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The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients.

Hair loss/thinning is a common side effect of tamoxifen in estrogen receptor (ER) positive breast cancer therapy. Some nutraceuticals known to promote hair growth are avoided during breast cancer therapy for fear of phytoestrogenic activity. However, not all botanical ingredients have similarities to estrogens, and in fact, no information exists as to the true interaction of these ingredients with tamoxifen. Therefore, this study sought to ascertain the effect of nutraceuticals (+/- estrogen/tamoxifen), on proliferation of breast cancer cells and the relative expression of ERα/β. Kelp, Astaxanthin, Saw Palmetto, Tocotrienols, Maca, Horsetail, Resveratrol, Curcumin and Ashwagandha were assessed on proliferation of MCF7, T47D and BT483 breast cancer cell lines +/- 17β-estradiol and tamoxifen. Each extract was analysed by high performance liquid chromatography (HPLC) prior to use. Cellular ERα and ERβ expression was assessed by qRT-PCR and western blot. Changes in the cellular localisation of ERα:ERβ and their ratio following incubation with the nutraceuticals was confirmed by immunocytochemistry. Estradiol stimulated DNA synthesis in three different breast cancer cell lines: MCF7, T47D and BT483, which was inhibited by tamoxifen; this was mirrored by a specific ERa agonist in T47D and BT483 cells. Overall, nutraceuticals did not interfere with tamoxifen inhibition of estrogen; some even induced further inhibition when combined with tamoxifen. The ERα:ERβ ratio was higher at mRNA and protein level in all cell lines. However, incubation with nutraceuticals induced a shift to higher ERβ expression and a localization of ERs around the nuclear periphery. As ERα is the key driver of estrogen-dependent breast cancer, if nutraceuticals have a higher affinity for ERβ they may offer a protective effect, particularly if they synergize and augment the actions of tamoxifen. Since ERβ is the predominant ER in the hair follicle, further studies confirming whether nutraceuticals can shift the ratio towards ERβ in hair follicle cells would support a role for them in hair growth. Although more research is needed to assess safety and efficacy, this promising data suggests the potential of nutraceuticals as adjuvant therapy for hair loss in breast cancer patients receiving endocrine therapy.

Nutraceuticals, natural dietary and botanical supplements offering health benefits, provide a basis for complementary and alternative medicine (CAM). Use of CAM by healthy individuals and patients with medical conditions is rapidly increasing. For the majority of breast cancer patients, treatment plans involve 5–10 yrs of endocrine therapy, but hair loss/thinning is a common side effect. Many women consider this significant, severely impacting on quality of life, even leading to non-compliance of therapy. Therefore, nutraceuticals that stimulate/maintain hair growth can be proposed. Although nutraceuticals are often available without prescription and taken at the discretion of patients, physicians can be reluctant to recommend them, even as adjuvants, since potential interactions with endocrine therapy have not been fully elucidated. It is, therefore, important to understand the modus operandi of ingredients to be confident that their use will not interfere/interact with therapy. The aim is to improve clinical/healthcare outcomes by combining specific nutraceuticals with conventional care whilst avoiding detrimental interactions. This review presents the current understanding of nutraceuticals beneficial to hair wellness and outcomes concerning efficacy/safety in breast cancer patients. We will focus on describing endocrine therapy and the role of estrogens in cancer and hair growth before evaluating the effects of natural ingredients on breast cancer and hair growth.

Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. Its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer.   Skin aging can be significantly delayed by the administration of estrogen. This paper reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SERMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. Understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies.

The silent pandemic, chronic, non-healing diabetic foot ulcers (DFUs), pose a significant rate of incidence for amputation and are a major cause of morbidity. The dynamic cutaneous microbiota is comprised of diverse microorganisms that often play a sword with double edged by causing opportunistic infections or aiding wound healing. We review recent advances in wound healing and provide new perspective on alternative treatments including phage and microbiome transplant therapies and how the definitive role of the cutaneous microbiota impacts the aetiology of DFUs. Abstract Background Notoriously known as the silent pandemic, chronic, non-healing diabetic foot ulcers (DFUs), pose a significant rate of incidence for amputation and are a major cause of morbidity. Alarmingly, the treatment and management strategies of chronic wounds represent a significant economic and health burden as well as a momentous drain on resources with billions per annum being spent in the US and UK alone. Defective wound healing is a major pathophysiological condition which propagates an acute wound to a chronic wound, further propelled by underlying conditions such as diabetes and vascular complications which are more prevalent amongst the elderly. Chronic wounds are prone to infection, which can exacerbate the condition, occasionally resulting in amputation for the patient, despite the intervention of modern therapies. However, amputation can only yield a 5-year survival rate for 50% of patients, highlighting the need for new treatments for chronic wounds. Findings The dynamic cutaneous microbiota is comprised of diverse microorganisms that often aid wound healing. Conversely, the chronic wound microbiome consists of a combination of common skin commensals such as Staphylococcus aureus and Staphylococcus epidermidis, as well as the opportunistic pathogen Pseudomonas aeruginosa. These bacteria have been identified as the most prevalent bacterial pathogens isolated from chronic wounds and contribute to prolific biofilm formation decreasing the efficiency of antimicrobials and further perpetuating a hyper-inflammatory state. Discussion and Conclusion Here, we review recent advances and provide a new perspective on alternative treatments including phage and microbiome transplant therapies and how the definitive role of the cutaneous microbiota impacts the aetiology of DFUs.

In humans, structural and functional changes attributable to aging are more visibly evident in the skin than in any other organ. Estrogens have significant effects on skin physiology and modulate epidermal keratinocytes, dermal fibroblasts and melanocytes, in addition to skin appendages including the hair follicle and the sebaceous gland. Importantly, skin aging can be significantly delayed by the administration of estrogen. This paper reviews the effects of estrogens on skin and the mechanisms by which estrogens can alleviate the changes due to aging that occur in human skin. The relevance of estrogen replacement therapy (HRT) in postmenopausal women and the potential value of selective estrogen receptor modulators (SERMs) as a therapy for diminishing skin aging are also highlighted.

Steroid hormones have important modulatory effects on the hair follicle, but the mechanisms by which they regulate human hair growth are still poorly understood. It is now clear that there are two distinct estrogen receptors (estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ)) that bind 17β-estradiol. Since the follicular dermal papilla is known to control hair growth, and steroid hormones regulate receptor and aromatase expression in other tissues, we tested the hypothesis that steroid hormones would similarly modulate estrogen receptor and/or aromatase expression in cultured dermal papilla cells derived from human hair follicles. Primary cultures of non-balding occipital and frontal scalp and beard dermal papilla cells (n=10) were established. Immunocytochemical studies showed the expression of ERα in both the cytoplasm and nucleus, whereas ERβ was confined to the nuclei. The cells derived from occipital scalp were also incubated for 24hours with 10nm of either 17β-estradiol, estrone, testosterone, 5α-dihydrotestosterone, 5α-androstane-3α, 17β-diol, 5α-androstane-3β, 17β-diol, or 100nm tamoxifen or dexamethasone in phenol red-free, serum-free medium to measure the steady-state levels of ERα, ERβ, and aromatase mRNA by semiquantitative reverse transcriptase-PCR. Although androgens and estrogens did not alter ERα mRNA levels, treatment with dexamethasone significantly reduced ERα levels to 38% of the untreated control. By contrast, ERβ mRNA levels were unaffected by any steroid treatment. Furthermore, dexamethasone significantly stimulated the expression of aromatase mRNA approximately 9-fold. Aromatase activity, assayed by the tritiated water method, was stimulated in both frontal scalp and beard dermal papilla cell cultures by dexamethasone. These observations provide evidence for a glucocorticoid-dependent mechanism whereby the selective action of estradiol via ERβ may be promoted. Additionally, upregulation of aromatase combined with downregulation of ERα provides a basis for selective action of estradiol produced locally by autocrine or paracrine mechanisms.

