Search

The systemic treatment of psoriasis has changed markedly with the introduction of many novel drugs. However, clinicians have had limited opportunities to evaluate these new therapies. One of the new drugs, apremilast (a phosphodiesterase‐4 inhibitor), was approved in 2017 in Japan. We previously reported oral treatment for psoriasis before the introduction of apremilast. In this study, we investigated the impact of apremilast on oral medication for psoriasis by comparing data obtained before and after apremilast became available. This retrospective study enrolled patients who visited the Department of Dermatology, Fukuoka University Hospital, who were diagnosed with psoriasis and treated with anti‐psoriatic oral medications. Patients were divided into two groups: Group 1, who first visited our clinic between January 2010 and March 2016; and Group 2, who first visited our clinic between April 2016 and March 2022. The information collected included patient demographics, drug use (apremilast, cyclosporine, methotrexate, and etretinate), and treatment duration. In Group 1 (n = 149 patients), cyclosporine, methotrexate, and etretinate were prescribed to 59.1%, 16.6%, and 24.3% of the patients, respectively. In Group 2 (n = 129 patients), apremilast was prescribed to 52.5% of patients, while the number of prescriptions for cyclosporine and etretinate had decreased to 17.1% and 8.3%, respectively. The number of methotrexate prescriptions did not change significantly. Apremilast, methotrexate, and etretinate had longer continuation rates than cyclosporine in Group 2. In conclusion, apremilast replaced cyclosporine and etretinate mainly because of its better safety profile, whereas methotrexate remained in constant demand in both eras. New oral treatments for psoriasis, such as tyrosine kinase‐2 inhibitors, are now in the pipeline, and our data will serve as a control for oral anti‐psoriatic medicine before the coming era. [ABSTRACT FROM AUTHOR]

Background: Lichen planus is an inflammatory disease that affects the skin, the oral mucosa, or both.  Generalized cutaneous lichen planus may pose a therapeutic challenge for clinicians if the condition persists or flares after topical or systemic corticosteroid therapy.Purpose: Acitretin, a systemic retinoid, can be considered a potential second-line treatment for patients with generalized cutaneous lichen planus.  Herein, we describe a postmenopausal woman with generalized cutaneous lichen planus who was successfully treated with acitretin.Methods: A 58-year-old woman presented with generalized cutaneous lichen planus involving her upper and lower extremities as well as her lower back.  After failing corticosteroid therapy, she was started on acitretin 20 mg/day, which was later increased to 30 mg/day.  To review the literature on the use of acitretin in cutaneous lichen planus, we used the PubMed search engine and searched for the terms “acitretin” and “cutaneous lichen planus.”Results: Our patient had complete resolution of pruritus within one week of initiating acitretin 20 mg/day.  After an increase in dose to 30 mg/day, the cutaneous lesions completely resolved over a 3-month period.  There was no recurrence of disease as acitretin was tapered and discontinued.Conclusion: Generalized cutaneous lichen planus may pose a therapeutic challenge for the symptomatic relief of skin lesions.  Topical and systemic corticosteroids are first-line treatments.  In patients who fail corticosteroids, relapse after corticosteroid therapy, or have contraindications to corticosteroids, acitretin may be considered a potential second-line therapy.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

Cutaneous-type adult T-cell leukemia-lymphoma is treated with antiviral or skin-directed therapy. Medications that are used to treat skin lesions of cutaneous T-cell lymphomas are also used for the cutaneous-type adult T-cell leukemia-lymphoma. Etretinate, a synthetic retinoid, has been used for treating cutaneous T-cell lymphomas; however, its clinical effectiveness for the treatment of cutaneous-type adult T-cell leukemia-lymphoma has not been fully studied. We conducted a retrospective assessment of the efficacy and safety of etretinate in 9 patients with cutaneous-type adult T-cell leukemia-lymphoma. Complete and partial responses to etretinate were observed in 1 and 7 patients, respectively. Among the responders, remission was maintained for more than 6 years in 2 patients. These results suggest that etretinate is a promising treatment option for cutaneous-type adult T-cell leukemia-lymphoma.

Background: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate., Objective: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments., Methods: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016-31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants' Dermatitis Quality of Life Index., Results: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS., Conclusion: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment., Competing Interests: Conflicts of interest The authors have no conflict of interest to declare., (Copyright © 2023. Published by Elsevier B.V.)

The article discusses case study of a 50-year-old man with palmoplantar psoriasis of 7 years' duration with medical history of mild hyperlipidemia treated with atorvastatin. It is evident that palmoplantar psoriasis is a debilitating dermatosis unresponsive to many modalities. It is evident that Acitretin, active metabolite of etretinate, is commonly used for treating palmoplantar psoriasis and in this case 90% improvement has been witnessed by apremilast and acitretin combination therapy.

The article presents case study of few members of a family involving 60‑year‑old male and his 31‑year‑old daughter diagnosed with Bazex‑Dupré‑Christol syndrome which is characterized by triad of congenital hypotrichosis, follicular atrophoderma and the development of basal cell carcinoma. Topics include information on genetic inheritance of the syndrome; use of retinoid acid and etretinate for tumor prevention; and observation of nuclear hyperchromasia and scant cytoplasm in tumor cells.

Summary: Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44‐year‐old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low‐dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large. [ABSTRACT FROM AUTHOR]

There are several treatment methods for localized scleroderma, but treatment is difficult when the lesion is widely distributed. We encountered a case who was treated successfully with etretinate, a vitamin A derivative. The usefulness of this agent is discussed.

Harlequin ichthyosis ( HI) is the most severe form of autosomal recessive congenital ichthyosis, with a high mortality rate. Recent advances in neonatal care and the early administration of retinoids have improved the survival rate of HI. Here, we present a case of HI who was successfully treated with early administration of etretinate and showed good prognosis. Next-generation sequencing identified novel mutations of the ATP-binding cassette subfamily A member 12 gene ( ABCA12), c.5884+4_+5del AA and c.7239G>A, which caused skipping of exons 39 and 48, respectively. Transcripts with exon 48 skipping, which cause a deletion in the second ATP-binding cassette of ABCA12, were dominantly expressed in the skin. Besides the early administration of etretinate, the differential expression of the mutant protein with limited segmental deletion of ABCA12 may be related to the favorable outcome of our patient. [ABSTRACT FROM AUTHOR]

Systemic sclerosis and morphea are connective tissue diseases characterized by tightening, thickening, and hardening of the skin, leading to significant morbidity. Unfortunately, current treatment options have limited efficacy for many patients. Cutaneous manifestations of these diseases arise from excess collagen deposition and fibrosis in the skin, through pathogenic mechanisms which have yet to be extensively detailed at the causal immune and cellular levels. Research elucidating the mechanism of action of retinoic acid on collagen production in the skin and case series highlighting the success of retinoic acid on the skin manifestations of systemic sclerosis and on morphea demonstrate its promise as a treatment. Herein they will briefly review the treatment options for both systemic sclerosis and morphea, and will discuss the potential of retinoic acid as a therapy and the supporting evidence from the literature, highlighting the previously published basic science and clinical studies investigating the role of retinoic acid in the treatment of sclerotic skin diseases. [ABSTRACT FROM AUTHOR]

Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory keratosis that is clinically characterized by gradually developing reddish or orange extending plaques and keratotic follicular papules. In pediatric patients, we frequently hesitate to administer certain medications for treatment of PRP, specifically etretinate, systemic corticosteroids, and biologics recommended by previous studies. Although administration of high-dose vitamin A was described in a previous textbook of dermatology, details about the lower limits and treatment periods were not provided. We presented a pediatric case of PRP that was successfully controlled with minimum dosage of systemic vitamin A in the literature. Before and 14 days after beginning the therapy, both vitamin A levels of peripheral blood were within the normal range. We considered that the clinical efficacy may not be due to a supplementary effect of vitamin A, but to a pharmacological action because serum vitamin A was within the normal limits during the therapy.

