RESUMEN
Hair growth, a complex process, has long been the subject of intense research. Recent developments in material technology have revealed boehmite as a new therapeutic modality for use in wound healing and scar reduction, indicating its beneficial effects. Nonetheless, the biological bases of the beneficial effects of boehmite remain unknown. We investigated the hair growth properties of boehmite in vitro and in vivo and observed dose-dependent proliferation of human dermal papilla cells (hDPCs) in vitro and hair regrowth in a mouse model. To investigate the effects of boehmite on the promotion of cell transition to the anagen phase, we evaluated hDPC viability, alkaline phosphatase (ALP) activity, protein expression and vascular endothelial growth factor (VEGF) secretion in vitro and assessed the anagen-promoting effects of boehmite via gross observation and histological analysis in a mouse model. Boehmite increased hDPC viability, ALP activity, AKT/GSK3ß/ß-catenin pathway activity, anagen-related gene expression and VEGF secretion; moreover, it accelerated hair regrowth in a catagen-anagen transition model via upregulation of ß-catenin signalling and follicular cell proliferation. Collectively, our results indicate that boehmite accelerates hair growth, partly via its effects on critical events in the active phase of the hair follicle cycle, including the promotion of the proliferation of hDPCs and their immediate progeny to the follicle base.
Asunto(s)
Hidróxido de Aluminio/farmacología , Óxido de Aluminio/farmacología , Folículo Piloso/efectos de los fármacos , Piel/metabolismo , beta Catenina/metabolismo , Animales , Proliferación Celular , Dermis/citología , Modelos Animales de Enfermedad , Femenino , Cabello/fisiología , Humanos , Ratones , Ratones Endogámicos C3H , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vía de Señalización Wnt , Cicatrización de Heridas , Difracción de Rayos XRESUMEN
Boehmite (γ-AlOOH) has a wide range of applications in a variety of industrial and biological fields. However, little is known about its potential roles in skin diseases. The current study investigated its effect on atopic dermatitis (AD). Following characterization, cytotoxicity, pro-inflammatory response and oxidative stress associated with boehmite were assessed, using TNF-α-induced keratinocytes and mast cells. In addition, therapeutic effects of boehmite, topically administered to Balb/c mice induced by 2,4-dinitrochlorobenzene (DNCB), were evaluated. Expression of cytokines (TLSP, IL-25 and IL-33) and the generation of ROS from keratinocytes induced by TNF-α were significantly inhibited by boehmite without affecting cell viability. MAPKs (ERK, JNK and p38) required for cytokine expression were suppressed by boehmite treatment. Up-regulation of cytokines (TSLP, IL-4, IL-5, IL-13, RANTES) in human mast cells treated with phorbol 12-myristate 13-acetate and calcium ionophore was also suppressed by boehmite. Boehmite improved the AD severity score, epidermal hyperplasia and transepidermal water loss in DNCB-induced AD-like lesions. Moreover, Th2-mediated cytokine expression, mast cell hyperplasia and destruction of the skin barrier were improved by boehmite treatment. Overall, we demonstrated that boehmite may potentially protect against AD.
Asunto(s)
Hidróxido de Aluminio/uso terapéutico , Óxido de Aluminio/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Enfermedades de la Piel/tratamiento farmacológico , Piel/efectos de los fármacos , Administración Tópica , Animales , Antiinflamatorios/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular , Dinitroclorobenceno , Epidermis/metabolismo , Humanos , Inflamación , Interleucina-33/metabolismo , Interleucinas/metabolismo , Queratinocitos/citología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo , Serina Endopeptidasas/metabolismo , Acetato de Tetradecanoilforbol , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Ultraviolet (UV) light produces an immunomodulatory effect on the skin and is widely used for the treatment of chronic inflammatory skin diseases. UV light emitting diodes (UV-LEDs) are a new and promising source of UV radiation. However, their mechanism of action remains largely unknown. In this study, we tested the safety and effectiveness of UV-LED irradiation for the treatment of atopic dermatitis (AD) in an NC/Nga mouse model. Mice were divided into seven groups of eight mice each. Application of Dermatophagoides farinae (Df) extract ointment for four weeks induced AD-like skin lesions. Subsequently, the mice were exposed to UV-LEDs, narrow band UVB, or UVA irradiation three times per week. We assessed the immunosuppressive effects of 310 nm (50 mJ cm-2) and 340 nm (5 J cm-2) UV-LED irradiation. Histological analyses using hematoxylin-eosin, toluidine blue, and immunohistochemical staining were performed. In addition, the serum levels of IgE, inflammatory cytokines and chemokines were measured using enzyme-linked immunosorbent assays (ELISAs). UV-LED irradiation significantly alleviated AD-like skin symptoms, including edema, erythema, dryness, and itching, by modulating Th1 and Th2 responses, transepidermal water loss (TEWL), and scratching behavior in NC/Nga mice. These results suggest that UV-LEDs can improve the treatment of inflammatory skin diseases.
