No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Resveratrol induces human keratinocyte damage via the activation of class III histone deacetylase, Sirt1
Abstract
Human skin diseases are various and induce chronic inflammatory disorders, including psoriasis, atopic dermatitis and certain forms of ichthyosis. Psoriasis is a chronic inflammatory skin disease characterized by circumscribed, red, thickened plaques. Regulation of the balance between growth, differentiation and death is critical to keratinocytes; when altered, epidermal keratinocytes undergo hyperproliferation, abnormal differentiation and inflammatory infiltration. In the present study, we focused on the effects of resveratrol, found in red wine and peanuts, on the cell death of keratinocytes. We additionally studied the mechanism of resveratrol on Sirt1, a class III histone deacetylase, and Akt phosphorylation. Resveratrol caused apoptosis and increased Sirt1 expression in human HaCaT keratinocytes, following a decrease in the p62 protein level. Inhibition of Sirt1 by Sirt1 inhibitor restored cell viability and protein levels. Furthermore, we showed that resveratrol-induced Sirt1 blocked Akt phosphorylation. The present results indicated that resveratrol inhibited the Akt pathways by inducing Sirt1, thus leading to cell death. These data suggest that resveratrol-mediated activation of Sirt1 histone deacetylase may be a potential therapeutic target for skin diseases including psoriasis.
... Previous studies have unambiguously demonstrated that the ~45 kDa form of PD-L1 corresponds to the fully Nglycosylated mature protein [41][42][43]. As glycosylation of proteins often generates a heterogeneous migration pattern on immunoblots, such as that observed for PD-L1 in response to RSV treatment, we hypothesized that RSV might promote the accumulation of an aberrantlyglycosylated form of PD-L1. ...
... To substantiate that the RSV-induced aberrant glycosylated form of PD-L1 occurred concomitantly with the expected mode(s) of action of RSV, we first confirmed the well-known capacity of RSV to induce the endogenous expression of SIRT1 protein [42][43][44] (Figure 2A, left panels). Likewise, consistent with the ability of RSV to bind and inhibit histone HDAC enzymes [45,46], RSV-treated JIMT-1 cells also showed increased p53 acetylation at lysine 382 [47]. ...
... A complex interplay thus exists between RSV and PD-L1 that might present mutually antagonistic effects and might differentially occur in settings where baseline PD-L1 is low or high [92,93]. Baseline PD-L1 expression differs according to the molecular phenotype of breast carcinomas, with the highest expression occurring in those with basal-like traits and the lowest expression in those with luminal traits [40,43,44]. Each breast cancer subentity responds differentially to extrinsic and intrinsic factors, and a significant heterogeneity in PD-L1 expression can be observed even within PD-L1-overexpressing breast cancer populations. ...
New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.
... Cellular signal transduction function is able to convert stimulation into a signal, and this process frequently involves a series of biochemical reactions (13). Resveratrol regulates a series of signal transduction pathways, such as the SIRT1 and NF-κB signaling pathways (14). Resveratrol is also able to increase the quantity and function of mitochondria (15). ...
... The current study found that resveratrol treatment significantly inhibited the serum levels of ALP and OC in osteoporosis rats. Similarly, Lee et al (14) have previously suggested that resveratrol promoted bone growth through the mediation of ALP levels in young rats. ...
... In the present study experiments, treatment with resveratrol significantly activated the protein expression of SIRT1 in osteoporosis rats. Sin et al supported that resveratrol has an effect on muscle injury induced by compression through SIRT1 protein expression (31). Lee et al (14) also showed that resveratrol induces human keratinocyte damage through the activation of SIRT1 (14). ...
The aim of the present study was to determine the protective effects of resveratrol on a rat model of osteoporosis and examine the associated mechanisms of its action. Rats were randomized into the following groups: Control, osteoporosis, osteoporosis + low-dose resveratrol, osteoporosis + middle-dose resveratrol and osteoporosis + high-dose resveratrol groups. Resveratrol treatment was administered 7 days after surgery for 8 weeks. ELISA assay was used to analyze alkaline phosphatase (ALP) and osteocalcin (OC) protein levels. Western blotting was performed to assess the protein expression of sirtuin 1 (SIRT1), nuclear factor (NF)-κB and NF-κB inhibitor (IkB) α. In the present study, the results indicated that resveratrol markedly improved the bone mineral density value, femoral porosity and bone mechanical tests in osteoporosis rats. Administration of resveratrol significantly decreased the serum levels of ALP and OC in rats with osteoporosis. Finally, treatment with resveratrol significantly promoted the protein expression of SIRT1, suppressed NF-κB and activated the IkBα protein expression in rats with osteoporosis. In conclusion, treatment with resveratrol significantly improved the final body weight of the osteoporosis rats via the SIRT1-NF-κB signaling pathway. The present study suggested that resveratrol exerted a protective effect on osteoporosis through activation of the SIRT1-NF-κB signaling pathway in rats.
... Dietary phytochemicals are compounds that exhibit potential antiinflammatory effects by reducing the generation of pro-inflammatory cytokines and promoting keratinocyte apoptosis. Administration of curcumin, EGCG, and resveratrol showed a reduction in proinflammatory markers such as TNF-α, IFN-γ, IL-2, IL-12, IL-17A, IL-17F, IL-22, and IL-23 in the plasma and tissues (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). Treatment with these dietary phytochemicals attenuates skin inflammation, reduces infiltration of T cells, leads to recruitment of reduced populations of dendritic cells, reduces malondialdehyde in plasma, increases populations of CD4(+) T cells of spleens, and increases the bioactivities of plasma SOD and CAT (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). ...
... Administration of curcumin, EGCG, and resveratrol showed a reduction in proinflammatory markers such as TNF-α, IFN-γ, IL-2, IL-12, IL-17A, IL-17F, IL-22, and IL-23 in the plasma and tissues (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). Treatment with these dietary phytochemicals attenuates skin inflammation, reduces infiltration of T cells, leads to recruitment of reduced populations of dendritic cells, reduces malondialdehyde in plasma, increases populations of CD4(+) T cells of spleens, and increases the bioactivities of plasma SOD and CAT (Kang et al., 2016;Lee et al., 2015;Zhang et al., 2016). In vitro studies have also shown that resveratrol stimulates apoptosis in the HaCaT keratinocyte cell line. ...
The intestinal epithelium acts as a key defensive barrier that protects internal organs from the detrimental gut environment. The homeostasis of the gut epithelium may be altered by environmental conditions and exogenous pathogens that can impair the integrity of the gut barrier, leading to immune response associated with low‐grade systemic inflammation, a known contributor to metabolic and inflammatory diseases. Autoimmune diseases (ADs) are a collection of abnormalities of the immune system, in which the immune system of an individual acts against healthy organs or systems, due to a failure in antigenic recognition. Hence, this review aims to focus on modulators of intestinal epithelial barrier dysfunction with effects on autoimmune disorders. All data on dietary phytochemicals and their impact on the modulation of the intestinal epithelium barrier and various ADs were collected from electronic searches of library databases (PubMed, Science Direct, and Google Scholar). An electronic search was conducted using PubMed, Science Direct, and Google Scholar by finding the keywords “phytochemicals” AND “bioactive compounds” AND “flavonoids” AND “polyphenols” OR “intestinal epithelium barrier” OR “autoimmune diseases” OR “inflammatory diseases” in “Title/Abstract/Keywords,” with the date from January 2011 to December 2020, to identify all published studies (in vitro, in vivo, clinical, and case‐control) that have investigated the connection between dietary phytochemicals and their various beneficial effects. Dietary phytochemicals are promising key modulators, stabilizing the integrity of the intestinal barrier and attenuating the progression of ADs. Health‐modulatory information was gathered and orchestrated in a suitable place in this review.
... RES has been experimented in psoriasis mainly characterized by hyper-proliferation of keratinocytes and production of IL-23 and IL-17 with inflammatory infiltrates in the dermis [249]. In vitro studies have demonstrated that RES induced apoptosis of HaCaT keratinocytes via Sirt-1 activation [250]. Furthermore, evidence has been provided that RES inhibited proliferation of normal human keratinocytes, hampering aquaporin 3 activation [251]. ...
... In vitro induction of keratinocyte apoptosis via Sirt-1 activation and keratinocyte inhibition via decrease of aquaporin 3 activation [250][251] ...
In this review, special emphasis will be placed on red grape polyphenols for their anti-oxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of pro-inflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Furthermore, the effects of red grape polyphenols will be analyzed in obesity, as a low grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great anti-oxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites and interaction with microbiota, deserve deeper studies.
... In vitro studies have shown that resveratrol induces cell death of the keratinocyte cell line HaCaT through the activation of SIRT1 that inhibits protein kinase B (Akt). This protein participates in the regulation of cell proliferation (Lee et al. 2016). In vivo studies in mice with induced psoriasis were treated with resveratrol, concluding that resveratrol reduce symptoms such as itching and decreases the production of cytokines that participate in the development of psoriasis such as IL-17 and IL-19 (Kjaer et al. 2015). ...
Resveratrol is a stilbenoid polyphenolic molecule widely known for its biological properties, which is available in nature in various varieties of grapes, berries, and some plants. It has been shown to play an important role in the prevention and treatment of chronic diseases such as cancer, heart disease, metabolic, degenerative, autoimmune diseases, and even viral infections. One of the main mechanisms of action that it presents is linked to its antioxidant capacity as it is a strict polyphenol, which gives it the ability to stimulate an immune response in the host by regulating and differentiating immune cells, promoting the synthesis of specific proteins, activate apoptosis, stimulate the secretion of pro-inflammatory cytokines, and even modulate gene expression. These effects have favored the decrease in the progression of various inflammatory and degenerative diseases, thus demonstrating the immunomodulatory capacity of resveratrol on in vitro and in vivo models.
... Reservatol, a polyphenol with anti-inflammatory properties, was shown to stimulate the expression of SIRT1 leading HaCaT cells to death [147]. Recently, trichostatin A (TSA), a class I and II HDAC inhibitor (HDACi), significantly decreased KC's proliferative phenotype, both in vitro and in vivo [148]. ...
Despite the increasing research and clinical interest in the predisposition of psoriasis, a chronic inflammatory skin disease, the multitude of genetic and environmental factors involved in its pathogenesis remain unclear. This complexity is further exacerbated by the several cell types that are implicated in Psoriasis’s progression, including keratinocytes, melanocytes and various immune cell types. The observed interactions between the genetic substrate and the environment lead to epigenetic alterations that directly or indirectly affect gene expression. Changes in DNA methylation and histone modifications that alter DNA-binding site accessibility, as well as non-coding RNAs implicated in the post-transcriptional regulation, are mechanisms of gene transcriptional activity modification and therefore affect the pathways involved in the pathogenesis of Psoriasis. In this review, we summarize the research conducted on the environmental factors contributing to the disease onset, epigenetic modifications and non-coding RNAs exhibiting deregulation in Psoriasis, and we further categorize them based on the under-study cell types. We also assess the recent literature considering therapeutic applications targeting molecules that compromise the epigenome, as a way to suppress the inflammatory cutaneous cascade.
... HDAC1 was overexpressed in psoriasis patients while SIRT1 was decreased in the basal layer of psoriasis patients compared to healthy controls (146). Activation of SIRT1 by resveratrol induced human keratinocyte damage through blocking the Akt pathway (147). The evidence linked histone modifications with psoriasis progression providing a therapeutic target for psoriasis. ...
Inflammation is a defensive reaction for external stimuli to the human body and generally accompanied by immune responses, which is associated with multiple diseases such as atherosclerosis, type 2 diabetes, Alzheimer’s disease, psoriasis, asthma, chronic lung diseases, inflammatory bowel disease, and multiple virus-associated diseases. Epigenetic mechanisms have been demonstrated to play a key role in the regulation of inflammation. Common epigenetic regulations are DNA methylation, histone modifications, and non-coding RNA expression; among these, histone modifications embrace various post-modifications including acetylation, methylation, phosphorylation, ubiquitination, and ADP ribosylation. This review focuses on the significant role of histone modifications in the progression of inflammatory diseases, providing the potential target for clinical therapy of inflammation-associated diseases.
... Furthermore, overexpression of SIRT1 by RSV may reduce the level of c-JNK via a mitogen-activated protein kinase pathway [90], which decreases the transcriptional activity of pro-apoptotic genes and p53 levels. Additionally, RSV can directly block the apoptosis pathway by increasing the binding between SIRT1 and p53 for deactivation [91], which decreases the level of p53, caspase-9/3 via serine/threonine kinase family [92]. Therefore, RSV-induced SIRT1 overexpression may hinder the pathway of apoptosis by declining the c-JNK transcript which blocks the activity of p53 in cardiomyocytes and suppresses the transcriptional activation of capase9/3 [93]. ...
Fenitrothion (FNT), a commonly used organophosphate, can cause oxidative damage and apoptosis on various organs. However, the underlying mechanisms for FNT-induced cardiotoxicity did not formally report. Here, we have evaluated the possible ameliorative roles of resveratrol (RSV) against FNT-induced cardiac apoptosis in male rats through the sirtuin1 (SIRT1)/c-Jun N-terminal kinase (c-JNK)/p53 pathway concerning pro-oxidant and inflammatory cytokines. Forty-eight male rats were equally grouped into control, RSV (20 mg/kg), 5-FNT (5 mg/kg), 10-FNT (10 mg/kg), 20-FNT (20 mg/kg), 5-FNT-RSV, 10-FNT-RSV, and 20-FNT-RSV where all doses administrated by gavage for four weeks. The present findings demonstrated that RSV markedly diminished the level of hyperlipidemia and elevation in lactate dehydrogenase (LDH), total creatine kinase (CK-T), and troponin T (TnT) levels following FNT intoxication. Furthermore, RSV significantly reduced FNT-induced cardiac oxidative injury by reducing malondialdehyde (MDA) level and improving the levels of glutathione (GSH), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and acetylcholinesterase (AchE). Also, the levels of interleukin-1β (IL1β,), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly attenuated in the co-treated groups. Moreover, RSV alleviated the histopathological changes promoted by FNT and repaired the transcript levels of SIRT1, c-JNK, and caspase-9/3 along with p53 immunoreactivity. In silico study revealed that the free binding energies of RSV complexes with protein and DNA sequences of SIRT1 were lower than docked complexes of FNT. Therefore, RSV reserved myocardial injury-induced apoptosis following exposure to FNT by modulating the SIRT1/c-JNK/p53 pathway through cellular redox status and inflammatory response improvements.
... In addition, RSV inhibits tyrosine kinase protein (PTK), which modulates cell proliferation and differentiation, signaling processes in immune system cells, and biological processes involved in inflammatory response and diseases, such as cancer, arteriosclerosis, and psoriasis [31][32][33]. RSV also plays a critical role in regulating the expression of the SIRT1 gene responsible for the activation of Th17 cells, which are important in the modulation of the epidermal keratinocyte proliferation that occurs in some inflammatory skin processes, such as psoriasis [34,35]. ...
Resveratrol (RSV) and omega 3 (ω3), because of their biological favorable properties, have become subjects of interest for researchers in dermocosmetic and pharmaceutical industries; however, these bioactives present technological limitations that hinder their effective delivery to the target skin layer. To overcome the stability and skin permeation limitations of free bioactives, this work proposes a combined strategy involving two different lipid nanosystems (liposomes and lipid nanoparticles) that include ω3 in their lipid matrix. Additionaly, RSV is only encapsulated in liposomes that provid an adequate amphiphilic environment. Each formulation is thoroughly characterized regarding their physical–chemical properties. Subsequently, the therapeutic performance of the lipid nanosystems is evaluated based on their protective roles against lipid peroxidation, as well as inhibition of cicloxygenase (COX) and nitric oxid (NO) production in the RWA264.7 cell line. Finally, the lipid nanosystems are incorporated in hydrogel to allow their topical administration, then rheology, occlusion, and RSV release–diffusion assays are performed. Lipid nanoparticles provide occlusive effects at the skin surface. Liposomes provide sustained RSV release and their flexibility conferred by edge activator components enhances RSV diffusion, which is required to reach NO production cells and COX cell membrane enzymes. Overall, the inclusion of both lipid nanosystems in the same semisolid base constitutes a promising strategy for autoimmune, inflammatory, and cancerous skin diseases.
... Resveratrol, a ROS scavenger extracted from red grape skins and peas [104,105], has many activities including antiaging and anticancer [106][107][108][109][110]. Studies have shown that resveratrol activates SIRT1, which may rely on the upstream of calmodulin kinase II to activate the AMPK-dependent increase in the ratio of NAD/NADH, thereby inducing SIRT1 activity. Resveratrol can promote p53 deacetylation and downregulate Akt phosphorylation, then increasing SIRT1 expression [111,112]. Resveratrol inhibitscancer cell growth through autophagic initiation. Resveratrol also increases the chemotherapeutic efficiency of gemcitabine via Nrf2 signaling [113]. ...
Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed.
... SIRT1 is another epigenetic therapeutic target for psoriasis. Some studies have reported that deacetylation of NF-κB by SIRT1 downregulates tumor necrosis factor (TNF)-α and other proinflammatory cytokines [27,28], while also inhibiting the cell cycle mediator retinoblastoma (Rb)/E2F1 and increasing cell death of keratinocytes [19,29]. Based on these studies, SIRT1 activators have been investigated as therapeutic agents for psoriasis; however, the treatment outcomes have been inconsistent [30]. ...
Abnormal histone modification by histone deacetylases (HDACs), including HDAC1 and sirtuin 1 (SIRT1), has been reported to play an important role in the pathogenesis of psoriasis by altering cell proliferation, differentiation, and inflammation. However, findings on the expression level of HDACs in psoriatic skin lack consistency. We assessed the expression of HDAC1, SIRT1, p63, and proliferating cell nuclear antigen (PCNA) in skin tissues from 23 patients with psoriasis (15 with plaque psoriasis and eight with guttate psoriasis) and five healthy individuals using immunohistochemistry, and analyzed their associations with clinical phenotypes of the disease. The expression of HDAC1 and keratinocyte proliferative markers, such as p63 and PCNA significantly increased, whereas that of SIRT1 decreased in the basal layer (p < 0.05) of the patients with psoriasis compared to those in healthy controls. Among the patients with psoriasis, expression of HDAC1, p63, and PCNA was significantly higher in plaque psoriasis than in guttate psoriasis. There was no significant differences in the level of SIRT1 between the two clinical phenotypes. The findings of this study suggest that histone modifications are involved in the pathogenesis of psoriasis and may contribute to the formation of clinical phenotypes.
... Psoriasis is an autoimmune disease mainly characterized by hyperproliferation of keratinocytes and production of IL-23 and IL-17 with inflammatory infiltrates in the dermis [253]. In vitro studies have demonstrated that RES induced apoptosis of HaCaT keratinocytes via Sirt-1 activation [254]. Furthermore, evidence has been provided that RES inhibited proliferation of normal human keratinocytes, hampering aquaporin 3 activation [255]. ...
In this review, special emphasis will be placed on red grape polyphenols for their antioxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of proinflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Additionally, the effects of red grape polyphenols will be analyzed in obesity, as a low-grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood–brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great antioxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites, and interaction with microbiota, deserve deeper studies.
... e inhibitory effects of resveratrol on keratinocyte proliferation occur via two mechanisms: (i) activation/upregulation of SIRT1 and (ii) inhibition of protein kinase D. In keratinocyte cultures, resveratrol upregulated expression of SIRT1, leading to elevation in aryl hydrocarbon receptor nuclear translocator (ARNT), resulting in downregulation of aquaporin 3, and consequently inhibiting cell proliferation [78]. Lee et al. showed that resveratrol increased the expression level and deacetylase activity of SIRT1, resulting in apoptosis [172]. Other studies suggest that resveratrol inhibits DNA synthesis, while increasing transglutaminase activity via inhibition of protein kinase D activity [84]. ...
Protective role of the skin is against external insults and maintenance of electrolyte homeostasis of the body. Cutaneous dysfunction can account for the development of both cutaneous and systemic disorders. Thus, improvements in cutaneous functions can benefit a number of extracutaneous and cutaneous functions. Resveratrol, a natural ingredient, displays multiple benefits for various systems/organs, including the skin. The benefits of resveratrol for cutaneous functions include stimulation of keratinocyte differentiation and antimicrobial peptide expression, inhibition of keratinocyte proliferation and cutaneous inflammation, UV protection, anticancer, antiaging, and inhibition of melanogenesis. The mechanisms of action of resveratrol include activation of sirtuin 1 and nuclear factor erythroid 2-related factor 2, and inhibition of mitogen-activated protein kinase signaling. Evidence suggests that topical resveratrol could be a valuable alternative not only for daily skin care, but also for the prevention and treatment of various cutaneous disorders. This review summarizes the benefits of resveratrol for cutaneous functions.
... www.nature.com/scientificreports/ deacetylation of p53, thereby downregulated Akt phosphorylation 65 . As we all known, The PI3K/Akt/mTOR signaling pathway is implicated in a diverse array of physiological and pathological cell functions, including growth, apoptosis and autophagy 66,67 . ...
Osteoporosis is widely regarded as one of the typical aging-related diseases due to the impairment of bone remodeling. The silent information regulator of transcription1 (SIRT1) is a vital regulator of cell survival and life-span. SIRT1 has been shown to be activated by resveratrol treatment, and also has been proved to prevent aging-related diseases such as osteoporosis. However, the role of SIRT1 about autophagy or mitophagy of osteoblasts in resveratrol-regulated osteoporotic rats remains unclear. This study seeks to investigate the role of SIRT1 about autophagy or mitophagy in osteoblasts through PI3K/Akt signaling pathway in resveratrol-regulated osteoporotic rats. The vivo experiment results have revealed that resveratrol treatment significantly improved bone quality and reduced the levels of serum alkaline phosphatase and osteocalcin in osteoporotic rats. Moreover, Western bolt analysis showed that expression of SIRT1, LC3, and Beclin-1 in osteoblasts increased, while p-AKT and p-mTOR were downregulated in osteoporosis rats with high dose resveratrol treatment. On the other hand, resveratrol treatment increased the SIRT1 activity, LC3 and Beclin-1 mRNA expression in the dexamethasone (DEX)-treated osteoblasts. More mitophagosomes were observed in the DEX-treated osteoblasts with resveratrol. Meanwhile, the TOM20, Hsp60, p-Akt and p-mTOR activities were decreased in the DEX-treated osteoblasts with resveratrol. Resveratrol treatment did not change the p-p38 and p-JNK activities in the osteoblasts. These results revealed that resveratrol treatment protected osteoblasts in osteoporosis rats by enhancing mitophagy by mediating SIRT1 and PI3K/AKT/mTOR signaling pathway.
... Interestingly, resveratrol, which is a well-known autophagy activator, did not show cytoprotective effects. While there are many reports addressing the beneficial effects of resveratrol as an anti-inflammatory, anti-cancer, and anti-aging ingredient [27], cytotoxicity on a culture keratinocyte was also reported [28], which is consistent with the present study's results. The potential involvement of autophagy signaling is also implicated by the decreased expression of the LC3-II protein by BaP and cadmium mixture treated cells, which was restored by the co-treatment of the CD extract. ...
Pollution-induced skin damage results in oxidative stress; cellular toxicity; inflammation; and, ultimately, premature skin aging. Previous studies suggest that the activation of autophagy can protect oxidation-induced cellular damage and aging-like changes in skin. In order to develop new anti-pollution ingredients, this study screened various kinds of natural extracts to measure their autophagy activation efficacy in cultured dermal fibroblast. The stimulation of autophagy flux by the selected extracts was further confirmed both by the expression of proteins associated with the autophagy signals and by electron microscope. Crepidiastrum denticulatum (CD) extract treated cells showed the highest autophagic vacuole formation in the non-cytotoxic range. The phosphorylation of adenosine monophosphate kinase (AMPK), but not the inhibition of mammalian target of rapamycin (mTOR), was observed by CD-extract treatment. Its anti-pollution effects were further evaluated with model compounds, benzo[a]pyrene (BaP) and cadmium chloride (CdCl2), and a CD extract treatment resulted in both the protection of cytotoxicity and a reduction of proinflammatory cytokines. These results suggest that the autophagy activators can be a new protection regimen for anti-pollution. Therefore, CD extract can be used for anti-inflammatory and anti-pollution cosmetic ingredients.
... Cellular and molecular mechanisms investigated in vivo are also referred. and proliferation such as aquaporin 3 (AQP3) and extracellular signalregulated kinase (ERK) (Lee, Kim, Park, & Lee, 2016). Additionally, resveratrol has also been ameliorated psoriasis in a mouse model by decreasing the IL-17 and IL-19 which were the critical cytokine marker for the progression of disease (Kjaer, Thorsen, Jessen, Stenderup, & Pedersen, 2015). ...
Flavonoids are natural polyphenolic compounds which are included in a panoply of drugs and used to treat and/or manage human diseases such as metabolic, cardiovascular, neurological diseases and cancer. Thus, the purpose of this review is to emphasize the importance of flavonoids for the treatment of autoimmune diseases and put into the limelight of the scientific community several health-promoting effects of flavonoids which could be beneficial for the development of novel drugs from natural products. Despite available reviews on flavonoids targeting various disease conditions, a comprehensive review of flavonoids for autoimmune diseases is still lacking. To the best of our knowledge, this is the first attempt to review the potential of flavonoids for autoimmune diseases. The structure-activity relationship of flavonoids in this review revealed that the rearrangement and introduction of other functional groups into the basic skeleton of flavonoids might lead to the development of new drugs that would be helpful in relieving the painful symptoms of various autoimmune diseases.
... The study demonstrated that stimulation with resveratrol could activate the SIRT1 pathway, by increasing its expression, leading to the inhibition of the Protein kinase B (Akt), due to its phosphorylation. This protein plays an important role in regulating cell survival and proliferation [58]. Another study demonstrated that resveratrol was able to inhibit the proliferation of normal human epidermal keratinocytes by inhibiting aquaporin 3 (AQP3), an important cellular survival regulator. ...
Autoimmune diseases are still considered to be pressing concerns due the fact that they are leaders in death and disability causes worldwide. Resveratrol is a polyphenol derived from a variety of foods and beverages, including red grapes and red wine. Anti-inflammatory, antioxidant, and antiaging properties of resveratrol have been reported, and in some animal and human studies this compound reduced and ameliorated the progression of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and type 1 diabetes mellitus. Thus, this review aims to summarize and critically analyze the role of resveratrol in the modulation of several organ-specific or systemic autoimmune diseases.
... SIRT1, a NAD+-dependent histone deacetylase, regulates important biological processes including neuronal protection, organ metabolism, cell apoptosis, cell senescence and tumorigenesis. Early studies identifies that resveratrol activates SIRT1 and inhibits tumor development in SIRT1-dependent manner in cancer cells, nude mice or transgenic mice [23][24][25][26][27][28][29]. To determine the role of SIRT1 in spontaneous neoplasms, SIRT1 level at three stages was detected in the fish. ...
Resveratrol, SIRT1 activator, inhibits carcinogenesis predominantly performed in transgenic animal models, orthotopic cancers of nude mice or different cancer cell lines, but its effects during process of spontaneous tumors using vertebrate models remain untested. Spontaneous liver neoplasm is an age-related disease and is inhibited by resveratrol in the annual fish Nothobranchius guentheri, which indicates that the fish can act as an excellent model to study spontaneous tumorigenesis. Totally, 175 fish were fed with resveratrol and another 175 fish for controls. Treated fish were fed with resveratrol (25 μg/fish/day) from sexual maturity (4-month-old) until they were sacrificed at 6-, 9- and 12-month-old. Immunoblot, immunohistochemistry and co-immunoprecipitation were employed to investigate the underlying mechanisms that resveratrol inhibited age-dependent spontaneous tumorigenesis in the fish. Results showed that resveratrol increased protein level of SIRT1 and alleviated age-associated tumorigenesis in liver. With SIRT1 up-regulation, resveratrol reduced proliferation by deacetylating K-Ras and inactivating K-Ras/PI3K/AKT pathway; and promoted apoptosis through deacetylation and dephosphorylation of FoxOs, up-regulation of DLC1 and interaction between SIRT1 and DLC1, and dephosphorylation of DLC1 in spontaneous neoplasms. We established a novel short-lived fish model for understanding the molecular mechanisms of drugs on age-dependent spontaneous tumorigenesis.
... It is known that a reasonable dose of resveratrol activates sirtuin 1 (SIRT1), a class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase [11]. SIRT1 deacetylates a variety of substrates to regulate the downstream signaling pathways. ...
Inflammation and reactive oxygen species (ROS) play important roles in the pathogenesis of atherosclerosis. Resveratrol has been shown to possess anti-inflammatory and antioxidative stress activities, but the underlying mechanisms are not fully understood. In the present study, we investigated the molecular basis associated with the protective effects of resveratrol on tumor necrosis factor-alpha (TNF-α)-induced injury in human umbilical endothelial cells (HUVECs) using a variety of approaches including a cell viability assay, reverse transcription and quantitative polymerase chain reaction, western blot, and immunofluorescence staining. We showed that TNF-α induced CD40 expression and ROS production in cultured HUVECs, which were attenuated by resveratrol treatment. Also, resveratrol increased the expression of sirtuin 1 (SIRT1); and repression of SIRT1 by small-interfering RNA (siRNA) and the SIRT1 inhibitor Ex527 reduced the inhibitory effects of resveratrol on CD40 expression and ROS generation. In addition, resveratrol downregulated the levels of p65 and phospho-p38 MAPK, but this inhibitory effect was attenuated by the suppression of SIRT1 activity. Moreover, the p38 MAPK inhibitor SD203580 and the nuclear factor (NF)-κB inhibitor pyrrolidine dithiocarbamate (PDTC) achieved similar repressive effects as resveratrol on TNF-α-induced ROS generation and CD40 expression. Thus, our study provides a mechanistic link between resveratrol and the activation of SIRT1, the latter of which is involved in resveratrol-mediated repression of the p38 MAPK/NF-κB pathway and ROS production in TNF-α-treated HUVECs.
Psoriasis is a common inflammatory skin disease involving interactions between keratinocytes and immune cells that significantly affects the quality of life. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes and excessive infiltration of immune cells in the dermis and epidermis. The immune mechanism underlying this disease has been elucidated in the past few years. Research shows that psoriasis is regulated by the complex interactions among immune cells, such as keratinocytes, dendritic cells, T lymphocytes, neutrophils, macrophages, natural killer cells, mast cells, and other immune cells. An increasing number of signaling pathways have been found to be involved in the pathogenesis of psoriasis, which has prompted the search for new treatment targets. In the past decades, studies on the pathogenesis of psoriasis have focused on the development of targeted and highly effective therapies. In this review, we have discussed the relationship between various types of immune cells and psoriasis and summarized the major signaling pathways involved in the pathogenesis of psoriasis, including the PI3K/AKT/mTOR, JAK-STAT, JNK, and WNT pathways. In addition, we have discussed the results of the latest omics research on psoriasis and the epigenetics of the disease, which provide insights regarding its pathogenesis and therapeutic prospects; we have also summarized its treatment strategies and observations of clinical trials. In this paper, the various aspects of psoriasis are described in detail, and the limitations of the current treatment methods are emphasized. It is necessary to improve and innovate treatment methods from the molecular level of pathogenesis, and further provide new ideas for the treatment and research of psoriasis.
Atopic dermatitis (AD) is a chronic and relapsing cutaneous disorder characterized by compromised immune system, excessive inflammation, and skin barrier disruption. Post-translational modifications (PTMs) are covalent and enzymatic modifications of proteins after their translation, which have been reported to play roles in inflammatory and allergic diseases. However, less attention has been paid to the effect of PTMs on AD. This review summarized the knowledge of six major classes (including phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, o-glycosylation, and glycation) of PTMs in AD pathogenesis and discussed the opportunities for disease management.
Lipids a source of energy and can also be stored in body cells for proper cellular functions. Defects in lipid metabolism can lead to a wide range of metabolic disorders. A number of risk factors are generally responsible for the dysregulation of lipid metabolism and subsequently the development of metabolic diseases. In this chapter, the pathophysiology of several lipid-metabolism-related diseases has been discussed, and the therapeutic potential of different phytochemicals or plant-derived phytonutrients in managing these disorders are highlighted. There are several medicinal secondary metabolites, which could be highly significant to manage the lipid profile and prevent the development of serious outcomes of lipid-metabolism abnormalities such as hyperchylomicronemia, hypercholesterolemia, atherosclerosis, cancer, obesity, insulin sensitivity, and resistance. Many phytonutrients isolated from fruits, vegetables, and plant sources have presented their broad spectrum of medicinal activities to modulate metabolic processes and are also involved in lipid metabolism and the management of cholesterol levels in body. Bioactive compounds such as small molecular phytonutrients from natural sources have suggested prospective treatments against lipid-metabolism-related abnormalities and have been defined in this chapter. Considering diverse physiochemical properties and therapeutic value of phytonutrients, it is highly recommended to introduce more vegetables, and fruits in the dietary regimen to intake food containing fewer fats and high fibers so that it could significantly aid the management of lipid-metabolism-related diseases.
The elaboration of therapeutic protocols using natural compounds can help in improving the outcomes of many human conditions such as malignant disorders, neurodegenerative diseases, and systemic disorders. Recently, the attention of scientists was more focused on nutraceuticals as potential candidates that can be administered in the management strategy of various pathologies. This rise in nutraceutical applications is due to their relative safety and their pleiotropic effects. Several studies suggest the use of dietary regimens and food-derived substances for the prevention and treatment of many metabolic disorders that affect the central nervous system. The neuroprotective actions offered by these substances are mediated by their pertinent antiapoptotic, antiinflammatory, and antioxidative potentials. Some compounds may also intervene in the promotion of individuals’ health via the regulation of the process of autophagy and via the enhancement of the functionality of intracellular organelles such as mitochondria. Furthermore, healthy diet and the use of dietary supplements can directly influence the functions and the progeny of neural stem cells and the metabolism of microglial cells and can influence the polarization of macrophages in the nervous tissue resulting in better outcomes in some pathologic situations. In this chapter, we review the different roles and applications of nutraceuticals in the treatment of the major brain disorders that can affect human beings.
Metabolic diseases are devastating abnormalities that address human lives toward death if they are not correctly managed. Obesity and diabetes mellitus are the prime factors that induce insulin resistance to signaling pathways and increase the risk of cardiovascular diseases. Phytonutrients are the biologically active agents derived from natural sources such as vegetables, fruits, grains, cereals, and medicinal plants, and present the ability to boost the immune system of patients with metabolic disease and also enhance the conditions by the management of lipid profiles, insulin resistance and glucose homeostasis, and chemopreventive events in case of cancer disease. This chapter highlights some phytonutrients that may have issues with the gene and produce healthy and unhealthy interactions. However, the interaction between genetic and environmental factors such as intake of particular healthy and sufficient diet plans with a good lifestyle encourages the development and pathogenesis of diseases of polygenic dietary components. Phytonutrients are critical tools for the modulation of gene expressions involved in signaling pathways and phenotypes linked with metabolic diseases. It is also noted that human health is also affected by dietary nutrients having carcinogens and aflatoxin attached with them and influence the genetic variants. As the knowledge of carcinogen and anticarcinogen increases, nutritional science leads to promising therapeutics for cancer management by healthy diet plans. This chapter has depicted essential aspects of phytonutrients and their interactions with genes in metabolic disease prevention and treatments.
In spite of the advanced researches, preventive measures, and treatment options, cancer remains a growing ailment all over the world and its prevalence is estimated to increase in future. Cellular metabolic alterations have been documented as a hallmark of cancer. Metabolic regulation is an intricately coupled process whose deregulation leads to tumor progression as well as metastasis. In order to thrive in the living system, cancer cells adapt different metabolic pathways (bioenergetics and biosynthesis). They replenish their metabolic demands by switching from normal metabolism to cancer metabolism by the process of metabolic rewiring. Recent researches suggest that starving cancer cells by the use of nontoxic chemical entities can give promising results regarding cancer proliferation. Natural products, especially those of plant origin, offer different chemical scaffolds to target cancer via modulation of multiple cell signaling cascades. Phytonutrients, the secondary metabolites from the plants, constitute edible phytochemicals which are abundantly found in vegetables, whole grains, and fruits. The growing numbers of evidences suggest that phytonutrients exhibit anticancer as well as chemopreventive activities of these bioactive molecules against several cancers by targeting the various significant enzymes of glycolysis, the PPP pathway, TCA cycle, and serine metabolism. This book chapter presents an update for the scientific community about targeting the cancer metabolism by phytonutrients. The alterations in the cancer metabolism in the context of bioenergetics, biosynthesis, and mitochondrial functions have been discussed while presenting the impact of phytonutrients as modulators of potential metabolic effectors in the cancer metabolism.
Mitochondria are the main organelles responsible for generating cellular energy. The common symptom of mitochondrial disorders is extreme fatigue. The lowered mitochondrial activity owing to lack of chemical transmembrane capacity, changes in the electron transport chain’s function, the maintenance of the inner mitochondrial membrane’s electrical and decrease in essential metabolites transport to the mitochondria. The change in mitochondrial activity is brought about by the reduction of adenosine-5′-triphosphate (ATP) and oxidative phosphorylation. The mitochondrial activity needs regular replacement of natural phytochemicals and supplementations that help to maintain the energy level. The efficacy of oral alternative nutrients like reduced nicotinamide adenine dinucleotide (NADH), alpha-lipoic acid, coenzyme Q10, alpha-lipoic acid carnitine, membrane phospholipids, and other supplements was evaluated in clinical studies and were found effective against mitochondrial disorders. Combinations of these supplements can substantially alleviate weakness and other symptoms associated with mitochondrial disorders in patients. The frequent intake of these nutrients can also help to reduce the onset of various neurological disorders along with mitochondrial dysfunction. These results have significant effects on the welfare of both the civilian and military communities.
Background
Psoriasis is characterized by aberrant activation of several pro-inflammatory circuits as well as abnormal hyperproliferation and dysregulated apoptosis of keratinocytes (KCs). Most currently available therapeutic options primarily target psoriasis-associated immunological defects rather than epidermal abnormalities.
Objective
To investigate the efficacy of the histone deacetylase (HDAC) inhibitor, Vorinostat, in targeting hyperproliferation and impaired apoptosis in psoriatic skin.
Methods
Vorinostat effect was investigated in primary KCs cell cultures using cell cycle analysis by flow cytometry, apoptosis assays (Annexin V-FICH and caspase – 3/7) and antibody arrays, qRT-PCR and immunohistochemistry. Vorinostat impact on clinical manifestations of psoriasis was investigated in a chimeric mouse model.
Results
Vorinostat was found to inhibit KCs proliferation and to induce their differentiation and apoptosis. Using a chimeric mouse model, vorinostat was found to result in marked attenuation of a psoriasiform phenotype with a significant decrease in epidermal thickness and inhibition of epidermal proliferation.
Conclusions
Our results support the notion that vorinostat, a prototypic HDAC inhibitor, may be of potential use in the treatment of psoriasis and other hyperproliferative skin disorders.
Psoriasis, an incurable autoimmune skin disease, is one of the most common immune-mediated disorders. Presently, numerous clinical research studies are underway, and treatment options are available. However, these treatments focus on improving symptoms of the disease and fail to achieve a radical cure; they also have certain toxic side effects. In recent years, natural products have increasingly gained attention because of their high efficiency and low toxicity. Despite their obvious therapeutic effects, natural products’ biological activity was limited by their instability, poor solubility, and low bioavailability. Novel drug delivery systems, including liposomes, lipospheres, nanostructured lipid carriers, niosomes, nanoemulsions, nanospheres, microneedles, ethosomes, nanocrystals, and foams could potentially overcome the limitations of poor water solubility and permeability in traditional drug delivery systems. Thus, to achieve a therapeutic effect, the drug can reach the epidermis and dermis in psoriatic lesions to interact with the immune cells and cytokines.
The observed incidence of psoriasis has been gradually increasing over time1, but the underlying pathogenic factors have remained unclear. Recent studies suggest the importance of epigenetic modification in the pathogenesis of psoriasis. Aberrant epigenetic patterns including changes in DNA methylation, histone modifications, and non‐coding RNA expression are observed in psoriatic skin. Reversing these epigenetic mechanisms have showed improvement in psoriatic phenotypes, making epigenetic therapy a potential avenue for psoriasis treatment. Here, we summarize relevant evidence for epigenetic dysregulation contributing to psoriasis susceptibility and pathogenesis, and the factors responsible for epigenetic modifications, providing directions for potential future clinical avenues.
Objective: By assessing silent mating-type information regulation 2 homolog 1 (SIRT1) nucleocytoplasmic shuttling and reactive oxygen species (ROS) levels in peripheral blood mononuclear cells (PBMCs), this study aimed to explore the role of SIRT1 in premature infants after exposure to hyperoxia and assess the protective effects of resveratrol (Res).
Methods: Firstly, ROS levels as well as SIRT1 translocation and expression in PBMCs samples were evaluated from 40 premature infants with different oxygen amounts received at birth. Then, PBMCs, from additional 40 premature infants administered no oxygen at birth, were used to establish an in vitro model of hyperoxia.
Results: In infants that received O2 at birth, ROS and MDA levels, and SIRT1 translocation rates gradually increased in a concentration-dependent manner, while SIRT1 gradually decreased. In agreement, PBMCs cultured in vitro showed increased ROS levels after exposed to hyperoxia, SIRT1 translocation increased as well. However, treatment with Res resulted in opposite effects.
Conclusion: Res inhibits ROS release in PBMCs from preterm infants exposed to hyperoxia, likely by preventing SIRT1 nucleocytoplasmic shuttling and increasing SIRT1 expression.
This chapter highlights published studies to understand “senescence,” focusing on senescence from the molecular level to the systemic level. Next, theoretical research strategies to develop antiaging cosmetics are discussed, taking into account age-associated decline and breakdown of homeostasis by the repair system against DNA and tissue damage, as well as cell senescence and chronic inflammation, which accelerates systemic senescence.
Smilacis Chinae Rhizome (SCR) has been used as an oriental folk medicine for various biological activities. However, its effect on atopic dermatitis (AD) remains undetermined to date. We assessed the effect of orally administered hot-water extract of SCR on AD-like skin lesions in mice and its underlying mechanisms. AD-like murine model was prepared by repeated alternate application of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) for 4 weeks, topically to the ears. Daily oral administration of SCR for 3 and 4 weeks significantly reduced inflammatory ear thickening, with the effect being enhanced at the earlier start and longer period of administration. This effect was accompanied by a significant decrease in both Th2 and Th1 serum antibodies (total IgE, DFE-specific IgE, and IgG2a). Histological analysis showed that SCR markedly decreased the epidermal/dermal ear thickening and the dermal infiltration of inflammatory cells. Furthermore, SCR suppressed DFE/DNCB-induced expression of IL-4, IL-13, IL-17, IL-18, TSLP, and IFN-γ genes in the ear tissue. Taken together, our observations demonstrate that chronic oral administration of SCR exerts beneficial effect in mouse AD model, suggesting that SCR has the therapeutic potential as an orally active treatment of AD by modulating both Th1 and Th2 responses. Copyright © 2016 John Wiley & Sons, Ltd.
UVB radiation causes about 90% of non-melanoma skin cancers by damaging DNA either directly or indirectly by increasing levels of reactive oxygen species (ROS). Skin, chronically exposed to both endogenous and environmental pro-oxidant agents, contains a well-organised system of chemical and enzymatic antioxidants. However, increased or prolonged free radical action can overwhelm ROS defence mechanisms, contributing to the development of cutaneous diseases. Thus, new strategies for skin protection comprise the use of food antioxidants to counteract oxidative stress. Resveratrol, a phytoalexin from grape, has gained a great interest for its ability to influence several biological mechanisms like redox balance, cell proliferation, signal transduction pathways, immune and inflammatory response. Therefore, the potential of resveratrol to modify skin cell response to UVB exposure could turn out to be a useful option to protect skin from sunlight-induced degenerative diseases. To investigate into this matter, HaCaT cells, a largely used model for human skin keratinocytes, were treated with 25 or 100 µM resveratrol for 2 and 24 hours prior to UVB irradiation (10 to 100 mJ/cm(2)). Cell viability and molecular markers of proliferation, oxidative stress, apoptosis, and autophagy were analyzed. In HaCaT cells resveratrol pretreatment: reduces UVB-induced ROS formation, enhances the detrimental effect of UVB on HaCaT cell vitality, increases UVB-induced caspase 8, PARP cleavage, and induces autophagy. These findings suggest that resveratrol could exert photochemopreventive effects by enhancing UVB-induced apoptosis and by inducing autophagy, thus reducing the odds that damaged cells could escape programmed cell death and initiate malignant transformation.
Background:
The understanding of the anti-inflammatory mechanisms of action of plant polyphenols (PPs) and clarification of the relationship between their anti-inflammatory and antioxidant properties may result in a new therapeutic approach to skin cancers.
Objective:
To elucidate the underlying mechanism, we analyzed the ability of PPs to attenuate inflammatory, metabolic and oxidative cellular responses to UV irradiation.
Methods:
Normal human epidermal keratinocytes (NHEK) were exposed to physiologically relevant dose of solar-simulated UV irradiation. Effects of pre- and post-treatment with PPs on the overproduction of peroxides and inflammatory mediators (mRNA and protein) were analyzed using real-time RT-PCR, enzyme-linked immunosorbent and fluorometric techniques.
Results:
Differences between the effectiveness of pre- and post-treatment with polyphenols was found. In particular, PPs post-treatment, but not pretreatment, completely abolished overexpression of Cyp1a1 and Cyp1b1 genes and elevation of intracellular peroxides in NHEK irradiated by UV. Post-treatment with PPs also more efficiently than pretreatment prevented UV-induced overexpression of IL-1 beta, IL-6 and COX2 mRNAs.
Conclusion:
Our data strongly suggest that PPs predominantly affect delayed molecular and cellular events initiated in NHEK by solar UV rather than primary photochemical reactions. PPs may be important component in cosmetic formulations for post-sun skin care.
Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol.
Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin) and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM) induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and apoptosis, and inhibition of cyclin D1 by resveratrol.
These data suggest that FOXO transcription factors mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due to activation of extrinsic apoptosis pathway.
Apurinic/apyrimidinic endonuclease-1 (APE1) is an essential enzyme in the base excision repair (BER) pathway. Here, we show
that APE1 is a target of the SIRTUIN1 (SIRT1) protein deacetylase. SIRT1 associates with APE1, and this association is increased
with genotoxic stress. SIRT1 deacetylates APE1 in vitro and in vivo targeting lysines 6 and 7. Genotoxic insults stimulate lysine acetylation of APE1 which is antagonized by transcriptional
upregulation of SIRT1. Knockdown of SIRT1 increases cellular abasic DNA content, sensitizing cells to death induced by genotoxic
stress, and this vulnerability is rescued by overexpression of APE1. Activation of SIRT1 with resveratrol promotes binding
of APE1 to the BER protein X-ray cross-complementing-1 (XRCC1), while inhibition of SIRT1 with nicotinamide (NAM) decreases
this interaction. Genotoxic insult also increases binding of APE1 to XRCC1, and this increase is suppressed by NAM or knockdown
of SIRT1. Finally, resveratrol increases APE activity in XRCC1-associated protein complexes, while NAM or knockdown of SIRT1
suppresses this DNA repair activity. These findings identify APE1 as a novel protein target of SIRT1, and suggest that SIRT1
plays a vital role in maintaining genomic integrity through regulation of the BER pathway.
The serine/threonine kinase Akt, or protein kinase B (PKB), has recently been a focus of intense research. It appears that Akt/PKB lies in the crossroads of multiple cellular signaling pathways and acts as a transducer of many functions initiated by growth factor receptors that activate phosphatidylinositol 3-kinase (PI 3-kinase). Akt/PKB is particularly important in mediating several metabolic actions of insulin. Another major activity of Akt/PKB is to mediate cell survival. In addition, the recent discovery of the tumor suppressor PTEN as an antagonist of PI 3-kinase and Akt/PKB kinase activity suggests that Akt/PKB is a critical factor in the genesis of cancer. Thus, elucidation of the mechanisms of Akt/PKB regulation and its physiological functions should be important for the understanding of cellular metabolism, apoptosis, and cancer.
The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents.
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation ( approximately 8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.
Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
Wine has been part of human culture for 6,000 years, serving dietary and socioreligious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high‐density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p‐coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl‐CoA derivatives. Polymeric aggregation gives rise, in turn, to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low‐density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo‐oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signaling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans. J. Clin. Lab. Anal. 11:287–313, 1997. © 1997 Wiley‐Liss, Inc.
Resveratrol is a natural polyphenolic compound with anti-inflammatory, antioxidant, and neuroprotective properties, and it serves as a chemopreventive and chemotherapeutic agent. However, only very limited data have been obtained regarding the effects of resveratrol on pre-adipocytes and the mechanisms of these effects remain largely unknown. In this study, murine 3T3-L1 pre-adipocytes were incubated with resveratrol and cell apoptosis was investigated. Resveratrol caused S-phase arrest to inhibit cell proliferation and significantly increased the LDH leaking ratio. Hoechst 33258 staining and transmission electron microscopy revealed the ultrastructural changes in nuclear chromatins of apoptotic cells. Furthermore, resveratrol activated the mitochondrial signaling with the decreases in the mitochondrial membrane potential (MMP), cytochrome C release and the activations of caspase 9 and caspase 3. Resveratrol treatment also increased the protein level of Sirt1. By using small interfering RNAs of Sirt1, AMP-activated protein kinase α (AMPKα), Survivin, and the AMPK agonist (AICAR) and specific inhibitors for protein kinase B (AKT) or caspases, it was demonstrated that activation of Sirt1 inhibited AKT activation and further decreased the expression of survivin. It could also increase AMPK activation. Both signaling pathways activated mitochondrion-mediated pathway. Our findings clarified the apoptotic effects of resveratrol in 3T3-L1 pre-adipocytes and revealed the involved pathway including AMPK, AKT, and survivin, suggesting its potential therapeutic application in the treatment or prevention of obesity and related metabolic symptoms.
Psoriasis is a chronic inflammatory skin disease affecting 1-3% of the world's population. Traditional Chinese medicines have been extensively used for treating psoriasis with promising clinical results. Celastrol, a triterpenoid isolated from a Chinese herb Celastrus orbiculatus caulis, has been known to have diverse pharmacological effects such as anti-inflammatory, anti-cancer and antioxidant activities. The present study aimed at evaluating the anti-proliferative action of celastrol on cultured HaCaT cells and elucidating the mechanisms of action involved. Celastrol was shown to inhibit HaCaT cells growth with an IC₅₀ value of 1.1 μM as measured by MTT assay. The ability of celastrol to induce apoptosis was studied by flow cytometric and western blot analyses. Celastrol was found to be capable of inducing apoptosis in HaCaT cells as characterized by phosphatidyl-serine (PS) externalization, depolarization of mitochondrial membrane potential and activation of caspase-3. The apoptosis induced by celastrol could be suppressed by Z-IETD-FMK and Z-LEHD-FMK, the respective caspase-8 and caspase-9 inhibitor. In addition, western blot analysis revealed a significant augmentation in the protein expression of Bax and attenuation in Bcl-2, suggesting that the celastrol-induced apoptosis acts through both death receptor and mitochondrial pathways. Moreover, western blot analysis on the expression of Rel/NF-κB demonstrated that the celastrol-mediated apoptosis on HaCaT cells was associated with the inhibition of the NF-κB pathway. Taken together, the present project has for the first time identified celastrol as a naturally occurring compound with potent apoptogenic action on cultured human keratinocytes, rendering it a promising candidate for further development into an anti-psoriatic agent.
Calorie restriction is one of the most effective nutritional interventions that reproducibly protects against obesity, diabetes and cardiovascular disease. Recent evidence suggests that even when implemented over a short period, calorie restriction is a safe and effective treatment for cardiovascular disease. Herein, we review the effects of calorie restriction on the cardiovascular system as well as the biological effects of resveratrol, the most widely studied molecule that appears to mimic calorie restriction. An overview of microarray data reveals that the myocardial transcriptional effects of calorie restriction overlap with the transcriptional responses to resveratrol treatment. In addition, calorie restriction and resveratrol modulate similar pathways to improve mitochondrial function, reduce oxidative stress and increase nitric oxide production that are involved in atherosclerosis prevention, blood pressure reduction, attenuation of left-ventricular hypertrophy, resistance to myocardial ischemic injury and heart failure prevention. We also review the data that suggest that the effects of calorie restriction and resveratrol on the cardiovascular system may involve signaling through the silent information regulator of transcription (SIRT), Akt and the AMP-activated protein kinase (AMPK) pathways. While accumulating data demonstrate the health benefits of calorie restriction and resveratrol in experimental animal models, whether these interventions translate to patients with cardiovascular disease remains to be determined.
CD160 is expressed by human and mouse natural killer (NK) cells and other cytotoxic lymphocyte subpopulations. CD160 is mostly expressed as a trimeric 83 kDa glycosylphosphatidylinositol (GPI)-anchored activating NK receptor, cleaved upon IL-15 stimulation in a secreted trimeric soluble form (sCD160) that binds to major histocompatibility complex (MHC) class I molecules, while a transmembrane isoform appears. sCD160 exhibits immunoregulatory function as it inhibits CD8(+) T-lymphocyte cytotoxic activity. We show that human mast cells (MCs) express CD160. In human and mouse skin, resident MCs expressed CD160, whereas in C57BL/6-Kit(W-sh/W-sh) mice, CD160(+) cells were only identified at the site of reconstitution with syngeneic cultured MCs. In the human mast cell line, HMC-1, we only identified the transcripts of the GPI-anchored CD160 isoform. Furthermore, CD160 was identified in HMC-1 and mouse MC supernatants, suggesting that MCs release sCD160. Supporting this hypothesis, HMC-1 express the GPI-specific phospholipase D variant 2 involved in the NK lymphocyte membrane cleavage of CD160, and morphological studies highlighted a relative loss of CD160 expression in inflammatory skin sites, where MC degranulation is expected to occur. We also demonstrated an inhibition of T-cell cytotoxicity by HMC-1 supernatant that was partially reversed by anti-CD160 mAb. In conclusion, sCD160, produced by MCs, may have a role in T-cell-MC interactions in vivo.
Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision
of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them
has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of
PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1
was also detected in hearts of SIRT1−/− mice, compared to that detected in the hearts of SIRT1+/+ mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1
activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity
of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level
as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival
of cells under stress conditions.
Resveratrol, a polyphenol found in fruits, has been demonstrated to activate Sir2. Though many studies have demonstrated that resveratrol can activate SIRT1, whether it has effect on other sirtuins (SIRT2-7) are unknown. The present study shows that exposure of H9c2 cells to 50 microM H(2)O(2) for 6 h caused a significant increase in apoptosis, as evaluated by TUNEL and flow cytometry (FCM), but pretreatment of resveratrol (20 microM) eliminated H(2)O(2)-induced apoptosis. Resveratrol also prevented H(2)O(2)-induced caspase-3 activation. Exposure of cells to resveratrol caused rapid activation of SIRT1,3,4,7. Sirtuin inhibitor, nicotinamide (20 mM) attenuated resveratrol's inhibitory effect on cell apoptosis and caspase-3 activity. These results suggest that resveratrol protects cardiomyocytes from H(2)O(2)-induced apoptosis by activating SIRT1,3,4,7.
To investigate the chemopreventive potential of resveratrol, a phytoalexin found in seeds and skin of grapes, berries and peanuts in 7,12 dimethyl benz(a)anthracene (DMBA) induced mouse skin tumorigenesis.
Topical treatment of resveratrol was given to the animals 1 h prior to DMBA for 28 weeks. At the end of the study period, the skin tumors were dissected out and western blotting was carried out to examine the regulation of proteins involved in anti-tumorigenesis in response to resveratrol.
Chemopreventive properties of resveratrol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Results of the western blotting showed that resveratrol treatment increased the DMBA suppressed p53 and Bax while decreased the expression of Bcl-2 and Survivin. Further, resveratrol supplementation resulted in release of cytochrome C, caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction. Resveratrol was also found to inhibit skin tumorigenesis through regulation of Phosphatidylinositol-3-kinase (PI3K)/ and AKT proteins which are implicated in cancer progression because it stimulates proliferation and suppresses apoptosis.
Based on the results we can conclude that resveratrol regulates apoptosis and cell survival in mouse skin tumors as mechanism of chemoprevention hence deserve to be a chemopreventive agent.
Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.
Previously we observed that hyperplastic epidermal keratinocytes characteristic of psoriasis had abundant amounts of the cell survival protein Bcl-xL; however, whether this overexpression correlated with enhanced survival was unclear because the majority of epidermal cells possess nuclei that are positively labeled by an assay typically regarded as indicative of cells undergoing apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining). To clarify this apparent discrepancy, we explored the propensity of keratinocytes derived from psoriatic plaques to undergo apoptosis and also determined the reliability of TUNEL staining as an indicator of apoptosis in keratinocytes in vitro and in vivo. First, a keratinocyte cell line, HaCat, was examined before and after being suspended in semisolid medium (methylcellulose) using flow cytometry to detect TUNEL-positive cells, and the percentage of positive cells was correlated to the presence or absence of double-stranded DNA fragmentation using pulsed field gel electrophoresis. After 18 hours in methylcellulose suspension, apoptosis was detected in HaCat cells when at least 5% of the cell population was undergoing programmed cell death. Second, we examined 23 clinical specimens of skin (13 from psoriatic patients and 10 from healthy control subjects) and observed that no double-stranded DNA fragmentation was present in any of the freshly isolated keratinocytes from either normal or psoriatic patients. Keratinocytes from 9 of 12 normal skin samples underwent double-stranded DNA fragmentation after being in methylcellulose for 18 to 24 hours, which contrasts with keratinocytes from lesions of psoriasis where only 1 of 13 of the skin samples had these changes. Third, two-color immunofluorescence staining of psoriatic plaques revealed that numerous TUNEL-positive keratinocytes were also positive for proliferating cell nuclear antigen and Ki-67 antigens and that by flow cytometry TUNEL-positive keratinocytes obtained from psoriatic plaques possessed a DNA content profile indicative of proliferating and not dying cells. These results demonstrate that keratinocytes within psoriatic plaques do not have double-stranded DNA breaks, that they have a prolonged capacity to resist induction of apoptosis compared with normal-skin-derived keratinocytes or cultured HaCat cells, and that caution is necessary for proper interpretation related to detection of 3'-OH DNA ends (ie, TUNEL positivity) in skin, as it can be associated with DNA synthesis as well as cell death.
We wish to thank Terry Schoop of Biomed Arts Associates, San Francisco, for preparation of the figures, Cori Bargmann and Zena Werb for insightful comments on the manuscript, and Normita Santore for editorial assistance. In addition, we are indebted to Joe Harford and Richard Klausner, who allowed us to adapt and expand their depiction of the cell signaling network, and we appreciate suggestions on signaling pathways from Randy Watnick, Brian Elenbas, Bill Lundberg, Dave Morgan, and Henry Bourne. R. A. W. is a Ludwig Foundation and American Cancer Society Professor of Biology. His work has been supported by the Department of the Army and the National Institutes of Health. D. H. acknowledges the support and encouragement of the National Cancer Institute. Editorial policy has rendered the citations illustrative but not comprehensive.
The serine/threonine protein kinase PKB (also known as Akt) is thought to be a key mediator of signal transduction processes. The identification of PKB substrates and the role PKB phosphorylation plays in regulating these molecules have been a major focus of research in recent years. A recently developed motif-profile scoring algorithm that can be used to scan the genome for potential PKB substrates is therefore a useful tool, although additional considerations, such as the evolutionary conservation of the phosphorylation site, must also be taken into account. Recent evidence indicates that PKB plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis and is also probably a key mediator of insulin signalling. These findings indicate that PKB is likely to be a hot drug target for the treatment of cancer, diabetes and stroke. There are, however, a number of pitfalls of methodologies currently employed to study PKB function, and therefore caution should be used in interpretation of such experiments.
It is ten years since the publication of three papers describing the cloning of a new proto-oncogene serine/threonine kinase termed protein kinase B (PKB)/Akt. Key roles for this protein kinase in cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration are now well established. The explosion of publications involving PKB/Akt in the past three years emphasizes the high level of current interest in this signalling molecule. This review focuses on tracing the characterization of this kinase, through the elucidation of its mechanism of regulation, to its role in regulating physiological and pathophysiological processes, to our current understanding of the biology of PKB/Akt, and prospects for the future.
Nonmelanoma skin cancer is the most common cancer among humans and solar UV radiation, particularly its UVB component (290-320 nm), is its major cause. One way to reduce the occurrence of the cancer is via the use of substances (often antioxidants) termed "photochemopreventive agents". Resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with strong anti-inflammatory and antiproliferative properties. This study was designed to examine whether resveratrol possesses the potential to ameliorate the damages caused by short-term UVB exposure to mouse skin. Single topical application of resveratrol (25 micromol/0.2 ml acetone per mouse) to SKH-1 hairless mice was found to result in significant inhibition of UVB (180 mJ/cm(2))-mediated increase in bifold skin thickness and skin edema. The resveratrol treatment to mouse skin was also found to result in significant inhibition of UVB-mediated induction of cyclooxygenase and ornithine decarboxylase (ODC) enzyme activities and protein expression of ODC, which are well-established markers for tumor promotion. We also observed that resveratrol inhibits UVB-mediated increased level of lipid peroxidation, a marker of oxidative stress. Taken together, our results suggest that resveratrol may afford substantial protection against the damages caused by UVB exposure, and these protective effects may be mediated via its antioxidant properties.
Recent breakthroughs in the treatment of psoriasis have led to improved understanding of the pathogenesis of this disease. Activation of T lymphocytes leading to release of cytokines results in proliferation of keratinocytes. Several new biological therapies have been developed, which target specific steps in the pathogenesis of psoriasis. With these new treatments, variable degrees of clearing occur. Initial data suggest improved safety over older agents such as methotrexate and ciclosporin, but long-term data are necessary. Enhancements in topical therapy and phototherapy have also increased the armamentarium of treatments available for this disorder.
The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.
Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.
Nonmelanoma skin cancer is the most frequently diagnosed malignancy in the United States, and multiple exposures to solar ultraviolet (UV) radiation (particularly its UV-B component, 290-320 nm), is its major cause. 'Chemoprevention' by naturally occurring agents is being appreciated as a newer dimension in the management of neoplasia including skin cancer. We recently demonstrated that resveratrol (trans-3, 5, 4-trihydroxystilbene), an antioxidant found in grapes, red wines and a variety of nuts and berries, imparts protection from acute UV-B-mediated cutaneous damages in SKH-1 hairless mice. Understanding the mechanism of resveratrol-mediated protection of UV responses is important. We earlier demonstrated that resveratrol imparts chemopreventive effects against multiple UV-exposure-mediated modulations in (1) cki-cyclin-cdk network, and (2) mitogen activated protein kinase (MAPK)-pathway. This study was conducted to assess the involvement of inhibitor of apoptosis protein family Survivin during resveratrol-mediated protection from multiple exposures of UV-B (180 mJ/cm(2); on alternate days; for a total of seven exposures) radiations in the SKH-1 hairless mouse skin. Our data demonstrated that topical pre-treatment of resveratrol (10 micromol in 200 microl acetone/mouse) resulted in significant inhibition of UV-B exposure-mediated increases in (1) cellular proliferations (Ki-67 immunostaining), (2) protein levels of epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, (3) protein and messenger RNA levels of Survivin, and (4) phosphorylation of survivin in the skin of SKH-1 hairless mouse. Resveratrol pretreatment also resulted in (1) reversal of UV-B-mediated decrease of Smac/DIABLO, and (2) enhancement of UV-B-mediated induction of apoptosis, in mouse skin. Taken together, our study suggested that resveratrol imparts chemopreventive effects against UV-B exposure-mediated damages in SKH-1 hairless mouse skin via inhibiting Survivin and the associated events.
Sirt1, a NAD(+)-dependent histone deacetylase, may regulate senescence, metabolism, and apoptosis. In this study, primary pig preadipocytes were cultured in DMEM/F12 medium containing 10% fetal bovine serum (FBS) with or without reagents affecting Sirt1 activity. The adipocyte differentiation process was visualized by light microscopy after Oil red O staining. Proliferation and differentiation of preadipocytes was measured using methylthiazolyldiphenyl-tetrazolium bromide (MTT) and Oil red O extraction. Expression of Sirt1, FoxO1, and adipocyte specific genes was detected with semi-quantitive RT-PCR. The results showed that Sirt1 mRNA was widely expressed in various pig tissues from different developmental stages. Sirt1 mRNA was expressed throughout the entire differentiation process of pig preadipocytes. Resveratrol significantly increased Sirt1 mRNA expression, but decreased the expression of FoxO1 and adipocyte marker gene PPARgamma2. Resveratrol significantly inhibited pig preadipocyte proliferation and differentiation. Nicotinamide decreased the expression of Sirt1 mRNA, but increased the expression of FoxO1 and adipocyte specific genes. Nicotinamide greatly stimulated the proliferation and differentiation of pig preadipocytes. In conclusion, these results indicate that Sirt1 may modulate the proliferation and differentiation of pig preadipocytes. Sirt1 may down-regulate pig preadipocytes proliferation and differentiation through repression of adipocyte genes or FoxO1.
Ten years of protein kinase B signalling: A hard Akt to follow
- Brazil
Brazil DP and Hemmings BA: Ten years of protein kinase B
signalling: A hard Akt to follow. Trends Biochem Sci 26:
657-664, 2001.
- M Lebwohl
- Psoriasis
Lebwohl M: Psoriasis. Lancet 361: 1197-1204, 2003.
Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells
- Mj Arboleda
- Jf Lyons
- Ff Kabbinavar
- Mr Bray
- Be Snow
- R Ayala
- M Danino
- By Karlan
- Dj Slamon
Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE,
Ayala R, Danino M, Karlan BY and Slamon DJ: Overexpression
of AKT2/protein kinase Bbeta leads to up-regulation of beta1
integrins, increased invasion, and metastasis of human breast and
ovarian cancer cells. Cancer Res 63: 196-206, 2003.
- D Hanahan
- R A Weinberg
Hanahan D and Weinberg RA: The hallmarks of cancer. Cell
100: 57-70, 2000.
Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells
- M J Arboleda
- J F Lyons
- F F Kabbinavar
- M R Bray
- B E Snow
- R Ayala
- M Danino
- Karlan By
- D J Slamon
Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE,
Ayala R, Danino M, Karlan BY and Slamon DJ: Overexpression
of AKT2/protein kinase Bbeta leads to up-regulation of beta1
integrins, increased invasion, and metastasis of human breast and
ovarian cancer cells. Cancer Res 63: 196-206, 2003.
Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells
- Arboleda
Wine as a biological fluid: History, production, and role in disease prevention
- Soleas
Prevention of ultraviolet-B radiation damage by resveratrol in mouse skin is mediated via modulation in survivin
- Aziz
Sirtuins in mammals: Insights into their biological function
- Michan