An analysis of gene expression data involving examination of signaling pathways activation reveals new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia

Androgenetic alopecia is the most common form of hair loss. Minoxidil has been approved for the treatment of hair loss, however its mechanism of action is still not fully clarified. In this study, we aimed to elucidate the effects of 5% minoxidil topical foam on gene expression and activation of signaling pathways in vertex and frontal scalp of men with androgenetic alopecia. We identified regional variations in gene expression and perturbed signaling pathways using in silico Pathway Activation Network Decomposition Analysis (iPANDA) before and after treatment with minoxidil. Vertex and frontal scalp of patients showed a generally similar response to minoxidil. Both scalp regions showed upregulation of genes that encode keratin associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after minoxidil treatment. Our results provide new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia.     

Chicken embryo as a model for regenerative medicine

Although the chick embryo, including its extraembryonic membranes, has long been used as a model for developmental biology, its potential as a model for the repair and regeneration of adult human tissues is often overlooked. The chick offers a well-defined profile of intercellular and intracellular signaling pathways regulating the development of nearly every organ system in conjunction with great flexibility for chimeric and transgenic experiments. Depending upon the system of interest, the chick can either directly reflect the human condition, as in spinal cord repair or in chorioallantoic membrane wound healing, and therefore act as an in vivo model for repair, or mirror our aspired therapy as in limb generation or otic restoration and therefore act as our guide. With these unique opportunities, the chick embryo is certainly a model to be considered when aiming to develop a regenerative therapy for human applications.     

雄激素性脱发的发病机制与激光治疗

雄激素性脱发(androgenetic alopecia,AGA)是皮肤科的常见病与多发病,雄激素性脱发的药物综合治疗及手术治疗的部分患者取得了一定的效果,但都存在副作用大、患者依从性差等问题,有研究表明低功率激光能够促进动物毛发的生长,因而可能在改善雄激素性脱发的症状方面具有重要的应用前景。本文回顾近年来对雄激素性脱发的可能发病机制、治疗现状及激光治疗的研究情况和进展,旨在为雄激素性脱发的治疗奠定科学依据。     

Thyroid receptor agonists for the treatment of androgenetic alopecia

A thyroid hormone receptor β subtype-selective thyromimetic 5 was found to be efficacious in both mouse and monkey hair growth models after topical applications. It penetrates the skin according to the test in human cadaver skin mounted onto Franz diffusion chambers. The serum drug level of 5 is below the limit of quantification during tests in the bald stump-tailed macaques (Macaca arctoides). It is tested negative in the 3T3 neutral red uptake (NRU) phototoxicity test, indicating a low risk for causing photo-irritation. It is also rapidly metabolized according to the PK data, thus the systemic exposure is limited.     

BMI and levels of zinc,copper in hair,serum and urine of Turkish male patients with androgenetic alopecia

ObjectiveMale pattern androgenetic alopecia is characterized by progressive hair loss from the scalp. It is known that imbalances of some trace elements play a role in the pathomechanism of many forms of alopecia. The aim of this study was to evaluate the levels of zinc and copper in hair, serum and urine samples of Turkish males with male pattern androgenetic alopecia and to compare with healthy controls.Material and methods116 males with male pattern androgenetic alopecia and 100 controls were involved in this study.ResultsLevels of zinc and copper in hair were decreased significantly in the patients (p < 0.05), although zinc and copper levels of serum and urine were not different between patients and controls (p > 0.05). Body mass index of patients were higher than control group. In addition, in the group with body mass index of 25 and lower zinc level in hair and urine, copper level in serum were significantly higher (p < 0.05). Body mass index was negatively correlated with hair zinc levels.ConclusionWe thought that decreased zinc and copper levels in hair may play a role in the etiology of male pattern androgenetic alopecia. In addition, obesity by making changes in the balance of the trace elements in hair, serum and urine may play a role in male pattern androgenetic alopecia. Hence, assessing the levels of trace elements in hair of male pattern androgenetic alopecia patients may be more valuable compared to serum and urine for treatment planning.     

