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Pinitol (3-O-Methyl-D-chiro-inositol) has been reported to possess insulin-like effects and is known as one of the anti-diabetic agents to improve muscle, liver, and endothelial cells. However, the beneficial effects of pinitol on the skin are not well known. Here, we investigated whether pinitol had effects on human dermal fibroblasts (HDFs), and human dermal equivalents (HDEs) irradiated with ultraviolet A (UVA), which causes various damages including photodamage in the skin. We observed that pinitol enhanced wound healing in UVA-damaged HDFs. We also found that pinitol significantly antagonized the UVA-induced up-regulation of matrix metalloproteinase 1 (MMP1), and the UVA-induced down-regulation of collagen type I and tissue inhibitor of metalloproteinases 1 (TIMP1) in HDEs. Electron microscopy analysis also revealed that pinitol remarkably increased the number of collagen fibrils with regular banding patterns in the dermis of UVA-irradiated human skin equivalents. Pinitol significantly reversed the UVA-induced phosphorylation levels of ERK and JNK but not p38, suggesting that this regulation may be the mechanism underlying the pinitol-mediated effects on UVA-irradiated HDEs. We also observed that pinitol specifically increased Smad3 phosphorylation, which is representative of the TGF-ß signaling pathway for collagen synthesis. These data suggest that pinitol exerts several beneficial effects on UVA-induced damaged skin and can be used as a therapeutic agent to improve skin-related diseases.

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BACKGROUND: Since 4 major diseases and geriatric diseases require consistent management, individuals with any of these diseases cannot live alone and need caregivers' assistance. Given these characteristics, an integrative medical service model for 4 major diseases and geriatric diseases was developed in Korea, currently. Dementia, one of the typical geriatric diseases, requires caregivers' assistance from the beginning because of its enormous burden. Thus, it is necessary to provide an integrative medical service that can improve the quality of life (QoL) for both patients and caregivers. Therefore, this study aims to collect various feedback by applying an integrative medical service, which was developed to improve the QoL in patients with dementia and their caregivers, to a single case, and to modify and improve the integrative medical service model based on the results. METHOD/DESIGN: The integrative medical service program, which was developed to improve the QoL in patients with dementia and their caregivers in Korea, will be used for a patient-caregiver pair. This is an observational study with quantitative and qualitative feedback from various viewpoints. The program will be conducted in 8 sessions (twice a week, within 120 minutes). The patient will receive both Western and Korean medicine, and an integrative service will be provided to improve cognitive rehabilitation and QoL. Feedback collected at each session will be reflected on the program of the subsequent session. RESULTS: This study will then modify and improve the program with feedback and provide integrative medical services to a patient with dementia and caregiver. DISCUSSION: Patients with dementia need a program that would help them maintain cognitive function, and caregivers need a program that would improve their QoL by reducing the caregiving burden. This study is unique because the developed program is performed after modification based on feedback from the previous session. Accordingly, the patient and caregiver can check which program is the most satisfactory and helpful in improving their QoL. We expect that this study can modify the integrative medical service model to the optimized patient-based model. This study can also be used as basic data for a clinical pathway development study that applies the modified model to medical institutes.

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Cortisol is an endogenous glucocorticoid (GC) and primary stress hormone that regulates a wide range of stress responses in humans. The adverse effects of cortisol on the skin have been extensively documented but the underlying mechanism of cortisol-induced signaling is still unclear. In the present study, we investigate the effect of cortisol on collagen type I expression and the effect of AP collagen peptides, collagen tripeptide-rich hydrolysates containing 3% glycine-proline- hydroxyproline (Gly-Pro-Hyp, GPH) from the fish skin, on the cortisol-mediated inhibition of collagen type I and the cortisol-induced signaling that regulates collagen type I production in human dermal fibroblasts (HDFs). We determine that cortisol downregulates the expression of collagen type I. AP collagen peptides or GC receptor (GR) inhibitors recover the cortisol-mediated inhibition of collagen type I and GR activation. AP collagen peptides or GR inhibitors also prevent the cortisol-dependent inhibition of transforming growth factor (TGF)-ß signaling. AP collagen peptides or GR inhibitors are effective in the prevention of collagen type I inhibition mediated by cortisol in senescent HDFs and reconstituted human skin models. Taken together, GR signaling might be responsible for the cortisol-mediated inhibition of TGF-ß. AP collagen peptides act as GR-mediated signaling blockers, preventing the cortisol-dependent inhibition of collagen type I. Therefore, AP collagen peptides have the potential to improve skin health.

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Background/Aims@#There have been few multicenter studies on colonic polyps conducted by primary medical institutions. This study examined the detection rate of colonic polyps in primary health care institutions and the related factors while following the guidelines. @*Methods@#The medical records of 14,029 patients who underwent colonoscopy between January-June 2020 at 40 primary medical institutions in Korea were analyzed. High-risk adenoma was defined as advanced adenoma, carcinoma, or ≥3 adenomas. @*Results@#Most patients (71.2%) aged ≥50 years underwent re-colonoscopy within 5 years (51.3%) for diagnostic purposes (61.3%) in Korean primary medical institutions. The detection rates of colon polyps, adenoma, advanced adenoma, high-risk adenoma, and carcinoma was 59.9%, 38.9%, 5.9%, 11.4%, and 0.3% in all subjects and 59.8%, 37.5%, 8.5%, 12.9%, and 0.3% in average-risk patients, respectively. The incidences of adenoma in average-risk patients increased significantly with age (30s/40s/50s: 20.1%/29.4%/43% for adenoma, 4.4%/6.7%/10.3% for advanced adenoma, and 5.6%/9.5%/14.6% for high-risk adenoma; p<0.05). Before 50 years of age, high-risk adenoma was detected in 9.1% of patients in the first-time screening group, and the significant risk factors were being male and ≥40 years of age. The detection rate of high-risk adenoma in the normal index colonoscopy group within 5 years was 9.0%. The significant risk factors included older age, male sex, positive fecal occult blood test, stool form changes, and nonspecific symptoms (gas and indigestion). @*Conclusions@#More colonic adenoma studies targeting real-world clinical practice will be needed to revise the Korean guidelines for colorectal cancer screening and surveillance.

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Probiotics offer various health benefits. Lactobacillus plantarum has been used for decades to enhance human intestinal mucosal immunity and improve skin barrier integrity. Extracellular vesicles (EVs) derived from eukaryotic or prokaryotic cells have been recognized as efficient carriers for delivery of biomolecules to recipient cells, and to efficiently regulate human pathophysiology. However, the mechanism underlying the beneficial effects of probiotic bacteria-derived EVs on human skin is unclear. Herein, we investigated how L. plantarum-derived EVs (LEVs) exert beneficial effects on human skin by examining the effect of LEVs on cutaneous immunity, particularly on macrophage polarization. LEVs promoted differentiation of human monocytic THP1 cells towards an anti-inflammatory M2 phenotype, especially M2b, by inducing biased expression of cell-surface markers and cytokines associated with M2 macrophages. Pre- or post-treatment with LEVs under inflammatory M1 macrophage-favouring conditions, induced by LPS and interferon-γ, inhibited M1-associated surface marker, HLA-DRα expression. Moreover, LEV treatment significantly induced expression of macrophage-characteristic cytokines, IL-1ß, GM-CSF and the representative anti-inflammatory cytokine, IL-10, in human skin organ cultures. Hence, LEVs can trigger M2 macrophage polarization in vitro, and induce an anti-inflammatory phenomenon in the human skin, and may be a potent anti-inflammatory strategy to alleviate hyperinflammatory skin conditions.

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The outer epidermal skin is a primary barrier that protects the body from extrinsic factors, such as ultraviolet (UV) radiation, chemicals and pollutants. The complete epithelialization of a wound by keratinocytes is essential for restoring the barrier function of the skin. However, age-related alterations predispose the elderly to impaired wound healing. Therefore, wound-healing efficacy could be also considered as a potent function of an anti-aging reagent. Here, we examine the epidermal wound-healing efficacy of the fourth-generation retinoid, seletinoid G, using HaCaT keratinocytes and skin tissues. We found that seletinoid G promoted the proliferation and migration of keratinocytes in scratch assays and time-lapse imaging. It also increased the gene expression levels of several keratinocyte proliferation-regulating factors. In human skin equivalents, seletinoid G accelerated epidermal wound closure, as assessed using optical coherence tomography (OCT) imaging. Moreover, second harmonic generation (SHG) imaging revealed that seletinoid G recovered the reduced dermal collagen deposition seen in ultraviolet B (UVB)-irradiated human skin equivalents. Taken together, these results indicate that seletinoid G protects the skin barrier by accelerating wound healing in the epidermis and by repairing collagen deficiency in the dermis. Thus, seletinoid G could be a potent anti-aging agent for protecting the skin barrier.

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Sugars are ubiquitous in organisms and well-known cosmetic ingredients for moisturizing skin with minimal side-effects. Glucose, a simple sugar used as an energy source by living cells, is often used in skin care products. Several reports have demonstrated that sugar and sugar-related compounds have anti-melanogenic effects on melanocytes. However, the underlying molecular mechanism by which glucose inhibits melanin synthesis is unknown, even though glucose is used as a whitening as well as moisturizing ingredient in cosmetics. Herein, we found that glucose significantly reduced the melanin content of α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells and darkly pigmented normal human melanocytes with no signs of cytotoxicity. Furthermore, topical treatment of glucose clearly demonstrated its whitening efficacy through photography, Fontana-Masson (F&M) staining, and multi-photon microscopy in a pigmented 3D human skin model, MelanoDerm. However, glucose did not alter the gene expression or protein levels of major melanogenic proteins in melanocytes. While glucose potently decreased intracellular tyrosinase activity in melanocytes, it did not reduce mushroom tyrosinase activity in a cell-free experimental system. However, glucose was metabolized into lactic acid, which can powerfully suppress tyrosinase activity. Thus, we concluded that glucose indirectly inhibits tyrosinase activity through conversion into lactic acid, explaining its anti-melanogenic effects in melanocytes.

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Lipin-1 is an Mg2+-dependent phosphatidate phosphatase (PAP1) that catalyzes a critical step in the synthesis of glycerophospholipids and is also a cotranscriptional regulator. The role of lipin-1 in the regulation of inflammatory responses has been extensively studied in various cell types but not in skin cells. In the present study, the function of lipin-1 in UVB-induced proinflammatory responses was assessed in normal human epidermal keratinocytes (NHEKs). UVB radiation downregulated lipin-1 expression. Lipin-1 inhibition was mediated by UVB-dependent sterol-response element binding protein-1 (SREBP-1) inhibition. The UVB-dependent inhibition of lipin-1 and SREBP-1 was mediated by AMPK activation. UVB-induced activation of JNK was dependent on AMPK activation and mediated lipin-1 inhibition. Prevention of UVB-mediated lipin-1 repression by introducing a lipin-1 expression vector stimulated IL-6 and IL-8 production, suggesting that lipin-1 inhibition attenuates UVB-induced IL-6 and IL-8 production. The downregulation of lipin-1 ameliorated UVB-induced NF-ĸB phosphorylation, which might be attributed to the suppression of UVB-induced accumulation of free fatty acids (FFAs). Pharmacological inhibition of PAP1 with propranolol suppressed UVB-induced production of IL-6 and IL-8 in NHEKs and reconstituted human skin models. Taken together, lipin-1 is downregulated by exposure to UVB radiation, which confers protection against UVB-induced proinflammatory responses; therefore, the inhibition of lipin-1 is a potential strategy for photoaging.

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Global incidence of neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) is rapidly increasing, but the diagnosis of these diseases at their early stage is challenging. Therefore, the availability of reproducible and reliable biomarkers to diagnose such diseases is more critical than ever. In addition, biomarkers could be used not only to diagnose diseases but also to monitor the development of disease therapeutics. Urine is an excellent biofluid that can be utilized as a source of biomarker to diagnose not only several renal diseases but also other diseases because of its abundance in invasive sampling. However, urine was conventionally regarded as inappropriate as a source of biomarker for neurodegenerative diseases because it is anatomically distant from the central nervous system (CNS), a major pathologic site of NDD, in comparison to other biofluids such as cerebrospinal fluid (CSF) and plasma. However, recent studies have suggested that urine could be utilized as a source of NDD biomarker if an appropriate marker is predetermined by metabolomic and proteomic approaches in urine and other samples. In this review, we summarize such studies related to NDD.

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Mannosylerythritol lipids (MELs) are glycolipids and have several pharmacological efficacies. MELs also show skin-moisturizing efficacy through a yet-unknown underlying mechanism. Aquaporin-3 (AQP3) is a membrane protein that contributes to the water homeostasis of the epidermis, and decreased AQP3 expression following ultraviolet (UV)-irradiation of the skin is associated with reduced skin moisture. No previous study has examined whether the skin-moisturizing effect of MELs might act through the modulation of AQP3 expression. Here, we report for the first time that MELs ameliorate the UVA-induced downregulation of AQP3 in cultured human epidermal keratinocytes (HaCaT keratinocytes). Our results revealed that UVA irradiation decreases AQP3 expression at the protein and messenger RNA (mRNA) levels, but that MEL treatment significantly ameliorated these effects. Our mitogen-activated protein kinase inhibitor analysis revealed that phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, mediates UVA-induced AQP3 downregulation, and that MEL treatment significantly suppressed the UVA-induced phosphorylation of JNK. To explore a possible mechanism, we tested whether MELs could regulate the expression of peroxidase proliferator-activated receptor gamma (PPAR-γ), which acts as a potent transcription factor for AQP3 expression. Interestingly, UVA irradiation significantly inhibited the mRNA expression of PPAR-γ in HaCaT keratinocytes, whereas a JNK inhibitor and MELs significantly rescued this effect. Taken together, these findings suggest that MELs ameliorate UVA-induced AQP3 downregulation in HaCaT keratinocytes by suppressing JNK activation to block the decrease of PPAR-γ. Collectively, our findings suggest that MELs can be used as a potential ingredient that modulates AQP3 expression to improve skin moisturization following UVA irradiation-induced damage.

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BACKGROUND/AIMS: Dehydroabietic acid (DAA) is a natural phytochemical found in red pine trees and herbal plants. While DAA and its derivatives are known for improving diabetes and hyperlipidemia, the antiaging effect and its underlying mechanisms of DAA on skin have not been fully examined. Here, we assessed the antiaging effects of DAA on human dermal fibroblasts and skin equivalents. METHODS: We investigated the effect of DAA on the secretion of type I procollagen and matrix metalloproteinase-1 (MMP-1) in ultraviolet B (UVB)-irradiated neonatal normal human dermal fibroblasts (NHDFn). Using nonlinear optical imaging techniques, we visualized quantitative and qualitative changes of collagen fibers by DAA treatment in human skin equivalent models. RESULTS: DAA induces increases in type I procollagen secretion when treated on UVB-irradiated NHDFn. DAA also downregulates secretion of MMP-1 through the inhibition of the JNK signaling pathway. In human skin equivalent models, we successfully visualized the spatial distribution of collagen fibers in the dermis and found that quantity, diameter, and arrangement of collagen fibers in the dermis were significantly improved by DAA treatment. CONCLUSION: Our results suggest that DAA could be a useful agent for improving skin photoaging through the protection and regeneration of collagen fibers in skin.

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Atopic dermatitis (AD) is a chronic inflammatory skin disease that is not fully understood. Defects in skin barrier function and dysregulation of the Th2 immune response are thought to be pivotal in AD pathogenesis. In this study, we used keratinocytes and AD-like skin equivalent models using Th2 cytokines IL-4 and IL-13. The keratinocytes and AD-like skin model were used to investigate the effect of dipotassium glycyrrhizinate (KG), which is widely used as an anti-inflammatory agent for AD treatment. KG decreased AD-related gene expression in keratinocytes stimulated with Th2 cytokines. KG alleviated AD-like phenotypes and gene expression patterns and inhibited release of AD-related cytokines in the AD-like skin equivalent models. These findings indicate KG has potential effectiveness in AD treatment and AD-like skin equivalent models may be useful for understanding AD pathogenesis.

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Hyperpigmentation is caused by excessive production of melanin in melanocytes. Mannosylerythritol lipids (MELs) are glycolipid biosurfactants that are abundantly produced by yeasts and used commercially in cosmetics. However, the potential depigmenting efficacy of MELs has not been evaluated. In this study, the depigmentary effect of MELs was tested in primary normal human melanocytes (NHMs), α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells (murine melanoma cells) and a human skin equivalent (MelanoDerm) using photography, Fontana-Masson (F&M) staining and two-photon microscopy. Mannosylerythritol lipids significantly decreased the melanin contents in NHMs and α-MSH-stimulated B16 cells. Consistent with these findings, MELs treatment had a clear whitening effect in a human skin equivalent, brightening the tissue colour and reducing the melanin content. The molecular mechanism underlying the anti-melanogenic effect of MELs treatment was examined by real-time PCR and Western blotting. Mechanistically, MELs clearly suppressed the gene expression levels of representative melanogenic enzymes, including tyrosinase, Tyrp-1 and Tyrp-2, by inhibiting the ERK/CREB/MiTF signalling pathway in NHMs. This work demonstrates for the first time that MELs exert whitening effects on human melanocytes and skin equivalent. Thus, we suggest that MELs could be developed as a potent anti-melanogenic agent for effective whitening, beyond their use as a biosurfactant in cosmetics.

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BACKGROUND: The safety and wrinkle-reducing effects of multipolydioxanone (PDO) scaffold have been confirmed in animal, and clinical tests for 3 months, but the 12-month outcomes, are unknown. OBJECTIVE: The safety and efficacy of multi-PDO scaffold were tested in animal models and in humans for 12 months. METHODS: In the animal study, a multi-PDO scaffold was implanted into the panniculus carnosus of rat dorsal skin (n = 18) and into the subcutaneous layer of minipig dorsal skin (n = 2) followed by histological staining and analysis. In a human study, a multi-PDO scaffold was implanted deep into the periosteal subcutaneous layer under the wrinkles on the upper lips and forehead, followed by evaluation of clinical changes using digital photography and PRIMOS. RESULTS: A multi-PDO scaffold was not observed after 6 months in rats and minipigs. However, the newly formed tissues within the hollow body of the scaffolds were maintained for up to 12 months. The enhanced effect on the upper lips and forehead wrinkles lasted up to 12 months without any side effects. CONCLUSION: A multi-PDO scaffold represents a new tool to improve upper lips and forehead wrinkles.

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Late epidermal differentiation is a key step of skin barrier formation; however, the specific genetic factors that distinguish late differentiation from early differentiation remain unknown. Here, we demonstrated that EGR3 is highly expressed in the stratum granulosum, and that it contributes to late epidermal differentiation. However, its expression is lost under poorly differentiated conditions, such as parakeratosis-lesional skin. EGR3 mediated the regulation of genes located in the epidermal differentiation complex through activation of enhancers and induction of enhancer RNAs. We further identified 20 targets of EGR3 specific for late differentiation. Additionally, we discovered that EGR3- and EGR3-related genes exhibited high tissue specificity on the skin. Through weighted gene co-expression analysis, EGR3 was found to be related to the keratinocyte differentiation-related module as an important part of the skin-specific genetic network. These findings shed light on the transcriptional regulation of late epidermal differentiation, highlighting candidate targets for diseases related to disrupted differentiation.

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Mannosylerythritol lipids (MELs) are glycolipids and have several pharmacological efficacies. MELs also show skin-moisturizing efficacy through a yet-unknown underlying mechanism. Aquaporin-3 (AQP3) is a membrane protein that contributes to the water homeostasis of the epidermis, and decreased AQP3 expression following ultraviolet (UV)-irradiation of the skin is associated with reduced skin moisture. No previous study has examined whether the skin-moisturizing effect of MELs might act through the modulation of AQP3 expression. Here, we report for the first time that MELs ameliorate the UVA-induced downregulation of AQP3 in cultured human epidermal keratinocytes (HaCaT keratinocytes). Our results revealed that UVA irradiation decreases AQP3 expression at the protein and messenger RNA (mRNA) levels, but that MEL treatment significantly ameliorated these effects. Our mitogen-activated protein kinase inhibitor analysis revealed that phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase or p38, mediates UVA-induced AQP3 downregulation, and that MEL treatment significantly suppressed the UVA-induced phosphorylation of JNK. To explore a possible mechanism, we tested whether MELs could regulate the expression of peroxidase proliferator-activated receptor gamma (PPAR-γ), which acts as a potent transcription factor for AQP3 expression. Interestingly, UVA irradiation significantly inhibited the mRNA expression of PPAR-γ in HaCaT keratinocytes, whereas a JNK inhibitor and MELs significantly rescued this effect. Taken together, these findings suggest that MELs ameliorate UVA-induced AQP3 downregulation in HaCaT keratinocytes by suppressing JNK activation to block the decrease of PPAR-γ. Collectively, our findings suggest that MELs can be used as a potential ingredient that modulates AQP3 expression to improve skin moisturization following UVA irradiation-induced damage.

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Mitochondrial dysfunction can drive cellular senescence, which is accompanied by changes in metabolism and increases in senescence-associated secretory phenotypes. Although pyruvate, a key metabolite for numerous aspects of metabolism, has been used as general supplement in synthetic media, the physiological function of pyruvate underlying its protective role against cellular senescence under normal conditions has remained unknown. Here, we show that extracellular pyruvate prevents senescence in normal human dermal fibroblasts through increasing the generation of oxidized nicotinamide adenine dinucleotide (NAD+) during the conversion to lactate. Acetylated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), vacuolar-type H+-ATPaseV0A1 (v-ATPaseV0A1), NF-κB p65 subunit (RelA), and histone H3 accumulate under pyruvate deprivation conditions, resulting in the onset of senescence in normal human dermal fibroblasts through the accumulation of abnormal mitochondria generated by lysosomal inactivation-induced mitophagy defects, and through an increase in senescence-associated secretory phenotypes. Furthermore, pyruvate showed a protective effect against aging phenotypes in skin equivalents, which consist of a dermis and epidermis that act similarly to in vivo skin tissues. Our findings reveal a connection between pyruvate and mitochondrial dysfunction in the progression of senescence that is, to our knowledge, previously unreported. These results suggest that the pyruvate deprivation-induced senescence model can be used to study the connection between metabolism and senescence under normal conditions.

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BACKGROUND: Although it is established that epidermal barrier disturbance and immune dysfunction resulting in IgE sensitization are critical factors in the development of cutaneous inflammation, the pathogenesis and targeted therapy of atopic dermatitis (AD)-specific pathways have still been unknown. OBJECTIVE: Taking into account the fact that Th2 cytokines in AD have both unique and overlapping functions including increased epidermal thickening, inflammation, and decreased expressing of the barrier proteins keratinocyte differentiation, we sought to clarify our hypothesis that TRPV1 antagonist plays a critical role in skin barrier function and can be a therapeutic target for AD. METHODS: AD-like dermatitis was induced in hairless mice by repeated oxazolone (Ox) challenges to hairless mice. The functional studies concerning skin barrier function, anti-inflammatory action, and molecular mechanism by TRPV1 antagonism were conducted by histopathological assays, ELISA, qPCR, western blotting, and skin blood flow measurement. RESULTS: Topically administered TRPV1 antagonist, PAC-14028 (Asivatrep: C21H22F5N3O3S), improved AD-like dermatitis and skin barrier functions, and restored the expression of epidermal differentiation markers. In addition, the PAC-14028 cream significantly inhibited cutaneous inflammation by decreasing the expression of serum IgE, and the epidermal expression of IL-4, and IL-13 in Ox-AD mice. These results may provide a novel insight into the molecular mechanism of PAC-14028 cream involved in anti-inflammatory effects and skin barrier functions by suppressing the multiple signaling pathways including IL-4/-13-mediated activation of JAK/STAT, TRPV1, and neuropeptides. CONCLUSION: PAC-14028 cream can be a potential therapeutic tool for the treatment of chronic inflammation and disrupted barrier function in patients with AD.