IntroductionSmooth muscle cells (SMC) are the principal cell type within the vascular wall and are critical for maintaining blood vessel physiology. Current SMC models are typically isolated from macrovessels including the aorta, coronary arteries or saphenous vein however these tissues require invasive surgery to access. SMC from a more accessible source such as skin would therefore be a valuable addition to the vascular biologists’ toolkit. The purpose of this work was to isolate human SMC from the subdermal plexus and characterise their phenotype in vitro to assess suitability as an alternative SMC source for vascular biologists.MethodsPrimary human SMC were isolated from subdermal plexus (DV) by explant technique from multiple donors undergoing lower limb amputation at the Bradford Royal Infirmary. SMC identity and purity was validated using immunocytochemistry for alpha smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-MHC). SMC phenotype was assessed by measuring cellular and nuclear morphological parameters (light microscopy and ImageJ), proliferation by cell counting, and expression of SMC-related microRNAs by qPCR.ResultsAll explanted cells stained positively for α-SMA and SM-MHC, confirming their identity as SMC. DV-SMC were spindle-shaped with an average spread cell area of 8279±1459µm2. They were typically mononucleated with over 90% of nuclei appearing ovoid. All cells expressed microRNAs miR-17, miR-29b2, miR-31, miR-130b and miR-491 which have been recently identified as important in SMC phenotypic regulation. Importantly, all of these parameters were consistent in matched cells, up to passage 9 in vitro.Discussion/ConclusionThis is the first characterisation of primary SMC from the subdermal plexus. DV-SMC appeared comparable and morphologically similar to other sources of SMC (e.g. saphenous vein) and proliferated in culture. The phenotypic characteristics were stable up to and including passage 9 indicating that DV-SMC are robust, expandable in culture, and make a valuable addition to the sources of SMC that are available for studying human vascular health and disease.Conflict of InterestNone

Interest in adipose tissue is fast becoming a focus of research after many years of being considered as a simple connective tissue. It is becoming increasingly apparent that adipose tissue contains a number of diverse cell types, including adipose-derived stem cells (ASCs) with the potential to differentiate into a number of cell lineages, and thus has significant potential for developing therapies for regenerative medicine. Currently, there is no gold standard treatment for scars and impaired wound healing continues to be a challenge faced by clinicians worldwide. This review describes the current understanding of the origin, different types, anatomical location, and genetics of adipose tissue before discussing the properties of ASCs and their promising applications for tissue engineering, scarring, and wound healing.

This study explored institutional and personal factors that influenced preparedness and experiences among undergraduate students who transferred from a state of Kansas community college to the University of Kansas (KU). This study was influenced by the work of Laanan et al. (2010) and the concept of Transfer Student Capital (TSC) where transfer students gain agency in advance of their transfer, learning about and garnering skills to prepare for and ultimately transfer. This qualitative research study utilized semi-structured interviews with ten KU transfer students to better understand how they experienced their transition to KU. Students were eligible if they had recently transferred to KU from one of the 19 state of Kansas community colleges. Data from the study revealed that these transfer students had strong relationships with many key institutional agents and family members pre- and post-transfer, while feeling they did not necessarily get the proper or timely support from KU admissions, college or school academic advising and/or new student orientation programs prior to enrollment and transfer. Study participants highlighted challenges with academic program understanding, credit transfer, course mobility, campus resource and service awareness, and social integration. Based on the data, I believe the University of Kansas has an opportunity to better support and build-up transfer student capital for those entering and enrolled students. This can be accomplished through bolstering transfer-specific programs and services for entering students; providing and encouraging more opportunities for students to engage in supportive transfer-specific relationships; initiating more structured partnerships between the state of Kansas community colleges and KU transfer admissions personnel; and creating and enhancing opportunities for transfer-students to engage in more meaningful ways that might boost their social integration upon transfer, such as the creation of a transfer student peer mentor program. And finally, although the study and recommendations are specific to the University of Kansas and the state of Kansas community colleges, I believe the recommendations are applicable to all sending and receiving institutions who engage with transfer students.