Vitamin D has a key role in stimulating calcium absorption from the gut and promoting skeletal health, as well as many other important physiological functions. Vitamin D is produced in the skin. It is subsequently metabolized to its hormonally active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), by the 1-hydroxylase and catabolized by the 24-hydroxylase. In this Review, we pay special attention to the effect of mutations in these enzymes and their clinical manifestations. We then discuss the role of vitamin D binding protein in transporting vitamin D and its metabolites from their source to their targets, the free hormone hypothesis for cell entry and HSP70 for intracellular transport. This is followed by discussion of the vitamin D receptor (VDR) that mediates the cellular actions of 1,25(OH)2D. Cell-specific recruitment of co-regulatory complexes by liganded VDR leads to changes in gene expression that result in distinct physiological actions by 1,25(OH)2D, which are disrupted by mutations in the VDR. We then discuss the epidermis and hair follicle, to provide a non-skeletal example of a tissue that expresses VDR that not only makes vitamin D but also can metabolize it to its hormonally active form. This enables vitamin D to regulate epidermal differentiation and hair follicle cycling and, in so doing, to promote barrier function, wound healing and hair growth, while limiting cancer development. This Review provides an overview of vitamin D production in the skin. The regulation of wound healing and hair growth by vitamin D are also discussed.

New aspects of vitamin D metabolism and action - addressing the skin as source and target.

The spread of novel SARS-CoV-2 virus, and the disease COVID-19 that is caused by SARS-CoV-2, continues apace. Saving lives and slowing the worldwide pandemic remain of utmost importance to everyone: the public, healthcare professionals, scientists, industry and governments.

It is absolutely essential that advice given to the public is evidence-based, accurate and timely; anything less would mislead and has the potential to cause harm. Popular information channels, such as social media platforms, have been rife with misinformation that has been perpetuated by fear and uncertainty. This has been the case particularly for diet and lifestyle advice. There are recommendations for the prevention of the spread of COVID-19 from the WHO,1 the UK,2 Irish3 and USA4 governments and the European Commission,5 as well as public health and healthcare agencies, including key direction on self-isolation.6 

This short original report aims to provide a balanced scientific view on vitamin D and SARS-CoV-2 virus/COVID-19 disease. It provides a succinct summary of the current scientific evidence of associations between vitamin D, influenza, upper respiratory tract infections (URTIs) and immune health. Importantly, the paper concludes with lifestyle strategies for avoiding vitamin D deficiency and ensuring a healthy balanced diet at any time, including during the current pandemic. The overarching messages are as follows: (1) Vitamin D is essential for good health. (2) Many people, particularly those living in northern latitudes (such as the UK, Ireland, Northern Europe, Canada and the northern parts of the USA, northern India and China), have poor vitamin D status, especially in winter or if confined indoors. (3) Low vitamin D status may be exacerbated during this COVID-19 crisis (eg, due to indoor living and hence reduced sun exposure), and anyone who is self-isolating with limited access to sunlight is advised to take a vitamin D …

https://nutrition.bmj.com/content/bmjnph/early/2020/05/15/bmjnph-2020-000089.full.pdf

Vitamin D and SARS-CoV-2 virus/COVID-19 disease.

The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment to combat dermal aging is relatively new. For example, the term cosmeceutical was first coined by Albert Kligman in 1984 to describe topical products that afford both cosmetic and therapeutic benefits. However, beauty comes from the inside. Therefore, for some time scientists have considered how nutrition reflects healthy skin and the aging process. The more recent link between nutrition and skin aging began in earnest around the year 2000 with the demonstrated increase in peer-reviewed scientific journal reports on this topic that included biochemical and molecular mechanisms of action. Thus, the application of: (a) topical administration from outside into the skin and (b) inside by oral consumption of nutritionals to the outer skin layers is now common place and many journal reports exhibit significant improvement for both on a variety of dermal parameters. Therefore, this review covers, where applicable, the history, chemical structure, and sources such as biological and biomedical properties in the skin along with animal and clinical data on the oral applications of: (a) collagen, (b) ceramide, (c) β-carotene, (d) astaxanthin, (e) coenzyme Q10, (f) colostrum, (g) zinc, and (h) selenium in their mode of action or function in improving dermal health by various quantified endpoints. Lastly, the importance of the human skin microbiome is briefly discussed in reference to the genomics, measurement, and factors influencing its expression and how it may alter the immune system, various dermal disorders, and potentially be involved in chemoprevention.

https://www.mdpi.com/1422-0067/19/10/3059/pdf

Enhancing Skin Health: By Oral Administration of Natural Compounds and Minerals with Implications to the Dermal Microbiome.

Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome-wide associated studies have identified single-nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte-specific antigens exposure. Of note, the self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type-1-skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8+ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well-established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

Mechanisms of melanocyte death in vitiligo.

Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (β)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases like cancer, diabetes, hypertension, cardiovascular, and autoimmune and dermatological diseases is being extensively explored. The non-classical function of vitamin D involves regulation of cellular proliferation, differentiation, apoptosis, and innate and adaptive immunity. In this review, we discuss and summarize the latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases.

https://www.mdpi.com/1422-0067/19/6/1618/pdf

Role of Vitamin D Beyond the Skeletal Function: A Review of the Molecular and Clinical Studies

Background: Vitamin D is a secosteroid, which was initially known for its skeletal role; however, in recent years, its functions in different organs have been increasingly recognized. In this review, we will provide an overview of vitamin D functions in the skin physiology with specific focus on its role in certain inflammatory skin conditions such as psoriasis and atopic dermatitis. Methods: A comprehensive literature search was carried out in PubMed and Google Scholar databases using keywords like “vitamin D,” “skin,” “atopic dermatitis,” and “psoriasis.” Only articles published in English and related to the study topic were included in this review. Results: Vitamin D is integrally connected to the skin for its synthesis, metabolism, and activity. It regulates many physiological processes in the skin ranging from cellular proliferation, differentiation, and apoptosis to barrier maintenance and immune functions. Vitamin D deficiency is associated with the risk of psoriasis and atopic dermatitis, and several clinical/observational studies have suggested the beneficial effect of vitamin D in the therapy of these 2 inflammatory skin disorders. Conclusions: Vitamin D exerts a pleiotropic effect in the skin and could be an important therapeutic option for psoriasis and atopic dermatitis.

Vitamin D and the Pathophysiology of Inflammatory Skin Diseases.

KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS). Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants. Whole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G > A in KCNH1, c.2131 T > C in STK36, and c.726C > A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect. Our findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.

/pdf/temple-baraitser-syndrome-and-zimmermann-laband-syndrome-one-45qf3e75xh.pdf

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

Oxidative stress is known to induce melanocyte death, but the underlying mechanisms are incompletely understood. To identify oxidative stress-induced global gene expression changes in melanocytes, we treated PIG1 melanocytes with H2O2 in a dose- and time-dependent manner and performed RNA-seq. This approach allowed us to capture the events occurring early as well as late phase after treatment with H2O2. Our bioinformatics analysis identified differentially expressed genes involved in various biological processes of melanocytes which are known to contribute to the vitiligo development, such as apoptosis, autophagy, cell cycle regulation, cell adhesion, immune and inflammatory responses, melanocyte pluripotency, and developmental signaling such as WNT and NOTCH pathways. We uncovered several novel genes that are not previously described to be involved in melanocytic response to stress nor in vitiligo pathogenesis. Quantitative PCR and western blot analysis of selected proteins, performed on PIG1 and primary human epidermal melanocytes, confirmed the RNA-seq data. Interestingly, we discovered an aberrant regulation of several transcription factors that are involved in diabetes, neurological, and psychiatric diseases, all of which are comorbid conditions in patients with vitiligo. Our results may lead to a better understanding of the molecular mechanisms underlying vitiligo pathogenesis and help developing new drug targets for effective treatment.

/pdf/rna-seq-reveals-dysregulation-of-novel-melanocyte-genes-upon-3iyk3gth27.pdf

RNA-seq Reveals Dysregulation of Novel Melanocyte Genes upon Oxidative Stress: Implications in Vitiligo Pathogenesis

Cancer stem cells (CSCs) are increasingly considered to be responsible for tumor initiation, metastasis and drug resistance The drug resistance mechanisms activated in CSCs have not been thoroughly investigated Although neuropeptides such as vasoactive intestinal peptide (VIP) can promote tumor growth and activate antiapoptotic signaling in differentiated cancer cells, it is not known whether they can activate antiapoptotic mechanisms in CSCs The objectives of this study are to unravel the cytoprotective effects of neuropeptides and identify antiapoptotic mechanisms activated by neuropeptides in response to anticancer drug treatment in CSCs We enriched and purified CSCs (CD44+/high/CD24-/low or CD133+ population) from breast and prostate cancer cell lines, and demonstrated their stemness phenotype Of the several neuropeptides tested, only VIP could protect CSCs from drug-induced apoptosis A functional correlation was found between drug-induced apoptosis and dephosphorylation of proapoptotic Bcl2 family protein BAD Similarly, VIP-induced cytoprotection correlated with BAD phosphorylation at Ser112 in CSCs Using pharmacological inhibitors and dominant-negative proteins, we showed that VIP-induced cytoprotection and BAD phosphorylation are mediated via both Ras/MAPK and PKA pathways in CSCs of prostate cancer LNCaP and C4-2 cells, but only PKA signaling was involved in CSCs of DUVIPR (DU145 prostate cancer cells ectopically expressing VIP receptor) and breast cancer MCF7 cells As each of these pathways partially control BAD phosphorylation at Ser112, both have to be inhibited to block the cytoprotective effects of VIP Furthermore, VIP is unable to protect CSCs that express phosphorylation-deficient mutant-BAD, suggesting that BAD phosphorylation is essential Thus, antiapoptotic signaling by VIP could be one of the drug resistance mechanisms by which CSCs escape from anticancer therapies Our findings suggest the potential usefulness of VIP receptor inhibition to eliminate CSCs, and that targeting BAD might be an attractive strategy for development of novel therapeutics

/pdf/cytoprotective-effect-of-neuropeptides-on-cancer-stem-cells-e9spevk1eh.pdf

Aouatef Ismail Chouchane

Papers

Role of Vitamin D Beyond the Skeletal Function: A Review of the Molecular and Clinical Studies

Vitamin D and the Pathophysiology of Inflammatory Skin Diseases.

Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

RNA-seq Reveals Dysregulation of Novel Melanocyte Genes upon Oxidative Stress: Implications in Vitiligo Pathogenesis

Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling