Decreased levels of serum retinoic acid in chinese children with autism spectrum disorder.
Zhou Wei,Li Sujuan
Previous studies framed a possible link of retinoic acid (RA) regulation in brain to autism spectrum disorders (ASD) etiology. The aim of this study was to measure serum levels of RA in relation to the degree of the severity of autism. Serum RA levels were measured by enzyme-linked immunosorbent assay (ELISA) colorimetric detection Kit in 81 children with autism and 81 age-sex matched typical development children. The severity of autistic symptomatology was measured by the Childhood Autism Rating Scale (CARS) score using the Chinese version. The serum levels of RA in the children with ASD (1.68 ± 0.52 ng/ml) were significantly lower than those of control subjects (2.13 ± 0.71 ng/ml) (P < 0.001). At admission, 57 children (70.4%) had a severe autism. In those children, the mean serum RA levels were lower than in those children with mild to moderate autism (1.57 ± 0.47 ng/ml VS. 1.95 ± 0.55 ng/ml; P = 0.003). Furthermore, in multivariate model, low RA level was associated with having/the presence of ASD (adjusted odd ratio[OR] 0.516; P = 0.003) and severe ASD (OR 0.415; P = 0.015) after adjusted for confounding factors. The data suggested that serum RA levels were reduced in the group with ASD, and the levels negative correlated significantly with the severity of autism.
Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer.
Adamson P C,Reaman G,Finklestein J Z,Feusner J,Berg S L,Blaney S M,O'Brien M,Murphy R F,Balis F M
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule. PATIENTS AND METHODS:Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week. RESULTS:Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d. CONCLUSION:An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.
Functional morphology of the blood-brain barrier in health and disease.
Liebner Stefan,Dijkhuizen Rick M,Reiss Yvonne,Plate Karl H,Agalliu Dritan,Constantin Gabriela
The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Moreover, angiopoietin/Tie2 signalling that is linked to angiogenic processes has gained attention in the BBB field. Blood vessels play an essential role in initiation and progression of many diseases, including inflammation outside the central nervous system (CNS). Therefore, the potential influence of CNS blood vessels in neurological diseases associated with BBB alterations or neuroinflammation has become a major focus of current research to understand their contribution to pathogenesis. Moreover, the BBB remains a major obstacle to pharmaceutical intervention in the CNS. The complications may either be expressed by inadequate therapeutic delivery like in brain tumours, or by poor delivery of the drug across the BBB and ineffective bioavailability. In this review, we initially describe the cellular and molecular components that contribute to the steady state of the healthy BBB. We then discuss BBB alterations in ischaemic stroke, primary and metastatic brain tumour, chronic inflammation and Alzheimer's disease. Throughout the review, we highlight common mechanisms of BBB abnormalities among these diseases, in particular the contribution of neuroinflammation to BBB dysfunction and disease progression, and emphasise unique aspects of BBB alteration in certain diseases such as brain tumours. Moreover, this review highlights novel strategies to monitor BBB function by non-invasive imaging techniques focussing on ischaemic stroke, as well as novel ways to modulate BBB permeability and function to promote treatment of brain tumours, inflammation and Alzheimer's disease. In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB.
Regulation of human hematopoietic stem cell self-renewal by the microenvironment's control of retinoic acid signaling.
Ghiaur Gabriel,Yegnasubramanian Srinivasan,Perkins Brandy,Gucwa Jessica L,Gerber Jonathan M,Jones Richard J
Proceedings of the National Academy of Sciences of the United States of America
The high expression of aldehyde dehydrogenase 1, also known as retinaldehyde dehydrogenase, by hematopoietic stem cells (HSCs) suggests an important role for retinoic acid (RA) signaling in determining the fate of these cells. We found that primitive human bone marrow-derived CD34(+)CD38(-) cells not only highly express aldehyde dehydrogenase 1, but also the RA receptor α. Despite the up-regulation of early components of RA signaling, the downstream pathway remained inactive in the primitive CD34(+)CD38(-) cells. Primitive hematopoietic cells rapidly undergo terminal differentiation when cultured away from their microenvironment; however, we found that inhibition of RA signaling maintained their primitive phenotype and function, and promoted their self-renewal. HSCs reside in a complex microenvironment that enforces the balance between self-renewal and differentiation. The exact physiologic mechanisms by which the niche controls HSC fate remain elusive. The embryonic gonadal microenvironment has recently been shown to determine germ-cell fate by degrading RA through expression of the P450 retinoid-inactivating enzyme CYP26B1. We found that the bone marrow microenvironment similarly can control primitive hematopoietic cell fate via modulation of retinoid bioavailability. Accordingly, we found that bone marrow stromal cell CYP26 was also able to inactivate retinoids in serum, preventing RA signaling. Thus, primitive hematopoietic cells appear to be intrinsically programmed to undergo RA-mediated differentiation unless prevented from doing so by bone marrow niche CYP26. Modulation of RA signaling also holds promise for clinical HSC expansion, a prerequisite for the wide-scale use of these cells in regenerative medicine and gene therapy.
