Clinical and metagenomic profiling of hormonal acne-prone skin in different populations.

INTRODUCTION: Acne is one of the most common skin concerns of unknown etiology, often connected to the menstrual cycle in women, and possibly to the microbial profile and function. OBJECTIVE: We aimed to investigate how hormonal fluctuation affects hormonal acne-prone skin in different populations in relation to skin clinical parameters and microbial profiles. METHODS: We evaluated skin features by using biophysical and topographical tools. For microbial profiling, we sequenced facial skin microbiota and associated the findings with the skin clinical parameters during the different phases of the menstrual cycle. RESULTS: We identified differences between and within hormonal phases in women of Chinese and Caucasian origin. Changes were discovered in transepidermal water loss (TEWL), sebum level, hydration level, and pore volume. The most abundant identifiable genera in both ethnicities were Cutibacterium, Staphylococcus, and Streptococcus, without any significant abundant differences within the menstrual cycle. Interestingly, 11 bacterial metabolic pathways were downregulated in Chinese compared to Caucasian skin during the follicular phase. The majority of these pathways were associated with skin redox balance, perhaps indicating a weaker oxidative stress response in Chinese versus Caucasian skin. Novosphingobium taxa were increased in the Chinese skin microbiome, which has been reported to protect skin from pollution-mediated oxidative stress. CONCLUSION: Thus, this pilot study explored some of the clinical and metagenomic changes in acne-prone skin, and provide guidance to tailor-personalized skin care regimes during the menstrual cycle. Also, the skin redox status in acne-prone skin, provides more opportunity to tailor-personalized skin care regimes.

Targeting microRNA for improved skin health.

BACKGROUND: In human skin, miRNAs have important regulatory roles and are involved in the development, morphogenesis, and maintenance by influencing cell proliferation, differentiation, immune regulation, and wound healing. MiRNAs have been investigated for many years in various skin disorders such as atopic dermatitis, psoriasis, as well as malignant tumors. Only during recent times, cosmeceutical use of molecules/natural active ingredients to regulate miRNA expression for significant advances in skin health/care product development was recognized. AIM: To review miRNAs with the potential to maintain and boost skin health and avoid premature aging by improving barrier function, preventing photoaging, hyperpigmentation, and chronological aging/senescence. METHODS: Most of the cited articles were found through literature search on PubMed. The main search criteria was a keyword "skin" in combination with the following words: miRNA, photoaging, UV, barrier, aging, exposome, acne, wound healing, pigmentation, pollution, and senescence. Most of the articles reviewed for relevancy were published during the past 10 years. RESULTS: All results are summarized in Figure 1, and they are based on cited references. CONCLUSIONS: Thus, regulating miRNAs expression is a promising approach for novel therapy not only for targeting skin diseases but also for cosmeceutical interventions aiming to boost skin health.

The Skin Interactome: A Holistic "Genome-Microbiome-Exposome" Approach to Understand and Modulate Skin Health and Aging.

Higher demands on skin care cosmetic products for strong performance drive intense research to understand the mechanisms of skin aging and design strategies to improve overall skin health. Today we know that our needs and influencers of skin health and skin aging change throughout our life journey due to both extrinsic factors, such as environmental factors and lifestyle factors, as well as our intrinsic factors. Furthermore, we need to consider our microflora, a collection of micro-organisms such as bacteria, viruses, and fungi, which is a living ecosystem in our gut and on our skin, that can have a major impact on our health. Here, we are viewing a holistic approach to understand the collective effect of the key influencers of skin health and skin aging both reviewing how each of them impact the skin, but more importantly to identify molecular conjunction pathways of these different factors in order to get a better understanding of the integrated "genome-microbiome-exposome" effect. For this purpose and in order to translate molecularly the impact of the key influencers of skin health and skin aging, we built a digital model based on system biology using different bioinformatics tools. This model is considering both the positive and negative impact of our genome (genes, age/gender), exposome: external (sun, pollution, climate) and lifestyle factors (sleep, stress, exercise, nutrition, skin care routine), as well as the role of our skin microbiome, and allowed us in a first application to evaluate the effect of the genome in the synthesis of collagen in the skin and the determination of a suitable target for boosting pro-collagen synthesis. In conclusion, we have, through our digital holistic approach, defined the skin interactome concept, as an advanced tool to better understand the molecular genesis of skin aging and further develop a strategy to balance the influence of the exposome and microbiome to protect, prevent, and delay the appearance of skin aging signs and preserve good skin health condition. In addition, this model will aid in identifying and optimizing skin treatment options based on external triggers, as well as helping to design optimal treatments modulating the intrinsic pathways.

