Administration Of Retinoids Research Articles

Advances in the treatment of autosomal recessive congenital ichthyosis, a look towards the repositioning of drugs.

Autosomal recessive congenital ichthyoses (ARCI) are a skin pathology due to genetic causes characterized by a variable degree of desquamation, accompanied by erythema. The degree of symptoms is variable, different altered genes are involved, and the symptoms drastically affect patients' quality of life. Topical treatments are a first-choice strategy due to their ease of application and cost; however, enteral administration of retinoids offers greater efficacy, although with certain limitations. Despite the treatment alternatives, ARCI will persist throughout life, disabling people. Therefore, the search for new treatments always remains necessary. Especially repositioning drugs could be a short-term alternative to new affordable treatments for patients. Taking advantage of extensive knowledge of known drugs or biologics could ensure more accessible and possibly lower-cost treatments. This review briefly and concisely addresses possible repositioning strategies with drugs and biologics for ichthyosis.

Retinoid therapy restores eye-specific cortical responses in adult mice with retinal degeneration

Despite the recent emergence of multiple cellular and molecular strategies to restore vision in retinal disorders, it remains unclear to what extent central visual circuits can recover when retinal defects are corrected in adulthood. We addressed this question in an Lrat-/- mouse model of Leber congenital amaurosis (LCA) in which retinal light sensitivity and optomotor responses are partially restored by 9-cis-retinyl acetate administration in adulthood. Following treatment, two-photon calcium imaging revealed increases in the number and response amplitude of visually responsive neurons in the primary visual cortex (V1). In particular, retinoid treatment enhanced responses from the ipsilateral eye, restoring the normal balance of eye-specific responses in V1. Additionally, the treatment rescued the modulation of cortical responses by arousal. These findings illustrate the significant plasticity of the adult central visual system and underscore the therapeutic potential of retinoid administration for adults with retinal diseases.

Algorithm of topical oxidant application in the treatment of seborrheic keratosіs based on ultrasound and pathomorphological features

Objective — to develop an algorithm for the use of a topical oxidizing agent (hydrogen peroxide) in the treatment of seborrheic keratosis (SK), taking into account the ultrasound (US) and pathomorphological data and using statistical models.
 Materials and methods. 35 patients aged 35 to 75 (32 (91.4 %) women and 3 (8.6 %) men) with seborrheic keratomas were examined on the basis of «University Clinic» Medical Educational and Scientific Center of Zaporizhzhia State Medi­cal University. Clinical, dermatoscopic and pathomorphological research methods were used for diagnostic purposes. To determine the thickness of keratosis, an ultrasound scan was performed.
 Results and discussion. Topical adapalene was applied locally to SK foci for 2 weeks, 2 times a day in 35 patients. After retinoid administration, the thickness of most foci decreased (n = 26; 74.3 %), but some of them did not change significantly (n = 9; 25.7 %). For the purpose of chemical destruction, it was recommended to use a topical oxidant — 30 % solution of hydrogen peroxide. Group 1 (application of topical oxidant in one cycle) included 20 patients who used the remedy for 5—6 days. The duration of treatment for ≥ 7—10 days was recommended for 15 patients of group 2. A comparison of keratoma thickness in patients of both groups with different duration of oxidant use revealed a statistically significant difference between subgroups (U = 88.500; p < 0.05). The greater the thickness of the keratoma was, the more it needed additional application of hydrogen peroxide. Taking into account the pathomorphological and ultrasound signs, a discriminant analysis was performed between groups of patients with 1 and 2 cycles of hydrogen peroxide application. In case of less than 0 index, longer therapy was recommended.
 Conclusions. The scheme using topical oxidant is a promising area of treatment for patients with SK and requires further study. The application of statistical methods made it possible to identify the main variable features (pathomorphological variant and keratoma thickness), which determine the choice of the duration of hydrogen peroxide application.