All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship.
Agadir A,Cornic M,Lefebvre P,Gourmel B,Jérôme M,Degos L,Fenaux P,Chomienne C
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:This study investigated the in vitro pharmacologic behavior and disposition kinetics of all-trans retinoic acid (ATRA) in acute myeloid leukemic (AML) cells, their sensitivity to its differentiating effect, and the in vivo response of acute promyelocytic leukemia (APL) patients after therapy. PATIENTS AND METHODS:Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspension culture in the absence or presence of 10(-6) mol/L ATRA. Intracellular ATRA concentration and ATRA metabolism was determined by high-performance liquid chromatography (HPLC). RESULTS:Immediate uptake is observed with maximal intracellular levels (Cmax) achieved after 24 hours of incubation. At this time, ATRA levels were variable, ranging from 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells). Comparison of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to discriminate a group of APL patients (n = 6) with high Cmax (group A; median, 200 pmol/10(6) cells) and maximal differentiation at day 3 (median, 80%), and a group of patients (n = 8, three APL and five non-APL) with low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patients, except one included in group A (rapid in vitro ATRA uptakers), achieved a complete remission. CONCLUSION:These findings suggest that intracellular ATRA concentrations are determinant for ATRA response and should be taken into account when monitoring the efficacy of ATRA differentiation therapeutic trials in malignant disorders.
Oral retinoids in the treatment of seborrhoea and acne.
Orfanos C E,Zouboulis C C
Dermatology (Basel, Switzerland)
Isotretinoin is an extremely effective drug if given systemically in severe forms of seborrhoea and acne, being the only retinoid with potent sebostatic properties. Its unique activity on the sebaceous gland still remains unclear since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors. Its bioavailability is approximately 25% and can be increased by food 1.5-2 times; after 30 min, the drug is detectable in the blood and maximal concentrations are reached 2-4 h after oral intake. The major metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady-state concentrations appear after 1 week. The half-life elimination rate of the parent compound ranges from 7 to 37 h while that of some metabolites does so from 11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong teratogenic compound. About 10-30% of the drug is metabolized via its isomer tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or after metabolization with the urine. The epidermal levels of isotretinoin are rather low and no progressive accumulation, either in serum or in the skin, is found. After discontinuation of therapy, isotretinoin disappears from serum and skin within 2-4 weeks. Isotretinoin is the most effective drug in reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation in vivo. The molecular basis for its antisebotrophic activity has not been fully elucidated. Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who have received oral isotretinoin therapy for seborrhoea do not usually experience a relapse for months or years. In severe acne, a 6- to 12-month treatment with isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the response is recommended (cumulative dose of > 120 mg/kg). Contraception is essential during isotretinoin treatment in women of childbearing age 1 month before, during and for 3 months after discontinuation of treatment.
Embryotoxicity of human sera from patients treated with isotretinoin.
Van Maele-Fabry G,Therasse P,Lenoir E,Desager J P,Despontin K,Gofflot G,Jacobs M C,Lecart C,Berthet P,Lachapelle J M,Picard J J
Toxicology in vitro : an international journal published in association with BIBRA
Sera of 20 patients treated with 20-40 mg isotretinoin/day were tested for embryotoxicity potential. For each patient, the first sample was taken before treatment (control sample) and the second was taken 2 months after the start of treatment (treated sample). Six embryos displaying six or seven pairs of somites were cultured for 26 hr in each serum sample, when sufficient serum was available. No deaths were observed in the control sample, whereas dead embryos (6%) were observed in the treated sample. The rates of malformed embryos were 13 and 81% in the control and in the treated sample, respectively. The most frequent abnormalities affected the cephalic neural tube, the branchial bars, the yolk sac circulation and the caudal neural tube. Growth and differentiation were significantly decreased in the treated sample. The concentrations of isotretinoin and of two metabolites (trans-retinoic acid and 4-oxo-isotretinoin) were measured in 12 sera. A correlation between embryotoxicity and concentration was established for two of the chemicals. Modulation of the embryotoxicity by drug-induced changes in the serum cannot be excluded.
Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin.
Chanson A,Cardinault N,Rock E,Martin J F,Souteyrand P,D'Incan M,Brachet P
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:In the last two decades, there has been an increasing use of isotretinoin (13-cis-retinoic acid or 13-CRA) for treatment of severe, and recently mild and moderate, acne in Westernized populations. Recent human and animal studies emphasized alterations caused by 13-CRA administration on folate-dependent, one-carbon metabolism. Folate deficiency and subsequent hyperhomocysteinemia increase the risk of degenerative diseases. OBJECTIVES:We determine whether a short-term supplementation with 13-CRA alters folate status and homocysteinemia in young and elderly healthy human subjects. METHODS:Twenty young and 20 elderly (age mean, 26.1 and 65.4 years, respectively) healthy male volunteers were supplemented with approximately 0.5 mg/kg/day of 13-CRA for 28 days. Fasting plasma concentrations of 13-CRA, 5-methyltetrahydrofolate (5-mTHF) as the main circulating form of folate, and homocysteine (Hcy), as well as haematologic parameters and biochemical markers of liver and renal function, were measured at baseline and at the end of supplementation. Statistical analyses were carried out using two-way anova and standard tests. RESULTS:In both groups, isotretinoin supplementation caused a dramatic increase in the circulating concentration of 13-CRA and its derivatives. It also led to significant increases in serum triglyceride (P < 0.0001) and creatinine (P = 0.002) concentrations and gamma-glutamyltranspeptidase activity (P = 0.0001) and decrease in serum level of urea (P = 0.027). However, the latter four parameters remained within normal ranges. These changes were accompanied by a 17.7% and 13.5% decrease in the plasma level of 5-mTHF (P = 0.001) in the young and elderly volunteers, respectively. Supplementation with 13-CRA did not cause significant variations in their plasma Hcy concentration. However, the latter parameter seemed to respond differently in each group of age (P = 0.046). CONCLUSIONS:Our data indicate that a 28-day supplementation with isotretinoin alters the plasma folate in young and old healthy individuals. This stresses the necessity of studying the long-term effects of retinoid therapy on folate status and homocysteinemia in acne patients, given that alteration in the latter parameters is known to increase the risk of degenerative diseases.
Expression of c-myc in human colonic tissue in response to beta-carotene supplementation.
Gowda B,Qin J,Mobarhan S,Frommel T O
Nutrition and cancer
Dietary supplementation with beta-carotene at 30 mg/day results in an increased serum trans-retinoic acid concentration in patients with a prior colonic polyp. In a number of human cell lines, trans-retinoic acid upregulates c-myc mRNA expression in colonic mucosa by reverse transcription polymerase chain reaction and correlated the results with serum concentrations of all-trans- (ATRA), 13-cis-(13-cRA), and total retinoic acid. Serum and colonic biopsy samples were obtained before and 90 days after administration of a placebo (n = 7) or 30 mg of beta-carotene (n = 5) daily. An increase in c-myc expression after supplementation was observed in 6 of 12 subjects, but 5 of these 6 subjects had decreased total serum retinoic acid concentration and 4 had decreased ATRA concentration. In addition, five of the six subjects with increased c-myc expression had received a placebo. Conversely, c-myc expression was increased in only two of five paired samples from subjects whose total serum retinoic acid concentration increased during the 90-day supplementation period. We conclude that c-myc expression is not correlated with ATRA, 13-cRA, or total retinoic acid concentration in vivo and that increased serum retinoic acid secondary to increased tissue beta-carotene is not sufficient to activate c-myc transcription.
Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation.
