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Research Papers

Effects of 3,5,3′-Triiodothyroacetic Acid, Nanoencapsulated or Not, on Intact and Atrophic Skin in Rats OPEN ACCESS

[+] Author and Article Information
Daniele Trevizan Pera

Postgraduate Program
in Biotechnology (PPGBiotec),
Federal University of São Carlos (UFSCar),
São Carlos, São Paulo CEP 13565-905, Brazil
e-mail: danitepe@gmail.com

Jéssica Freitas Planello

Department of Medicine (DMed),
Federal University of São Carlos (UFSCar),
São Carlos, São Paulo CEP 13565-905, Brazil
e-mail: jplanello@yahoo.com.br

Juliana Cancino

Physics Institute of São Carlos (IFSC),
University of São Paulo (USP),
São Carlos, São Paulo CEP 13566-590, Brazil
e-mail: jucancino@yahoo.com.br

Igor Polikarpov

Physics Institute of São Carlos (IFSC),
University of São Paulo (USP),
São Carlos, São Paulo CEP 13566-590, Brazil
e-mail: ipolikarpov@ifsc.usp.br

Valtencir Zucolotto

Physics Institute of São Carlos (IFSC),
University of São Paulo (USP),
São Carlos, São Paulo CEP 13566-590, Brazil
e-mail: zuco@ifsc.usp.br

Lucimar Retto da Silva de Avó

Department of Medicine (DMed),
Federal University of São Carlos (UFSCar),
São Carlos, São Paulo CEP 13565-905, Brazil
e-mail: lucimar@ufscar.br

Carla Maria Ramos Germano

Department of Medicine (DMed),
Federal University of São Carlos (UFSCar),
São Carlos, São Paulo CEP 13565-905, Brazil
e-mail: cgermano@ufscar.br

Débora Gusmão Melo

Department of Medicine (DMed),
Federal University of São Carlos (UFSCar),
São Carlos, São Paulo CEP 13565-905, Brazil
e-mail: dgmelo@ufscar.br

1Corresponding author.

Manuscript received March 18, 2014; final manuscript received September 26, 2014; published online October 15, 2014. Assoc. Editor: Malisa Sarntinoranont.

J. Nanotechnol. Eng. Med 5(3), 031001 (Oct 15, 2014) (8 pages) Paper No: NANO-14-1024; doi: 10.1115/1.4028695 History: Received March 18, 2014; Revised September 26, 2014

We aimed to investigate 3,5,3′-triiodothyroacetic acid (TRIAC) effects on intact and atrophic skin induced by glucocorticoids (GCs) in rats and the effects induced by nanoencapsulation. The effects of TRIAC and nanoencapsulated TRIAC were evaluated on intact and atrophic skin in TRIAC experiment and nanoencapsulated TRIAC experiment, respectively. Both experiments had two phases: phase I, cutaneous atrophy was induced; phase II, TRIAC or nanoencapsulated TRIAC was administrated. Our results showed that topical use of TRIAC with or without nanoencapsulation was able to reverse cutaneous atrophy. Nanoencapsulated TRIAC showed less systemic changes than TRIAC; therefore, it is possibly a safer drug for topical administration.

FIGURES IN THIS ARTICLE
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Skin atrophy is the most important adverse effect following prolonged topical GCs use and it has been argued that deiodinases, enzymes involved in thyroid metabolism, are essential for GC-induced skin atrophy [1,2]. Thyroid is the main source of thyroid hormones (THs) and secretes primarily 3,5,3′,5′-l-tetraiodothyronine (tyroxine, T4) and a smaller amount of 3,5,3′-l-triiodothyronine (T3), that is mostly originated through the extrathyroidal deiodinization of T4. As shown before in literature, high dosages of GCs reduce the ratio of T3 to T4 in plasma by blocking deiodinase-1 (D1) and deiodinase-2 (D2) and increasing deiodinase-3 (D3) action [3]. D2 and D3 deiodinases are crucial for intracellular THs control in skin, whereas D1 is not expressed [4]. GCs inhibit the activity of D2 present in skin, leading to lower concentrations of T3 and since T3 is about four to five times biologically more active than T4, there is local hypothyroidism followed by collagen synthesis reduction [5,6].

The TH binds to two main isoforms of specific nuclear receptors, TRα and TRβ, with different patterns of expression in developing and adult tissues [7]. TRα and TRβ are present in normal skin and knockout animals as these receptors have less epidermal proliferation and increased expression of inflammatory cytokines and chemokines, which emphasizes the importance of thyroid action on skin physiology [8,9]. Taking this into account, TH is a strategy for treating atrophic skin. The possibility of using selective ligands for different varieties of TH receptors is of clinical relevance and may be interesting for the pharmaceutical industry [10,11].

TRIAC is a T3 acetic acid metabolite and represents 2% of circulating THs. It is present in various tissues and is a selective activator of TRβ [12,13]. TRIAC has been used to increase the metabolic rate and induce weight loss [14]. Topical application of TRIAC increases skin thickness and is capable of reversing skin atrophy induced by GC in mouse models [15]. An increased synthesis of procollagen in human skin treated with topical TRIAC was also observed [16].

The stratum corneum, which is the nonviable uppermost layer of the epidermis, is an obstacle for the delivery of many molecules at therapeutic levels. Drug transport across the stratum corneum is complex. Therefore, in order to enhance the transfer of a molecule across this layer, parameters such as partition, diffusion, and solubility coefficients need to be manipulated and targeted. In addition, aspects related to physicochemical and pharmacokinetic properties and linkage capability with cell membrane also influence molecular penetration–absorption of specific drugs [17].

Nanotechnology has emerged as an important tool in medicine, especially in drug carrier and delivery systems development, which may affect the bioavailability of the active molecule and improve its therapeutic efficacy [18,19]. The technological development of new administration forms has been a promising strategy to increase and control drug skin penetration [20,21]. In the past years, different strategies have been proposed to increase drug skin permeation and to circumvent the inadequate physicochemical characteristics of several substances. Nanometric systems have a great surface area, which renders them highly satisfactory for the application of lipophilic substances, promoting a homogeneous drug release. Nanostructured systems for drug release are basically colloidal aqueous suspensions containing nanospheres, nanocapsules, nanoemulsion, solid lipid nanoparticles, microemulsions, liposomes, or niosomes [22].

Using polymeric materials for encapsulating drugs or other active agents can help to hide physicochemical properties of these substances, facilitating skin penetration [23]. Polymeric nanoparticles for drug release usually refer to carrier systems comprising nanocapsules or nanospheres with diameters lower than 1 μm. The basic difference between the latter systems is the type of entrapment of the active material by the polymeric agent. For nanospheres, the combination of active molecule and polymer forms a matrix pattern structure and the active molecule is homogeneously dispersed or solubilized within the polymer matrix. On the other hand, nanocapsules are reservoirs and the active molecule is surrounded by a polymeric membrane, insulating the core from the external environment. Choosing the best nanostructured system depends on the type of material, application, and release mechanism required for its action [22,24,25]. The polymeric shell of the nanocapsules can be design in order to improve their biodistribution profile and to extend the half-life of the encapsulated molecule. Moreover, the nanocapsules can be formulated to be more stable over time compared to nanospheres which lose their stability and active molecule easily [26]. An efficient nanostructured system depends on the type of material to be encapsulated, application, and release mechanism required for its action.

The aim of this study is to investigate the TRIAC effects on intact and atrophic skin induced by GCs in rats, analyzing possible differences depending on hormone presentation form: nanoencapsulated or not.

Animals.

Fifty-two Wistar male rats (Rattus norvegicus albinus, Rodentia mammalian), weighing 250–280 g, were kept in individual cages in a room with a controlled temperature, humidity, and lighting (lights on from 0600 to 1800 h), with free access to food and water and were allowed to adapt to the environment for 3 days prior to the experiments. The study outline and procedure was approved by the Institutional Animal Research Ethical Committee (Document No. 034/2009).

Experimental Design.