Harlequin Ichthyosis in a Filipino Newborn: Management Pearls in a Resource-limited Setting

Introduction. Harlequin ichthyosis (HI) is a rare type of autosomal recessive congenital ichthyosis. There are approximately 200 documented cases worldwide, with less than five published reports in the Philippines. Despite its rarity, current literature suggests a better prognosis for these patients.
 Case description. We describe a preterm male newborn who presented at birth enclosed in a thick hyperkeratotic armor-like scale plates with areas of fissures, with associated ectropion, conjunctiva dehiscence, and eclabium. The thickened encasement also covered the hands and feet, causing severe contractures. A diagnosis of harlequin ichthyosis was given based on the clinical features. The patient was managed through a multidisciplinary approach, including referral to the tele-ichthyosis platform of a US-based foundation for patients with ichthyosis. Thermoregulation, nutrition, and hydration were carefully managed. Bland emollients were applied generously following normal saline soaks to improve barrier protection. Acitretin was administered on day 2 of life to facilitate the desquamation of the thickened encasement. A marked decrease in erythema and the thickness of the hyperkeratotic skin, and reduced conjunctival dehiscence were noted after one week of therapy. However, the constrictions on the hands and feet showed bluish discoloration and signs of necrosis. Linear band excision was performed to release the constrictors. Despite aggressive management, the patient succumbed to sepsis on day 12 of life.
 Conclusion. Improved prognosis amongst HI patients is correlated with optimal quality of care regardless of resource limitations. A multidisciplinary approach and early administration of retinoids cannot be overemphasized. Linear band excision within the first week of life is suggested for constrictions on the extremities that do not improve with retinoids to avoid necrosis and autoamputation.

Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors.

Retinoids are a class of natural and synthetic compounds derived from vitamin A. They are involved in several biological processes like embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. In light of their important functions, retinoids have been widely investigated for their therapeutic applications. Thus far, their use for the treatment of several types of cancer and skin disorders has been reported. However, these therapeutic agents present several limitations for their widespread clinical translatability, i.e., poor solubility and chemical instability in water, sensitivity to light, heat, and oxygen, and low bioavailability. These characteristics result in internalization into target cells and tissues only at low concentration and, consequently, at an unsatisfactory therapeutic dose. Furthermore, the administration of retinoids causes severe side-effects. Thus, in order to improve their pharmacological properties and circulating half-life, while minimizing their off-target uptake, various retinoids delivery systems have been recently developed. This review intends to provide examples of retinoids-loaded nano-delivery systems for cancer treatment. In particular, the use and the therapeutic results obtained by using fenretinide-loaded liposomes against neuroectodermal-derived tumors, such as melanoma, in adults, and neuroblastoma, the most common extra-cranial solid tumor of childhood, will be discussed.

Retinoid based nanoemulsions: Preparation to therapeutic applications

Modern mode of drug delivery system has been constructed to defeat the main issues linked with the traditional drug delivery system. This particular review will give an idea about the retinoid based nanoemulsion system. The main focus is to briefly explain the different aspects of nanoemulsion formulations, procedure of preparation, portrayal procedures with special focus on different utilizations of nanoemulsion in various area. Nanoemulsions are colloidal dispersion system that are composed of two non-miscible mixtures mixed along with surfactants and co-surfactants emulsifier to develop a single phase which is thermodynamically balanced. Nanoemulsion droplet sizes commonly fall in the range of 20-200 nm and show thin size distributions. Nanoscale dispersions of droplets of one liquid in another insoluble liquid can be achieved by using extreme emulsification procedures. Retinoid, better known as vitamin A are lipophillic in nature. They are vastly used for therapeutic purpose in skin disorders. Retinoid are among one of the fundamental compound found in cosmeceuticals. They are the most investigated compound with sufficient information supporting them. Retinoid include natural or synthetic derivatives that decrease hyperpigmentation and limit collagen breaking enzymes. Nanoemulsions comprise of tiny oil-in-water globules, havingless than 100 nm diameter. They are delicate frameworks by nature. Traditional formulations are restricted becauseof irritation, poor aqueous solubility and high instability of retinoid. But administration of retinoid in aqueous mediais enabled due to nanoemulsion based formulation, decreasing degradation, controlled release, high stability,improve targeting and enhance efficacy. Nanoemulsion show incredible guarantee for the future of beauty careproducts, diagnostics, treatments, and biotechnologies. The unique properties of nanoemulsions such as highstability, translucent appearance and efficient drug delivery attribute has attracted researchers interest which is oneof the reason why the usage of nanoscale emulsion has grown rapidly during the recent decades. Nanoemulsionformulation might be considered as viable, safe and with enhanced bioavailability. Comparing to the conventionaltopical formulation, nanoemulsion possess advance transdermal permeation of various drugs such as gels andemulsions. Nanoemulsion is significantly important in modern pharmaceutical industry and provide many benefitsin drug delivery systems. This review is focused on the most recent literature on developments of retinoid basednanoemulsions.

Constitutive androstane receptor mediates PCB-induced disruption of retinoid homeostasis

Environmental exposure to polychlorinated biphenyls (PCBs) is associated with an increased risk of incidence of metabolic disease, however the molecular mechanisms underlying this phenomenon are not fully understood. Our study provides new insights into molecular interactions between PCBs and retinoids (vitamin A and its metabolites) by defining a role for constitutive androstane receptor (CAR) in the disruption of retinoid homeostasis by non-coplanar 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153). Administration of four weekly 50 mg/kg doses of PCB153 to C57BL/6 male mice resulted in a significant decline in the tissue concentrations of retinyl esters, retinol and all-trans-retinoic acid (atRA), while no decline in hepatic and adipose tissue retinoid levels were detected in Car-null littermates. Our data imply that disrupted retinoid homeostasis occurs as a consequence of PCB153-induced activation of CAR, and raise the possibility that CAR signaling can affect atRA homeostasis in vivo. A strong correlation between the changes in retinoid metabolism and extensive upregulation of hepatic CAR-driven Cyp2b10 expression implicates this CYP isoform as contributing to retinoid homeostasis disruption via atRA oxidation during PCB153 exposure. In response to PCB153-induced CAR activation and disruption of retinoid homeostasis, expression of hepatic Pepck, Cd36 and adipose tissue Pparγ, Cd36, Adipoq, and Rbp4 were altered; however, this was reversed by administration of exogenous dietary retinoids (300 IU daily for 4 weeks). Our study establishes that PCB153 exposure enables a significant disruption of retinoid homeostasis in a CAR-dependent manner. We propose that this contributes to the obesogenic properties of PCB153 and may contribute to the predisposition to the metabolic disease.

Optimization of nanostructured lipid carriers loaded with retinoids by central composite design