Khan A A,Villablanca J G,Reynolds C P,Avramis V I
Cancer chemotherapy and pharmacology
A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertaken to determine the maximally tolerated dose (MTD) and pharmacokinetics (PK) of cis-RA following bone marrow transplantation (BMT) in children with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 31 pediatric patients ranged from 4.9 to 8.9 microM following doses of 100-200 mg/m2 per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following first-order absorption in the majority of patients. A linear increase in the mean peak serum levels and area under the time-concentration curve (AUC) with increasing dose was observed. The average half-lives of absorption and elimination were 1.0 and 5.8 h, respectively. At the MTD of 160 mg/m2 per day, the mean cis-RA peak serum concentration was 7.2 +/- 5.3 microM. AUC values were not altered significantly during a 2-week course of treatment or over a long period of multiple courses. Levels of trans-retinoic acid, a metabolite of cis-RA, remained low but were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolite had increased in 64% of patients by day 14. Peak serum cis-RA concentrations correlated with clinical toxicity as grade 3 to 4 toxicity was seen in 44% of patient-courses (8/18) with peak serum levels > 10 microM, but only 13% (12/96) with peak serum levels < 10 microM. These results show that cis-RA given at 160 mg/m2 to children achieved serum concentrations known to be effective against neuroblastoma in vitro, and the PK for cis-RA differs from that reported for trans-retinoic acid in children.
Serum retinoids in retinitis pigmentosa patients treated with vitamin A.
Fex G A,Andréasson S,Ehinger B
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
BACKGROUND:Patients with retinitis pigmentosa have been suggested to benefit from treatment with moderate doses of retinyl palmitate. Retinyl palmitate is not an active retinoid in itself but is metabolised to active components in the body. To find out which metabolites of retinyl palmitate were formed and at which concentrations, we measured the concentrations of retinol, retinyl palmitate, retinoic acids and tocopherol in serum of patients treated with oral retinyl palmitate for retinitis pigmentosa. METHODS:Nine male patients and one female diagnosed as having retinitis pigmentosa after a complete ophthalmological examination including a full-field electroretinogram were given vitamin A at their own request as one daily morning dose of 16600 IU vitamin A. Blood samples were obtained before and after > 2 weeks of treatment. The concentrations of retinoids and tocopherol were measured with established methods. RESULTS:The patients were not deficient in vitamin A or vitamin E as judged from the serum vitamin concentrations. Treatment with retinyl palmitate significantly increased the serum concentration of retinyl palmitate and of 13-cis-retinoic acid but not of retinol, tocopherol or all-trans-retinoic acid. CONCLUSIONS:Neither retinyl palmitate nor 13-cis-retinoic acid, are known to be biologically active. However, 13-cis-retinoic acid can isomerise to the active vitamin A derivative, all-trans-retinoic acid. It is suggested that patients may be treated with a small dose of 13-cis-retinoic acid instead, to avoid the relatively long metabolic detour from retinyl palmitate.
Retinoic acid concentrations in patients with squamous cell carcinoma of the head and neck.
Wahlberg P,Fex G
European journal of cancer (Oxford, England : 1990)
The serum concentrations of all-trans (atRA) and 13-cis (13cRA) retinoic acid were determined by high performance liquid chromatography in 27 patients with squamous cell carcinoma of the head and neck and in 80 healthy controls. This investigation seemed relevant as ethanol is an aetiological factor in these cancers and has been suggested to interfere with the synthesis of atRA. Neither the serum concentration of atRA nor that of 13cRA differed between patients and controls. The serum atRA concentration did not differ between fasting and non-fasting patients, but the serum 13cRA concentration was significantly higher in non-fasting than in fasting patients, probably due to the dietary retinoid content.
Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity.
Fex G,Larsson K,Andersson A,Berggren-Söderlund M
Archives of toxicology
All-trans retinoic acid deficiency resulting from ethanol's interference with the synthesis of all-trans retinoic acid from retinol was recently suggested to cause the malformations of the fetal alcohol syndrome. Phenytoin, carbamazepine and valproate, might be teratogenic because they lower the concentration of all-trans retinoic acid in serum, by inducing the enzyme systems in the liver responsible for the metabolism of the all-trans retinoic acid, or by other mechanisms. Here we show, that in patients given therapeutic doses of phenytoin, carbamazepine and valproate, serum all-trans and 13-cis retinoic acid concentrations are indeed significantly lowered. We propose that drugs with this ability should be considered as potential teratogens.
Retinoids, carotenoids, and tocopherols in breast adipose tissue and serum of benign breast disease and breast cancer patients.