基于肠-皮肤轴的益生菌改善脱发机制研究进展

随着人们生活压力的提升,许多男性在中年时期出现脱发,严重者甚至会出现斑秃、全秃现象,其中以雄激素脱发最为常见。雄激素脱发的发生主要由于头皮中睾酮(testosterone,T)及其代谢产物二氢睾酮(dihydrotestosterone,DHT)含量较多,其主要机制为毛囊中5α-还原酶将游离的T转化为活性更高的DHT,导致雄激素水平过高。雄激素水平过高会引起毛囊微小化,使毛发生长周期变短而产生脱发。基于肠-皮肤轴的理论,越来越多的研究表明益生菌(probiotics)能够改善或治疗脱发症状。通过益生菌调节肠道菌群的平衡,可促进体内毛发生长因子的表达和毛囊细胞的生长,改善由于压力过大或雄激素水平过高等因素引起的脱发症状。本文主要探讨益生菌与毛发生长的相关性,通过其对神经系统、免疫系统和内分泌系统的调节作用,对益生菌改善脱发的功能和机理进行综述,以期为研发改善脱发的食品和药物提供理论依据。     

Ratio of the zygote cytoplasm to the paternal genome affects the reprogramming and developmental efficiency of androgenetic embryos

Uniparental embryos have uniparental genomes and are very useful models for studying the specific gene expression of parents or for exploring the biological significance of genomic imprinting in mammals. However, the early developmental efficiency of androgenetic embryos is significantly lower than that of parthenogenetic embryos. In addition, oocytes are able to reprogram sperm nuclei after fertilization to guarantee embryonic development by maternally derived reprogramming factors, which accumulate during oogenesis. However, the importance of maternal material in the efficiency of reprogramming the pronucleus of androgenetic embryos is not known. In this study, androgenetic embryos were constructed artificially by pronucleus transfer (PT) or double sperm injection (DS). Compared with DS embryos, PT embryos that were derived from two zygotes contained more maternal material, like 10–11 translocation methylcytosine deoxygenase 3 (Tet3) and histone variant 3.3 (H3.3). Our experiments confirmed the better developmental potential of PT embryos, which had higher blastocyst rates, a stronger expression of pluripotent genes, a lower expression of apoptotic genes, and superior blastocyst quality. Our findings indicate that the aggregation of more maternal materials in the paternal pronucleus facilitate the reprogramming of the paternal genome, improving embryonic development in PT androgenesis.     

The osteochondral interface as a gradient tissue: From development to the fabrication of gradient scaffolds for regenerative medicine

The osteochondral (OC) interface is not only the interface between two tissues, but also the evolution of hard and stiff bone tissue to the softer and viscoelastic articular cartilage covering the joint surface. To generate a smooth transition between two tissues with such differences in many of their characteristics, several gradients are recognizable when moving from the bone side to the joint surface. It is, therefore, necessary to implement such gradients in the design of scaffolds to regenerate the OC interface, so to mimic the anatomical, biological, and physicochemical properties of bone and cartilage as closely as possible. In the past years, several scaffolds were developed for OC regeneration: biphasic, triphasic, and multilayered scaffolds were used to mimic the compartmental nature of this tissue. The structure of these scaffolds presented gradients in mechanical, physicochemical, or biological properties. The use of gradient scaffolds with already differentiated or progenitor cells has been recently proposed. Some of these approaches have also been translated in clinical trials, yet without the expected satisfactory results, thus suggesting that further efforts in the development of constructs, which can lead to a functional regeneration of the OC interface by presenting gradients more closely resembling its native environment, will be needed in the near future. The aim of this review is to analyze the gradients present in the OC interface from the early stage of embryonic life up to the adult organism, and give an overview of the studies, which involved gradient scaffolds for its regeneration. Birth Defects Research (Part C) 105:34–52, 2015. © 2015 Wiley Periodicals, Inc.     

