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1.
Acne Vulgaris.
Zaenglein, AL
The New England journal of medicine. 2018;(14):1343-1352
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2.
[Drug therapy of acne inversa].
Schneider-Burrus, S, Arpa, E, Kors, C, Stavermann, T, Sabat, R, Kokolakis, G
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2018;(1):58-63
Abstract
Acne inversa is a chronic inflammatory destructive skin disease that affects about 1% of the population. The therapy should be personalized and consists of surgical and conservative procedures. Antibiotics are administered either topically or systemically. Combination therapy with clindamycin and rifampicin for 10-12 weeks can be very effective. Furthermore, TNF-α inhibitors show adequate efficacy and can be recommended. Adalimumab is the only approved drug product for systemic treatment of acne inversa. The efficacy of retinoids is controversial. Isotretinoin cannot be recommended for the treatment of acne inversa; however, acitretin has been proven to be more effective. Immune-modulating substances, like dapsone, cyclosporine A, methotrexate, colchicine, or corticosteroids, can be considered; however, the study data are insufficient for recommendation. Hormonal therapies can influence the course of the disease. Antiseptics are applied independent of the stage of disease. Patients should be informed about triggering factors.
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3.
Protagonist or antagonist? The complex roles of retinoids in the regulation of hematopoietic stem cells and their specification from pluripotent stem cells.
Grace, CS, Mikkola, HKA, Dou, DR, Calvanese, V, Ronn, RE, Purton, LE
Experimental hematology. 2018;:1-16
Abstract
Hematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the hematopoietic system throughout life. Dysregulation of the balance in HSC self-renewal, death, and differentiation can have serious consequences such as myelodysplastic syndromes or leukemia. All-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A/RA, has been shown to have pleiotropic effects on hematopoietic cells, enhancing HSC self-renewal while also increasing differentiation of more mature progenitors. Furthermore, ATRA has been shown to have key roles in regulating the specification and formation of hematopoietic cells from pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Here, we summarize the known roles of vitamin A and RA receptors in the regulation of hematopoiesis from HSCs, ES, and iPSCs.
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4.
New Treatment Modalities for Geographic Atrophy.
Kandasamy, R, Wickremasinghe, S, Guymer, R
Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2017;(6):508-513
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Abstract
Age‑related macular degeneration (AMD) is a significant cause of global visual morbidity and is projected to affect 288 million people by the year 2040. The advent of treatment with anti‒vascular endothelial growth factor (anti‑VEGF) drugs has revolutionized the treatment of neovascular AMD (nAMD) but there have been no similar breakthroughs for the treatment of geographic atrophy (GA) to retard its progression. The advancements in imaging and new understanding of disease mechanisms, based on molecular and genetic models, have paved the way for the development of novel experimental treatment options for GA that aim to cater to a thus far largely unmet need. This review paper focuses on the recent clinical trials of new treatment options for slowing GA progression rates with emphasis on the agents that are currently undergoing, or have already undergone, significant clinical trial testing. Several new groups of drugs, including those targeting the complement cascade and agents considered as neuroprotective, have shown some promising results and could potentially pave the way forward in the treatment of this devastating disease.
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Topical agents for oral cancer chemoprevention: A systematic review of the literature.
Chau, L, Jabara, JT, Lai, W, Svider, PF, Warner, BM, Lin, HS, Raza, SN, Fribley, AM
Oral oncology. 2017;:153-159
Abstract
OBJECTIVES/HYPOTHESIS We review the use of topical chemoprevention agents in patients with oral potentially malignant disorders (PMD). METHODS A systematic review of studies on topical chemoprevention agents for oral PMD from 1946 to November 2016 was conducted using the MEDLINE database, Embase, and Cochrane Library. Data were extracted and analyzed from selected studies including study type, sample size, demographics, treatment length, response rate, follow-up time, adverse effects, and recurrence. RESULTS Of 108 studies, twenty-four, representing 679 cases met the inclusion criteria. The clinical lesions evaluated included oral leukoplakia, erythroplakia (OEL), verrucous hyperplasia (OVH), oral lichen planus, larynx squamous cell carcinoma, and oral squamous cell carcinoma (OSCC). The mean complete response rate for topical retinoid therapy was 32%. The mean complete response rate for 1% bleomycin therapy and 0.5% bleomycin was 40.2% and 25%, respectively. The complete response rate of OVH, OEL, and OSCC to photodynamic therapy ranged from 66.7% to 100%. CONCLUSION There are a paucity of data examining topical treatment of oral PMDs. However, the use of topical agents among patients with oral lesions may be a viable complement or even alternative to traditional surgery, radiation, or systemic chemotherapy, with the advantage of reducing systemic side effects and sparing important anatomic structures. This study of 679 cases represents the largest pooled sample size to date, and the preliminary studies in this systematic review provide support for further inquiry.
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Antagonist-perturbation mechanism for activation function-2 fixed motifs: active conformation and docking mode of retinoid X receptor antagonists.
Tsuji, M
Journal of computer-aided molecular design. 2017;(6):577-585
Abstract
HX531, which contains a dibenzodiazepine skeleton, is one of the first retinoid X receptor (RXR) antagonists. Functioning via RXR-PPARγ heterodimer, this compound is receiving a lot of attention as a therapeutic drug candidate for diabetic disease controlling differentiation of adipose tissue. However, the active conformation of HX531 for RXRs is not well established. In the present study, quantum mechanics calculations and molecular mechanical docking simulations were carried out to precisely study the docking mode of HX531 with the human RXRα ligand-binding domain, as well as to provide a new approach to drug design using a structure-based perspective. It was suggested that HX531, which has the R configuration for the bent dibenzodiazepine plane together with the equatorial configuration for the N-methyl group attached to the nitrogen atom in the seven-membered diazepine ring, is a typical activation function-2 (AF-2) fixed motif perturbation type antagonist, which destabilizes the formation of AF-2 fixed motifs. On the other hand, the docking simulations supported the experimental result that LG100754 is an RXR homodimer antagonist and an RXR heterodimer agonist.
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Proteomic analysis of cell cycle arrest and differentiation induction caused by ATPR, a derivative of all-trans retinoic acid, in human gastric cancer SGC-7901 cells.
Xia, Q, Zhao, Y, Wang, J, Qiao, W, Zhang, D, Yin, H, Xu, D, Chen, F
Proteomics. Clinical applications. 2017;(7-8)
Abstract
PURPOSE 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) was reported to potentially inhibit proliferation and induce differentiation activity in some tumor cells. In this study, a proteomics approach was used to investigate the possible mechanism by screening the differentially expressed protein profiles of SGC-7901 cells before and after ATPR-treatment in vitro. EXPERIMENTAL DESIGN Peptides digested from the total cellular proteins were analyzed by reverse phase LC-MS/MS followed by a label-free quantification analysis. The SEQUEST search engine was used to identify proteins and bioinformatics resources were used to investigate the involved pathways for the differentially expressed proteins. RESULTS Thirteen down-regulated proteins were identified in the ATPR-treated group. Bioinformatics analysis showed that the effects of ATPR on 14-3-3ε might potentially involve the PI3K-AKT-FOXO pathway and P27Kip1 expression. Western blot and RT-PCR analysis showed that ATPR could inhibit AKT phosphorylation, up-regulate the expression of FOXO1A and P27Kip1 at both the protein and mRNA levels, and down-regulate the cytoplasmic expression of cyclin E and CDK2. ATPR-induced G0/G1 phase arrest and differentiation can be ablated if the P27kip1 gene is silenced with sequence-specific siRNA or in 14-3-3ε overexpression of SGC-7901 cells. CONCLUSION AND CLINICAL RELEVANCE ATPR might cause cell cycle arrest and differentiation in SGC-7901 cells by simultaneously inhibiting the phosphorylation of AKT and down-regulating 14-3-3ε. This change would then enhance the inhibition of cyclin E/CDK2 by up-regulating FOXO1A and P27Kip1. Our findings could be of value for finding new drug targets and for developing more effective differentiation inducer.
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Climbazole boosts activity of retinoids in skin.
Adamus, J, Feng, L, Hawkins, S, Kalleberg, K, Lee, JM
International journal of cosmetic science. 2017;(4):411-418
Abstract
OBJECTIVE To explore whether climbazole enhances retinoid-associated biological activities in vitro and in vivo. METHODS Primary human dermal fibroblasts (HDFs) were treated from six to 48 h with either retinoids (retinol, retinyl propionate, retinyl palmitate) alone or in combination with climbazole, and then assessed for cellular retinoic acid-binding protein 2 (CRABP2) mRNA expression by RT-qPCR. Next, skin equivalent (SE) cultures were topically treated with retinol or retinyl propionate, with or without climbazole, and then measured for biological changes in retinoid biomarkers. Lastly, an IRB-approved clinical study was conducted on the outer forearm of 16 subjects to ascertain the effects of low (0.02%) or high (0.1%) levels of retinol, retinyl propionate (0.5%), climbazole (0.5%) or a combination of retinol (0.02%)/climbazole (0.5%). Indicators of retinoid activities were measured after 3 weeks. RESULTS Treatment of HDFs with retinol or retinyl propionate was unaffected by climbazole but alone, resulted in a significantly (P < 0.01) higher sustained CRABP2 mRNA expression than those treated with retinyl palmitate or vehicle control. In SEs, climbazole combined with either retinol or retinyl propionate boosted retinoid related activity greater than the retinoid only, reflected by a dose-response, downregulation of loricrin (LOR) and induction of keratin 4 (KRT4) proteins. In vivo, retinol (0.1%) and retinyl propionate (0.5%) significantly increased most evaluated biomarkers, as expected. Low-dose retinol or climbazole alone did not increase these biomarkers; however, in combination, significant (P < 0.05) increases in retinoid and ageing biomarkers were detected. CONCLUSION Climbazole boosted retinoid activity both in the SE model, after a combined topic treatment with either retinol or retinyl propionate, and in vivo, in combination with a low level of retinol. Based upon the evidence presented here, we suggest that the topical skin application of climbazole in combination with retinoids could deliver skin ageing benefits more than a less robust retinoid alone.
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Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.
Riancho, J, Berciano, MT, Ruiz-Soto, M, Berciano, J, Landreth, G, Lafarga, M
Journal of the neurological sciences. 2016;:115-20
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Abstract
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS.
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The Relationship of Proper Skin Cleansing to Pathophysiology, Clinical Benefits, and the Concomitant Use of Prescription Topical Therapies in Patients with Acne Vulgaris.
Levin, J
Dermatologic clinics. 2016;(2):133-45
Abstract
Patients often perceive the cause of their acne to be related to a lack of proper cleansing, therefore many patients attempt to treat their acne either alone or with prescription therapy by frequent aggressive cleansing with harsh cleansing agents. Altered epidermal barrier function, inflammation, and Propionibacterium acnes are related to acne vulgaris (AV) pathophysiology; proper cleansing can favorably modulate the development of AV. The available clinical studies support gentle cleansing in AV by showing the ability to contribute to improving AV lesion counts and severity and minimizing the irritation seen with topical AV therapies such as retinoids and BP.