Top PDF Retinoic acid glucuronide preparations for application to the skin

Retinoic acid glucuronide preparations for application to the skin

Retinoic acid glucuronide preparations for application to the skin

A method and preparation are described for treating human skin with retinoic acid glucuronide (RAG) in a topical carrier. For treatment of acne or wrinkled skin, RAG can be applied in an effective amount which is nonirritating to the skin. Retinoid dermatitis, an objectionable side effect of topical application of retinoid compounds, can thereby be avoided.

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Human skin levels of retinoic acid and cytochrome P 450 derived 4 hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor mediated transcription in vitro

Human skin levels of retinoic acid and cytochrome P 450 derived 4 hydroxyretinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor mediated transcription in vitro

Cotransfection of individual retinoic acid receptors (RARs) or retinoid X receptor-alpha (RXR-alpha) and a chloramphenicol acetyl transferase (CAT) reporter plasmid containing a retinoic acid responsive element into CV-1 cells was used to determine the ED50 values for stimulation of CAT activity by retinoic acid and its metabolites. Levels of all trans and 13-cis RA in RA-treated tissues were greater than the ED50 values […]

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“Topical Gels as Drug Delivery Systems: A Review” by Ashni Verma, Sukhdev Singh, Rupinder Kaur, Upendra K Jain, India.

“Topical Gels as Drug Delivery Systems: A Review” by Ashni Verma, Sukhdev Singh, Rupinder Kaur, Upendra K Jain, India.

into the underlying layers of skin or mucous membranes. The main advantage of topical delivery system is to bypass first pass metabolism. Avoidance of the risks and inconveniences of intravenous therapy and of the varied conditions of absorption, like pH changes, presence of enzymes, gastric emptying time are other advantage of topical preparations. Semi-solid formulation in all their diversity dominate the system for topical delivery, but foams, spray, medicated powders, solution, and even medicated adhesive systems are in use. The topical drug delivery system is generally used where the others system of drug administration fails or it is mainly used in pain management, contraception, and urinary incontinence. Over the last decades the treatment of illness has been accomplished by administrating drugs to human body via various routes namely oral, sublingual, rectal, parental, topical, inhalation etc. Topical drug delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease (e.g. psoriasis) with the intent of confining the pharmacological or other effect of the drug to the surface of the skin or within the skin. Topical activities may or may not require intra-cutaneous penetration or deposition 7, 8 . Topical drug delivery systems include a large variety of pharmaceutical dosage form like semisolids, liquid preparation, sprays and solid powders. Most widely used semisolid preparation for topical drug delivery includes gels, creams and ointments 9 .
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Efficacy and safety of fibrin sealant for tissue adherence in facial rhytidectomy

Efficacy and safety of fibrin sealant for tissue adherence in facial rhytidectomy

As soon as possible after application of fibrin sealant, gentle pressure should be applied to all flaps (Figure 3, bottom portion) for at least 3 minutes to assure bonding between the flap and underlying tissues. Pressure dressings may be useful in helping to assure this bonding as well. It is critical not to do any further flap or skin manipulation after this period of initial bonding. The lifting of skin for placement of additional sutures or manipulation with forceps as well as any further movement of the flaps needs to be strictly avoided. This is necessary because breaking of the fibrin sealant bonds at this point will create a smooth non sticky polymerized fibrin seal- ant interface between the flap and underlying tissues which has been shown to be an excellent anti-adhesive. 44 The placement
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A phosphorylation defective retinoic acid receptor mutant mimics the effects of retinoic acid on EGFR mediated AP-1 expression and cancer cell proliferation

A phosphorylation defective retinoic acid receptor mutant mimics the effects of retinoic acid on EGFR mediated AP-1 expression and cancer cell proliferation

Previously we characterized another RAR a mutant in which the receptor protein was truncated after amino acid 403, thereby deleting the AF-2 domain [11]. This truncat- ed receptor exhibited similar properties to the S77A mu- tant (growth inhibition and repression of RA responsive gene expression including EGFR). Repression of RA re- sponsive gene expression was believed due to the inability of this RAR to interact with CBP via its shortened carboxyl terminus [5]. By the same token this mutant receptor did not affect RA inhibition of AP-1 activity, presumably due to its inability to compete for CBP [11]. We observed de- creased AP-1 activity in transient transfections using the RAR403 mutant likely due to decreased EGFR expression. However, the mechanisms by which the S77A mutant in- hibits RA responsive gene expression is unknown. The RARa amino terminus is not known to interact with CBP or its associated factor PCAF [5,18]. Additionally, RARs bind to the interaction domains of repressor proteins such as NCoR via region D of the receptor rather than the ami- no terminus [4]. Despite the lack of obvious interaction of the RAR amino terminus with nuclear receptor cofactors, the S77A mutation may alter the three dimensional struc- ture of the receptor. This altered configuration may pre- vent the mutant receptor from releasing repressor proteins or recruiting coactivators in the presence of ligand. The S77A mutant receptor was shown to inhibit ligand de- pendent transactivation of RA responsive promoters [7], but the mechanism of this reduction (e.g., competition for binding sites, cofactor interaction, ligand binding) has not been determined.
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All trans retinoic acid modulates the retinoic acid receptor alpha in promyelocytic cells

All trans retinoic acid modulates the retinoic acid receptor alpha in promyelocytic cells

We have recently demonstrated that all-trans retinoic acid (RA), the active metabolite of vitamin A, is an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (AML3). We have further shown that, in these AML3 cells, the gene of the retinoic acid receptor-alpha (RAR alpha) is translocated from chromosome 17 to chromosome 15, and fused to a new gene, PLM. This results in the expression of both normal and chimeric RAR alpha transcripts in AML3 cells. The PLM-RAR alpha protein may account for the impairment of differentiation and thus leukemogenesis, but not for the paradoxical efficacy of RA in these cells. In an attempt to elucidate RA's differentiative effect in AML3 patients, the present work examined the in vitro and in vivo modulation of the normal RAR alpha
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Characterization of cDNAs encoding two chick retinoic acid receptor alpha isoforms and distribution of retinoic acid receptor alpha, beta and gamma transcripts during chick skin development

Characterization of cDNAs encoding two chick retinoic acid receptor alpha isoforms and distribution of retinoic acid receptor alpha, beta and gamma transcripts during chick skin development

Int J De, BioI 39 587 596 (1995) Original Article Characterization of cDNAs encoding two chick retinoic acid receptor a isoforms and distribution of retinoic acid receptor a, Band y transcripts during[.]

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Original Article MiR-140-5p suppresses the adipogenic differentiation of mesenchymal stem cells in rats with steroid-induced osteonecrosis of the femoral head

Original Article MiR-140-5p suppresses the adipogenic differentiation of mesenchymal stem cells in rats with steroid-induced osteonecrosis of the femoral head

increased and RARα and RARγ expressions decreased. This may be one of the mechanisms by which miR-140-5p enhances ATRA-induced inhibition of the adipogenic differentiation of MSCs. Promoting the expression levels of reti- noic acid receptor RARβ can enhance the effect of ATRA treatment on the inhibition of the adip- ogenic differentiation of MSCs. However, no studies have reported functional interaction between miR-140-5p and ATRA. Therefore, more experiments are warranted to corrobo- rate the results of this study, and we hope that additional scholars are drawn to participate in this research.
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Modulation of T cell and innate immune responses by retinoic Acid

Modulation of T cell and innate immune responses by retinoic Acid

Retinoic acid (RA) is produced by a number of cell types, including macrophages and dendritic cells, which express retinal dehydrogenases that convert vitamin A to its main biologically active metabolite, all-trans RA. All-trans RA binds to its nuclear retinoic acid receptors that are ex- pressed in lymphoid cells and act as transcription factors to regulate cell homing and differentiation. RA produc- tion by CD103 + dendritic cells and alveolar macrophages functions with TGF-b to promote conversion of naive T cells into Foxp3 + regulatory T cells and, thereby, main- tain mucosal tolerance. Furthermore, RA inhibits the differentiation of naive T cells into Th17 cells. However, Th1 and Th17 responses are constrained during vitamin A deficiency and in nuclear RA receptor a–defective mice. Furthermore, RA promotes effector T cell responses during infection or autoimmune diseases. Thus, RA plays a role in immune homeostasis in the steady-state but activates pathogenic T cells in conditions of inflam- mation. The Journal of Immunology, 2014, 192: 2953–2958.
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Identification of influential proteins in the classical retinoic acid signaling pathway