Background: We recently demonstrated that the vitamin A derivative etretinate was clinically effective in the treatment of skin disorders in patients with systemic sclerosis (SSc). The aim of the present study is to investigate whether the oral treatment with etretinate improves sclerosis in bleomycin (BLM)-induced sclerotic skin mice. Methods: BLM-induced sclerotic skin mice were treated orally with 10 mg/kg etretinate for 1 to 28 days. One control group received only the vehicle, 50 μl peanut oil, while another group received no agents. BLM-treated skin was removed and dermal thickness was measured histologically. Histopathological observation and TUNEL assay were also studied. Messenger RNA (mRNA) ratios for procollagen α 1 (I) chain to β actin from etretinate-treated and control mice were quantified at 1, 6, 14, and 28 days post-treatment, using quantitative RT-PCRs. Results: There was a significant decrease in mean dermal thickness (P < 0.05) and changes in collagen bundles in the etretinate-treated mice group for a 28-day period compared to control groups. TUNEL assay showed that the density of TUNEL-positive cells in the dermis of etretinate-treated mice for a 14-day period was significantly increased (P < 0.05). The ratio of procollagen α 1 (I) chain to β actin mRNA from etretinate-treated mice for a 1-day period decreased significantly compared to that of the control mice, but the ratio from etretinate-treated mice for a 14-day period increased significantly (P < 0.05). Conclusions: Etretinate improved BLM-induced scleroderma. These results suggest that etretinate can be applied to the treatment of SSc skin disorders.

The present report describes the condition in a three day old male child with bilateral ,linear, hyperpigmented and hyperkeratotic verrucous plaques and patchy alopecia over scalpe without any nail and skeletal abnormalities. It was suggestive of ichthyosis hystrix type of epidermal nevus,and is being reported in view of the rarity of this condition.

This cross sectional study was carried out between 1993 to 1998 at Razi Skin Hospital, the affiliated Dermatology Department of Tehran University of Medical Sciences. Eight hundred patients receiving etretinate for various skin diseases took part in this study. Among them, 457 patients with first admission to dermatologic clinic who had at least four regular sequential visits and responding to our questionnaire were selected to enter the study for evaluating acute toxicity of etretinate. Cheilitis with a frequency of 88 percent was the most frequent side effect. Hair loss (22.97%), dry mouth with thirst (15.09%), dryness of mucous membranes (13.12%), xerosis with pruritus (11.15%), nose bleeding (8.31%), paronychia (5.47%), facial dermatitis (3.06%), conjunctivitis (2.84%) and in addition to mucocutaneous ones, chills (2.63%), headache (2.19%), mental depression (2.19%), urinary frequency (1.53%) and papilledema (0.44%) were among the other observed toxicities, The relationship between mucocutaneous side effect with dosage of etretinate, sex and, age of the patients was evaluated. The association between mucoctaneous toxicities and sex was significant, sex and, age of the patients was evaluated. The association between mucocutaneous toxicities and sex was significant (P

Se presentó 1 caso de pitiriasis rubra pilaris eritrodérmica de 10 años de evolución en 1 paciente de 74 años de edad. Se observó que la enfermedad cutánea se asoció con artritis reumatoidea lo que hizo pensar a los autores en el posible papel etiológico de los factores inmunológicos en la pitiriasis rubra pilaris. Durante su evolución también se presentó un carcinoma papilar de vejiga, queratosis seborreicas múltiples, nódulo laríngeo benigno, carcinomas basales y un queratoacantoma. Se impuso tratamiento con methotrexate, pero no resultó satisfactorio para su PRP. Se obtuvo una buena respuesta con el etretinatoThe case of a 74-year-old patient with pityriasis rubra pilaris of 10 years of evolution was presented. It was observed that the skin disease was associated with rheumatoid arthritis, which made the authors think about the possible etiologic role played by the immunological factors in pityriasis rubra pilaris. A bladder papillary carcinoma, mutiple seborrheic keratosis, a laryngeal bening tumor, basal carcinomas and a keratoacanthoma appeared during its evolution. The patient received treatment with methotrexate, but it was not successful for its PRP. A good response was observed with etretinate

Punctate palmoplantar keratoderma type 1 ( PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss-of-function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis-based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame-shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low-dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1. [ABSTRACT FROM AUTHOR]

Lichen planus is an immune, infl ammatory reaction with characteristic clinical and histological lesions. It is a benign disorder, often chronic or recurrent, characterized by fl at-topped, pink to purple, shiny pruritic polygonal papules on the skin, or milky white reticular papules on the visible mucous membranes. Hypertrophic lichen planus is a chronic form of lichen planus with marked epidermal hyperplasia and intense pruritus. It is characterized by symmetrical hypertrophic plaques, usually located on the pretibial or perimalleolar regions. Lesions are often resistant to treatment. This paper presents a patient with a giant form of verrucous lichen planus on the lower extremities, with a chronic course and resistance to various forms of therapy (keratolytics, local and intralesional corticosteroids, radiotherapy, systemic antibiotics, cryotherapy). Significant improvement was seen after 8-month treatment with etretinate (initial dose of 75 mg per day, with progressive reduction to 10 mg per day). Etretinate therapy resulted in a significant regression of the disease. [ABSTRACT FROM AUTHOR]

Acitretin, an active metabolite of etretinate, is the most widely used systemic retinoid in the treatment of psoriasis. There are several unique characteristics of this drug, which set it apart from other options in the therapeutic armamentarium of psoriasis. It is highly efficacious as monotherapy in some specific clinical subtypes of psoriasis. It has dose-sparing effects when used as combination therapy with conventional systemic drugs as well as the biologics. It is a good option for long-term maintenance therapy. Side effects are common but usually mild and can be managed by its proper dosing and monitoring. With appropriate patient selection, gradual dose escalation, and patient counseling, we can deliver good results in psoriasis with this useful drug. This review gives a comprehensive recount of acitretin use in the present era of biologics in psoriasis. [ABSTRACT FROM AUTHOR]

Infantile generalized pustular psoriasis is a rare form of psoriasis and the best treatment is controversial. We experienced a 2-year-old female with erythema on her neck and axilla starting at 3 months of age. She presented with recurrent annular and geographic scaly erythema with a few pustules on the neck, precordium and axilla, but no fever. The histopathology revealed subcorneal neutrophilic infiltration and microabscesses without Kogoj's spongiform pustules. The initial diagnosis was subcorneal pustular dermatosis. However, she developed widespread geographic erythema and numerous pustules over her entire body with a fever when she got a cold. A second skin biopsy revealed monolocular pustules and Kogoj's spongiform pustules in the subcorneal layer. Etretinate was administrated after a diagnosis of pustular psoriasis was made and her condition improved gradually. The choice of treatment depends on patient age, general condition and the disease severity. [ABSTRACT FROM AUTHOR]

Background: Lipoid proteinosis (Urbach-Wiethe disease) is a rare progressive autosomal recessive disorder, characterized histologically by deposition of periodic acid Schiff-positive, diastase resistant, hyaline-like material into the skin, upper aerodigestive tract, and internal organs. Main observation: We report two cases of lipoid proteinosis. A 2-year-old girl presented with vesiculobullous skin lesions on her face, trunk, extremities and scalp, inability to protrude the tongue and hoarseness of voice that appeared few months after birth. The other case is a 4-year-old girl, who presented with waxy papules on face and trunk, hoarseness of voice and enlarged lips and tongue. The lesions healed leaving pitted scars in both cases. Based on clinical, histopathological and laryngoscopy findings, lipoid proteinosis was diagnosed in both cases. Acitretin was started in a dose of 0.5 mg/kg/day in every child. Complete remission of cutaneous lesions and improvement of the hoarseness was observed after one year. Conclusion: Acitretin may be benificial for treatment of mucosal and cutaneous lesions in lipoid proteinosis. [ABSTRACT FROM AUTHOR]