The aim of this study was to design and optimize a new formulation of lipid nanoparticles for the topical administration of retinoids. The standard procedure involves nanostructured lipid carriers (NLCs) synthesized by the miniemulsion methodology, using sunflower oil as a bioactive ingredient and retinyl palmitate (RP) as model retinoid.A 5-factor, 3-level central composite design was used to predict responses and construct 3D-response contour plots. The independent variables were the concentration of total lipids, solid lipid, surfactant, encapsulated retinoid and number of carbons on the solid lipid fatty acid chain length, in function of the selected responses as the particle size, surface charge of the nanoparticles and the encapsulation efficiency (EE %) at 3 levels. Experimental trials were performed at all 31 possible combinations.An optimized NLC composition of 2.5% total lipids, 2.0% myristic acid and 0.5% sunflower oil and 1.5% of surfactant Tween 80 was reached. The type of surfactant was adjusted from Tween 80 to Span 80 to improve the electrostatic stability of the lipid nanoparticles and the resultant optimized NLC formulation was evaluated to incorporate another two retinoids as tretinoin (TRT) and adapalene (ADP).The resultant retinoid delivery systems were characterized in terms of particle size and electrostatic stability, morphology, crystallinity of the lipid matrix, EE (%) and drug loading capacity and release profile. Particle sizes of 134.5 ± 5.4 nm and zeta potential values of −57.0 ± 2.8 mV were obtained for optimized ADP-NLCs and high entrapment efficiency values were obtained for RP-NLC, TRT-NLC and ADP-NLC as 84.4 ± 3.0%, 84.1 ± 7.8% and 73.7 ± 3.3%, respectively. DSC analysis indicated that the melting temperatures of the three optimized NLCs loaded with the retinoids were above 40 °C, proving to be suitable for use in topical administration. The in vitro drug release studies were conducted for 48 h, using a dialysis regenerated cellulose membrane. The results demonstrated a very well-controlled release of RP and TRT, which improves the stability of these active compounds and confirms a high encapsulation efficiency.

Prediction of neuroblastoma cell response to treatment with natural or synthetic retinoids using selected protein biomarkers.

Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.

A harlequin ichthyosis pig model with a novel ABCA12 mutation can be rescued by acitretin treatment.

Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.

Clinical response to isotretinoin and interferon-\u03b1 of two dogs with cutaneous epitheliotropic T-cell lymphoma: a case report

BackgroundThere is no specific therapy for cutaneous epitheliotropic T-cell lymphoma (CETL). The administration of retinoids in conjunction with interferon-α (IFN-α) in CETL has not been reported in dogs.Case presentationTwo dogs (Shih tzu and Miniature pinscher) presented with multiple nodular skin lesions. Histopathological examination revealed diffuse infiltrations of lymphocytes in the epidermis and dermis, with a CD3-positive immunophenotypic profile. Based on the clinical and histopathological examination, CETL was diagnosed. Both dogs were treated with isotretinoin in combination with IFN-α and showed clinical improvement with complete or partial remission. The disease in these dogs was well-controlled for more than 264 days of overall median survival time without any additional clinical signs after initiation of the treatment. In both the cases, the dogs were followed up for 27 months, and 10 months without any evidence of recurrence or metastasis, respectively.ConclusionsWe describe the clinical efficacy of isotretinoin combined with IFN-α in 2 dogs with CETL. Long-term management with isotretinoin combined with IFN-α was effective in treating CETL in these cases.

PO-215 Resistance to retinoids – analysis of putative biomarkers in neuroblastoma cells and tumour tissue samples

IntroductionRetinoids represent a popular group of differentiation inducers that are successfully used in oncology for treatment of neuroblastoma (NBL) in children. However. differentiation therapy has some limitations including toxicity and intrinsic or acquired resistance to retinoids observed in many patients. Therefore, seeking for molecular markers able to predict therapeutic response to retinoid administration is undoubtedly an important aspect of their use in clinical practice. Several putative biomarkers indicating sensitivity or resistance of NBL cells to retinoids were reported in recent studies. The main aim of our study was to analyse the expression of five candidate proteins (PBX1, HOXC9, HMGA1, HMGA2 and DDX39A) in one experimental cohort (NBL cell lines; relevant FFPE tumour samples).Material and methodsIn this study, 20 patient-derived NBL cell lines were used for the experiments. Sensitivity or resistance to natural (all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid) and synthetic (fenretinide, bexarotene) retinoids was determined by MTT assay. Endogenous expression of the candidate biomarkers was analysed both on mRNA (RT-PCR) and protein (immunoblotting) levels in cell lines and on protein level (immunohistochemistry) in FFPE tumour samples. Changes in expression of these markers after treatment with retinoids were also analysed.Results and discussionsNBL cell lines resistant to retinoids showed either presence of HMGA2 or increased expression of HMGA1 together with PBX1. Cell lines without a detectable expression of HOXC9 is on both mRNA and protein level are resistant to retinoids. Increase of expression of HOXC9 protein after retinoid treatment was detected in sensitive cell lines only. Very strong expression of PBX1 protein was found in tumour samples taken from patients showing resistance or poor clinical outcome after treatment with retinoids.ConclusionOur experimental study confirmed the usefulness of selected putative markers indicating sensitivity or resistance of NBL cells to retinoids in one experimental cohort consisting of patient-derived cell lines and respective tumour samples.This study was supported by the project AZV MZCR 15-34621A.

