated) Akt translocates into the nucleus for FoxO phosphorylation. Phosphorylated FoxOs leave the nucleus, thereby changing gene regulation (Fig. 1). Dysregulation of FoxO1 and its nuclear export by insulin, IGF-1, fibroblast growth factors (FGFs) or other growth factors modify- ing the activation of PI3K/Akt affect the transcriptional activity of key target genes and nuclear receptors involved in acne patho- genesis. Increased growth factor signaling is an endocrinological ...
Context 3
... critical role of FoxO1 in hepatic glucose and lipid metab- olism is well established and reviewed extensively elsewhere in reference 19. Under ordinary conditions, feeding stimulates insu- lin secretion from pancreatic β-cells, and FoxO1 in the liver is inhibited by insulin signal via IRS/PI3K/Akt cascade (Fig. 1). In fasting state, insulin signal is weak and FoxO1 is activated by translocation into the nuclei to trigger gluconeogenesis for glucose supply. Under insulin resistance conditions, however, hyperactive FoxO1 promotes gluconeogenesis in such an uncontrolled way that it leads to hyperglycemia. It is well known that isotretinoin impairs ...
Similar publications
Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. Isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastom...
Citations
... [5] Isotretinoin, an USA Food and Drug Administration (US FDA) approved drug, is known to improve severe nodulocystic acne. [6] The unifying concept of mechanism of isotretinoin action as hypothesized by Melnik stems from upregulation of expression of Forkhead box O transcription factor (FoxO1). [6] Increased growth factor signalling associated with the pubertal growth spurt activates phosphoinositol-3-kinase (PI3K)/Akt kinase resulting in nuclear deficiency of FoxO1 which in turn increases androgen This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ...
... [5] Isotretinoin, an USA Food and Drug Administration (US FDA) approved drug, is known to improve severe nodulocystic acne. [6] The unifying concept of mechanism of isotretinoin action as hypothesized by Melnik stems from upregulation of expression of Forkhead box O transcription factor (FoxO1). [6] Increased growth factor signalling associated with the pubertal growth spurt activates phosphoinositol-3-kinase (PI3K)/Akt kinase resulting in nuclear deficiency of FoxO1 which in turn increases androgen This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ...
Background:
Nodulocystic acne is a severe type of acne that is known to improve after treatment with isotretinoin. Melnik has hypothesized a unifying concept on the mechanism of acne pathogenesis involving altered expression of Forkhead box O transcription factor (FoxO1) and role of isotretinoin in improving acne via modulating this pathway.
Aim:
To evaluate the pathway proposed by Melnik in acne pathogenesis by analysing the difference in the expression of FoxO1, peroxisome proliferator-activated receptor (PPARγ), and androgen receptor (AR) between acne patients and non-acne controls and the effect of treatment with isotretinoin on change in expression of these genes in acne patients.
Results:
The gene expression of FoxO1 was non significantly higher in acne patients as compared to controls. After treatment with isotretinoin, a significant decrease in FoxO1 expression in acne patients at mRNA (P = 0.05) level was observed. There was a significant decrease in grade 3 positivity of FoxO1 at protein level (P = 0.0009). A decrease in androgen receptor positivity (P = 0.055) at protein level was also observed.
Conclusion:
Reduction in FoxO1 expression appears to be an important mechanism of action of isotretinoin in acne.
... It also increase levels of dermicidin (or proteolysis-inducing factor), an antimicrobial peptide of eccrine/sebaceous glands [10][11][12] . Meanwhile, it is suggested that isotretinoin may upregulate forkhead box class O (FoxO) transcription factors which may explain its unexplained actions 13 . The mean half-life of isotretinoin is 20 hours (ranges 7-39 hours). ...
The achievement of best outcome in rhinoplasty is very important for both of the patients and plastic surgeons. Since the skin characteristics (e.g. nasal thickness and sebaceous hypertrophy) has clear role on the result, many related interventions have been proposed in recent decades to gain an appropriate result. Accordingly, isotretinoin firstly introduced to treat some type of acne, has been suggested controversially to be used in rhinoplasty. Although the early uncertain studies implied on its side effects, the recent more powerful studies and evidences indicate that isotretinoin is remarkably effective to obtain proper outcome. Nevertheless, its prescription to patients need to be evaluated and personalized. More discussion on this regard are presented in the text.