tBHP treatment as a model for cellular senescence and pollution-induced skin aging.

Accumulation of senescent cells promotes the development of age-related pathologies and deterioration. In human skin, senescent cells potentially impair structure and function by secreting a mixture of signaling molecules and proteases that influence neighboring cells and degrade extracellular matrix components, such as elastin and collagen. One of the key underlying mechanisms of senescence and extrinsic skin aging is the increase of intracellular reactive oxygen species and resulting oxidative stress. Tert-butyl hydroperoxide (tBHP) is a known inducer of oxidative stress and cellular damage, acting at least in part by depleting the antioxidant glutathione. Here, we provide a detailed characterization of tBHP-induced senescence in human dermal fibroblasts in monolayer culture. In addition, results obtained with more physiological experimental models revealed that tBHP treated 3D reconstructed skin and ex vivo skin developed signs of chronic tissue damage, displaying reduced epidermal thickness and collagen fiber thinning. We, therefore, propose that tBHP treatment can be used as a model to study the effects of extrinsic skin aging, focusing mainly on the influence of environmental pollution.

A novel multifunctional skin care formulation with a unique blend of antipollution, brightening and antiaging active complexes.

BACKGROUND: High demand on anti-aging skin care encourage the improvement and development of more personalized formulations with additional benefits for general skin health and age associated skin signs. The skin aging physical and biological phenotypes manifest differently between diverse ethnic populations. A highly polluted environment can be viewed as an extrinsic factor accelerating the skin aging process. AIM: To develop a unique formula with active complexes, having multifunctional effects for anti-pollution, brightening and anti-aging/barrier strengthening purposes with confirmed activities in vitro and ex vivo skin models, suitable for polluted skin. METHODS: In vitro culture model with primary human skin cells, ex vivo studies with full-thickness human skin, melanocyte 3D coculture model, gene expression of epidermal and dermal genes, anti-glycation, proteasomal activity, melanin, and cytokine assays. RESULTS: In vitro and ex vivo studies clearly demonstrated that diglucosyl gallic acid (active A) and the formulation complex inhibited pollution mediated MMP1 protein, CYP1A1 gene expression, and IL-6 protein secretion, while caprylic/capric triglyceride, diacetyl boldine (active B) had anti-melanogenic effect in in vitro primary melanocyte monoculture and 3D spheroid model. Another active compound, acetyl dipeptide 1 cetyl ester (active D), significantly upregulated epidermal barrier genes (Aquaporin 3 [AQP3], Filaggrin [FLG], caspase 14, and keratin 10) in human primary keratinocytes. Interestingly, both acetyl dipeptide 1 cetyl ester (active D) and niacinamide (active C) improved dermal gene expression (fibrillin-1, Collagen type 1 alpha 1, Decorin, Lysyl oxidase-like 1) and, moreover, had significant anti-glycant and proteasomal promoter activity in human primary fibroblasts. CONCLUSION: Considering consumers need in heavily polluted areas, we developed a multipurpose formulation comprised of unique active complexes toward pollution, pollution induced inflammation, skin brightening, and antiaging concerns with beneficial results demonstrated by in vitro and ex vivo studies.

Lactobacillus reuteri DSM 17938-A comparative study on the effect of probiotics and lysates on human skin.