Vitamin A and retinoic acid combination attenuates neonatal hyperoxia-induced neurobehavioral impairment in adult mice

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well.

Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors.

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors.

Hepatic Detoxification of Bisphenol A is Retinoid-Dependent.

Bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl) propane) is a widely used industrial chemical. The extensive distribution of BPA in the environment poses risks to humans. However, the molecular mechanisms underlying BPA toxicity as well as its effective detoxification and elimination are not well understood. We have investigated specifically for BPA the notion raised in the literature that the optimal sensing, detoxification, and elimination of xenobiotics requires retinoid (natural derivatives and synthetic analogs of vitamin A) actions. The objective of the study was to explore how retinoids, both those stored in the liver and those originating from recent oral intake, help maintain an optimal xenobiotic detoxification response, affecting mRNA expression and activities of elements of xenobiotic detoxification system upon BPA administration to mice. Wild-type and mice lacking hepatic retinoid stores (Lrat-/-) were acutely treated with BPA (50 mg/kg body weight), with or without oral supplementation with retinyl acetate. Hepatic mRNA expression levels of the genes encoding nuclear receptors and their downstream targets involved in xenobiotic biotransformation, phase I and phase II enzyme activities, and levels of oxidative damage to cellular proteins and lipids in hepatic microsomes, mitochondria and cytosol, were assessed. BPA treatment induced hepatic activities needed for its detoxification and elimination in wild-type mice. However, BPA failed to induce these activities in the livers of Lrat-/- mice. Oral supplementation with retinyl acetate restored phase I and phase II enzyme activities, but accelerated BPA-induced oxidative damage through enhancement of non-mitochondrial ROS production. Thus, the activities of the enzymes involved in the hepatic elimination of BPA require hepatic retinoid stores. The extent of hepatic damage that arises from acute BPA intoxication is directly affected by retinoid administration during the period of BPA exposure and hepatic retinoid stores that have accumulated over the lifetime of the organism.

An animal model of detrusor overactivity induced by depression

IntroductionDepression is frequently found in patients suffering from overactive bladder. The aim of the study was to verify whether the 13-cis-retinoic acid, a synthetic retinoid used in the treatment of acne, which was proven to induce depressive changes in both humans and animals, can cause detrusor overactivity symptoms in conscious rats. MethodsIn order to assess the 13-cis-retinoic acid impact on the behavioural parameters, after 6weeks of intraperitoneal administration of retinoid in a dose of 1mg/kg/day, a forced swim test and cystometry were performed, and the locomotor activity of animals was assessed. The control group received a mixture of DMSO and physiological saline at a 1:1 ratio. Results13-cis-retinoic acid caused cystometric parameter changes analogous to those observed in people with a urodynamic diagnosis of detrusor overactivity. The retinoid caused also an extension of the immobility time in the forced swim test which is consistent with increased depression-related behaviour, with no impact on the locomotor activity of rats. The intravenous administration of solifenacin succinate in a single dose of 0.03mg/kg turned out to reverse changes in the cystometric parameters modified by 13-cis-retinoic acid treatment. The histopathological analysis of bladders did not show any lesions in the upper layer of the umbrella cells, urothelium or muscles. The retinoid concentration level achieved in the animals tested turned out to be identical to that occurring in humans. Discussion13-cis-retinoic acid can induce detrusor overactivity symptoms that are reversed by solifenacin succinate.

Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents.

Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC.

Impaired aldehyde dehydrogenase 1 subfamily member 2A-dependent retinoic acid signaling is related with a mesenchymal-like phenotype and an unfavorable prognosis of head and neck squamous cell carcinoma.

BackgroundAn inverse correlation between expression of the aldehyde dehydrogenase 1 subfamily A2 (ALDH1A2) and gene promoter methylation has been identified as a common feature of oropharyngeal squamous cell carcinoma (OPSCC). Moreover, low ALDH1A2 expression was associated with an unfavorable prognosis of OPSCC patients, however the causal link between reduced ALDH1A2 function and treatment failure has not been addressed so far.MethodsSerial sections from tissue microarrays of patients with primary OPSCC (n = 101) were stained by immunohistochemistry for key regulators of retinoic acid (RA) signaling, including ALDH1A2. Survival with respect to these regulators was investigated by univariate Kaplan-Meier analysis and multivariate Cox regression proportional hazard models. The impact of ALDH1A2-RAR signaling on tumor-relevant processes was addressed in established tumor cell lines and in an orthotopic mouse xenograft model.ResultsImmunohistochemical analysis showed an improved prognosis of ALDH1A2high OPSCC only in the presence of CRABP2, an intracellular RA transporter. Moreover, an ALDH1A2highCRABP2high staining pattern served as an independent predictor for progression-free (HR: 0.395, p = 0.007) and overall survival (HR: 0.303, p = 0.002), suggesting a critical impact of RA metabolism and signaling on clinical outcome. Functionally, ALDH1A2 expression and activity in tumor cell lines were related to RA levels. While administration of retinoids inhibited clonogenic growth and proliferation, the pharmacological inhibition of ALDH1A2-RAR signaling resulted in loss of cell-cell adhesion and a mesenchymal-like phenotype. Xenograft tumors derived from FaDu cells with stable silencing of ALDH1A2 and primary tumors from OPSCC patients with low ALDH1A2 expression exhibited a mesenchymal-like phenotype characterized by vimentin expression.ConclusionsThis study has unraveled a critical role of ALDH1A2-RAR signaling in the pathogenesis of head and neck cancer and our data implicate that patients with ALDH1A2low tumors might benefit from adjuvant treatment with retinoids.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0476-0) contains supplementary material, which is available to authorized users.

Retinoid treatment of skin diseases.

Retinoids (vitamin A and its metabolites) are potent natural regulators of cellular activities, including cell growth and differentiation, and they mediate many essential regulatory functions, especially in the skin. Biologically active retinoids exert their effects by binding to nuclear retinoic acid receptors and retinoid-X-receptors. The group of pharmacologically used retinoids include naturally occurring and chemically synthesised vitamin A derivatives. Due to their influence on keratinocyte proliferation, epidermal differentiation and keratinisation, retinoids are commonly used in the field of dermatopharmacology. For safe administration of retinoids, in-depth information about adverse effects and comprehensive information of the patient are important. This article gives an overview on the effects, use, and side-effects of topical and systemic retinoids in dermatology.

Lipid nanoparticles for the topical delivery of retinoids and derivatives.

Retinoids are lipophilic compounds that are highly used in cosmetics/therapeutics for skin disorders. Conventional formulations are limited by poor water solubility, high chemical/photochemical instability and the irritation of retinoids. Interestingly, lipid nanoparticles enable the administration of retinoids in aqueous media, providing drug stabilization and controlled release. Recently, it has been demonstrated that retinoids in solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions and nanocapsules can decrease degradation, improve targeting and enhance efficacy for the treatment of skin disorders. This article focuses on the formulation, fabrication, characterization and in vitro/in vivo evaluation of solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions and nanocapsules loaded with retinoids for skin administration. Furthermore, the incorporation of these lipid nanoparticles into secondary vehicles is discussed.