... The therapeutic action of isotretinoin lies in the upregulation of the forkhead box class O transcription factors, which were deficient in acne vulgaris and causing pilosebaceous keratinocyte proliferation and sebaceous lipogenesis. [14,15] As treatment-naïve acne vulgaris patients already had a greater predisposition to develop meibomian gland dysfunction (MGD) and ocular surface damage in the first place, [16] ophthalmologists should recognize and provide treatment targeting blepharitis and associated dry eye, especially when these patients are prescribed systemic isotretinoin. [ Fig. 1a] b. ...
Dry eye disease encompasses a broad range of etiologies and disease subtypes which have similar clinical manifestations. Medications can cause dry eye disease or symptoms of dryness as a side effect by either interfering with the lacrimal gland or meibomian gland function, or both, and by other mechanisms that affect the ocular surface homeostasis. This is important to know and recognize as eliminating the offending medication can reverse the symptoms and, in many cases, prevent further deterioration of the ocular surface inflammation. This review focuses on drugs like systemic isotretinoin and taxanes, which cause meibomian gland dysfunction; immune checkpoint inhibitors that cause lacrimal gland dysfunction; gliptins and topical antiglaucoma medications that cause cicatrizing conjunctivitis; and epidermal growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, and belantamab mafodotin, which cause mucosal epitheliopathy. Many of these medications, particularly the newer anticancer agents, have only recently been introduced for clinical use, and knowledge and awareness of their ocular side effects are still evolving. This review aims to update ophthalmologists on the drug-induced causes of dry eye disease or symptoms of dryness, which is avoidable by discontinuation of the incriminating agent or can be mitigated by reducing the dose or frequency of usage.
... Notably, p53 maintains baseline expression of common tumour suppressor genes including FoxO1 [23]. Over the last 10 years, decreased FoxO1 expression has been linked to acne pathogenesis [11,16,53,103], whereas isotretinoin treatment increases FoxO1 expression in sebaceous glands of acne patients [53,104,105]. The p53 target gene FoxO1 is a nuclear co-suppressor of multiple transcription factors critically involved in acne pathogenesis such as AR [19], SREBF1 [106], PPARA [107] and is a crucial promoter of genes involved in apoptosis. ...
The transcriptomic regulation induced by isotretinoin ( 13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.
... Notably, p53 maintains baseline expression of common tumour suppressor genes including FoxO1 [23]. Over the last 10 years, decreased FoxO1 expression has been linked to acne pathogenesis [11,16,55,106], whereas isotretinoin treatment increases FoxO1 expression in sebaceous glands of acne patients [55,107,108]. The p53 target gene FoxO1 is a nuclear co-suppressor of multiple transcription factors critically involved in acne pathogenesis such as AR [19], SREBF1 [109], PPARA [110] and is a crucial promoter of genes involved in apoptosis [54]. ...
The transcriptomic regulation induced by isotretinoin ( 13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty -five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.
... Notably, p53 maintains baseline expression of common tumour suppressor genes including FoxO1 [23]. Over the last 10 years, decreased FoxO1 expression has been linked to acne pathogenesis [11,16,55,106], whereas isotretinoin treatment increases FoxO1 expression in sebaceous glands of acne patients [55,107,108]. The p53 target gene FoxO1 is a nuclear co-suppressor of multiple transcription factors critically involved in acne pathogenesis such as AR [19], SREBF1 [109], PPARA [110] and is a crucial promoter of genes involved in apoptosis [54]. ...
The transcriptomic regulation induced by isotretinoin ( 13-cis retinoic acid) is still a matter of debate as short-term exposures of immortalized sebocytes with isotretinoin produced conflicting results. Based on translational evidence, it has been hypothesized that oral isotretinoin treatment upregulates the expression of the transcription factor p53. Twenty-five patients suffering from acne vulgaris were treated with isotretinoin (0.6 mg/kg body weight) for 6 weeks. Biopsies from back skin were taken before and after isotretinoin treatment for the determination of p53 expression by immunohistochemical staining, quantification of p53 protein concentration by enzyme-linked immunosorbent assay and TP53 gene expression by quantitative reverse transcription real time PCR. Fifteen socio-demographically cross-matched healthy volunteers served as controls. Isotretinoin treatment significantly increased the nuclear expression of p53 in sebaceous glands of treated patients compared to pre-treatment levels and p53 levels of untreated controls. Furthermore, the p53 protein and gene expression significantly increased in the skin after treatment. The magnitude of p53 expression showed an inverse correlation to acne severity score and body mass index. Under clinical conditions, isotretinoin induced the expression of p53, which controls multiple transcription factors involved in the pathogenesis of acne vulgaris including FoxO1, androgen receptor and critical genes involved in the induction of autophagy and apoptosis. Increased p53-FoxO1 signalling enhanced by systemic isotretinoin treatment explains the underlying transcriptomic changes causing sebum suppression but also the adverse effects associated with systemic isotretinoin therapy.