Shim Eugene,Yeum Kyung-Jin,Tang Guangwen,Ahn Sei Hyun,Hwang Jinah,Lee-Kim Yang Cha
Nutrition and cancer
Various retinoic acid (RA) isomers (all-trans, 13-cis, 11-cis, and 9-cis) as well as retinol, carotenoids, and tocopherol concentrations were determined in both serum and breast adipose tissue of 22 benign breast disease patients and 52 breast cancer patients categorized into 4 stages by malignancy. Serum RA isomers were analyzed by a newly developed sensitive method combining a high-performance liquid chromatography and a gas chromatography-mass spectrometry, and retinol, carotenoid, and tocopherol concentrations using a high-performance liquid chromatography system. The breast cancer patients showed significantly lower serum retinol, whereas significantly higher breast adipose tissue retinol concentration than those of benign breast disease patients. Although breast cancer patients showed significantly higher serum all-trans and 13-cis RA concentrations, 11-cis RA in breast adipose tissue was significantly lower in the breast cancer patients than those of benign breast disease patients and it was associated with the stage of malignancy. The current study indicates that the retinol and RA isomers in the target tissue of breast tumor patients are not reflecting their concentrations in circulation. The mechanisms of tissue specific uptake of RA isomers and their functions warrant further studies.
Decreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol during fasting and caloric restriction.
Berggren Söderlund M,Fex G,Nilsson-Ehle P
Journal of internal medicine
OBJECTIVES:To investigate the effects of caloric restriction on the serum concentrations of retinoids in man. DESIGN:Samples were drawn before and during caloric restriction by fasting or 4-6 weeks after gastric surgery. SUBJECTS:The fasting group included 17 healthy subjects (11 women and six men) and 16 obese patients (10 women and six men) who underwent bariatric surgery (vertical banded gastroplasty). MAIN OUTCOME MEASURES:Serum concentrations of all-trans, 13-cis, 4-oxo-13-cis retinoic acids and retinol. RESULTS:The serum concentrations of retinol, all-trans and 13-cis retinoic acids decreased by about 20% after 5 days of fasting. After gastroplasty, the serum concentration of retinol, all-trans, 13-cis retinoic acids, retinol-binding protein and transthyretin also decreased to a similar extent after 1 month. In both groups we found a correlation between the delta values of 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic acid. In all subjects there were also correlations between the delta values of the retinoids. However, these correlations were comparatively weak (e.g. r2 = 0.36 for retinol--all-trans retinoic acid). The change in retinoid concentrations did not correlate to the change of weight or body mass index. CONCLUSION:Our results support the hypothesis that serum retinol is one of the determinants of serum concentrations of all-trans and 13-cis retinoic acid and that the catabolism of 13-cis retinoic acid is not affected by fasting. However, in the individual case, S-Retinol is a poor predictor of S-All-trans retinoic acid.
Decreased retinoid concentration and retinoid signalling pathways in human atopic dermatitis.
Mihály Johanna,Gamlieli Anat,Worm Margitta,Rühl Ralph
Atopic dermatitis (AD) is one of the most common skin diseases. Various features present in AD like inflammation, reduced apoptosis, altered epidermal differentiation and hyperproliferation as well as permeability dysfunction are also regulated by retinoids. The aim of our study is to identify the retinoid signalling pathways and retinoid concentration profiles in AD skin. Human skin biopsies were obtained from healthy volunteers (HS) (n=6) and patients with AD (n=6), with both affected (AS) and non-affected (NAS) skin. The gene expression of retinoid receptors, retinoid-binding proteins and retinoid-metabolizing enzymes was investigated by QRT-PCR. Retinoid concentrations in serum and skin were measured via high performance liquid chromatography mass spectrometry-mass spectrometry. Our results show that the target gene expression of retinoid receptor regulated pathways is significantly decreased in AS and NAS of patients with AD. CYP26A1, transglutaminase 2 and retinoic acid receptor responder 1 decreased in NAS and AS in comparison with HS. The main retinoic acid synthesizing enzyme, retinal dehydrogenase 1, was significantly lower expressed in NAS (0.1%) and AS (1%) in patients with AD. Analysis of retinoid concentration in serum and skin showed comparable all-trans retinoic acid (ATRA) and retinol (ROL) concentrations from AD and healthy serum, but strongly reduced ATRA and ROL concentrations in affected and non-affected skin in comparison with healthy skin. Our data indicate that retinoid transport, synthesis, concentrations and signalling are strongly decreased in the affected but also in non-affected skin of patients with AD suggesting a general intrinsic influence on skin retinoid signalling pathway in patients with AD.
Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections.
Campione Elena,Cosio Terenzio,Lanna Caterina,Mazzilli Sara,Ventura Alessandra,Dika Emi,Gaziano Roberta,Dattola Annunziata,Candi Eleonora,Bianchi Luca
Journal of pharmacological sciences
The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.
Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.
Liu Yan,Chen Hongen,Wang Jingjing,Zhou Wenjing,Sun Ruifang,Xia Min
The American journal of clinical nutrition
BACKGROUND:Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. OBJECTIVE:This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. DESIGN:Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. RESULTS:Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P < 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 ± 0.52 (n = 28) vs. 2.32 ± 0.44 ng/mL (n = 13)], NAFLD [1.61 ± 0.37 (n = 29) vs. 1.28 ± 0.41 ng/mL (n = 16)], and NASH [1.35 ± 0.34 (n = 24) vs. 1.07 ± 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRα mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P < 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRα protein was lower in more severe grades in patients with NAFLD. CONCLUSION:These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.
Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): A pilot study.
Guo Min,Zhu Jiang,Yang Ting,Lai Xi,Liu Xiao,Liu Juan,Chen Jie,Li Tingyu
Brain research bulletin
Autism spectrum disorders (ASD) are complicated neurodevelopmental disorders. Many studies have demonstrated that children with autism have multiple nutritional deficiencies and increased serum 5-hydroxytryptamine (5-HT) levels. In our previous study, 77.9% of autistic children were found to have vitamin A deficiency, and the concentration of vitamin A was negatively associated with the CARS score. In the present study, we sought to test whether vitamin A supplementation could improve autistic symptoms and decrease serum 5-HT levels. The DSM-V criteria and CARS score were used for symptom description and symptom assessment of the patients, respectively, before and after vitamin A supplementation (VAS). Serum retinol and 5-HT levels, mRNA levels of RAR α, β, and γ and TpH 1 expression were detected in autistic children before and after VAS and in normal children. Serum retinol levels in children with ASD were significantly lower than in control children. Serum 5-HT levels in children with ASD were higher than in control children, which were correlated with symptom severity of children with autism. After VA supplementation, the children with ASD exhibited significant improvement in autism symptoms. Serum retinol concentrations of children with ASD were significantly increased, and serum 5-HT levels were decreased. Moreover, statistically significant changes were observed in mRNA expression levels of RAR α, RAR γ and TpH 1 after VAS compared to baseline. This study suggested that VA supplementation may improve symptoms and reduce 5-HT levels in children with ASD, indicating that VA supplementation is a reasonable therapy at least for a subset of children with autism.
Vitamin A Deficiency Induces Autistic-Like Behaviors in Rats by Regulating the RARβ-CD38-Oxytocin Axis in the Hypothalamus.
Lai Xi,Wu Xiaofeng,Hou Nali,Liu Shu,Li Qing,Yang Ting,Miao Jingkun,Dong Zhifang,Chen Jie,Li Tingyu
Molecular nutrition & food research
SCOPE:Vitamin A (VA) is an essential nutrient for the development of the brain. We previously found that children with autism spectrum disorder (ASD) have a significant rate of VA deficiency (VAD). In the current study, we aim to determine whether VAD is a risk factor for the generation of autistic-like behaviors via the transcription factor retinoic acid receptor beta (RARβ)-regulated cluster of differentiation 38 (CD38)-oxytocin (OXT) axis. METHODS AND RESULTS:Gestational VAD or VA supplementation (VAS) rat models are established, and the autistic-like behaviors in the offspring rats are investigated. The different expression levels of RARβ and CD38 in hypothalamic tissue and serum retinol and OXT concentration are tested. Primary cultured rat hypothalamic neurons are treated with all-trans retinoic acid (atRA), and recombinant adenoviruses carrying the rat RARβ (AdRARβ) or RNA interference virus RARβ-siRNA (siRARβ) are used to infect neurons to change RARβ signal. Western blotting, chromatin immunoprecipitation (ChIP), and intracellular Ca detections are used to investigate the primary regulatory mechanism of RARβ in the CD38-OXT signaling pathway. We found that gestational VAD increases autistic-like behaviors and decreases the expression levels of hypothalamic RARβ and CD38 and serum OXT levels in the offspring. VAS ameliorates these autistic-like behaviors and increases the expression levels of RARβ, CD38, and OXT in the gestational VAD pups. In vitro, atRA increases the Ca excitability of neurons, which might further promote the release of OXT. Different CD38 levels are induced in the neurons by infection with different RARβ adenoviruses. Furthermore, atRA enhances the binding of RARβ to the proximal promoter of CD38, indicating a potential upregulation of CD38 transcriptional activity by RARβ. CONCLUSIONS:Gestational VAD might be a risk factor for autistic-like behaviors due to the RARβ signal suppression of CD38 expression in the hypothalamus of the offspring, which improves with VAS during the early-life period. The nutritional status during pregnancy and the early-life period is important in rats.