An ex vivo model using human osteoarthritic cartilage demonstrates the release of bioactive insulin‐like growth factor‐1 from a collagen–glycosaminoglycan scaffold

Biomimetic scaffolds hold great promise for therapeutic repair of cartilage, but although most scaffolds are tested with cells in vitro, there are very few ex vivo models (EVMs) where adult cartilage and scaffolds are co‐cultured to optimize their interaction prior to in vivo studies. This study describes a simple, non‐compressive method that is applicable to mammalian or human cartilage and provides a reasonable throughput of samples. Rings of full‐depth articular cartilage slices were derived from human donors undergoing knee replacement for osteoarthritis and a 3 mm core of a collagen/glycosaminoglycan biomimetic scaffold (Tigenix, UK) inserted to create the EVM. Adult osteoarthritis chondrocytes were seeded into the scaffold and cultures maintained for up to 30 days. Ex vivo models were stable throughout experiments, and cells remained viable. Chondrocytes seeded into the EVM attached throughout the scaffold and in contact with the cartilage explants. Cell migration and deposition of extracellular matrix proteins in the scaffold was enhanced by growth factors particularly if the scaffold was preloaded with growth factors. This study demonstrates that the EVM represents a suitable model that has potential for testing a range of therapeutic parameters such as numbers/types of cell, growth factors or therapeutic drugs before progressing to costly pre‐clinical trials. © 2015 The Authors. Cell Biochemistry and Function Published by John Wiley & Sons Ltd.     

Photoactivation of DNA thiobases as a potential novel therapeutic option

The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.     

Three‐dimensional imaging technologies: a priority for the advancement of tissue engineering and a challenge for the imaging community

Tissue engineering/regenerative medicine (TERM) is an interdisciplinary field that applies the principle of engineering and life sciences to restore/replace damaged tissues/organs with in vitro artificially‐created ones. Research on TERM quickly moves forward. Today newest technologies and discoveries, such as 3D‐/bio‐printing, allow in vitro fabrication of ex‐novo made tissues/organs, opening the door to wide and probably never‐ending application possibilities, from organ transplant to drug discovery, high content screening and replacement of laboratory animals. Imaging techniques are fundamental tools for the characterization of tissue engineering (TE) products at any stage, from biomaterial/scaffold to construct/organ analysis. Indeed, tissue engineers need versatile imaging methods capable of monitoring not only morphological but also functional and molecular features, allowing three‐dimensional (3D) and time‐lapse in vivo analysis, in a non‐destructive, quantitative, multidimensional analysis of TE constructs, to analyze their pre‐implantation quality assessment and their fate after implantation. This review focuses on the newest developments in imaging technologies and applications in the context of requirements of the different steps of the TERM field, describing strengths and weaknesses of the current imaging approaches.

     

Acid phosphatase and leucine aminopeptidase isozymes as biochemical markers of homogeneity in oil seed rape androgenetic lines

Extracts of cotyledons of Brassica napus plants (seed progenies of doubled haploid plants) were separated by electrophoresis on polyacrylamide gels and stained for acid phosphatase (ACP-E.C. 3.1.3.2.) and leucine aminopeptidase (LAP-E.C. 3.4.11.1.) enzymes to investigate the possibility of utilising isozymes as markers of homogeneity (purity) of plant populations. One zone of activity for acid phosphatase and two zones of activity for leucine aminopeptidase were identified on gels, some variation in isozyme patterns occurred in several androgenetic lines. This method is appropriate and consistent for testing the homogeneity of breeding lines-progenies of double haploid (D.H.) plants.     

Investigating the feasibility of spatially offset Raman spectroscopy for in‐vivo monitoring of bone healing in rat calvarial defect models

A wide range of biomaterials and tissue‐engineered scaffolds are being investigated to support and stimulate bone healing in animal models. Using phantoms and rat cadavers, we investigated the feasibility of using spatially offset Raman spectroscopy (SORS) to monitor changes in collagen concentration at levels similar to those expected to occur in vivo during bone regeneration (0‐0.84 g/cm³). A partial least squares (PLS) regression model was developed to quantify collagen concentration in plugs consisting of mixtures or collagen and hydroxyapatite (predictive power of ±0.16 g/cm³). The PLS model was then applied on SORS spectra acquired from rat cadavers after implanting the collagen: hydroxyapatite plugs in drilled skull defects. The PLS model successfully predicting the profile of collagen concentration, but with an increased predictive error of ±0.30 g/cm³. These results demonstrate the potential of SORS to quantify collagen concentrations, in the range relevant to those occurring during new bone formation.     

Induced pluripotent stem cell-derived extracellular vesicles: A novel approach for cell-free regenerative medicine

In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients’ somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole-cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine.