Article

Dietary supplementation with sulforaphane ameliorates skin aging through activation of the Keap1-Nrf2 pathway

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Abstract

Visible impairments in skin appearance, as well as a subtle decline in its functionality at the molecular level, are hallmarks of skin aging. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-pathway, which is important in controlling inflammation and oxidative stress that occur during aging, can be triggered by sulforaphane (SFN), an isothiocyanate found in plants from the Brassicaceae family. This study aimed to assess the effects of SFN intake on age-related skin alterations. Male C57BL6 young (2 months) and old (21 months) mice were treated for 3 months with SFN diet (442.5 mg per kg) or control diet. The antioxidant capacities of the skin were increased in old SFN-treated animals as measured by mRNA levels of Nrf2 (p<0.001) and its target genes NQO1 (p<0.001) and HO1 (p<0.001). Protein expression for Nrf2 was also increased in old SFN fed animals (p<0.01), but not the protein expression of NQO1 or HO1. Additionally, ROS and MMP9 protein levels were significantly decreased (p<0.05) in old SFN fed animals. Histopathological analysis confirmed that there was no difference in epidermal thickness in old, when compared to young, SFN treated animals, while the dermal layer thickness was lower in old vs. young, treated animals (p<0.05). Moreover, collagen deposition was improved with SFN treatment in young (p<0.05) and structurally significantly improved in the old mice (p<0.001). SFN dietary supplementation therefore ameliorates skin aging through activation of the Nrf2-pathway.

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... Sulforaphane (SFN) is an isothiocyanate produced in broccoli (Brassica oleracea) and other cruciferous vegetables (Petkovic et al., 2021). Isothiocyanates are phytochemicals characterized by an RdN]C]S functional group (Petkovic et al., 2021). ...
... Sulforaphane (SFN) is an isothiocyanate produced in broccoli (Brassica oleracea) and other cruciferous vegetables (Petkovic et al., 2021). Isothiocyanates are phytochemicals characterized by an RdN]C]S functional group (Petkovic et al., 2021). SFN has anti-tumorigenic and cardioprotective properties, and it is an activator of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway (Petkovic et al., 2021). ...
... Isothiocyanates are phytochemicals characterized by an RdN]C]S functional group (Petkovic et al., 2021). SFN has anti-tumorigenic and cardioprotective properties, and it is an activator of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway (Petkovic et al., 2021). NRF2 is a leucine-zipper transcription factor triggered by free radicals that act as the stress response master regulator in the skin, where it is expressed by keratinocytes, melanocytes, and Langerhans cells (Kahremany et al., 2022). ...
... SFN is the primary hydrolysis product of glucoraphanin (GLR, also known as 4methylsulfinylbutyl glucosinolate), which is the primary GSL found in mature broccoli, and at 15 times greater quantities in broccoli sprouts [88,99,100]. SFN has been shown to operate through inflammation pathways by inhibiting NF-ᴋB, thereby downregulating pro-inflammatory cytokines important to IBD development and maintenance [101][102][103][104]. SFN inhibition of NF-ᴋB translocation has been established, however the underlying mechanisms are yet to be elucidated. ...
... SFN has been shown to operate through inflammation pathways by inhibiting NF-ᴋB, thereby downregulating pro-inflammatory cytokines important to IBD development and maintenance [101][102][103][104]. SFN inhibition of NF-ᴋB translocation has been established, however the underlying mechanisms are yet to be elucidated. It has been theorized that SFN inhibits NF-ᴋB by interacting with Keap1, which inhibits polyubiquitination and binding of Nrf2 and thereby allows Nrf2 nuclear accumulation [101]. Nrf2 activity is inversely linked to NF-ᴋB activity, perhaps due to competition for CREB binding protein (CBP) [102,103]. ...
... Isothiocyanates, derived from broccoli compounds glucosinolates, have been identified as bioactive candidates for inflammation reduction in IBD [115,139]. Specifically, sulforaphane (SFN), perhaps the most well-studied ITC, has been shown to inhibit NF-kB, resulting in downregulation of multiple inflammatory signaling molecules [87,101,103,134,139]. ...
Article
Inflammatory Bowel Diseases (IBD) are chronic, reoccurring, and debilitating conditions characterized by inflammation in the gastrointestinal tract, some of which can lead to more systemic complications and can include autoimmune dysfunction, a change in the taxonomic and functional structure of microbial communities in the gut, and complicated burdens in a person’s daily life. Like many diseases based in chronic inflammation, research on IBD has pointed towards a multifactorial origin involving factors of the host’s lifestyle, immune system, associated microbial communities, and environmental conditions. Too often, research focuses on just one aspect of IBD or uses one model with a narrow scope, that may result in unanticipated microbial changes, or that are not representative of genetic factors. This is reflected in the absence of genetic models in biochemical-centric research focused on the role of broccoli-metabolite sulforaphane (SFN) in preventing and treating IBD. To be an accurate reflection of IBD, research studies should expand their scope, for example by addressing the concepts of biogeographic specificity of both nutrient absorption and microbial community dynamics, or by using multiple research tools to better mimic the multiple presentations of IBD. To date, no previous SFN or broccoli diet studies have used the IL-10-ko mouse model. With our study, we sought to cover this research gap by, first, proofing broccoli dietary measures in IL-10-ko mice that have a Crohn’s disease-like presentation of inflammation. We fed IL-10-ko mice either a broccoli diet or a control diet, initiated inflammation, and assessed that inflammation using bodyweight gain, a disease activity index score, and immunohistology. All three of the parameters measured showed a consistent and marked reduction of inflammation in mice that were fed a broccoli diet. To assess the performance of this study, we also compared the bodyweight results of our novel IL-10-ko model to the results of an established dextran sulfate sodium (DSS) model of IBD. As expected, the broccoli diet prevented inflammation in the DSS model when compared to control diet fed mice. Excitingly, the IL-10 model had a much more pronounced effect on bodyweight gain, suggesting IL-10-ko mice may be an excellent environment for studying broccoli diet and SFN interactions with gut microbes.
... In a recent nematode study, the authors indicate that SFN prolongs the life and health span of C. elegans through insulin/IGF-1 signaling. Moreover, oral supplementation of SFN has been shown to dramatically prevent skin aging, through the activation of the Keap1-Nrf2 pathway [73]. These results provide the basis for a nutritional SFN-enriched strategy for the promotion of healthy aging and disease prevention [74]. ...
... Decreased dermal layer thickness and improved collagen deposition [73] Abbreviations ...
Article
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The worldwide obesity epidemic has led to a drastic increase in diabetes and cardiovascular disease in younger generations. Further, maintaining metabolic health during aging is frequently a challenge due to poor diets and decreased mobility. In this setting, bioactive nutrients that are naturally occurring antioxidants, such as sulforaphane (SFN), are of high nutritional interest. SFN, a bioactive compound that is present in cruciferous vegetables, is a molecule that protects cells from cytotoxic damage and mitigates oxidative stress, protecting against disease. It exerts its action through the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Many studies have been performed in animals and humans to evaluate its effects on cancer, brain health, and neurodegenerative disorders. However, fewer clinical studies have been performed to evaluate its effects on insulin resistance and the development of type 2 diabetes mellitus (T2DM) across the lifespan. Given that, in some parts of the world, particularly in Europe, the population is growing older at a significant rate, it is crucial to promote healthy habits (healthy foods, dietary pattern, precision nutrition, and physical activity) from an early stage in life and across the lifespan to avoid debilitating health conditions occurring during adulthood and aging. Thus, in this narrative review, we discuss the protective effects of SFN supplementation on inflammatory and oxidative stress pathways and relate them to metabolic disease.
... SFN is the primary hydrolysis product of glucoraphanin (GLR, also known as 4methylsulfinylbutyl glucosinolate), which is the primary GSL found in mature broccoli, and at 15 times greater quantities in broccoli sprouts [109 , 120 , 121] . SFN has been shown to operate through inflammation pathways by inhibiting NF-ᴋB, thereby downregulating pro-inflammatory cytokines important to IBD development and maintenance [122][123][124][125] . SFN inhibition of NF-ᴋB translocation has been established, however the underlying mechanisms are yet to be elucidated. ...
... SFN inhibition of NF-ᴋB translocation has been established, however the underlying mechanisms are yet to be elucidated. It has been theorized that SFN inhibits NF-ᴋB by interacting with Keap1, which inhibits polyubiquitination and binding of Nrf2 and thereby allows Nrf2 nuclear accumulation [122] . Nrf2 activity is inversely linked to NF-ᴋB activity, perhaps due to competition for CREB binding protein (CBP) [123 , 124] . ...
Article
Inflammatory Bowel Diseases (IBD) are chronic, reoccurring, and debilitating conditions characterized by inflammation in the gastrointestinal tract, some of which can lead to more systemic complications and can include autoimmune dysfunction, a change in the taxonomic and functional structure of microbial communities in the gut, and complicated burdens in a person's daily life. Like many diseases based in chronic inflammation, research on IBD has pointed towards a multifactorial origin involving factors of the person's lifestyle, immune system, associated microbial communities, and environmental conditions. Treatment currently exists only as palliative care, and seeks to disrupt the feedback loop of symptoms by reducing inflammation and allowing as much of a return to homeostasis as possible. Various anti-inflammatory options have been explored, and this review focuses on the use of diet as an alternative means of improving gut health. Specifically, we highlight the connection between the role of sulforaphane from cruciferous vegetables in regulating inflammation and in modifying microbial communities, and to break down the role they play in IBD.
... Nrf2 is negatively regulated by kelch-like ECH-associated protein 1 (Keap1), which promotes its degradation through the ubiquitin-proteasome pathway. Naturally occurring ITCs such as AITC, BITC and SFN can promote Nrf2 dissociating from Keap-1 [76,77]. Although there is little evidence that SFN can activate Nrf2 in humans [78], as an electrophile, SFN could react with the cysteine residues in Keap1 [79,80], forming a sulfenic acid-based adduct with Keap1 [81] and thereby rendering Nrf2 binding ineffective and inducing Nrf2 expression [82]. ...
Article
Full-text available
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract which affects millions of individuals worldwide. Despite advancements in treatment options, there is increasing interest in exploring natural interventions with minimal side effects. Cruciferous vegetables, such as broccoli, cabbage, and radishes, contain bioactive compounds known as glucosinolates (GLSs), which have shown promising effects in alleviating IBD symptoms. This review aims to provide a comprehensive overview of the physiological functions and mechanisms of cruciferous GLSs and their metabolites in the context of IBD. Reviewed studies demonstrated that GLSs attenuated all aspects of IBD, including regulating the intestinal microbiota composition, exerting antioxidant and anti-inflammatory effects, restoring intestinal barrier function, and regulating epigenetic mechanisms. In addition, a few interventions with GLS supplementation in clinical studies were also discussed. However, there are still several challenges and remaining knowledge gaps, including variations in animals’ experimental outcomes, the bioavailability of certain compounds, and few clinical trials to validate their effectiveness in human subjects. Addressing these issues will contribute to a better understanding of the therapeutic potential of cruciferous GLSs and their metabolites in the management of IBD.
... Nrf2 activators have received increasing interest in the recent years regarding various diseases. Sulforaphane, for example, is a widely explored phenolic compound that primarily targets NF-κB to repress inflammation through Nrf2 activation [53,54]. Other natural compounds include curcumin, resveratrol, epigallocatechin gallate, bardoxolone methyl, dimethyl fumarate, and oltipraz, which have been shown to regulate Nrf2 and reduce inflammation in preclinical studies [55]. ...
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Inflammation in macrophages is exacerbated under hyperglycemic conditions, contributing to chronic inflammation and impaired wound healing in diabetes. This study investigates the potential of mangiferin, a natural polyphenol, to alleviate this inflammatory response by targeting a redox-sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Mangiferin, a known Nrf2 activator, was evaluated for its ability to counteract the hyperglycemia-induced inhibition of Nrf2 and enhance antioxidant defenses. The protective effects of mangiferin on macrophages in a hyperglycemic environment were assessed by examining the expression of Nrf2, NF-κB, NLRP3, HO-1, CAT, COX-2, IL-6, and IL-10 through gene and protein expression analyses using qPCR and immunoblotting, respectively. The mangiferin-mediated nuclear translocation of Nrf2 was evidenced, leading to a robust antioxidant response in macrophages exposed to a hyperglycemic microenvironment. This activation suppressed NF-κB signaling, reducing the expression of pro-inflammatory mediators such as COX-2 and IL-6. Additionally, mangiferin decreased NLRP3 inflammasome activation and reactive oxygen species accumulation in hyperglycemia exposed macrophages. Our findings revealed that mangiferin alleviated hyperglycemia-induced reductions in AKT phosphorylation, highlighting its potential role in modulating key signaling pathways. Furthermore, mangiferin significantly enhanced the invasiveness and migration of macrophages in a hyperglycemic environment, indicating its potential to improve wound healing. In conclusion, this study suggests that mangiferin may offer a promising therapeutic approach for managing inflammation and promoting wound healing in diabetic patients by regulating Nrf2 activity in hyperglycemia-induced macrophages.
... The utilization of natural products in the cosmetic application is becoming a great interest nowadays as phenolic compound biological activity proved to have anti-aging activity and the ability to protect skin from ultraviolet radiation [31]. An animal study conducted by Marija et al. [47] shows that a dietary supplement derived from a vegetable from the genus Brassica reduced the effect of skin aging. Puxvadee et al. [48] use Phyllanthus emblica L. branch in topical gel to evaluate the efficacy of the anti-aging activity. ...
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Cascara dry coffee skin (coffee cherry tea) is one of the waste products of dried coffee pulp, which is useful as an inhibitor of free radicals, protects the stomach, and is beneficial for the skin. One that can inhibit free radicals is antioxidants. This study assessed the effect of different solvents on Arabica Gayo coffee pulp cascara's antioxidant activity and analyzed the components of Arabica Gayo coffee pulp compounds. This study's experimental methods include cascara extraction, antioxidant assay, and metabolite identification by GCMS analysis. Water, ethanol, methanol, n-hexane, and ethyl acetate were used to extract the cascara Arabica Gayo coffee, then the various concentration of extract was prepared and tested with DPPH solutions. Extracts also identified their secondary metabolites by using GCMS analysis. The antioxidant assay revealed all extracts showed DPPH reduction with performing by changing color into a yellow color. A high concentration of extract positively correlated with percent DPPH inhibition. The highest antioxidant was the ethanol extract of cascara, followed by n-hexane, water, methanol, and ethyl acetate. The metabolites profile of each extract might cause different antioxidant activities. Metabolite profiles showed caffeine in all extracts, with the highest concentration in the n-hexane extract. Hexadecenoic acid was dominated at n-hexane extract, methanol, and ethyl acetate showed unique compounds, quinic acid in methanol and 1(2H)-Naphthalene, octahydro-4a,8a-dim at ethyl acetate extract. Both reported potential antioxidant activity. In summary, ethanol was recommended solvent with high antioxidant performance.
... The process of wound healing is significantly aided by SF, which acts as a ROS inhibitor and cell protector with antioxidant characteristics. SF ameliorates skin aging, ultraviolet-induced skin damage, and maintenance of collagen levels during photo-aging via the activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway, the inhibition of the activator protein-1 (AP-1), and the expression of metalloproteinases [14,15]. However, the therapeutic potential of SF is confined due to its linear and hydrophobic structure, poor solubility in water, and low bioavailability. ...
Article
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Hydrogel scaffold has been widely applied as drug delivery systems for treating skin injuries. However, the poor drug loading and rapid drug release of hydrogel restricted their application. In the current study, we present a nanoliposome containing sulforaphane (SF) as a nano-drug delivery system that is encapsulated within the scaffold hydrogel system to overcome these limitations and improve wound healing. The hydrogel substrate consisting of 10% polyvinyl alcohol (PVA)/5% polyethylene glycol 400 (PEG400) was prepared by the freeze–thaw method, and the nanoliposomal system was manufactured by the thin film hydration method at different molar ratios of cholesterol: SPC: DPPC: DSPE-PEG2000. The nanoliposome and hydrogel system was characterized by physicochemical analyses. The findings achieved from the optimization of the sulforaphane-loaded nanoliposome (SFNL) displayed an increase in the molar ratio of SPC, leading to a higher entrapment efficiency and a gradual release profile. Narrow size distribution, optimal electrical charge, and the lack of molecular interactions between SF and nanoliposome components in the FTIR analysis make SFNL a suitable drug delivery system for the wound healing process. The obtained SFNL-encapsulated freeze–thawed hydrogel system has sufficient and specific swelling ability at different pH values and increased mechanical strength and elongation. Additionally, the release pattern of SFNL at different pH values showed that the release of SF from liposomes depends on the pH value of the environment and accelerates in line with decreasing pH values. Encapsulation of nanoliposomal SF in the hydrogel structure provides a sustained release pattern of SF compared to its free form and increased as the pH environments continued to raise. The cytotoxicity and cell uptake of SFNL-loaded hydrogels against human skin fibroblasts (HFF cell line) were investigated. The in vitro analyses displayed that the toxicity properties of SF and SFNL were dose-dependent, and SFNL exhibited lower toxicity compared to free SF. Furthermore, the proper cell compatibility of the prepared hydrogel against the HFF cell line was confirmed by the MTT assay. These findings imply that the hydrogel scaffold loaded with SFNL may have wound-healing potential
... Sulforaphane is also used as a protective agent against photoaging due to UV damage and it seems to be a very promising ingredient in upcoming anti-aging drugs and cosmetics. It has been shown to increase Nrf2-dependent antioxidant response in epithelial cells isolated from old rats and elderly humans (Petkovic et al., 2021). Treatment with 1 μM sulforaphane once per week delayed the senescence of human fibroblasts, exhibiting a caloric restriction mimetic-like activity and decreased oxidative damage to proteins and DNA (Hariton et al., 2018). ...
Article
So far, the search for a cure for Alzheimer Disease (AD) has been unsuccessful. The only approved drugs attenuate some symptoms, but do not halt the progress of this disease, which affects 50 million people worldwide and will increase its incidence in the coming decades. Such scenario demands new therapeutic approaches to fight against this devastating dementia. In recent years, multi-omics research and the analysis of differential epigenetic marks in AD subjects have contributed to our understanding of AD; however, the impact of epigenetic research is yet to be seen. This review integrates the most recent data on pathological processes and epigenetic changes relevant for aging and AD, as well as current therapies targeting epigenetic machinery in clinical trials. Evidence shows that epigenetic modifications play a key role in gene expression, which could provide multi-target preventative and therapeutic approaches in AD. Both novel and repurposed drugs are employed in AD clinical trials due to their epigenetic effects, as well as increasing number of natural compounds. Given the reversible nature of epigenetic modifications and the complexity of gene-environment interactions, the combination of epigenetic-based therapies with environmental strategies and drugs with multiple targets might be needed to properly help AD patients.
... Notably, Arcidiacono et al. demonstrated that in higher doses (5 µg/mL which is equivalent to 28 μM), SFN has the ability to induce apoptosis of human epidermal melanocytes [69], indicating [70], suggesting that apoptotic characteristics of SFN could also be time-dependent. Sulforaphane-mediated activation of Nrf2-pathways has also been proposed as a mechanism which ameliorates skin aging in male mice [71], as well as in normal human keratinocytes when treated with the combination of patented extract Fernblock® XP, obtained from Polypodium leucotomos and SFN [72]. Thus, SFN dose and treatment duration should be carefully selected to ensure the best risk-to-benefit ratio. ...
Article
Full-text available
Sulforaphane (SFN) is a naturally occurring molecule present in plants from Brassica family. It becomes bioactive after hydrolytic reaction mediated by myrosinase or human gastrointestinal microbiota. Sulforaphane gained scientific popularity due to its antioxidant and anti-cancer properties. However, its toxicity profile and potential to cause adverse effects remain largely unidentified. Thus, this study aimed to generate SFN-triggered adverse outcome pathway (AOP) by looking at the relationship between SFN-chemical structure and its toxicity, as well as SFN-gene interactions. Quantitative structure-activity relationship (QSAR) analysis identified 2 toxophores (Derek Nexus software) that have the potential to cause chromosomal damage and skin sensitization in mammals or mutagenicity in bacteria. Data extracted from Comparative Toxicogenomics Database (CTD) linked SFN with previously proposed outcomes via gene interactions. The total of 11 and 146 genes connected SFN with chromosomal damage and skin diseases, respectively. However, network analysis (NetworkAnalyst tool) revealed that these genes function in wider networks containing 490 and 1986 nodes, respectively. The over-representation analysis (ExpressAnalyst tool) pointed out crucial biological pathways regulated by SFN-interfering genes. These pathways are uploaded to AOP-helpFinder tool which found the 2321 connections between 19 enriched pathways and SFN which were further considered as key events. Two major, interconnected AOPs were generated: first starting from disruption of biological pathways involved in cell cycle and cell proliferation leading to increased apoptosis, and the second one connecting activated immune system signaling pathways to inflammation and apoptosis. In both cases, chromosomal damage and/or skin diseases such as dermatitis or psoriasis appear as adverse outcomes.
... In humans, isothiocyanates have been identified as bioactive candidates for reducing gut inflammation (19)(20)(21). Specifically, sulforaphane (SFN), a well-studied isothiocyanate (22), has been shown to inhibit the action of Nuclear Factor -B (NF-κB) and Signal Transducer and Activator Of Transcription 3 (STAT3) which are responsible for upregulation of inflammatory cytokines interleukins-6, -8, -12, -21, and -23 (19,(23)(24)(25)(26). However, raw broccoli and broccoli sprouts contain small amounts of this anti-inflammatory, as broccoli-sourced enzymes preferentially metabolize the precursor of sulforaphane, glucoraphanin (GLR), to an inactive byproduct instead (22). ...
Preprint
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... In addition, recent findings suggest that some phytochemicals, such as sulforaphane, exhibit an hormetic effect in cells at low doses, activating signaling pathways that result in the increased expression of genes encoding cytoprotective proteins and antioxidant enzymes [96,97]. As such, the relatively small doses of phytochemicals ingested by humans are not toxic and instead induce mild cellular stress responses. ...
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The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.
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Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE) cells from subjects of young adult (21-29 years) and older (60-69 years) non-smokers, and explored factors affecting expresion. The basal expression of three representative Nrf2-regulated genes, the catalytic and modulator subunits of glutamate cysteine ligase (GCLC and GCLM, respectively), and NAD(P)H quinone oxidoreductase 1 (NQO1), was higher in cells from the older donors compared with cells from the young adult donors. Upon exposure to the Nrf2 activator, sulforaphane (SF), the expression of these antioxidant genes was increased in cells from both the young adults and the older donors; however, the induction by SF in older donor cells was significantly less than that seen in young adult cells. In addition, the activation of an EpRE-driven reporter by SF was lower in cells from older donors compared to cells from young adults. The basal expression of Nrf2 protein was also lower in cells from older donors than cells from young adults. Furthermore, we found that the basal expression of both Bach1 and c-Myc, two Nrf2 suppressors, was higher in cells from older adults than from young adult donors. In summary, our data suggest that, as in other species, basal expression of Nrf2-regulated genes increases with aging, while inducibility declines with aging. The increased expression of Nrf2 suppressors such as Bach1 and c-Myc may contribute to the impaired inducibility of the Nrf2-regulated antioxidant genes with aging in human bronchial epithelial cells.
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Background Aging human skin undergoes significant morphological and functional changes such as wrinkle formation, reduced wound healing capacity, and altered epidermal barrier function. Besides known age-related alterations like DNA-methylation changes, metabolic adaptations have been recently linked to impaired skin function in elder humans. Understanding of these metabolic adaptations in aged skin is of special interest to devise topical treatments that potentially reverse or alleviate age-dependent skin deterioration and the occurrence of skin disorders. ResultsWe investigated the global metabolic adaptions in human skin during aging with a combined transcriptomic and metabolomic approach applied to epidermal tissue samples of young and old human volunteers. Our analysis confirmed known age-dependent metabolic alterations, e.g. reduction of coenzyme Q10 levels, and also revealed novel age effects that are seemingly important for skin maintenance. Integration of donor-matched transcriptome and metabolome data highlighted transcriptionally-driven alterations of metabolism during aging such as altered activity in upper glycolysis and glycerolipid biosynthesis or decreased protein and polyamine biosynthesis. Together, we identified several age-dependent metabolic alterations that might affect cellular signaling, epidermal barrier function, and skin structure and morphology. Conclusions Our study provides a global resource on the metabolic adaptations and its transcriptional regulation during aging of human skin. Thus, it represents a first step towards an understanding of the impact of metabolism on impaired skin function in aged humans and therefore will potentially lead to improved treatments of age related skin disorders.
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Aging is tightly associated with redox events. The free radical theory of aging indicates that redox imbalance may be an important factor in the aging process. Most studies about redox and aging focused on the static status of oxidative stress levels, there has been little research investigating differential responses to redox challenge during aging. In this study, we used Caenorhabditis elegans and human fibroblasts as models to compare differential responses to oxidative stress challenge in young and old individuals. In response to paraquat stress, young individuals generated more ROS and activated signaling pathways including p-ERK, p-AKT and p-AMPKα/β. After the initial response, young individuals then promoted NRF2 translocation and induced additional antioxidant enzymes and higher expression of phase II enzymes, including SOD, CAT, GPX, HO-1, GSTP-1and others, to maintain redox homeostasis. Moreover, young individuals also demonstrated a better ability to degrade damaged proteins by up-regulating the expression of chaperones and improving proteasome activity. Based on these data, we propose a new concept "Redox-stress Response Capacity (RRC)", which suggests cells or organisms are capable of generating dynamic redox responses to activate cellular signaling and maintain cellular homeostasis. The decay of RRC is the substantive characteristic of aging, which gives a new understand of the redox theory of aging.
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Ultraviolet A (UVA) irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds which can activate Nrf2, a transcription factor regulating antioxidant gene expression, should therefore serve as effective anti-photoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of MAPK/AP-1 signaling using human keratinocyte cell line (HaCaT). Anti-photoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed, on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (ERK, JNK and p38), c-Jun and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pre-treatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising anti-photoaging candidates.
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All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3′ untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes.
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Everyone desires healthy and beautiful-looking skin. However, as we age, our skin becomes old due to physiological changes. Reactive oxygen species (ROS) is an important pathogenic factor involved in human aging. Human skin is exposed to ROS generated from both extrinsic sources such as as ultraviolet (UV) light from the sun, and intrinsic sources such as endogenous oxidative metabolism. ROS-mediated oxidative stress damages the collagen-rich extracellular matrix (ECM), the hallmark of skin connective tissue aging. Damage to dermal collagenous ECM weakens the skin’s structural integrity and creates an aberrant tissue microenvironment that promotes age-related skin disorders, such as impaired wound healing and skin cancer development. Here, we review recent advances in our understanding of ROS/oxidative stress and skin connective tissue aging.
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The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap 'n' Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.
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Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases. Copyright © 2015. Published by Elsevier B.V.
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Introduction: Sulforaphane (SFN) is an isothiocyanate derived from glucoraphanin (GRA), which is found in great amounts especially in broccoli. Its consumption has been reported to be associated with a lower risk of myocardial infarction and cancer development. Additionally, its effects have been studied in neurodegenerative diseases, diabetes, and atherosclerosis, most of the times using animal models and cell cultures. Objectives: Given the promising results of SFN, this review aimed to investigate evidence documented in human intervention studies with broccoli, GRA and SFN. Methods: A search was performed on PubMed and Virtual Health Library databases by two independent researchers using the descriptors "broccoli" or "glucoraphanin" or "sulforaphane", which should appear on the study's title or abstract. This review included randomized clinical trials performed in humans that were published in English and Portuguese from 2003 to 2013 and that considered clinical and molecular parameters of cell damage as outcomes of interest. Results: Seventeen studies were selected, and the predominant type of intervention was broccoli sprouts. More consistent results were obtained for the clinical parameters blood glucose and lipid profile and for molecular parameters of oxidative stress, indicating that there was an improvement in these parameters after intervention. Less solid evidence was found with regard to decreased inflammation, Helicobacter pylori colonization, and protection against cancer. Conclusion: Although being relevant, the evidence for the use of broccoli, GRA and SFN in humans are limited; thus, further intervention studies are needed to evaluate outcomes more consistently and reach better grounded conclusions. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.
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Hydrogen sulfide (H2S) can protect the liver against ischemia-reperfusion (I/R) injury. However, it is unknown whether H2S plays a role in the protection of hepatic I/R injury in both young and old patients. This study compared the protective effects of H2S in a rat model (young and old animals) of I/R injury and the mechanism underlying its effects. Young and old rats were assessed following an injection of NaHS. NaHS alone reduced hepatic I/R injury in the young rats by activating the nuclear erythroid-related factor 2 (Nrf2) signaling pathway, but it had little effect on the old rats. NaHS pretreatment decreased miR-34a expression in the hepatocytes of the young rats with hepatic I/R. Overexpresion of miR-34a decreased Nrf-2 and its downstream target expression, impairing the hepatoprotective effect of H2S on the young rats. More importantly, downregulation of miR-34a expression increased Nrf-2 and the expression of its downstream targets, enhancing the effect of H2S on hepatic I/R injury in the old rats. This study reveals the different effects of H2S on hepatic I/R injury in young and old rats and sheds light on the involvement of H2S in miR-34a modulation of the Nrf-2 pathway.
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The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.
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Aim Skin aging is caused by intrinsic and extrinsic mechanisms. Because it is difficult to distinguish intrinsic mechanisms from extrinsic skin aging, the mechanisms of intrinsic skin aging remain unclear. The present study aimed to characterize age‐associated alterations in murine skin and investigate the mechanisms of intrinsic skin aging. Methods We measured morphological changes in dorsal skin from young (aged 2 months) and old (aged 22–24 months) mice by histological analysis. Age‐associated alteration of gene expression patterns was determined by quantitative polymerase chain reaction and immunohistochemistry. Reactive oxygen species production in mouse dorsal skin was detected by confocal laser scanning microscopy. Mitochondrial DNA deletions were detected by conventional polymerase chain reaction and quantitative polymerase chain reaction analyses. Results Chronologically aged skin had dermal atrophy caused by increased matrix‐degrading enzymes and decreased collagen synthesis. Chronologically aged skin samples also had increased senescence‐associated secretory phenotype factors, elevated reactive oxygen species production and a higher frequency of the mitochondrial DNA common deletion. Conclusions These observations suggest that chronological skin aging is associated with increased frequency of the mitochondrial DNA common deletion and chronic inflammation through the reactive oxygen species–senescence‐associated secretory phenotype axis. Geriatr Gerontol Int 2019; ••: ••–••.
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Increase in life-span is commonly related with age-related diseases and with gradual loss of genomic, proteomic and metabolic integrity. Nrf2 (Nuclear factor-erythroid 2-p45 derived factor 2) controls the expression of genes whose products include antioxidant proteins, detoxifying enzymes, drug transporters and numerous cytoprotective proteins. Several experimental approaches have evaluated the potential regulation of the transcription factor Nrf2 to enhance the expression of genes that contend against accumulative oxidative stress and promote healthy aging. Negative regulators of Nrf2 that act preventing it´s binding to DNA-responsive elements, have been identified in young and adult animal models. However, it is not clearly established if Nrf2 decreased activity in several models of aging results from disruption of that regulation. In this review, we present a compilation of evidences showing that changes in the levels or activity of Keap1 (Kelch-like ECH associated protein 1), GSK-3β (glycogen synthase kinase-3), Bach1, p53, Hrd1 (E3 ubiquitin ligase) and miRNAs might impact on Nrf2 activity during elderly. We conclude that understanding Nrf2 regulatory mechanisms is essential to develop a rational strategy to prevent the loss of cellular protection response during aging.
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The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function but the precise mechanism of action remains poorly understood. We report that itaconate is required for the activation of the anti-inflammatory transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) by LPS. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteines 151, 257, 288, 273 and 297 on Kelch-Like ECH-Associated Protein 1 (Keap1) enabling Nrf2 to increase expression of down-stream genes with anti-oxidant and anti-inflammatory capacity. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate (OI), which is protective against LPS-induced lethality in vivo and decreases cytokine production. We show that type I interferons (IFN) boost immunoresponsive gene 1 (Irg1) expression and itaconate production. Furthermore, we find that itaconate production limits the type I IFN response indicating a negative feedback loop involving IFNs and itaconate. Our findings demonstrate that itaconate is a critical anti-inflammatory metabolite acting via Nrf2 to limit inflammation and modulate type I IFNs.
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Background: Visible age-related signs indicate biological age, as individuals that appear old for their age are more likely to be at poor health, compared with people that appear their actual age. The aim of this study was to investigate whether alcohol and smoking are associated with four visible age-related signs (arcus corneae, xanthelasmata, earlobe crease and male pattern baldness). Methods: We used information from 11 613 individuals in the Copenhagen City Heart Study (1976-2003). Alcohol intake, smoking habits and other lifestyle factors were assessed prospectively and visible age-related signs were inspected during subsequent examinations. Results: The risk of developing arcus corneae, earlobe crease and xanthelasmata increased stepwise with increased smoking as measured by pack-years. For alcohol consumption, a high intake was associated with the risk of developing arcus corneae and earlobe crease, but not xanthelasmata. Conclusions: High alcohol consumption and smoking predict development of visible age-related signs. This is the first prospective study to show that heavy alcohol use and smoking are associated with generally looking older than one's actual age.
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A high matrix metalloproteinase–9/tissue inhibitor of metalloproteinase–1 (MMP9/TIMP1) ratio is associated with poor ulcer healing, yet how the ratio of MMP9/TIMP1 changes in diabetic foot ulcers (DFUs) with infection and how these changes may affect wound healing remain unclear. Therefore, the objective of this investigation was to explore relationships among the MMP9/TIMP1 ratio, infection, and DFUs. After being informed of the details of this study, 32 patients signed consent forms. Skin biopsies were performed for all patients. Wound tissues were obtained from all patients with wounds, and healthy skin samples were collected from patients without wounds during orthopedic surgery. Microbial cultures were obtained using the samples from diabetic patients with wounds. All patients were divided into 4 groups according to colony-forming units (CFUs) per gram of tissue (>1 × 10⁶ or <1 × 10⁶): group A (diabetic wounds with high quantities of bacteria), group B (diabetic wounds with low quantities of bacteria), group C (diabetic patients without wounds), and group D (nondiabetic patients with wounds). In addition, the biopsies were evaluated by both reverse transcription–quantitative polymerase chain reaction and Western blotting to assess the levels of MMP9, TIMP1, and vascular endothelial growth factor (VEGF). The results show that for both mRNA and protein, expression of MMP9 (fold change 1.14 ± 0.12 vs 0.60 ± 0.08 vs 0.39±0.09 vs 0.13 ± 0.06, P < .01) decreased, whereas that of TIMP1 (1.01 ± 0.09 vs 2.86 ± 0.85 vs 4.88 ± 0.83 vs 7.29 ± 1.55, P < .01) and VEGF (1.01 ± 0.22 vs 3.55 ± 0.97 vs 5.72 ± 0.55 vs 6.92 ± 1.55, P < .01) increased from group A to group D. These results suggest that an increase in the MMP9/TIMP1 ratio in infected DFUs may induce a decrease in VEGF expression.
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To identify endogenous miRNA-target sites, we isolated AGO-bound RNAs from Caenorhabditis elegans by individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP), which fortuitously also produced miRNA-target chimeric reads. Through the analysis of thousands of reproducible chimeras, pairing to the miRNA seed emerged as the predominant motif associated with functional interactions. Unexpectedly, we discovered that additional pairing to 3' sequences is prevalent in the majority of target sites and leads to specific targeting by members of miRNA families. By editing an endogenous target site, we demonstrate that 3' pairing determines targeting by specific miRNA family members and that seed pairing is not always sufficient for functional target interactions. Finally, we present a simplified method, chimera PCR (ChimP), for the detection of specific miRNA-target interactions. Overall, our analysis revealed that sequences in the 5' as well as the 3' regions of a miRNA provide the information necessary for stable and specific miRNA-target interactions in vivo.
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Background: Skin aging is a process of structural and compositional remodeling that can be manifested as wrinkling and sagging. Remarkably, the dermis plays a dominant role in the process of skin aging. Recent studies suggest that microRNAs (miRNAs) may play a role in the regulation of gene expression in organism aging. However, studies about age-related miRNAs in human skin remain limited. Objective: To obtain an overall view of miRNAs expression in human aged dermis by comparison of dermis samples between young and elderly, construct the miRNA-gene-network and reveal the pivotal miRNAs in the regulatory network. Methods: Human dermis tissue was obtained from 12 donors, including 6 of young group and 6 of elderly one. The miRNA microarray and data analysis were performed. Target genes of differentially expressed miRNAs were predicted, followed by a gene ontology and pathway enrichment analysis. A miRNA-gene-network was then constructed, and the pivotal miRNAs in the network was revealed. Primary human dermal fibroblasts (HDFs) were isolated, and the cellular senescence was induced by serial passaging. Alteration in the expression of miRNAs between young and senescent fibroblasts was evaluated by real-time quantitative RT-PCR. MiR-34b-5p mimics were transfected into primary HDFs. Subsequent cell cycle analysis was performed and expression level of COL1A1, elastin and MMP-1 were evaluated. Results: The expression of a total of 40 miRNAs (25 upregulated and 15 downregulated) was found to be significantly altered in aged dermis compared with young dermis. Real-time quantitative PCR results confirmed the differential expression of miR-34 family and miR-29 family between young and aged dermis. A computational approach demonstrated that predicted target genes of the miRNA profile were found to be mainly involved in processes including cell adhesion, collagen synthesis, positive or negative regulation of transcription, as well as pathways such as insulin signaling pathway, ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) signaling pathway and Focal adhesion pathway. The miRNA-Gene-Network revealed that miR-34 family, miR-29 family and miR-424 may play a dominant role in the regulatory network. A similar miRNA alteration was observed in senescent fibroblasts in vitro, and the age-related miRNA profile may interact with p16 pathway to regulate the fibroblasts' senescence. Additionally, transfection of miR-34b-5p mimics induced cell cycle arrest in HDFs, decreased the expression of both COL1A1 and elastin and increased MMP-1 expression. Conclusion: The miR-34 family and miR-29 family expressed differentially in young and aged dermis. MiR-34 in HDFs modulated the cell function and expression of MMP-1, COL1A1 and elastin. The miRNAs may play critical roles in affecting dermis aging.
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Sulforaphane (SFN), a natural compound occurring in cruciferous vegetables, has been known for years as a chemopreventive agent against many types of cancer. Recently, it has been investigated as an antioxidant and anti-aging agent, and interesting conclusions have been made over the last decade. SFN demonstrated protective effects against ultraviolet (UV)-induced skin damage through several mechanisms of action, for example, decrease of reactive oxygen species production, inhibition of matrix metalloproteinase expression, and induction of phase 2 enzymes. SFN used as a protective agent against UV damage is a whole new matter, and it seems to be a very promising ingredient in upcoming anti-aging drugs and cosmetics.
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Context: Polycystic ovary syndrome (PCOS) has a largely unknown etiology and presents with a clinical heterogeneous patient group. Small non-coding microRNA (miRNA) might prove promising as biomarker candidates for PCOS patient stratification. Altered miRNA expression profiles have been observed in few studies. Objective: The aim was to assess the miRNA expression profile in follicular fluid from PCOS patients and healthy, regularly-cycling, matched controls. Design and setting: Experimental case-control study including forty-nine PCOS women (nineteen of which were hyper-androgenic and thirty normo-androgenic) and twenty-one healthy matched women all undergoing in vitro fertilization (IVF) treatment. Interventions and Main Outcome: Anthropometric and relevant clinical baseline measurements were obtained. Relative expression of miRNA levels were estimated using miRNA Q-PCR arrays and validated by RT-qPCR. Correlation between miRNAs and clinical relevant measurements was estimated. Results: PCOS women, both normo-androgenic and hyper-androgenic, had decreased levels of miR-24-3p, -29a, -151-3p and -574-3p compared with controls. Furthermore, miR-518f-3p was differentially expressed within the PCOS group with high levels observed in the hyper-androgenic group compared with the normo-androgenic PCOS patients. Serum levels of total and free testosterone were positively correlated with miR-518f-3p in PCOS subjects (p = 0.001). Distinction between PCOS and controls could be made using miR-151-3p alone with an area under the curve (AUC) of 0.91 or a combination of four selected miRNAs (AUC of 0.93). Bioinformatic target analysis points to an involvement of these miRNAs in biological pathways involving regulation of cell proliferation, extracellular matrix and processes in intermediary metabolism. Conclusion: Our study provides evidence that the miRNA expression profile in follicular fluid is altered in PCOS and indicates that specific follicular fluid miRNAs are associated with phenotypical traits of PCOS. An altered miRNA profile holds potentials for new methods of PCOS patient stratification and may contribute to and in part explain the heterogeneous nature found within PCOS women.
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Nrf2 regulates the expression of numerous anti-oxidant, anti-inflammatory, and metabolic genes. We observed that, paradoxically, Nrf2 protein levels decline in the livers of aged rats despite the inflammatory environment evident in that organ. To examine the cause(s) of this loss, we investigated the age-related changes in Nrf2 protein homeostasis and activation in cultured hepatocytes from young (4-6 months) and old (24-28 months) Fischer 344 rats. While no age-dependent change in Nrf2 mRNA levels was observed (p>0.05), Nrf2 protein content, and the basal and anetholetrithione (A3T)-induced expression of Nrf2-dependent genes were attenuated with age. Conversely, overexpression of Nrf2 in cells from old animals reinstated gene induction. Treatment with A3T, along with bortezomib to inhibit degradation of existing protein, caused Nrf2 to accumulate significantly in cells from young animals (p<0.05), but not old, indicating a lack of new Nrf2 synthesis. We hypothesized that the loss of Nrf2 protein synthesis with age may partly stem from an age-related increase in microRNA inhibition of Nrf2 translation. Microarray analysis revealed that six microRNAs significantly increase >2-fold with age (p<0.05). One of these, miRNA-146a, is predicted to bind Nrf2 mRNA. Transfection of hepatocytes from young rats with a miRNA-146a mimic caused a 55% attenuation of Nrf2 translation that paralleled the age-related loss of Nrf2. Overall, these results provide novel insights for the age-related decline in Nrf2 and identify new targets to maintain Nrf2-dependent detoxification with age.
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The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation. Copyright © 2015. Published by Elsevier Inc.
Article
Increasing oxidative stress, a major characteristic of aging, has been implicated in variety of age-related pathologies. In aging, oxidant production from several sources is increased while antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins also declines. Importantly, the adaptive response to oxidative stress declines with aging. Nrf2/EpRE signaling regulates the basal and inducible expression of many antioxidant enzymes and the proteasome. Nrf2/EpRE activity is regulated at several levels including transcription, post-translation, and interaction with other proteins. This review summarizes current studies on age-related impairment of Nrf2/EpRE function and discusses the change of Nrf2 regulatory mechanisms with aging. Copyright © 2015. Published by Elsevier Inc.
Article
Older adults have been reported to have a lower evaporative heat loss capacity than younger adults during exercise when full sweat evaporation is permitted. However, it is unclear how conditions of restricted evaporative and convective heat loss (i.e., high humidity, clothing insulation) alter heat stress. PURPOSE: To examine the heat stress responses of young and older males during and following exercise in a warm/humid environment under two different levels of air velocity. METHODS: Ten young (YOUNG: 24±2 yr) and 10 older (OLDER: 59±3 yr) males, matched for body surface area performed 4x15-min cycling bouts (15-min rest) at a fixed rate of heat production (400 W) in warm/humid conditions (35°C, 60% relative humidity) under 0.5 (Low) and 3.0 (High) m·s−1 air velocity while wearing work coveralls. Rectal (Tre) and mean skin (MTsk) temperatures, heart rate (HR), local sweat rate, % max skin blood flow (SkBF) (continuously), and blood pressure (recovery) were measured. RESULTS: High air velocity reduced core and skin temperatures (p0.05) but was more effective in reducing cardiovascular strain (absolute and % max HR; p
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Dermal and epidermal structures in human skin change during intrinsic and extrinsic aging. Epidermal thickness is one of the most often reported parameters for the assessment of skin aging in cross-sectional images captured by optical coherence tomography (OCT). We aimed to identify further parameters for the noninvasive measurement of skin aging of sun-exposed and sun-protected areas utilizing OCT. Based on a literature review, seven parameters were inductively developed. Three independent raters assessed these parameters using four-point scales on images of female subjects of two age groups. All items could be detected and quantified in our sample. Interrater agreement ranged between 25.0% and 83.3%. The item scores "stratum corneum reflectivity," "upper dermal reflectivity," and "dermoepidermal contrast" showed significant differences between age groups on the volar and dorsal forearm indicating that they were best able to measure changes during skin aging. "Surface unevenness" was associated with the skin roughness parameters, Rz and Rmax, on the inner upper arm and volar forearm supporting the criterion validity of this parameter on sun-protected skin areas. Based on the interrater agreement and the ability to differentiate between age groups, these four parameters are being considered as the best candidates for measuring skin aging in OCT images. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE).
Article
Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Article
With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.