The effects of TRIAC (TRIAC experiment) and nanoencapsulated TRIAC (nanoencapsulated TRIAC experiment) were evaluated on intact and atrophic skin. In each experiment, 24–32 aged and size-matched Wistar rats were used. Each experiment was carried out in two phases. In phase I, animals were divided into two groups (12–15 rats in each group): in group 1, animals remained with intact skin; in group 2, cutaneous atrophy was induced by topical administration of Clobetasol propionate for 10 days. In phase II, each group of animals with atrophic or intact skin were subdivided into two subgroups A and B (4–8 rats in each subgroup): in subgroups 1 A and 2 A, the vehicle was used; in subgroups 1B and 2B, TRIAC or nanoencapsulated TRIAC was administered daily for 14 days, depending on the experiment (TRIAC in the first experiment and nanoencapsulated TRIAC in the second experiment).

The experimental design is illustrated in Fig. 1. During 26 days, the animals' weight, temperature, and food intake were measured in the morning, between 8:00 and 10:00 AM, every other day, by the same person. Three cutaneous biopsies were taken from the dorsal area of each animal on experimental days 0, 11, and 26. At the end of the experiments, animals were sacrificed and retroperitoneal and epididymal fat were removed and weighed immediately. Blood samples were collected, and T3 and free T4 measurements were performed in plasma samples stored at −20 °C, using a chemiluminescence method.

Drugs.

TRIAC was obtained from Sigma Aldrich Corporation. For TRIAC experiment, the hormone was diluted in a 50–50 alcohol–water solution for a final concentration of 10 nmol/cm2 and the vehicle was diluted in a 50–50 alcohol–water solution that was applied to the vehicle group.

For nanoencapsulated TRIAC experiment, TRIAC was nanoencapsulated in a poly(d,l-lactide) (PLA) polymer developed by the Nanomedicine and Nanotoxicology Group from the Physics Institute of São Carlos, University of São Paulo. The nanoencapsulation technique utilized was an adaptation from the coprecipitation method combined with nanoprecipitation by solvent evaporation, with a 98% yield [27,28]. For the encapsulation process, an aqueous solution with PLA polymer was mixed to an organic solution containing 20 nM TRIAC in order to induce immediate capsular formation by enclosing the active hormone in its nucleus. As a result of this process modification, there was no need to use surfactant or oil to obtain the nanoencapsulated material. The result of this encapsulated process revealed that the average diameter of the nanocapsules without TRIAC was 160 ± 37 nm and polydispersion index (PdI) was 0.108 ± 0.024. For nanocapsules containing TRIAC, the average diameter increased to 231 ± 59 nm and PdI to 0.062 ± 0.009, indicating a high stability of nanocapsules-TRIAC generated by this process. The nanocapsules containing the active were resuspended in ultrapure water (MilliQ) in a final concentration of 10 nM, once conformational instability was detected using alcoholic solution. Moreover, it was used in a concentration of 10 nmol/cm2. The vehicle in this experiment was composed of PLA polymer resuspended in water.

Skin Histopathology.

Punch skin biopsies were immediately wrapped in individual pre-identified recipients with 10% buffered formaldehyde. After tissue fixation, each biopsy was separated in two halves and one fragment was stored while the other one was submitted to histological processing, including: dehydration in ethanol, clearing in xylem, and embedding in paraffin. At least three serial histological sections (4 μm thick) were obtained per biopsy and stained with hematoxylin and eosin (HE) or picrosirius red for microscopic examination.

Images were captured and analyzed by a system composed of a video camera coupled to an Olympus BX51 microscope, which was linked to a microcomputer with an image digitalizing plate and Uthscsa Imagetool software, version 3.0 (program developed at the University of Texas Health Science Center at San Antonio, TX and available from the Internet by anonymous FTP).2 Five captures of the slides stained with HE were performed at 400 times magnification for epidermal evaluation and another five captures of the slides stained with picrosirius were done for dermal evaluation.

Slides stained with HE were coded and blindly evaluated for epidermal thickness. The thickness of the epidermis (in μm) was measured at five different points in three different sections per biopsy. The mean value was calculated and considered as final.

Slides stained with picrosirius red were examined under polarized light and classified as 0, 1, or 2, meaning no dermal change, dermal partial atrophy, and intense dermal atrophy, respectively. This histological score was based on the extracellular matrix architecture and the outlook of dermal collagen fibers. Collagen type I fibers were recognized in picrosirius staining by their birefringence and red tonality, while collagen type III fibers were seen as less birefringent and yellow–green fibers. The histological appearance of sections classified as 0 showed cytological and architectural characteristics similar to the normal adjacent dermis, meaning no atrophic changes. The slides classified as 1 were the ones that presented the following alterations in 25–50% of the dermal cells: reduced thickness of collagen fibers type I (1.0–20.0 μm) and type III (<0.5–2.0 μm) and increased ratio of collagen fibers type I to type III (normal values of 80–85% type I/15–20% type III). The slides classified as 2 were the ones with intense atrophy, meaning the tissue analyzed had the same characteristics described above in a percentage greater than 50% of the cells [29,30].

Results were presented as mean ± standard error of the mean or percentage. Differences between groups were assessed by Wilcoxon Mann–Whitney or Fischer exact tests, depending on the variable analyzed. The level of significance was set at p < 0.05.

Physiologic parameters are illustrated in Table 1. There was not a significant statistical difference in temperature among the groups in both experiments. TRIAC topical administration determined, in animals with atrophied skin, a significant (p < 0.05) increase in cumulative food ingestion and a decrease in retroperitoneal fat weight, without any difference in weight gain. Nevertheless, nanoencapsulated TRIAC resulted in only an isolated decrease in weight gain in animals with atrophied skin. There were no differences in epididymal fat weight among groups in both experiments.

T3 levels were significantly higher and free T4 were significantly lower (p < 0.0001) in animals treated with TRIAC (TRIAC experiment), compared to those treated with vehicle. On the other hand, in nanoencapsulated TRIAC experiment, there was no difference between T3 and free T4 levels in animals treated with nanoencapsulated TRIAC compared to those treated with vehicle.

At the end of phase I in both experiments, there was a significant decrease in the epidermal thickness after topical GC use (p < 0.0001), confirming the induction of epidermal atrophy.

In TRIAC experiment, the mean values of epidermal thickness, before and after vehicle administration, were, respectively: 2.87 ± 0.23 μm and 2.42 ± 0.18 μm in the intact skin subgroup (1 A) and 2.20 ± 0.46 μm and 1.95 ± 0.37 μm in the atrophic skin subgroup (2 A). The mean values of epidermal thickness, before and after TRIAC topical administration, were, respectively: 2.71 ± 0.30 μm and 2.35 ± 0.05 μm in the intact skin subgroup (1B) and 1.20 ± 0.1 μm and 1.85 ± 0.13 μm in the atrophic skin subgroup (2B). There was no difference in the epidermal thickness among animals with atrophic skin neither among animals with intact skin before TRIAC or vehicle administration (beginning of phase II). Epidermal thickness increased significantly after TRIAC topical administration in animals from the atrophic group (p < 0.0335). There was no significant difference in epidermal thickness at the end of phase II among other groups. Figures 2 and 3 illustrate these results.

In nanoencapsulated TRIAC experiment, the mean values of epidermal thickness, before and after vehicle topical administration, were respectively: 3.25 ± 0.48 μm and 3.25 ± 0.48 μm in the intact skin subgroup (1 A) and 2.06 ± 0.35 μm and 2.91 ± 0.19 μm in the atrophic skin subgroup (2 A). The mean values of epidermal thickness, before and after nanoencapsulated TRIAC topical administration, were, respectively: 2.56 ± 0.13 μm and 2.40 ± 0.10 μm in intact skin subgroup (1B) and 1.71 ± 0.23 μm and 2.18 ± 0.13 μm in atrophic skin subgroup (2B). There was no significant difference in epidermal thickness among groups (Figs. 2 and 3).

Concerning the dermis, GC use resulted in significant skin atrophy in both experiments (p < 0.0001).

In TRIAC experiment, at the end of phase II, 33% of animals treated with vehicle did not show dermal atrophy reversion and 67% had partial reversion. On the other hand, 44% of the animals treated with TRIAC did not present dermal atrophy reversion, 28% had partial reversion, and 28% had total atrophy reversion. It should be mentioned that not a single animal treated with vehicle had total atrophy dermal reversion (Fig. 4).

In nanoencapsulated TRIAC experiment, at the end of phase II, 100% of animals treated with vehicle did not show dermal atrophy reversion, although 14% of the animals treated with nanoencapsulated TRIAC showed partial reversion and 86% had total atrophy reversion. There was a significant increase in the degree of dermal skin atrophy reversal in animals that used nanoencapsulated TRIAC as compared to vehicle (p < 0.0001) (Fig. 4).

