tretinoin and Hearing-Loss--Sensorineural

Developmental defects of primitive choanae, an anatomical path to connect the embryonic nasal and oral cavity, result in disorders called choanal atresia (CA), which are associated with many congenital diseases and require immediate clinical intervention after birth. Previous studies revealed that reduced retinoid signaling underlies the etiology of CA. In the present study, by using multiple mouse models which conditionally deleted Rdh10 and Gata3 during embryogenesis, we showed that Gata3 expression is regulated by retinoid signaling during embryonic craniofacial development and plays crucial roles for development of the primitive choanae. Interestingly, Gata3 loss of function is known to cause hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome, which exhibits CA as one of the phenotypes in humans. Our model partially phenocopies HDR syndrome with CA, and is thus a useful tool for investigating the molecular and cellular mechanisms of HDR syndrome. We further uncovered critical synergy of Gata3 and retinoid signaling during embryonic development, which will shed light on novel molecular and cellular etiology of congenital defects in primitive choanae formation.

Topics: Animals; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Hypoparathyroidism; Mice; Nasopharynx; Nephrosis; Tretinoin

In this study, we attempted to differentiated human bone marrow-derived mesenchymal stem cells (hBMSCs) to auditory hair cells using growth factors.. Retinoic acid (RA), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) were added to hBMSCs cell culture medium. The cells were evaluated morphologically and the expression of SOX2, POU4F3, MYO7A, and Calretinin at mRNA level and ATOH1 mRNA and protein expression.. After treatment with the growth factors, the morphology of the cells did not change, but evaluation of gene expression at the mRNA level increased the expression of the ATOH1, SOX2, and POU4F3 markers. Growth factors increased the expression of ATOH1 at the protein level. The expression of calretinin showed decreased and MYO7A no significant change in expression.. hBMSCs have the potential to differentiate to hair cell-like using the RA, bFGF, and EGF.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Proliferation; Cell- and Tissue-Based Therapy; Cells, Cultured; Epidermal Growth Factor; Fibroblast Growth Factor 2; Gene Expression Regulation; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Mesenchymal Stem Cells; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tretinoin

Hearing loss is a substantial public health problem with profound social and economic consequences in the developing world. The World Health Organization (WHO) estimates that there are 360 million people living with disabling hearing loss globally, and 80% of these individuals are from low- and middle-income countries. The epidemiology of hearing impairment remains poorly defined in most impoverished societies. Middle ear infections in childhood are a key determinant; however, congenital anomalies may also comprise an important etiology and may arise from gestational malnutrition. While evidence exists that preventable vitamin A deficiency exacerbates the severity of ear infections and, consequently, hearing loss, antenatal vitamin A deficiency during sensitive periods of fetal development may represent an etiologically distinct and virtually unexplored causal pathway. Evidence from multiple animal systems clearly shows that fetal inner ear development requires adequate vitamin A nutriture to proceed normally. Inner ear malformations occur in experimentally imposed maternal vitamin A deficiency in multiple species in a dose-response manner. These anomalies are likely due to the loss of retinoic acid-dependent regulation of both hindbrain development and otic morphogenic processes. Based on in vivo evidence in experimental animals, we hypothesize that preventable gestational vitamin A deficiency, especially during early stages of fetal development, may predispose offspring to inner ear malformations and sensorineural hearing loss. As vitamin A deficiency affects an estimated 20 million pregnant women globally, we hypothesize that, in undernourished settings, routine provision of supplemental vitamin A at the recommended allowance throughout pregnancy may promote normal inner ear development and reduce risk of an as yet unknown fraction of sensorineural hearing loss. If our hypothesis proves correct, gestational vitamin A deficiency would represent a potentially preventable etiology of sensorineural hearing loss of substantial public health significance.

Topics: Developing Countries; Dietary Supplements; Ear, Inner; Female; Hearing Loss, Sensorineural; Humans; Models, Biological; Pregnancy; Tretinoin; Vitamin A; Vitamin A Deficiency

Different pharmacotherapies for sensorineural hearing loss (SNHL) are interconnected in metabolic networks with molecular hubs.. Sensorineural hearing loss is the most common sensory deficit worldwide. Dozens of drugs have shown efficacy against SNHL in animal studies and a few in human studies. Analyzing metabolic networks that interconnect these drugs will point to and prioritize development of new pharmacotherapies for human SNHL.. Drugs that have shown efficacy in treating mammalian SNHL were identified through PubMed literature searches. The drugs were analyzed using the metabolomic analysis and the "grow-tool function" in ingenuity pathway analysis (IPA). The top 3 most interconnected molecules and drugs (i.e., the hubs) within the generated networks were considered important targets for the treatment of SNHL.. A total of 70 drugs were investigated with IPA. The metabolomic analysis revealed 2 statistically significant networks (Networks 1 and 2). A network analysis using the "grow-tool function" generated one statistically significant network (Network 3). Hubs of these networks were as follows: P38 mitogen-activated protein kinases (P38 MAPK), p42/p44 MAP kinase (ERK1/2) and glutathione for Network 1; protein kinase B (Akt), nuclear factor kappa B (NFkB) and ERK for Network 2; and dexamethasone, tretinoin, and cyclosporin A for Network 3.. Metabolomic and network analysis of the existing pharmacotherapies for SNHL has pointed to and prioritized a number of potential novel targets for treatment of SNHL.

Topics: Cyclosporine; Dexamethasone; Hearing Loss, Sensorineural; Humans; Metabolomics; Signal Transduction; Tretinoin

Topics: Adult; Cornea; Female; Hearing Loss, Sensorineural; Humans; Ichthyosis; Isotretinoin; Keratitis; Neovascularization, Pathologic; Syndrome; Tretinoin