Asunto(s)
Dermatitis Atópica/prevención & control , Piel/efectos de la radiación , Rayos Ultravioleta , Alérgenos/efectos adversos , Animales , Quimiocinas/sangre , Citocinas/sangre , Dermatitis Atópica/etiología , Dermatitis Atópica/patología , Dermatophagoides farinae/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina E/sangre , Masculino , Ratones , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de la radiación , Piel/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: Various studies have investigated treatment for vaginal laxity with microablative fractional carbon dioxide CO2 laser in humans; however, this treatment has not yet been studied in an animal model. Herein, we evaluate the therapeutic effects of fractional CO2 laser for tissue remodeling of vaginal mucosa using a porcine model, with the aim of improving vaginal laxity. STUDY DESIGN/MATERIALS AND METHODS: The fractional CO2 laser enables minimally invasive and non-incisional procedures. By precisely controlling the laser energy pulses, energy is sent to the vaginal canal and the introitus area to induce thermal denaturation and contraction of collagen. We examined the effects of fractional CO2 laser on a porcine model via clinical observation and ultrasound measurement. Also, thermal lesions were histologically examined via hematoxylin-eosin staining, Masson's trichrome staining, and Elastica van Gieson staining and immunohistochemistry. RESULTS: The three treatment groups, which were determined according to the amount of laser-energy applied (60, 90, and 120 mJ), showed slight thermal denaturation in the vaginal mucosa, but no abnormal reactions, such as excessive hemorrhaging, vesicles, or erythema, were observed. Histologically, we also confirmed that the denatured lamina propria induced by fractional CO2 laser was dose-dependently increased after laser treatment. The treatment groups also showed an increase in collagen and elastic fibers due to neocollagenesis and angiogenesis, and the vaginal walls became firmer and tighter because of increased capillary and vessel formation. Also, use of the fractional CO2 laser increased HSP (heat shock protein) 70 and collagen type I synthesis. CONCLUSION: Our results show that microablative fractional CO2 laser can produce remodeling of the vaginal connective tissue without causing damage to surrounding tissue, and the process of mucosa remodeling while under wound dressings enables collagen to increase and the vaginal wall to become thick and tightened. Lasers Surg. Med. 50:940-947, 2018. © 2018 Wiley Periodicals, Inc.
Asunto(s)
Terapia por Láser , Láseres de Gas/uso terapéutico , Vagina/efectos de la radiación , Animales , Femenino , Modelos Animales , Porcinos , Vagina/diagnóstico por imagen , Vagina/patologíaRESUMEN
Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) are used in tissue repair and regeneration; however, the mechanisms involved are not well understood. We investigated the hair growth-promoting effects of hUCB-MSCs treatment to determine whether hUCB-MSCs enhance the promotion of hair growth. Furthermore, we attempted to identify the factors responsible for hair growth. The effects of hUCB-MSCs on hair growth were investigated in vivo, and hUCB-MSCs advanced anagen onset and hair follicle neogeneration. We found that hUCB-MSCs co-culture increased the viability and up-regulated hair induction-related proteins of human dermal papilla cells (hDPCs) in vitro. A growth factor antibody array revealed that secretory factors from hUCB-MSCs are related to hair growth. Insulin-like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF) were increased in co-culture medium. Finally, we found that IGFBP-1, through the co-localization of an IGF-1 and IGFBP-1, had positive effects on cell viability; VEGF secretion; expression of alkaline phosphatase (ALP), CD133, and ß-catenin; and formation of hDPCs 3D spheroids. Taken together, these data suggest that hUCB-MSCs promote hair growth via a paracrine mechanism.