In this work, systemic effects of topical TRIAC (nanoencapsulated or not) were evaluated by the following parameters: temperature, weight gain, food ingestion, and epididymal and retroperitoneal fat weight.

The mean temperature of experimental animals was not modified by TRIAC topical administration. It is known that THs exert their actions in almost every body cell and are responsible for increasing lipid metabolism and oxygen consumption, as well as having essential actions in specific systems such as cardiovascular system, causing tachycardia, arrhythmias, and cardiac hypertrophy. The expected effects of therapies that lead to hyperthyroidism are: decreased weight and increased appetite due to high energy expenditure, reduced fat stores, and increased basal body temperature [31]. Although the thermogenic effects of topical TRIAC are not well established, Yazdanparast et al. [16] did not show a change in temperature in studies with humans, and laboratory parameters were within the normal range. Nonetheless, an important thermogenic effect of TRIAC systemic administration has been demonstrated by enhancing adrenergic stimulation of uncoupling protein-1 mRNA in brown adipocytes, in vitro [32] and in vivo [33]. One possible explanation for these findings is that the TRIAC effects vary according to their dose and administration route, and accordingly, the low doses of TRIAC applied topically might not have been sufficient to cause significant thermogenic effects. Additionally, in this study, the animal's temperature was evaluated by rectal measurements, once a day, every other day, which might not be sufficient to reveal small temperature changes.

TRIAC did not modify the animal's weight gain. Although, there was a significant increase in cumulative ingestion in animals with atrophic skin that had TRIAC administration compared to those that had vehicle. This result, as well as the decrease in the mean retroperitoneal fat weight in atrophic skin animals that used TRIAC, suggests that the TRIAC dose used had a stimulatory effect on food ingestion, possibly by decreasing leptin secretion [32], but its lipolitic action resulted in a decline in retroperitoneal fat deposits which resulted in maintaining the animals' body weight. The atrophy group received nanoencapsulated TRIAC has decreased weight gain. More experiments need to be done to confirm and better explain these data.

As for thyroid function evaluation, T3 values were higher in experimental groups treated with TRIAC than in groups that used vehicle, suggesting that there was a cross reactivity between TRIAC and the assay's antibody, which was previously described by Anzai et al. [34]. Additionally, thyroxine values (free T4) were significantly reduced in the group of animals treated with TRIAC suggesting that there was a suppression of endogenous hormone production by systemic absorption of topically applied TRIAC, as was previously described for topical T3 [35]. Experiments that evaluated topical TRIAC to reverse skin atrophy did not show a change in THs plasma levels both in humans [6] and in mice [36]. This could be attributed to methodological differences in drug doses and the administration schedule. It may reflect differences secondary to the animal species studied as in this work, rats were used as experimental animals.

Our results showed a significant effect of TRIAC topical administration on reversing epidermal atrophy secondary to GC in line with previous published data [16]. As for the mechanisms related to this effect, Zhang et al. [37] suggested that TRIAC could act to stimulate epidermal thickening in mice and keratinocyte proliferation in humans by activation of cyclin D1 expression.

TRIAC topical administration was also shown to result in significant dermis thickness increase [15], collagen production, elastic fibers synthesis, and dermal proliferation [31] similarly to what was demonstrated by Safer et al. [38] with T3 topical use. Yazdanparast et al. [6] suggested that topical treatment with TRIAC could restore skin local hypothyroidism induced by GC and thus reverse impaired skin procollagen I expression. The dermal atrophy reversal found in this study could be the result of TRIAC action on collagen synthesis [15,39] as suggested by histological analyses of Picrosirius red staining material.

In our study, nanoencapsulated TRIAC did not show effects significantly different from those observed with vehicle on epidermal thickness. On the other hand, animals that received nanoencapsulated TRIAC were able to partially (14%) and fully (86%) reverse dermal atrophy caused by GC, while animals receiving vehicle showed no effect on dermal atrophy reversion. These different effects on epidermis and dermis may be related to the degree of skin penetration of the nanoencapsulated drug and/or its higher activity in deeper skin layers as a result of their better biodistribution profile and to the extended half-life of the encapsulated TRIAC compared to the nonencapsuleted molecule as a result of its lower degradation in epidermis [23,40]. It was demonstrated that TRIAC is rapidly inactivated by skin deiodinases and may have a short life in skin [41]. Another possibility is that the process of atrophy, by changing skin function as a protective barrier [42], facilitated nanoencapsulated TRIAC dermal penetration [16].