... 8 In the studies of sebaceous gland, isotretinoin inhibits lipid synthesis in sebocyte, suppresses cell proliferation, and induces sebocyte apoptosis through upregulation of the transcription factor forkhead box protein O1 (FoxO1). 9,10 However, no studies have shown the role of FoxO1 in isotretinoin induced MGD, our study is to investigate the effect of isotretinoin treatment on the ocular surface, and the change of FoxO1 expression in the MG and to explore the role of the peroxisome proliferator-activated receptor γ (PPARγ ) pathway involved in it. We found that isotretinoin induced MGD is not FoXO1 mediated but through PPARγ pathway. ...
... 9 Isotretinoin treatment of acne by affecting the sebaceous glands through the isotretinoin→ATRA→RAR→FoxO1 pathway, and it is speculated that possibly isotretinoin affects the MG also via FoxO1. 10 In our study, the expression level did not significantly increase in the MG by systemic isotretinoin treatment. This may be related to the disease state. ...
Purpose:
To investigate the effects of isotretinoin on the ocular surface and to explore the possible mechanisms.
Methods:
Rats were treated with isotretinoin 20 mg/kg/d for five months and tested monthly for tear secretion, fluorescein staining, and infrared photography. After five months of treatment, tissues were harvested for routine staining to evaluate the morphological changes; and real-time polymerase chain reaction, Western blot, and immunohistochemistry to study the expression of associated genes and their products such as forkhead box protein O1 (FoxO1), forkhead box protein O3, peroxisome proliferator-activated receptor γ (PPARγ), adipose differentiation-related protein, elongation of very long chain fatty acids protein 4, fatty acid binding protein 4, matrix metalloproteinase-9, and interleukin-6.
Results:
Systemically, isotretinoin-treated rats have a significantly lower body weight that controls and apparent skin damage. Locally, although there was no alteration in tear secretion, a significant corneal involvement indicated by increased fluorescein staining scores, and also the contrast of meibomian gland was significantly reduced but no significant atrophy of the acinus was found. In addition, isotretinoin causes a decrease in conjunctival goblet cells. Furthermore, isotretinoin treatment did not cause the upregulation of FoxO1 and inflammation related genes but significantly suppressed the expression of PPARγ pathway.
Conclusions:
Isotretinoin does not cause a significant atrophy of the acinus and a significant change of FoxO1 expression in the meibomian gland. Isotretinoin causes meibomian gland dysfunction, affecting meibocyte differentiation and qualitative and quantitative changes in the meibum, through PPARγ pathway.
... In this way, FoxO1 connects nutrients availability to mTORC1-driven processes such as cell differentiation, hyperproliferation of acroinfundibular keratinocytes, hyperplasia of sebaceous glands, enhanced sebaceous lipogenesis, elevated BMI, and insulin resistance. By upregulating the FoxO1 transcription factor, the mTORC signal was engaged in the therapeutic response to isotretinoin or metformin treatment for acne [68][69][70]. Isotretinoin also increased p53 expression, which further upregulated FoxO1 and PTEN expression while suppressing the IGF-1 levels and androgen receptors, leading to decreased IGF-1/mTORC1 and androgen signaling (Figure 3) [68,71,72]. ...
The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation of cell proliferation, survival, and motility in response to availability of energy and nutrients as well as mitogens. The mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, and survival in many tissues. In the skin, dysregulation of PI3K/AKT/mTOR pathway may lead to severe pathological conditions characterized by uncontrolled proliferation and inflammation, including skin hyperproliferative as well as malignant diseases. Herein, we provide an update on the current knowledge regarding the pathogenic implication of the mTOR pathway in skin diseases with inflammatory features (such as psoriasis, atopic dermatitis, pemphigus, and acne) and malignant characteristics (such as cutaneous T cell lymphoma and melanoma) while we critically discuss current and future perspectives for therapeutic targeting of mTOR axis in clinical practice.
... 27,28 This materially mitigates the effect of androgens on the pilosebaceous unit and is considerably more effective than other sebum inhibitors, such as combination oral contraceptives and spironolactone. 29 Additionally, isotretinoin modifies keratinocyte maturation, differentiation and adhesion, resolving the follicular hyperkeratinization that is a hallmark of the disorder. 30 By reducing the food source for C. acnes and changing the microenvironment of the follicle, isotretinoin creates an inhospitable milieu for the bacterium, resulting in a log3 reduction, much more than is seen with oral antibiotics. ...
Background
Acne is a common, chronic inflammatory condition seen in nearly all teenagers and many adult females, with a global lifetime prevalence between 70-85%. While a majority of individuals with acne can be appropriately managed with a combination of topical therapies, oral antibiotics, and/or oral anti-androgens, 10-20% of individuals will have acne severe enough to warrant isotretinoin. When necessary, isotretinoin is highly effective and the only drug to offer the likelihood of a durable response.
Aims
To review the literature regarding known adverse effects of isotretinoin therapy and nuances during and post-isotretinoin therapy important to patient care.
Materials and Methods
A literature search was conducted for original, English-language case reports, case series, original studies and/or meta-analyses published between 1982-2021 on isotretinoin, related adverse effects, and laboratory assessment and treatment nuances during and after a course of isotretinoin.
Results
Adverse events categories include mucocutaneous (e.g., xerosis, cheilitis, epistaxis), ocular (xerophthalmia, nyctalopia, blepharitis, conjunctivitis), non-specific gastrointestinal, musculoskeletal (myalgia, pre-mature epiphyseal plate closure, DISH), neurologic (idiopathic intracranial hypertension, hearing loss, tinnitus). Most adverse events are mild, self-limiting, and/or resolve with drug discontinuation. Teratogenicity is of utmost concern especially given the risk of patient nonadherence to iPLEDGE precautions. Laboratory testing at baseline and after month 2 of therapy or upon reaching maximum daily dose may be sufficient. Utilizing creatine kinase and gamma-glutamyl transferase in lieu of aspartate aminotransferase and alanine aminotransferase may better assess hepatic function during treatment. Improved formulations of isotretinoin may improve absorption and decrease reliance on patient adherence to a high-fat diet. Dermabrasion and fully ablative laser procedures should be avoided in the immediate post-isotretinoin period.
Discussion
Although adverse events associated with isotretinoin therapy are common, a majority of side effects are limited, self-resolving (with completion of treatment course) without long-term implications, and/or easily managed. Unfortunately, the advent of the internet and social media has given a platform to misleading law-firm claims and medical pseudoscience inaccuracies that may frighten patients in need of treatment, ultimately delaying or even preventing therapy.
Conclusion
It is important that physicians are knowledgeable about the nuances of isotretinoin therapy, including efficacy, real potential adverse events, and appropriate laboratory monitoring. By honing this expertise, physicians may confidently counsel and guide patients through a course of isotretinoin to achieve a more permanent solution for their acne and improve their quality of life.
... It has been approved by FDA to be used as a treatment for acne in the United States since 1982 [3]. In terms of mechanism of action; INN is the only therapy that targets all major etiological factors implicated in acne [4]. This is achieved by influencing cell-cycle progression, cellular differentiation, cell survival, and apoptosis. ...
Aims: to evaluate changes in clinical periodontal parameters, salivary levels of MMP-8 and MMP-9, in individuals taking Isotretinoin (INN), and compare with individuals not taking the medication and to compare findings among different stages of periodontal disease and healthy periodontium. Material and methods: A case-control study was conducted with a total of 180 human adults divided into six groups. Clinical parameters, including pocket depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were measured at six sites per tooth. Whole unstimulated saliva samples were collected from all subjects to detect salivary level of MMP-8, MMP-9 using Enzyme-linked immunosorbent assay (ELISA). Data were analyzed using IBM SPSS Software. Kruskal Wallis test and Mann-Whitney U-tests were used to test any significant differences in any of the groups on all parameters. Pearson Chi-square test was used to compare the distribution of categorical responses across the study groups. All tests were compared at a significance level of 0.05. Results: In Gingivitis cases, INN group was found to have significantly less BOP (P < 0.0001). In Periodontitis cases, INN group showed significant difference in BOP (P < 0.0001). MMP-8 and MMP-9 were significantly lower among Periodontitis cases taking INN compared to the same group not taking the medication (P < 0.0001). Conclusion: INN assists in reducing clinical and biological signs of inflammation related to periodontal disease progression. INN may be a future additive medication to be further evaluated for treating periodontal disease.