RESUMEN
Alopecia is a common and distressing condition, and developing new therapeutic agents to prevent hair loss is important. Human umbilical cord bloodderived mesenchymal stem cells (hUCBMSCs) have been studied intensively in regenerative medicine. However, the therapeutic potential of these cells against hair loss and hair organ damage remains unclear, and the effects of hUCBMSC transplantation on hair loss require evaluation. The current study aimed to investigate the effects of hUCBMSCs on hair regression in vivo and restoration of anagen conduction on hair growth in vitro. The effects of hUCBMSCs were explored in mouse catagen induction models using a topical treatment of 0.1% dexamethasone to induce hair regression. Dexamethasone was also used to simulate a stress environment in vitro. The results demonstrated that hUCBMSCs significantly prevented hair regression induced by dexamethasone topical stimulation in vivo. Additionally, hUCBMSCs significantly increased the proliferation of human dermal papilla cells (hDPCs) and HaCaT cells, which are key constituent cells of the hair follicle. Stimulation of vascular endothelial growth factor secretion and decreased expression of DKK1 by hUCBMSCs were also observed in hDPCs. Restoration of cell viability by hUCBMSCs suggested that these cells exerted a protective effect on glucocorticoid stressassociated hair loss. In addition, antiapoptotic effects and regulation of the autophagic flux recovery were observed in HaCaT cells. The results of the present study indicated that hUCBMSCs may have the capacity to protect hair follicular dermal papilla cells and keratinocytes, thus preventing hair loss. Additionally, the protective effects of hUCBMSCs may be resistant to dysregulation of autophagy under harmful stress.
Asunto(s)
Antiinflamatorios/efectos adversos , Dexametasona/efectos adversos , Folículo Piloso/citología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Células Cultivadas , Femenino , Sangre Fetal/citología , Cabello/citología , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Cabello/ultraestructura , Folículo Piloso/efectos de los fármacos , Folículo Piloso/ultraestructura , Humanos , Ratones Endogámicos C57BLRESUMEN
A new type A botulinum toxin (BoNT/A) preparation, JTM201 (NCBI chromosomal DNA ID: CP046450), has been developed, which comprises 900-kDa complexed toxin purified from Clostridium botulinum (strain: NCTC13319), but its safety and efficacy have not yet been evaluated. The purpose of this study was to evaluate the long-term efficacy and safety of JTM201 at different concentrations in comparison to another commercially available BoNT/A product, Botox® (onabotulinumtoxin A, ONA), using a mouse model. The LD50 of JTM201 was similar to that of ONA, but the intrinsic activity of JTM201 was higher than that of ONA. Functional recovery of the nerves and muscles in SKH-1 mice after administration of the two BoNT/A preparations (JTM201 and ONA) to the right gastrocnemius muscle was observed over 24 weeks. In addition, JTM201 did not induce any skin or muscle inflammatory response in 24 weeks. Paralysis induced by neurotransmitter blockade after JTM201 administration was comparable to that of ONA treatment. Both muscle weight and volume decreased in a concentration-dependent manner following JTM201 or ONA toxin injection until week 4. Reduced muscle fiber size due to atrophy and consequent fibrosis were detected following injection of JTM201 or ONA. Moreover, we assessed the extent of diffusion of JTM201 or ONA to the tibialis anterior and quadriceps femoris muscles, demonstrating limited diffusion to off-target muscles. In conclusion, JTM201 demonstrated long-term efficacy and safety equivalent to those of ONA based on compound muscle action potential, muscle volume, and histology analyses. These data suggest that JTM201 is a new BoNT/A formulation with safety and efficacy comparable to those of ONA.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Músculo Esquelético , Animales , RatonesRESUMEN
Botulinum toxin A (BoNT-A) is used clinically for various muscle disorders and acts by preventing the release of the neurotransmitter acetylcholine into the synapse space. Here, we compared the efficacy of prabotulinumtoxinA (PRA) and onabotulinumtoxinA (ONA) for the reduction in hypertrophy in myostatin-deficient (Mstn-/- ) mice. Two different BoNT-A products (2.5, 10 and 25 U/kg) were injected to paralyse the hindlimb for 2 months, after which sciatic nerve conduction study, 3D micro-CT, haematoxylin and eosin (H&E) and dystrophin staining were conducted. Administration of BoNT-A products induced denervation-mediated atrophy and alleviated muscle hypertrophy generated in Mstn-/- mice. The present study revealed that each BoNT-A regulates skeletal muscle size, myofibre number and myofibre diameter in Mstn-/- mice. The potential applicability of BoNT-A for the treatment of rare muscle hypertrophic diseases was demonstrated. Compared with ONA, PRA had a comparable ability to act in the local area.
Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Toxinas Botulínicas/farmacología , Hipertrofia/tratamiento farmacológico , Enfermedades Musculares/tratamiento farmacológico , Miostatina/genética , Animales , Toxinas Botulínicas/administración & dosificación , Toxinas Botulínicas Tipo A/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Miembro Posterior , Hipertrofia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/patología , Enfermedades Musculares/fisiopatología , Fármacos Neuromusculares/administración & dosificación , Fármacos Neuromusculares/farmacologíaRESUMEN
The use of finasteride for alleviating hair loss has been investigated, and it has been applied as an oral dose medication. However, due to the inconvenience of daily drug administration over long period of time, novel controllable finasteride delivery has been actively investigated. As a novel method of finasteride delivery, the development of finasterideloaded microspheres for subcutaneous administration is becoming increasingly pharmaceutically important. Therefore, the present study aimed to use finasterideloaded microspheres in a controlled manner in an attempt to overcome the limitations of the oral administration of finasteride and to cause fewer adverse effects. Finasterideloaded microspheres containing poly(lacticcoglycolic acid) and finasteride at a ratio of 4:1 were prepared, and a testosteroneinduced androgenic alopecia mouse model was used. Following observation for 10 weeks, the percentage hair growth was 86.7% (total hair growth 60%, partial hair growth 26.7%) in the orallyapplied finasteridetreated group as a positive control, and 93.3% (total hair growth 60%, partial hair growth 33.3%) in the finasterideloaded microspherestreated group. Serum dihydrotestosterone levels began to decrease at week 6 in the orallyapplied finasteride and finasterideloaded microspheretreated groups. In addition, the finasterideloaded microspherestreated group exhibited similar follicular number, follicular length, anagen/telogen ratio and hair bulb diameter values to those of the orallyapplied finasteridetreated group. Furthermore, the finasterideloaded microspheres increased the activities of phosphoinositide 3kinase/protein kinase B and Wnt/ßcatenin in relation to hair follicle cell growth signaling in mouse skin, and suppressed the apoptosis of hair follicle cells by reducing the expression of transforming growth factorß2 and caspase3, which are indicators of apoptosis. In conclusion, the administration of a single injection of finasterideloaded microspheres was effective in treating testosteroneinduced alopecia. Furthermore, it led to equivalent hair growth effects when compared with orallyapplied finasteride, thus revealing the possibility of effective treatment via different routes of administration.
Asunto(s)
Inhibidores de 5-alfa-Reductasa/administración & dosificación , Alopecia/tratamiento farmacológico , Portadores de Fármacos/química , Finasterida/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Alopecia/patología , Animales , Modelos Animales de Enfermedad , Finasterida/uso terapéutico , Folículo Piloso/efectos de los fármacos , Folículo Piloso/patología , Inyecciones , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Apoptosis and oxidative stress are essential for the pathogenesis of acute liver failure and fulminant hepatic failure. Human placental hydrolysate (hPH) has been reported to possess antioxidant and antiinflammatory properties. In the present study, the protective effects of hPH against Dgalactosamine (DGalN) and lipopolysaccharide (LPS)induced hepatocyte apoptosis were investigated in vivo. In addition, the molecular mechanisms underlying the antiapoptotic activities of hPH against DGalNinduced cell death in vitro were examined. Male SpragueDawley rats were injected with DGaIN/LPS with or without the administration of hPH. Rats were sacrificed 24 h after DGaIN/LPS intraperitoneal injection, and the blood and liver samples were collected for future inflammation and hepatotoxicity analyses. Changes in cell viability, apoptosis protein expression, mitochondrial mass, mitochondrial membrane potential, reactive oxygen species generation, and the levels of proteins and mRNA associated with a protective mechanism were determined in HepG2 cells pretreated with hPH for 2 h prior to DGalN exposure. The findings suggested that hPH treatment effectively protected against DGalN/LPSinduced hepatocyte apoptosis by reducing the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, interleukin6, and tumor necrosis factorα, and increasing the level of proliferating cell nuclear antigen. It was also found that hPH inhibited the apoptotic cell death induced by DGalN. hPH activated the expression of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, and catalase, which were further upregulated by the Kelchlike ECH2associated protein 1p62nuclear factorerythroid 2related factor 2 pathway, a component of oxidative stress defense mechanisms. Furthermore, hPH markedly reduced cytosolic and mitochondrial reactive oxygen species and rescued mitochondrial loss and dysfunction through the reduction of damageregulated autophagy modulator, p53, and C/EBP homologous protein. Collectively, hPH exhibited a protective role in hepatocyte apoptosis by inhibiting oxidative stress and maintaining cell homeostasis. The underlying mechanisms may be associated with the inhibition of endoplasmic reticulum stress and minimization of the autophagy progress.
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Apoptosis/fisiología , Estrés Oxidativo/fisiología , Placenta/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/genética , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Femenino , Galactosamina/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Lipopolisacáridos , Potencial de la Membrana Mitocondrial/fisiología , Estrés Oxidativo/genética , Embarazo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a complex, heterogeneous pathogenesis including skin barrier dysfunction, immunology, and pruritus. Although epidermal growth factor (EGF) is essential for epithelial homeostasis and wound healing, the effect of EGF on AD remains to be explored. To develop a new therapy for AD, the anti-AD potential of EGF was investigated by inducing AD-like skin lesions in NC/Nga mice using 2,4-dinitrochlorobenzene (DNCB). EGF was administrated to NC/Nga mice to evaluate its therapeutic effect on DNCB-induced AD. EGF treatment improved dermatitis score, ear thickness, epidermal hyperplasia, serum total immunoglobulin E level, and transepidermal water loss in NC/Nga mice with DNCB-induced AD. In addition, levels of skin barrier-related proteins such as filaggrin, involucrin, loricrin, occludin, and zonula occludens-1 (ZO-1) were increased by EGF treatment. These beneficial effects of EGF on AD may be mediated by EGF regulation of Th1/Th2-mediated cytokines, mast cell hyperplasia, and protease activated receptor-2 (PAR-2) and thymic stromal lymphopoietin (TSLP), which are triggers of AD. Taken together, our findings suggest that EGF may potentially protect against AD lesional skin via regulation of skin barrier function and immune response.
Asunto(s)
Dermatitis Atópica/prevención & control , Factor de Crecimiento Epidérmico/farmacología , Mastocitos/efectos de los fármacos , Piel/efectos de los fármacos , Administración Tópica , Animales , Citocinas/inmunología , Citocinas/metabolismo , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/inmunología , Dinitroclorobenceno , Factor de Crecimiento Epidérmico/administración & dosificación , Proteínas Filagrina , Proteínas de Filamentos Intermediarios/inmunología , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacología , Receptor PAR-2/inmunología , Receptor PAR-2/metabolismo , Piel/inmunología , Piel/metabolismo , Proteína de la Zonula Occludens-1/inmunología , Proteína de la Zonula Occludens-1/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population. METHODS: A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models. RESULTS: Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing. DISCUSSION: We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.