Our results, based on physiological parameters and hormone levels, suggested that there was a greater systemic TRIAC absorption compared to nanoencapsulated TRIAC, resulting in the inhibition of endogenous thyroid function. Nevertheless, topical application of nanoencapsulated TRIAC did not determine changes in the hypothalamic–pituitary–thyroid axis. The finding of an isolated decrease in weight gain in the atrophy group that received nanoencapsulated TRIAC, compared to animals that received vehicle, could be interpreted as a result of systemic catabolic actions induced by this drug [31]. However, measurements of cumulative food ingestion, visceral fat weight, and hormone levels do not support this hypothesis and more studies are needed to confirm and elucidate nanoencapsulated TRIAC action on weight gain.

The results of this work show that topical use of TRIAC and nanoencapsulated TRIAC determined significant reversal of dermal atrophy. Nanoencapsulated TRIAC may be a promising option for the treatment of cutaneous atrophy, because of its deeper layer skin action and less systemic effects, although further studies are necessary to confirm this conclusion.

Funding from Brazilian Coordination for the Improvement of Higher Education Personnel (CAPES), Program NANOBIOTEC 856/2009, Process No. 23038.027482/2009-60, and São Paulo Research Foundation (FAPESP), Process No. 12/03984-9 is appreciated.

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Medina-Gomez, G., Hernàndez, A., Calvo, R. M., Martin, E., and Obregón, M. J., 2003, “Potent Thermogenic Action of Triiodothyroacetic Acid in Brown Adipocytes,” Cell Mol. Life Sci., 60(9), pp. 1957–1967. [CrossRef] [PubMed]
Medina-Gomez, G., Calvo, R. M., and Obregon, M. J., 2008, “Thermogenic Effect of Triiodothyroacetic Acid at Low Doses in Rat Adipose Tissue Without Adverse Side Effects in the Thyroid Axis,” Am. J. Physiol. Endocrinol. Metab., 294(4), pp. E688–E697. [CrossRef] [PubMed]
Anzai, R., Adachi, M., Sho, N., Muroya, K., Asakura, Y., and Onigata, K., 2012, “Long-Term 3,5,3′-Triiodothyroacetic Acid Therapy in a Child With Hyperthyroidism Caused by Thyroid Hormone Resistance: Pharmacological Study and Therapeutic Recommendations,” Thyroid, 22(10), pp. 1069–1075. [CrossRef] [PubMed]
Safer, J. D., Fraser, L. M., Ray, S., and Holick, M. F., 2011, “Topical Triiodothyronine Stimulates Epidermal Proliferation, Dermal Thickening, and Hair Growth in Mice and Rats,” Thyroid, 11(8), pp. 717–724. [CrossRef]
Yazdanparast, P., Carlsson, B., Sun, X. Y., Zhao, X. H., Hedner, T., and Faergemann, J., 2006, “Action of Topical Thyroid Hormone Analogues on Glucocorticoid-Induced Skin Atrophy in Mice,” Thyroid, 16(3), pp. 273–280. [CrossRef] [PubMed]
Zhang, B., Zhang, A., Zhou, X., Webb, P., He, W., and Xia, X., 2012, “Thyroid Hormone Analogue Stimulates Keratinocyte Proliferation but Inhibits Cell Differentiation in Epidermis,” Int. J. Immunopathol. Pharmacol., 25(4), pp. 859–869. Available at: http://connection.ebscohost.com/c/articles/89166477/thyroid-hormone-analogue-stimulates-keratinocyte-proliferation-but-inhibits-cell-differentiation-epidermis [PubMed]
Safer, J. D., Crawford, T. M., Fraser, L. M., Hoa, M., Ray, S., Chen, T. C., Persons, K., and Holick, M. F., 2003, “Thyroid Hormone Action on Skin: Diverging Effects of Topical Versus Intraperitoneal Administration,” Thyroid, 13(2), pp. 159–165. [CrossRef] [PubMed]
Safer, J. D., 2013, “Thyroid Hormone and Wound Healing,” J. Thyroid Res., 2013, p. 124538. [CrossRef] [PubMed]
Elsabahy, M., and Wooley, K. L., 2012, “Design of Polymeric Nanoparticles for Biomedical Delivery Applications,” Chem. Soc. Rev., 41(7), pp. 2545–2561. [CrossRef] [PubMed]
Santini, F., Vitti, P., Chiovato, L., Ceccarini, G., Macchia, M., Montanelli, L., Gatti, G., Rosellini, V., Mammoli, C., Martino, E., Chopra, I. J., Safer, J. D., Braverman, L. E., and Pinchera, A., 2003, “Role for Inner Ring Deiodination Preventing Transcutaneous Passage of Thyroxine,” J. Clin. Endocrinol. Metab., 88(6), pp. 2825–2830. [CrossRef] [PubMed]
Schoepe, S., Vonk, R., Schäcke, H., Zollner, T. M., Asadullah, K., and Röse, L., 2011, “Shortened Treatment Duration of Glucocorticoid-Induced Skin Atrophy in Rats,” Exp.Dermatol., 20(10), pp. 853–855. [CrossRef] [PubMed]
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Topics: Skin , Vehicles , Drugs
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References