Acitretin, a synthetic retinoid has gradually replaced etretinate in today's dermatologic practice because of its more favorable pharmacokinetics. Acitretin over the past 20 years has proven useful in a number of difficult-to-treat hyperkeratotic and infl ammatory dermatoses and nonmelanoma skin cancers. It is effective both as monotherapy and in combination with other drugs for hyperkeratotic disorders. It is considered to be an established second line treatment for psoriasis and exerts its effect mainly due to its antikeratinizing, antiinflammatory, and antiproliferative effect. Its antineoplastic properties make it a useful agent for cancer prophylaxis. Evidence-based efficacy, side-effect profile, and approach to the use of acitretin would be discussed in this review. In addition to its approved uses, the various off label uses will also be highlighted in this section. Since its use is limited by its teratogenic potential and other adverse effects, including mucocutaneous effects and hepatotoxicity, this review would summarize the contraindications and precautions to be exercised before prescribing acitretin. [ABSTRACT FROM AUTHOR]

Abstract: Acitretin is currently used alone or combined with PUVA (psoralen + UVA) or with narrow-band ultraviolet B (NBUVB), to treat moderate and severe psoriasis. However, little is known about the potential genotoxic/carcinogenic risk and the cytostatic/cytotoxic effects of these treatments. Our aim was to study the cytotoxic and genotoxic effects of acitretin – alone or in combination with PUVA or NBUVB – by performing studies with blood from patients with psoriasis vulgaris who were treated with acitretin, acitretin+PUVA or acitretin+NBUVB for 12 weeks, and in vitro studies with blood from healthy volunteers, which was incubated with acitretin at different concentrations. The cytotoxic and genotoxic effects were evaluated by the cytokinesis-blocked micronucleus test and the comet assay. Our results show that psoriatic patients treated with acitretin alone or with acitretin+NBUVB, did not show genotoxic effects. In addition, these therapies reduced the rate of proliferation and induced apoptosis and necrosis of lymphocytes; the same occurred with lymphocyte cultures incubated with acitretin (1.2–20μM). The acitretin+PUVA reduced also the proliferation rate, and increased the necrotic lymphocytes. Our studies suggest that therapy with acitretin alone or combined with NBUVB, as used in psoriatic patients, does not show genotoxic effects, reduces the rate of proliferation and induces apoptosis and necrosis of lymphocytes. The combination of acitretin with PUVA also reduces the proliferation rate and increases the number of necrotic lymphocytes. However, as it induced slight genotoxic effects, further studies are needed to clarify its genotoxic potential. [Copyright &y& Elsevier]

Abstract: Four pharmaceuticals (β-carotene (1), retinoic acid (2), isotretinoin (3), and etretinate (4)) were analyzed using Raman spectroscopy and quantum-chemical calculations followed by potential energy distribution (PED) analysis to gain deeper insight into the experimental vibrational spectra. Small shifts of characteristic bands of (4) upon change of solvent and pH were interpreted as a result of molecular aggregation. Temperature-dependent studies on the Raman spectrum of (1) were performed in the temperature region of −150°C to +150°C. The observed small shifts in the experimental spectra upon heating were explained by increase of the high-energy conformers (of the trans type) in the population of (1) related to weakening of the intermolecular interactions that enables rotation of the terminal rings with respect to the polyene chain. Deconvolution of the ν1 band showed changes in intensity and position of the deconvoluted bands with the increase of temperature. [Copyright &y& Elsevier]

Abstract: Two aromatic retinoids were synthesized from styrene derivatives using a novel strategy with a cross-metathesis reaction as a key step. The biological activity of the new etretinate analogues was tested. Cross-metathesis reactions were also employed for the preparation of ethyl retinoate and its 9Z-isomer via the C15 +C5 route. [Copyright &y& Elsevier]

Acitretin is a synthetic retinoid, a pharmacologically active metabolite of etretinate. It is characterized by very favourable pharmacological profile: its period of half-life is approximately 2 days, it is nearly 50 times less lipophilic than etretinate, and its efficacy in the treatment of psoriasis is comparable to etretinate. The mechanism of its action is not yet fully understood, but it is known that acitretin normalizes all processes typical for psoriasis. The paper discusses in details the indications for acitretin, its efficacy in monotherapy and combination therapy, the principles of alternate therapy, and also the most common side effects during treatment. In addition, we classify the most important recommendations to be aware of before, during and after treatment. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is characterized by a profound deregulation of the mechanisms controlling cell-cycle progression and survival. We herein show that the combination of 9-cis-retinoic acid (RA) and IFN-α induces marked antiproliferative and proapoptotic effects in MCL cells through the modulation of critical targets. Particularly, IFN-α enhances RA-mediated G0-G1 cell accumulation by downregulating cyclin D1 and increasing p27Kip1 and p21WAF1/Cip1 protein levels. Furthermore, RA/IFN-α combination also induces apoptosis by triggering both caspases-8 and -9 resulting in Bax and Bak activation. In particular, RA/IFN-α treatment downregulates the antiapoptotic Bcl-xL and Bfl-1 proteins and upregulates the proapoptotic BH3-only Noxa protein. Sequestration of Mcl-1 and Bfl-1 by upregulated Noxa results in the activation of Bid, and the consequent induction of apoptosis is inhibited by Noxa silencing. Noxa upregulation is associated with nuclear translocation of the FOXO3a transcription factor as consequence of RA/IFN-α-induced Akt inhibition. Pharmacologic suppression of Akt, but not of TORC1, increases Noxa protein levels and downregulates Bfl-1 protein supporting the conclusion that the inhibition of the Akt pathway, the resulting FOXO3a activation and Noxa upregulation are critical molecular mechanisms underlying RA/IFN-α-dependent MCL cell apoptosis. These results support the potential therapeutic value of RA/IFN-α combination in MCL management. [ABSTRACT FROM AUTHOR]

Introduction: Constipation, soiling, and incontinence are common problems after definitive repair of anorectal malformations (ARMs) in children. We studied the expression of substance P (SP), vasoactive intestinal peptide (VIP), and c-kit in the rectum of murine embryos with or without ARMs at later developmental stages. Methods: On the 9th embryonic day (E9), pregnant Institute of Cancer Research mice were fed etretinate, a synthetic vitamin A analogue (60 mg/kg), whereas controls were fed only with sesame oil. Embryos were excised between E14 and E18, and prepared for histological examination. The SP, VIP, and c-kit expressions were examined by immunohistochemical staining for the SP, VIP, and c-kit antigens, respectively. Results: On E14 and E15, the expression levels of the anti-SP and anti-VIP antibodies in the rectum did not differ between the control and etretinate-treated group. However, as compared to the controls, a decreased SP and VIP immunoreactivity was observed in the circular muscle layer of the rectum between E16 and E18. On the other hand, on E14 and E15, the expression of anti-c-kit antibody in the rectum did not differ between the etretinate-treated and control group. However, c-kit immunoreactivity was slightly higher in the circular muscle layer of the rectum in the controls on E16 and E17, and considerably higher on E18 than that of the muscle layer in the etretinate-treated group. Conclusion: At later developmental stages, the expression levels of SP, VIP, and c-kit reduced in the circular muscle layer of the rectum in mice with etretinate-induced ARMs. This result indicates that reduced SP, VIP, and c-kit expression levels in the circular muscle layer may cause severe constipation in children who develop severe ARMs after definitive surgery. [ABSTRACT FROM AUTHOR]

Abstract: The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds. [Copyright &y& Elsevier]