Abnormal serum vitamin A levels and retinoic acid receptor α expression patterns in children with anorectal malformation.
Wang Zhili,Wang Quan,Gu Chengchao,Zhang Jingjie,Wang Yi
Pediatric surgery international
BACKGROUND:Anorectal malformation (ARM) is known to be associated with maldevelopment of the enteric nervous system (ENS), and vitamin A (VA) and its metabolite retinoic acid (RA) play important roles in ENS development. Thus, our aim was to investigate serum VA levels in ARM newborns and RA receptor (RAR) expression in the rectum of ARM patients and animal models. METHODS:Serum VA concentrations were detected in newly diagnosed ARM neonates (n = 32) and neonates with non-alimentary tract malformations (n = 30). Intestinal specimens were divided into three groups: rectum from ARM patients (n = 30), colon from a stoma (n = 30) and rectum from controls (n = 4). RAR mRNA expression was evaluated by RT-qPCR. Rectum specimens from ARM patients were divided into two groups by postoperative pathology: the normal and lesion ganglion cell groups. Immunohistochemistry and Western blot were employed to detect RARα protein expression in rectum specimens. In addition, the ARM mouse model was induced by all-trans retinoid acid (ATRA), and the expression levels of RARα and the neuronal marker NeuN in the rectum of mice on embryonic day 16.5-18.5 (E16.5-18.5) were investigated. RESULTS:The serum concentration of VA in ARM neonates was lower than that in control neonates (P < 0.0001), and RARα mRNA expression was lower in the rectum specimens from ARM patients than in the colon specimens from a stoma and the rectum specimens from controls (P < 0.05); there was no significant difference between the colon from a stoma and the rectum from controls. RARα protein was expressed in the nucleus of ganglion cells and nerve fibers, and RARα protein expression in the lesion ganglion cell group was significantly lower than that in the normal ganglion cell group (P < 0.01). Compared with the control mice, ARM mice at E16.5-18.5 showed decreased fluorescence intensity of RARα and NeuN in the rectum. RARα and NeuN mRNA expression in the rectum on E16.5-18.5 was lower in ARM mice than in control mice (P < 0.05). CONCLUSION:Serum VA concentration and the RARα expression pattern are abnormal in the rectum in ARM and may contribute to the ENS maldevelopment in ARM.
Post-natal all-trans-retinoic acid biosynthesis.
Napoli Joseph L
Methods in enzymology
Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol binding-protein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin: retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes.
Serum retinoic acid, retinol and retinyl palmitate levels in patients with lung cancer.
Moulas Anargyros N,Gerogianni Irini C,Papadopoulos Dimitrios,Gourgoulianis Konstantinos I
Respirology (Carlton, Vic.)
OBJECTIVES:Epidemiological studies have shown an inverse relationship between dietary vitamin A intake and the risk of developing lung cancer. The aim of this study was to investigate the vitamin A status in patients with lung cancer, by determining the serum levels of retinoic acid, retinol and retinyl palmitate. METHODS:In total, 36 patients with lung cancer and 27 controls were assessed. Of the patients 14 had squamous cell carcinoma, 3 adenocarcinoma, 15 non-small cell lung cancer and 4 small cell lung cancer. Serum retinoic acid, retinol and retinyl palmitate levels were determined with HPLC and UV detection, after liquid extraction. RESULTS:Serum retinol levels did not differ between patients (733.5 +/- 326.4 ng/mL) and controls (734.5 +/- 337.1 ng/mL). The retinyl palmitate concentration tended to be lower in patients (14.3 +/- 9.7 ng/mL) than in controls (16.7 +/- 13.7 ng/mL). The serum retinoic acid levels were significantly lower in patients (1.9 +/- 0.6 ng/mL) than in controls (2.5 +/- 1.1 ng/mL, P < 0.05). A positive correlation was observed between the retinol and retinoic acid levels and retinyl palmitate and retinoic acid levels. CONCLUSIONS:The lower levels of retinoic acid in patients with lung cancer suggest there may be a deficiency or impairment in retinol metabolism in these patients. Further studies with larger numbers of patients are needed to evaluate the possible relationship between serum retinoid levels and lung cancer.