Human skin microbiota might play an important role in maintaining skin health and potentially prevent premature skin ageing. The use of probiotics in therapeutic skin applications is an attractive idea, as it could offer an alternative option for certain inflammatory skin disorders and dry or sensitive skin. Here, we investigated for the first time, a comparative study of live and the lysate products of probiotic strain Lactobacillus reuteri DSM 17938 in skin topical applications using ex vivo skin models focusing on anti-inflammatory and skin barrier function and in vitro assays for antimicrobial activity. Our results in ultraviolet B radiation (UVB-R)-induced inflammation model demonstrated that both live bacteria and the lysate of L. reuteri DSM 17938 reduced proinflammatory IL-6 and IL-8, illustrated in both reconstructed human epidermis (RHE) and native skin models. Live L reuteri DSM 17938 significantly increased aquaporin 3 (AQP3) gene expression, while the lysate enhanced laminin A/B levels in a healthy (unstimulated) state of RHE, suggesting a positive impact on skin barrier. In addition, live L. reuteri DSM 17938 had antimicrobial action against pathogenic skin bacteria (Staphylococcus aureus, Streptococcus pyogenes M1, Cutibacterium acnes AS12, Pseudomonas aeruginosa), whereas the lysate did not have such an effect. Therefore, it is hypothesized that L. reuteri DSM 17938 could be beneficial for general skin health, to avoid the UVB-R-mediated inflammatory cascade and/or prevent photoageing, improve barrier function or in the management of unhealthy skin prone to inflammatory conditions due to its antimicrobial, anti-inflammatory and skin barrier enhancing functions.

Longitudinal stability evaluation of biomarkers and their correlation in cerebrospinal fluid and plasma from patients with Alzheimer's disease.

There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of α- and ß-cleaved soluble amyloid-ß protein precursor (sAßPPα and sAßPPß), Aß1-40 together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of Aß1-40, Aß1-42, and sAßPPß in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sAßPPß (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.

Genetic association to the amyloid plaque associated protein gene COL25A1 in Alzheimer's disease.

The COL25A1 gene, located in 4q25, encodes the CLAC protein, which has been implicated in Alzheimer's disease (AD) pathogenesis. CLAC was originally identified in amyloid preparations from AD brain and has been shown to be associated with amyloid plaques, inhibition of Abeta-fibril elongation and increased protease resistance of Abeta-fibrils through direct binding to Abeta. These biochemical data as well as the genomic location of the COL25A1 gene in chromosome 4q25 where we previously have reported a weak linkage-signal in Swedish AD families encouraged us to perform a case-control association study of two LD blocks in COL25A1 using 817 AD cases and 364 controls. The LD blocks cover a putative Abeta-binding motif and the variable 3' end of the gene. The analyses indicated association to three of eight analysed SNPs. We found further support for the association by replication in a Swedish population-based longitudinal sample set (n=926). Thus, in addition to the biochemical data, there is now genetic evidence of association between COL25A1 and risk for Alzheimer's disease.

Methodological aspects of rat beta-endorphin analysis-influence of diurnal variation.

Beta-endorphin radioimmunoassays (RIAs) are widely performed following physical, emotional and environmental challenges in the rat. In the literature, a wide range of techniques have been described, but in the present study, we have focused on methodological aspects of beta-endorphin RIAs, investigating various characteristics of human and rat specific antibodies. Initial studies verified that the RIA outcome was not appropriate when using non-species compatible components. Novel rat beta-endorphin antibodies, r 4114 and r 4268, were raised in rabbits and characterised in terms of specificity, avidity and titer. Both of the new antisera showed 68.1% cross-reactivity with human beta-endorphin. The ED50 was 50+/-8 pmol/l, and the mean ED80 was 17 pmol/l for r 4268 but three-fold higher for r 4114. The intra-assay coefficient of variation (CV) was 7% at 100 pmol/l and the inter-assay CV was 10% at the same level for r 4268 and similar for r 4114. Using this novel rat beta-endorphin RIA for analyses of diurnal influence and removal from the Animal House cage, no significant changes were observed in either the hypothalamus or peri-aqueductal grey regions. These results suggest that rat beta-endorphin concentrations in these brain areas are not affected by order of removal or diurnal variation.