Identification of influential proteins in the classical retinoic acid signaling pathway

Retinoic acid, a metabolite of vitamin A, modulates a wide variety of biological processes such as cell growth, cell differentiation and cell proliferation. RA has also been known to be effective in treatment of various types of cancer. Even though a vast number of studies have focused on exploring the regulatory target genes for RA, the significance and roles of various intracellular RA re- ceptors in transduction of the RA signal have not been fully understood. CRABP1, CRABP2, CYP enzymes and RARs are the main intracellular proteins which can bind to RA as receptors. Few previous studies have attempted to investigate the effects of overexpression of CRABPs on the RA signaling pathway, and in some cases some- what contradictory results have been reported for differ- ent cell lines [2–4]. In this study, we developed a mathematical model to analyze the importance of CRABP1, CRABP2, CYP and RAR in production of mRNA and RA metabolites. In this regard, after propos- ing a well-mixed model of the RA signaling pathway, we performed a global sensitivity analysis to investigate the relative importance of RA binding receptors in total mRNA production via the RA pathway. Our results indicate that CRABP2 is the most important RA recep- tor at physiological levels of RA, while RAR concentra- tion has the least importance among all four RA receptors. At pharmacological levels of RA, the total mRNA production was more sensitive to variations in RAR and CYP levels than CRABP1 and CRABP2 levels. It is important to note that all RA binding receptors could influence RA-induced mRNA production within the entire region of parameter space where the concen- trations of RA binding proteins change considerably. They are all important since their sensitivity indices were
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Nuclear hormone receptors in podocytes

Nuclear hormone receptors in podocytes

As mentioned earlier, proteinruia in diabetic and non- diabetic diseases is associated with reduced podocyte ex- pression of nephrin and podocin. All-trans retinoic acid protected podocytes from injury and enhanced nephrin and podocin expression in vitro and in vivo [90,112]. The promoter of the human and mouse nephrin gene (NPHS1) contains three putative retinoic acid response elements (RAREs) [59,66] and all-trans retinoic acid enhances nephrin promoter activity in a dose-dependent manner. However, there is no evidence demonstrating that RARs or RXRs directly target the putative RAREs in primary or cultured podocytes. In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers. Although the exact mechanisms underlying the ability of all-trans ret- inoic acid to inhibit apoptosis remain unclear, suppres- sion of a cell death pathway mediated by JNK and activator protein −1 (AP-1) has been proposed [85]. In cultured podocytes, high glucose rapidly up-regulates the monocyte chemoattractant peptide (MCP-1) mRNA transcript and protein release; however, treatment with all-trans retinoic acid suppresses MCP-1 transcription, and significantly inhibits high glucose-induced MCP-1 protein synthesis [113]. Another study demonstrated that retinoids slow down progression of renal disease by suppressing important mediators such as angiotensin II, endothelin and TGF-β in an anti-Thy1.1 nephritis rat model [114]. Moreover, recent studies have indicated that retinoids suppress NF-κB and AP-1 in non-diabetic nephropathy [115,116]. Thus, RARs may have additional renoprotective functions through the transcriptional control of podocyte-specific proteins and pro-inflammatory cytokines that are know to further escalate pathogenic cascades in the kidney.
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Stage dependent responses of the developing lung to retinoic acid signaling

Stage dependent responses of the developing lung to retinoic acid signaling

Vitamin A (retinol) exerts multiple effects upon vertebrate devel- opment through binding of active metabolites, retinoic acids (RA), to two families of nuclear receptors, the retinoic acid receptors (RAR isotypes α , β and γ and their isoforms) and the retinoid X receptors (RXR isotypes α , β and γ and their isoforms) (reviewed in Kastner et al., 1995; and Chambon, 1996). RARs bind all-trans RA (t-RA) and 9-cis RA (9c-RA), whereas RXRs bind only 9c-RA. RAR/RXR heterodimers regulate transcription of RA target genes through their activation function domains (AF1 and AF2) and their binding to conserved cis-acting RA response elements (RAREs; reviewed in Mangelsdorf et al., 1995 and Chambon, 1996). Retin- oid metabolism might be controlled by cytoplasmic binding pro- teins such as the cellular retinol binding proteins (CRBPI and II) and cellular retinoic acid binding proteins (CRABPI and II) (Napoli, 1999).
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Retinoic acid signaling pathways