Serum retinoic acid and atopy among children of different ethnic origin living in Germany.
Grüber Christoph,Taner Ceylan,Mihály Johanna,Matricardi Paolo M,Wahn Ulrich,Rühl Ralph
Journal of pediatric gastroenterology and nutrition
We hypothesized that higher provitamin A carotenoid serum levels may be associated with higher concentrations of all-trans retinoic acid (ATRA) and atopy. Concentration of ATRA was measured by high-performance liquid chromatography in sera from German domestic and Turkish migrants' children. ATRA serum levels were significantly higher in German children if compared with Turkish children and correlated with those of β-carotene (rs = 0.692) and other provitamin A carotenoids. They did not differ significantly between atopic and nonatopic individuals. Serum levels of ATRA are related to those of provitamin A carotenoids but are not directly related to atopy in the present study.
Binding sites of retinol and retinoic acid with serum albumins.
Belatik A,Hotchandani S,Bariyanga J,Tajmir-Riahi H A
European journal of medicinal chemistry
Retinoids are effectively transported in the bloodstream via serum albumins. We report the complexation of bovine serum albumin (BSA) with retinol and retinoic acid at physiological conditions, using constant protein concentration and various retinoid contents. FTIR, CD and fluorescence spectroscopic methods and molecular modeling were used to analyze retinoid binding site, the binding constant and the effects of complexation on BSA stability and secondary structure. Structural analysis showed that retinoids bind BSA via hydrophilic and hydrophobic interactions with overall binding constants of K(Ret)(-BSA) = 5.3 (±0.8) × 10(6) M(-1) and K(Retac-BSA) = 2.3 (±0.4) × 10(6) M(-1). The number of bound retinoid molecules (n) was 1.20 (±0.2) for retinol and 1.8 (±0.3) for retinoic acid. Molecular modeling showed the participation of several amino acids in retinoid-BSA complexes stabilized by H-bonding network. The retinoid binding altered BSA conformation with a major reduction of α-helix from 61% (free BSA) to 36% (retinol-BSA) and 26% (retinoic acid-BSA) with an increase in turn and random coil structures indicating a partial protein unfolding. The results indicate that serum albumins are capable of transporting retinoids in vitro and in vivo.
Serum Retinoic Acid Level and The Risk of Poststroke Cognitive Impairment in Ischemic Stroke Patients.
Hou Le,Ding Caixia,Chen Zhao,Liu Yuanyue,Shi Haishan,Zou Cong,Zhang Hui,Lu Zhiwei,Zheng Dong
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
BACKGROUND:Retinoic acid (RA), an active metabolite of vitamin A, possesses enormous protective effects on vascular systems. It may also be positively related to good functional outcome after ischemic stroke. However, whether circulating RA concentration is associated with poststroke cognitive impairment (PSCI) remains unclear. This study aimed to detect the association between RA level and PSCI among patients with first-ever acute ischemic stroke. METHODS:Two hundred and 61 consecutive patients were prospectively recruited during March 2018 and March 2019. Serum RA concentration was measured at admission for all patients. We also performed cognitive function examination using the Montreal Cognitive Assessment (MoCA) at admission and at every follow-up visit. Patients with MoCA score less than 26 were identified as developing PSCI. RESULTS:The median serum RA level was 2.0 ng/mL (interquartile range, 1.1-3.2 ng/mL) after admission. Patients diagnosed as PSCI at admission, 1-month and 3-month were 53 (20.3%), 91 (34.6%), and 141 (54.0%), respectively. Univariate analysis showed that reduced RA level was correlated with PSCI at 3-month (P = .003), but not at admission (P = .416) and 1-month poststroke (P = .117). After adjusting for all potential confounders, the odds ratio for the lowest tertile of RA, compared with the highest tertile, was 1.97 (95% confidence interval, 1.01-3.83, P = .046) for PSCI at 3 months. Furthermore, multiple-adjusted spline regression model further confirmed the dose-response relationships between RA level and 3-month PSCI (P < .001). CONCLUSIONS:Decreasing serum RA level might be associated with 3-month PSCI in ischemic stroke patients.
Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication.
Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system.