Familial presenile dementia with bitemporal atrophy.

This study describes the clinical, neuropsychological, neuroimaging and genetic characteristics in two generations of a Swedish family affected by presenile dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of progressive dementia with onset between 54 and 62 years. The clinical picture is characterized by insidious onset and progressive decline in episodic memory without spatial impairment or dyspraxia, followed by changes in personality and behaviour, with signs of disinhibition, irritability, impulsivity and loss of social awareness. Three siblings, examined after 10 years of duration, showed moderate language deficits but preserved spatial function and praxis. CT and MRI showed progressive bilateral temporal atrophy and moderate frontal white matter changes. Regional cerebral blood flow measurements showed hypoperfusion in temporal areas bilaterally. Quantitative EEG was normal within 5 years after symptom onset and thereafter showed a moderate increase in relative theta power. Sequencing of the tau gene (chromosome 17) revealed the previously described R406W mutation in exon 13 as a likely cause of the disease. This mutation was identified in all affected cases. The clinical picture of this family shows striking similarities not only to frontotemporal dementia but also to Alzheimer's disease.

The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy.

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.

Clinical and molecular aspects of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer's disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30-50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.

Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP-17 family.

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive and motor disturbances. It was recently discovered that the majority of the FTDP-17 families carry missense or 5' splice mutations in the exons coding for the microtubule-binding domains of the tau protein. However, in at least five FTDP-17 families, no such mutations could be identified. In the present study, we aimed at further investigate abnormalities in the tau gene in a Swedish FTDP-17 family, where no mutations in the tau gene previously have been identified. Initially, we searched for larger deletions by Southern blot hybridization. Furthermore, possible abnormal splicing events was investigated by RT-PCR from brain tissue of affected individuals. In addition, we investigated the presence of mutations in other genes in the FTDP-17 candidate region on chromosome 17q21; Gamma-tubulin, Glial Fibrillary Acid Protein (GFAP), Human dual specificity phosphatase tyrosine/serine (VHR), Rap-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. In conclusion, no pathological changes in the tau gene were observed, neither was any mutations segregating with the disease detected in the investigated candidate genes. Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP-17.

No evidence of linkage to chromosome 9q21-22 in a Swedish family with frontotemporal dementia and amyotrophic lateral sclerosis.

Frontotemporal dementia (FTD) is a neurodegenerative disorder, sometimes occurring together with amyotrophic lateral sclerosis (ALS) within the same family. Recently, a region on chromosome 9q21-22 was reported to harbour a locus that may participate in both disorders [Hosler, B.A., et al., JAMA., 284 (2000) 1664-1669]. In the present study, a Swedish pedigree with both ALS and FTD segregating in the family was investigated by linkage analysis with five markers on chromosome 9q21-22. The pedigree included 17 individuals in two generations, with five affected cases available for analysis. As two-point logarithm of odds scores close to zero were obtained for all markers tested, the region on chromosome 9q21-22 is suggested to be excluded as candidate region in this Swedish FTD/ALS family. Our conclusion is therefore that additional loci involved in these two disorders must be operating.

Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A.

Native N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of four or five subunits. The NMDA receptor subunits, NR1, NR2A, NR2B, NR2C, and NR2D have been cloned in several species, including man. The NR3A subunit, which in rodents is predominantly expressed during early development, seems to function by reducing the NMDA receptor response. The human homologue to the rat NR3A, however, had not been cloned. In order to study the functions of the human NR3A (hNR3A), we have cloned and sequenced the hNR3A. It was found to share 88% of the DNA sequence with the rat gene, corresponding to a 93% homology at the amino acid level. Based on available data from human genome databases, we localized the gene to chromosome 9. The transcript could be detected by in situ hybridization in human fetal spinal cord and forebrain. Two splice variants of NR3A have been reported in rat brain, the longer of the two containing a 60 bp insert in the intracellular domain. We were unable to detect this 60 bp insert in fetal or adult human brain, suggesting that only the short variant is expressed in humans.