Retinoic acid signaling pathways

Retinoic acid (RA) is derived from retinol (vitamin A) as a metabolic product. RA exists in several isomeric forms including all-trans-RA, 9-cis-RA and 13-cis-RA; however, all-trans-RA is the primary ligand during development (Cunningham and Duester, 2015). Early studies uncovered the roles of RA during embryogenesis by subjecting mammalian or avian embryos to vitamin A deficiency, revealing that retinol (and thus likely RA) is essential for development of many organs including the hindbrain, spinal cord, forelimb buds, skeleton, heart, eye, pancreas, lung and genitourinary tract (Clagett-Dame and DeLuca, 2002). Subsequent studies have shown that RA is essential for embryonic development of chordate animals (Marlétaz et al., 2006). Although nuclear
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Retinoic acid prevents experimental Cushing syndrome

Retinoic acid prevents experimental Cushing syndrome

Moreover, retinoic acid inhibited the complete POMC promoter after 6 hours under basal conditions and forskolin or CRH stimulation (Figure 1f). Using a POMC promoter with a mutant NurRE, which is less responsive to forskolin (10–12), we observed that retinoic acid effect was abolished (Figure 1g). Similar results were obtained with all the constructs after a 24- hour retinoic acid treatment (not shown). These results demonstrate that the inhibition of the POMC pro- moter produced by retinoic acid is mediated by Nur77/Nurr1. The expression of c-Fos and Ptx-1 detect- ed by Northern blot analysis was not affected, demon- strating that retinoic acid does not produce a general inhibition of transcription (not shown). Moreover, the transcriptional activities of the glucocorticoid receptor (GR) and CREB, detected by MTV-LUC and CRE-LUC reporters, respectively, were not affected by retinoic acid under basal or stimulated conditions, demonstrating that the inhibition of AP-1–directed and Nur77/Nurr1- directed transcription is specific (Figure 1, d and e). The retinoic acid inhibition of the POMC-LUC reporter activity was blocked by COUP-TFI expression (Figure 1h). Retinoic acid inhibited not only reporter con- structs but also the endogenous ACTH production, which was only observed after 24 hours, suggesting that retinoic acid affects biosynthesis but not ACTH liberation (Figure 2). The inhibition of ACTH pro- duced by dexamethasone was not affected by retinoic acid, and the combined effect of submaximal doses of both substances was additive (Figure 2), in agreement with the effects on POMC transcription (Figure 1f). This suggests that there is no interplay between retinoic acid and the physiological glucocorticoid- mediated inhibition of ACTH. Toxic or proliferative effects after a 6- or 24-hour treatment were ruled out by annexin V staining (see Figure 4), acridine orange– ethidium bromide staining, and WST-1 assay (not shown). These results demonstrate that retinoic acid specifically inhibits the transcriptional activity of AP-1 and Nur77/Nurr1, thereby reducing POMC transcrip- tion and consequently ACTH production.
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<p>A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review</p>

<p>A rare case of acute promyelocytic leukemia with IRF2BP2-RARA fusion; and literature review</p>

A 32-year old woman was fi rst hospitalized for menorrhagia and severe tiredness. Anemia with a hemoglobin of 64 g/L and low platelet count of 33×10 9 /L were noted. Blast cells were also observed in the peripheral blood smear. However, a normal activated partial prothrombin time (aPTT), fi brinogen level, and thrombin time were observed in addition to the prolonged prothrombin time (PT) of 14 s. Her bone marrow was hypercellular with 57% promyelocytes, frequent Auer rods, and strong myeloperoxidase (Figure 1). All-trans retinoic acid (ATRA) and arsenic

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Expression of retinoic acid-binding proteins and retinoic acid receptors in sebaceous cell carcinoma of the eyelids

Expression of retinoic acid-binding proteins and retinoic acid receptors in sebaceous cell carcinoma of the eyelids

Background: Sebaceous cell carcinoma of the eyelid is a malignant tumor. However, the pathoetiology of sebaceous cell carcinoma is not clear. Retinoic acid (RA) signaling is essential for skin epidermal differentiation including the eyelids. In this study, we investigate the expression of β -catenin, RA-binding proteins and RA receptors in sebaceous cell carcinoma of the eyelid and try to estimate their influence on its pathoetiology. Methods: Retrospective, noncomparative, consecutive interventional case series. Sixteen cases of eyelid sebaceous gland carcinoma who received tumor excision at our hospital between 2001 and 2011 were included. Immunohistochemical staining for β -catenin, cellular retinoic acid binding protein 1 (CRABP1), cellular retinoic acid binding protein 2 (CRABP2), fatty acid-binding protein 5 (FABP5), retinoic acid receptors (RAR- α , −β , −γ ), and retinoid X receptors (RXR- α , −β , −γ ) was performed on tissue samples obtained from tumor excision.
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Conjugation of benzoic acid in marsupials

Conjugation of benzoic acid in marsupials

Most of the estimationsof the hydrolytic product of benzoyl glucuronide wereobscured by the presence of benzoyl glycine, free benzoic acid and endogenous glucuronic acid.. and Marsh et a[r]

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Upregulation of Rarb, Rarg, and Rorc Genes in Clear Cell Renal Cell Carcinoma

Upregulation of Rarb, Rarg, and Rorc Genes in Clear Cell Renal Cell Carcinoma

57. Wang J., Barsky L. W., Shum Ch. H., Jong A., Weinberg K.I., Collins S.J., Triche T.J. and Wu L. Retinoid-induced G1 Arrest and Differentiation Activation Are Associated with a Switch to Cyclin-dependent Kinase- activating Kinase Hypophosphorylation of Retinoic Acid Receptor á. The Journal of biological chemistry; 45: 43369–76 (2002). 58. Wang Y., Kumar N., Nuhant P., Cameron M.D.,

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First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: A new dimension to the STRA6 phenotype

First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: A new dimension to the STRA6 phenotype

In vitro analyses demonstrated that the G304K STRA6 mutant has a severely diminished ability to transport retinoids into cells. Therefore, it is likely that retinoic acid levels, synthesised intracellularly, will also be diminished in MCOPCB patients homozygous for the missense mutation. Differences in retinoic acid levels within individual patients could account for the varying severity of MAC malformations. We chose a pharmacological approach to reduce retinoic acid levels during zebrafish eye development. Zebrafish embryos were used to model different levels of retinoic acid using citral dimethyl acetal, a precursor to the retinoic acid synthesis inhibitor citral (Marsh-Armstrong, et al., 1994). Inhibition of retinoic acid synthesis produced a dose-dependent microphthalmia at 3 dpf, with an average of 40% reduction in eye size with 5 µM inhibitor (Figure 5A and 5E–G). At 5 dpf, the effect of the retinoic acid inhibitor on eye size was even more pronounced. The inhibitor produced developmental eye defects ranging from mild to severe microphthalmia (Figure 5B–D). Furthermore, retinal pigment epithelium coloboma was also apparent and again with a range of severity (Figure 5H–J). Other developmental defects were visible, including defects in heart morphogenesis, consistent with the role of retinoic acid in multiple developmental processes.
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The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression

The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression

Subjects underwent lymphapheresis (National Institutes of Health Clinical Center Department of Transfusion Medicine), and PBMC were isolated as described [17]. Donors used for lymphapheresis included healthy non- allergic control, eosinophilic gastrointestinal disease and allergic asthmatic subjects. Allergic asthmatic subjects had a minimum one-year history of episodic broncho- spasm relieved by β-agonist medications and three or more positive skin test responses (≥3 mm) out of a panel of 10 aeroallergens. The National Institute of Allergy and Infectious Diseases Institutional Review Board
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