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Oishi, Y., Fu, Z. W., Ohnuki, Y., Kato, H., and Noguchi, T., 2002, “Molecular Basis of the Alteration in Skin Collagen Metabolism in Response to in Vivo Dexamethasone Treatment: Effects on the Synthesis of Collagen Type I and III, Collagenase, and Tissue Inhibitors of Metalloproteinases,” Br. J. Dermatol., 147(5), pp. 859–868 [CrossRef] [PubMed]
Moreno, M., de Lange, P., Lombardi, A., Silvestri, E., Lanni, A., and Goglia, F., 2008, “Metabolic Effects of Thyroid Hormone Derivatives,” Thyroid, 18(2), pp. 239–253. [CrossRef] [PubMed]
Medina-Gomez, G., Hernàndez, A., Calvo, R. M., Martin, E., and Obregón, M. J., 2003, “Potent Thermogenic Action of Triiodothyroacetic Acid in Brown Adipocytes,” Cell Mol. Life Sci., 60(9), pp. 1957–1967. [CrossRef] [PubMed]
Medina-Gomez, G., Calvo, R. M., and Obregon, M. J., 2008, “Thermogenic Effect of Triiodothyroacetic Acid at Low Doses in Rat Adipose Tissue Without Adverse Side Effects in the Thyroid Axis,” Am. J. Physiol. Endocrinol. Metab., 294(4), pp. E688–E697. [CrossRef] [PubMed]
Anzai, R., Adachi, M., Sho, N., Muroya, K., Asakura, Y., and Onigata, K., 2012, “Long-Term 3,5,3′-Triiodothyroacetic Acid Therapy in a Child With Hyperthyroidism Caused by Thyroid Hormone Resistance: Pharmacological Study and Therapeutic Recommendations,” Thyroid, 22(10), pp. 1069–1075. [CrossRef] [PubMed]
Safer, J. D., Fraser, L. M., Ray, S., and Holick, M. F., 2011, “Topical Triiodothyronine Stimulates Epidermal Proliferation, Dermal Thickening, and Hair Growth in Mice and Rats,” Thyroid, 11(8), pp. 717–724. [CrossRef]
Yazdanparast, P., Carlsson, B., Sun, X. Y., Zhao, X. H., Hedner, T., and Faergemann, J., 2006, “Action of Topical Thyroid Hormone Analogues on Glucocorticoid-Induced Skin Atrophy in Mice,” Thyroid, 16(3), pp. 273–280. [CrossRef] [PubMed]
Zhang, B., Zhang, A., Zhou, X., Webb, P., He, W., and Xia, X., 2012, “Thyroid Hormone Analogue Stimulates Keratinocyte Proliferation but Inhibits Cell Differentiation in Epidermis,” Int. J. Immunopathol. Pharmacol., 25(4), pp. 859–869. Available at: http://connection.ebscohost.com/c/articles/89166477/thyroid-hormone-analogue-stimulates-keratinocyte-proliferation-but-inhibits-cell-differentiation-epidermis [PubMed]
Safer, J. D., Crawford, T. M., Fraser, L. M., Hoa, M., Ray, S., Chen, T. C., Persons, K., and Holick, M. F., 2003, “Thyroid Hormone Action on Skin: Diverging Effects of Topical Versus Intraperitoneal Administration,” Thyroid, 13(2), pp. 159–165. [CrossRef] [PubMed]
Safer, J. D., 2013, “Thyroid Hormone and Wound Healing,” J. Thyroid Res., 2013, p. 124538. [CrossRef] [PubMed]
Elsabahy, M., and Wooley, K. L., 2012, “Design of Polymeric Nanoparticles for Biomedical Delivery Applications,” Chem. Soc. Rev., 41(7), pp. 2545–2561. [CrossRef] [PubMed]
Santini, F., Vitti, P., Chiovato, L., Ceccarini, G., Macchia, M., Montanelli, L., Gatti, G., Rosellini, V., Mammoli, C., Martino, E., Chopra, I. J., Safer, J. D., Braverman, L. E., and Pinchera, A., 2003, “Role for Inner Ring Deiodination Preventing Transcutaneous Passage of Thyroxine,” J. Clin. Endocrinol. Metab., 88(6), pp. 2825–2830. [CrossRef] [PubMed]
Schoepe, S., Vonk, R., Schäcke, H., Zollner, T. M., Asadullah, K., and Röse, L., 2011, “Shortened Treatment Duration of Glucocorticoid-Induced Skin Atrophy in Rats,” Exp.Dermatol., 20(10), pp. 853–855. [CrossRef] [PubMed]

Figures

Grahic Jump Location
Fig. 3

Illustrative photomicrography of epidermal thickness at the end of the experiments in different groups. In TRIAC experiment: intact skin vehicle (subgroup 1 A), intact skin TRIAC (subgroup 1B), atrophic skin vehicle (subgroup 2 A), and atrophic skin TRIAC (subgroup 2B). In nanoencapsulated TRIAC experiment: intact skin vehicle (subgroup 1 A), intact skin nanoencapsulated TRIAC (subgroup 1B), atrophic skin vehicle (subgroup 2 A), and atrophic skin nanoencapsulated TRIAC (subgroup 2B) (400×).

Grahic Jump Location
Fig. 1

Schematic representation of experimental design. Each experiment was carried out in two phases. In phase I, animals were divided into two groups: in group 1, animals remained with intact skin; in group 2, cutaneous atrophy was induced by topical administration of Clobetasol propionate for 10 days. In phase II, each group of animals with intact (group 1) or atrophic skin (group 2) was subdivided 2 subgroups: in subgroups A, the vehicle was used; in subgroups B, TRIAC or nanoencapsulated TRIAC was administered daily for 14 days, depending on the experiment.

Grahic Jump Location
Fig. 2

Effects of vehicle or TRIAC/nanoencapsulated TRIAC in epidermal thickness of rats with intact or atrophic skin—data are represented as mean ± SE (bars). In TRIAC experiment: intact skin vehicle (subgroup 1 A), intact skin TRIAC (subgroup 1B), atrophy skin vehicle (subgroup 2 A), and atrophy skin TRIAC (subgroup 2B). In nanoencapsulated TRIAC experiment: intact skin vehicle (subgroup 1 A), intact skin nanoencapsulated TRIAC (subgroup 1B), atrophic skin vehicle (subgroup 2 A), and atrophic skin nanoencapsulated TRIAC (subgroup 2B). *p < 0.05.

Grahic Jump Location
Fig. 4.

Illustrative photomicrography of dermal appearance in picrosirius staining histological slides: no atrophy reversion (a), partial atrophy reversion (b), and total atrophy reversion (c) in TRIAC experiment; and no atrophy reversion (d), partial atrophy reversion (e), and total atrophy reversion (f) in nanoencapsulated TRIAC experiment (400×).

Tables

Table Grahic Jump Location
Table 1 Physiological parameters in experiments 1 and 2
Table Footer Note*p < 0.05

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